U.S. patent application number 15/110824 was filed with the patent office on 2017-09-07 for process for improved oxymorphone synthesis.
This patent application is currently assigned to RHODES TECHNOLOGIES. The applicant listed for this patent is RHODES TECHNOLOGIES. Invention is credited to Joshua Robert GIGUERE, Keith Edward MCCARTHY, Marcel SCHLEUSNER.
Application Number | 20170253604 15/110824 |
Document ID | / |
Family ID | 52440748 |
Filed Date | 2017-09-07 |
United States Patent
Application |
20170253604 |
Kind Code |
A9 |
GIGUERE; Joshua Robert ; et
al. |
September 7, 2017 |
PROCESS FOR IMPROVED OXYMORPHONE SYNTHESIS
Abstract
Processes for preparing oxymorphone are provided. Said processes
encompass a step which is a hydrogenation of an
14-hydroxymorphinone salt in the presence of trifluoroacetic acid
and/or a glycol.
Inventors: |
GIGUERE; Joshua Robert;
(Coventry, RI) ; MCCARTHY; Keith Edward;
(Coventry, RI) ; SCHLEUSNER; Marcel; (Groningen,
NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
RHODES TECHNOLOGIES |
Coventry |
RI |
US |
|
|
Assignee: |
RHODES TECHNOLOGIES
Coventry
RI
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20170022209 A1 |
January 26, 2017 |
|
|
Family ID: |
52440748 |
Appl. No.: |
15/110824 |
Filed: |
January 15, 2015 |
PCT Filed: |
January 15, 2015 |
PCT NO: |
PCT/IB2015/050295 PCKC 00 |
371 Date: |
July 11, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61927938 |
Jan 15, 2014 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 489/08 20130101;
C07D 489/02 20130101; A61P 25/04 20180101 |
International
Class: |
C07D 489/02 20060101
C07D489/02 |
Claims
1. A process for preparing oxymorphone or a salt or solvate thereof
from a 14-hydroxymorphinone salt or a solvate thereof ##STR00055##
the process comprising the steps of (a) providing a solution or
suspension of the 14-hydroxymorphinone salt or a solvate thereof;
(b) adding trifluoroacetic acid and/or a glycol; and (c)
hydrogenating the resulting mixture, to reduce the
14-hydroxymorphinone to the oxymorphone, wherein X.sup.n- is an
anion selected from the group consisting of Cl.sup.-,
HSO.sub.4.sup.-, SO.sub.4.sup.2-, methanesulfonate, tosylate,
trifluoroacetate, H.sub.2PO.sub.4.sup.-, HPO.sub.4.sup.2-,
PO.sub.4.sup.3-, oxalate, perchlorate, and any mixtures thereof;
and n is 1,2, or 3.
2. The process of claim 1, wherein trifluoroacetic acid and the
glycol are added in step (b).
3. The process of claim 1, wherein n is 2 and X.sup.n- is
SO.sub.4.sup.2-.
4. The process of claim 1, wherein the amount of trifluoroacetic
acid is 99 mol % or less as compared to the molar amount of
14-hydroxymorphinone contained in the 14-hydroxymorphinone
salt.
5. The process of claim 4, wherein the amount of trifluoroacetic
acid is from 30 mol % to 50 mol % as compared to the molar amount
of 14-hydroxymorphinone contained in the 14-hydroxymorphinone
salt.
6. The process of claim 1, wherein the glycol is selected from the
group consisting of ethylene glycol, propylene glycol,
1,3-propanediol, 1,2-butanediol, 1,3-butanediol, neopentylglycol,
and mixtures thereof.
7. The process of claim 6, wherein the glycol is ethylene glycol,
propylene glycol, or a mixture thereof.
8. The process of claim 1, wherein the glycol added in step (b) is
in the range of 1 to 8 volumes in mL in relation to the weight in
grams of the 14-hydroxymorphinone salt.
9. The process of claim 1, wherein the hydrogenation in step (c) is
performed with H.sub.2 and a hydrogenation catalyst.
10. The process of claim 1, wherein a mixture of water and the
glycol is used as solvent, wherein the mixture is in a range from
20:80 to 45:55 glycol:water.
11. The process of claim 1, additionally comprising the step: (d)
adding a base, thus raising the pH to a pH where the oxymorphone
precipitates as its free base, and isolating the oxymorphone as its
free base or a solvate thereof.
12. The process of claim 11, wherein the base added in step (d) is
NaOH.
13. A process for preparing oxymorphone or a salt or solvate
thereof from oripavine, the process comprising of the steps
##STR00056## (aa) oxidizing the oripavine to 14-hydroxymorphinone;
(bb) adding an acid H.sup.+.sub.nX.sup.n- to the reaction mixture
before, during and/or after the oxidation reaction; (cc) optionally
precipitating the resulting 14-hydroxymorphinone as
14-hydroxyrmorphinone salt or a solvate thereof; (dd) optionally
isolating the precipitated14-hydroxymorphinone salt or solvate
thereof; and (ee) performing the process according to claim 1, and
optionally adding a base, thus raising the pH to a pH where the
oxymorphone precipitates as its free base, and isolating the
oxymorphone as its free base or a solvate thereof; wherein X.sup.n-
is an anion selected from the group consisting of Cl.sup.-,
HSO.sub.4.sup.-, SO.sub.4.sup.2-, methanesulfonate, tosylate,
trifluoroacetate, H.sub.2PO.sub.4.sup.-, HPO.sub.4.sup.2-,
PO.sub.4.sup.3-, oxalate, perchlorate, and any mixtures thereof;
and n is 1, 2, or 3.
14. Oxymorphone prepared by the process of claim 1.
15. The oxymorphone of claim 14, which contains less than 1 ppm
8-hydroxyoxymorphone and less than 1 ppm 14-hydroxymorphinone.
16. The process of claim 13, additionally comprising the step of
adding the base, thus raising the pH to a pH where the oxymorphone
precipitates as its free base, and isolating the oxymorphone as its
free base or a solvate thereof.
17. Oxymorphone prepared by the process of claim 13.
18. The oxymorphone of claim 17, which contains less than 1 ppm
8-hydroxyoxymorphone and less than 1 ppm 14-hydroxymorphinone.
Description
[0001] The present invention is in the field of oxymorphone
synthesis. It provides processes for preparing oxymorphone, in
particular oxymorphone base. The resulting oxymorphone base may be
used in the preparation of APIs like oxymorphone hydrochloride.
Said APIs may be used in pharmaceutical dosage forms.
BACKGROUND OF THE INVENTION
[0002] Oxymorphone and its hydrochloride salt have long been used
as analgesics.
[0003] Oxymorphone base is conventionally prepared by
O-demethylation of oxycodone. Oxymorphone base can also be prepared
by oxidation of oripavine to 14-hydroxymorphinone, and reducing the
14-hydroxymorphinone to oxymorphone base. A route for the
preparation of oxymorphone via oxidation of oripavine to
14-hydroxymorphinone is illustrated in Scheme 1:
##STR00001##
[0004] Once the oxymorphone base has been prepared, it is usually
reacted with an acid to produce an oxymorphone salt, typically
oxymorphone hydrochloride (which is the API form in which
oxymorphone is generally used therapeutically), as shown below in
Scheme 2:
##STR00002##
[0005] The oxidation step in the synthetic route illustrated in
Scheme 1 can yield by-products which may be converted into other
by-products during further conversion of the oxidation product
(e.g., during the reaction shown in Scheme 2) or may be carried
over into the final oxymorphone salt or other opioid made from the
oxymorphone base, final pharmaceutical composition or final dosage
form. These by-products may be undesired in the final
pharmaceutical composition or final dosage form. Separation of
these by-products from the final product may often be difficult,
time-consuming and not volume efficient (e.g., if a separation by
HPLC is required).
[0006] For example, during oxidation of oripavine to
14-hydroxymorphinone, certain by-products can be formed, in
particular 8-hydroxyoxymorphone:
##STR00003##
[0007] The 8-hydroxyoxymorphone can be converted to
14-hydroxymorphinone when HCl is added, as illustrated in Scheme
4:
##STR00004##
[0008] Thus, the 14-hydroxymorphinone intermediate shown in Scheme
1 is not only the immediate precursor to oxymorphone, it is also
often found in the final oxymorphone salt used in pharmaceutical
compositions, which is usually oxymorphone hydrochloride.
14-hydroxymorphinone belongs to a class of compounds known as
.alpha.,.beta.-unsaturated ketones (ABUKs). These compounds contain
a substructural component (the .alpha.,.beta.-unsaturated ketone
component) which produces a structure-activity relationship alert
for genotoxicity. Their presence may be undesired in a
pharmaceutical composition. Some regulatory authorities do not
approve a pharmaceutical composition or dosage form for use and
sale to the public if the amount of ABUKs in the pharmaceutical
composition or dosage form exceeds the amount set by these
authorities.
[0009] In PCT/IB2013/001541 reactions are described which allow
reduction of the amount of undesired by-products caused by the
oxidation step. In particular, PCT/IB2013/001541 describes the
performance of the oxidation reaction in the presence of an acid
H.sub.nX.sup.n-, e.g. H.sub.2SO.sub.4, such that a
14-hydroxymorphinone salt with X.sup.n-, e.g. SO.sub.4.sup.2-, as
counterion is formed:
##STR00005##
[0010] However, even under these reaction conditions, some
8-hydroxyoxymorphone might be carried over into oxymorphone in a
subsequent reduction reaction.
[0011] Even in spite of the improvements achieved by recent
developments like the processes described in PCT/IB2013/001541,
there is still a continuing need for processes for preparing
oxymorphone which exhibit a reduced amount of by-products in the
final product. In particular, a process for preparing oxymorphone
base with a reduced amount of 8-hydroxyoxymorphone, preferably with
no (detectable) 8-hydroxyoxymorphone would be advantageous.
SUMMARY OF THE INVENTION
[0012] The present invention provides a hydrogenation process for
preparing oxymorphone from 14-hydroxymorphinone, which process is
suitable to reduce or even completely suppress the presence of
undesired byproducts of the oxidation reaction leading from
oripavine to 14-hydroxymorphinone, in particular of
8-hydroxyoxymorphone, in the resulting oxymorphone.
[0013] The hydrogenation process according to the invention is
useful for preparing oxymorphone base from 14-hydroxymorphinone
sulfate which was made via an oxidation process as described above.
Even if this starting material contains 8-hydroxyoxymorphone, the
resulting oxymorphone base made via the hydrogenation process
according to the invention contains very small amounts or even no
detectable amounts of 8-hydroxyoxymorphone. It also contains very
small amounts or even no detectable amounts of
14-hydroxymorphinone, which can be formed from 8-hydroxyoxymorphone
under acidic conditions (like the acidic conditions of the
hydrogenation process).
[0014] In one aspect, the present invention provides a process for
preparing oxymorphone or an (optionally pharmaceutically
acceptable) salt or solvate thereof, the process comprising or
consisting of a conversion of a 14-hydroxymorphinone salt or a
solvate thereof to oxymorphone or salt or solvate thereof, by
hydrogenation of the 14-hydroxymorphinone salt or solvate thereof
in the presence of trifluoroacetic acid (abbreviated as "TFA")
and/or a glycol. Preferably, both trifluoroacetic acid and a glycol
are present during the hydrogenation. In said process, the
14-hydroxymorphinone salt or a solvate thereof may be used as a
starting material or as an intermediate material. In each of these
cases, said 14-hydroxymorphinone salt or solvate thereof may be
prepared by the following process starting from oripavine as
described in PCT/IB2013/001541 (see also detailed description of
the present invention below):
##STR00006##
[0015] The process for preparing oxymorphone or an (optionally
pharmaceutically acceptable) salt or solvate thereof according to
the present invention is represented by the following reaction
Scheme 7:
##STR00007##
wherein [0016] X.sup.n- is an anion selected from the group
consisting of Cl.sup.-, HSO.sub.4.sup.-, SO.sub.4.sup.2-,
methanesulfonate, tosylate, trifluoroacetate,
H.sub.2PO.sub.4.sup.-, HPO.sub.4.sup.2-, PO.sub.4.sup.3-, oxalate,
perchlorate, and any mixtures thereof; and [0017] n is 1, 2, or
3.
[0018] Preferably, X.sup.n- is SO.sub.4.sup.2-. So, the
14-hydroxymorphinone salt is preferably 14-hydroxymorphinone
sulfate.
[0019] Given the ingredients of the hydrogenation reaction,
depending on the subsequent workup the resulting oxymorphone could
be isolated (1) as free base, (2) as salt with X.sup.n- as anion,
(3) as oxymorphone trifluoroacetate, or (4) as a salt with a
combination of X.sup.n- and trifluoroacetate as anion. In a
preferred embodiment of the present invention, it is isolated as
free base.
[0020] The 14-hydroxymorphinone salt is represented by the
following structure:
##STR00008##
wherein X.sup.n- and n are defined as above.
[0021] In one embodiment, the 14-hydroxymorphinone salt is
##STR00009##
or a solvate thereof. In the context of the present invention, this
compound will be designated as 14-hydroxymorphinone sulfate.
Because of its stoichiometric composition, it may also be
designated as bis(14-hydroxymorphinone)sulfate. The terms
14-hydroxymorphinone sulfate and bis(14-hydroxymorphinone)sulfate
are used interchangeably in the context of the present
invention.
[0022] In the 14-hydroxymorphinone salt, the 14-hydroxymorphinone
is typically protonated by a proton (H.sup.+), and thus forms a
cation. For example, when n=2, the two protons and two molecules of
14-hydroxymorphinone which are present in the 14-hydroxymorphinone
salt form two cations of 14-hydroxymorphinone in its protonated
form.
[0023] According to the present invention, the hydrogenation is
performed in the presence of trifluoroacetic acid and/or a glycol.
In a preferred embodiment, TFA is present, and preferably in a
substoichiometric amount. In another preferred embodiment, glycol
is present. Even more preferably, both glycol and TFA are present,
wherein TFA is preferably present in a substoichiometric
amount.
[0024] Preferably, the glycol is selected from the group consisting
of ethylene glycol, propylene glycol, 1,3-propanediol,
1,2-butanediol, 1,3-butanediol, neopentylglycol, and mixtures
thereof. More preferably, the glycol is ethylene glycol, propylene
glycol, or a mixture thereof.
[0025] The advantages of the hydrogenation reaction characterizing
the process of the present invention are explained in the
following: The presence of trifluoroacetic acid and glycol during
hydrogenation has the technical effect that less
8-hydroxyoxymorphone will be present in the reaction product than
in a reaction product made in the absence of trifluoroacetic acid
and glycol. As shown in Example 16, by performing the hydrogenation
in the presence of trifluoroacetic acid and glycol, even
oxymorphone without any detectable amount of 8-hydroxyoxymorphone
or 14-hydroxymorphinone can be prepared from a starting material
containing 8-hydroxyoxymorphone. Said 8-hydroxyoxymorphone is an
undesired by-product of the oxidation of oripavine to
14-hydroxymorphinone, and it is carried over into the final
oxymorphone in conventional reduction reactions leading from
14-hydroxymorphinone (made by oxidation of oripavine) to
oxymorphone. The hydrogenation reaction of the present invention
can reduce or even completely suppress this carryover. Without
being bound by theory, the reaction conditions of the hydrogenation
reaction, in particular the low content of acid (typically a
substoichiometric amount of TFA is used) in the reaction mixture,
might also prevent acid-catalyzed conversion of
14-hydroxymorphinone into 8-hydroxyoxymorphone during the
hydrogenation reaction. Moreover, 8-hydroxyoxymorphone might be
more soluble in the reaction solvent (which contains the glycol
characterizing the hydrogenation reaction of the present invention)
than oxymorphone base or an oxymorphone salt. Thus, oxymorphone or
a salt thereof can be purified from 8-hydroxyoxymorphone by
precipitation. A preferred embodiment of the present invention
makes use of this effect by precipitating and isolating the
oxymorphone base.
[0026] Processes using a 14-hydroxymorphinone trifluoroacetate salt
as starting material for a reduction reaction are already described
in PCT/IB2013/001541. However, for performing the process of the
present application, it is sufficient to use trifluoroacetic acid
in substoichiometric amounts (less than 1 molar equivalent of
14-hydroxymorphinone), together with a different
14-hydroxymorphinone salt, e.g., 14-hydroxymorphinone sulfate.
[0027] In certain embodiments, trifluoroacetic acid is the sole
acid added to the hydrogenation reaction mixture, and it is added
in substoichiometric amounts, i.e. less than 100 mol % of the
14-hydroxymorphinone in the starting material 14-hydroxymorphinone
salt. This can greatly reduce the amount of base which has to be
added to precipitate the oxymorphone free base after the
hydrogenation reaction. As already mentioned above, this low amount
of acid in the reaction mixture might also prevent acid-catalyzed
conversion of 14-hydroxymorphinone into 8-hydroxyoxymorphone during
the hydrogenation reaction.
[0028] A process according to the present invention comprises the
steps of providing a solution or suspension of the
14-hydroxymorphinone salt or a solvate thereof; adding
trifluoroacetic acid and/or a glycol; and subsequently
hydrogenating the 14-hydroxymorphinone to the oxymorphone, which
may then be isolated as its base or as an (optionally
pharmaceutically acceptable) salt or solvate thereof.
[0029] Hence, the present invention provides a process for
preparing oxymorphone or a salt or solvate thereof from a
14-hydroxymorphinone salt or a solvate thereof
##STR00010##
the process comprising or consisting of the steps of [0030] (a)
providing a solution or suspension of the 14-hydroxymorphinone salt
or a solvate thereof; [0031] (b) adding trifluoroacetic acid and/or
a glycol, preferably trifluoroacetic acid and a glycol; and [0032]
(c) hydrogenating the resulting mixture, thus reducing the
14-hydroxymorphinone to oxymorphone, wherein X.sup.n- and n are
defined as above.
[0033] After the hydrogenation reaction, the oxymorphone may be
present as its salt or solvate in the reaction mixture, e.g., as
its sulfate salt and/or trifluoroacetate salt. In a subsequent
step, it may be converted into its free base and/or converted into
a different salt or solvate, e.g., a pharmaceutically acceptable
salt or solvate. It may be isolated from the reaction mixture in
one or more of these forms.
[0034] In a preferred embodiment, the oxymorphone is isolated from
the reaction mixture as free base, e.g. by precipitation and
subsequent isolation of the precipitate. In said embodiment, the
process may be represented by the following reaction scheme:
##STR00011##
the process comprising or consisting of the steps of [0035] (a)
providing a solution or suspension of the 14-hydroxymorphinone salt
or a solvate thereof; [0036] (b) adding trifluoroacetic acid and/or
a glycol, preferably trifluoroacetic acid and a glycol; and [0037]
(c) hydrogenating the resulting mixture, thus reducing the
14-hydroxymorphinone to the oxymorphone; and [0038] (d) adding a
base, thus raising the pH to a pH where the oxymorphone
precipitates, and isolating the oxymorphone as its free base or a
solvate thereof, wherein X.sup.n- and n are defined as above, and X
is preferably SO.sub.4.sup.2-.
[0039] In a preferred aspect of this process, 14-hydroxymorphinone
sulfate (or a solvate thereof) is converted into oxymorphone base
(or a solvate thereof).
[0040] Usually, the oxymorphone resulting from a conventional
reduction of a 14-hydroxymorphinone salt (e.g.,
14-hydroxymorphinone sulfate) may contain certain by-products, as
shown in the following Scheme 8:
##STR00012##
[0041] 8-Hydroxyoxymorphone is undesired in the final oxymorphone
because it may convert to 14-hydroxymorphinone, an ABUK, under
acidic conditions, in particular when oxymorphone is converted to
oxymorphone hydrochloride (the API). Apart from
8-hydroxyoxymorphone, 14-hydroxymorphinone is also undesired in the
final oxymorphone. Such 14-hydroxymorphinone may be unreacted
starting material, or it may be formed from 8-hydroxyoxymorphone
because of the presence of acid in the hydrogenation mixture during
the hydrogenation or after the hydrogenation reaction has been
stopped. It is an advantage of the present invention that the
hydrogenation reaction according to the present invention allows
formation of oxymorphone which does neither contain
14-hydroxymorphinone nor 8-hydroxyoxymorphone.
[0042] The hydrogenation reaction characterizing the process of the
present invention is suitable for reducing the amount of
8-hydroxyoxymorphone and/or 14-hydroxymorphinone in the resulting
oxymorphone or salt or solvate thereof, in comparison to processes
utilizing a different reduction or hydrogenation reaction which
also starts with 14-hydroxymorphinone salt as starting material,
and especially in comparison to processes not utilizing a salt of
14-hydroxymorphinone, in particular not 14-hydroxymorphinone
sulfate, as starting material.
[0043] The hydrogenation process of the present invention differs
from the hydrogenation described in PCT/IB2013/001541 and similar
prior art hydrogenations in that TFA and/or glycol, preferably both
TFA and glycol are present during the hydrogenation. This has the
surprising effect that the resulting oxymorphone base contains very
small amounts or even no detectable amounts of
8-hydroxyoxymorphone. It also contains very small amounts or even
no detectable amounts of 14-hydroxymorphinone, which can be formed
from 8-hydroxyoxymorphone under acidic conditions (like the acidic
conditions of the hydrogenation process).
[0044] It may also be because of the use of the
14-hydroxymorphinone salt as starting material for said
hydrogenation reaction that the process of the present invention is
suitable for reducing the amount of 14-hydroxymorphinone and/or
8-hydroxyoxymorphone in oxymorphone or a salt or solvate thereof
prepared from said 14-hydroxymorphinone salt, in comparison to
processes using other intermediates or starting materials.
14-hydroxymorphinone salt made from oripavine, e.g. according to
the processes described in PCT/IB2013/001541, contains reduced
amounts of 8-hydroxyoxymorphone in comparison to
14-hydroxymorphinone made via other routes from oripavine. The
lower amount of 8-hydroxyoxymorphone in the 14-hydroxymorphinone
salt may result in less 8-hydroxyoxymorphone in oxymorphone made
from said 14-hydroxymorphinone salt, which in turn may result in
less 14-hydroxymorphinone in an oxymorphone salt made from said
oxymorphone, because 14-hydroxymorphinone can be formed from
8-hydroxyoxymorphone during the conversion of oxymorphone to a salt
thereof by acid addition.
[0045] In those embodiments of the present invention which
encompass precipitation and isolation of the oxymorphone as free
base, typically, at least some 8-hydroxyoxymorphone or salt or
solvate thereof remains in the supernatant. Thus, a separation of
the 8-hydroxyoxymorphone from the oxymorphone or solvate thereof
may be achieved by the precipitation. The precipitated and
optionally isolated precipitate, which contains the oxymorphone
base or the solvate thereof, may contain a lower ratio of the
8-hydroxyoxyomrphone to the oxymorphone than the ratio of the
8-hydroxyoxymorphone to the oxymorphone in the mother liquor.
[0046] 8-hydroxyoxymorphone has the following formula:
##STR00013##
[0047] The stereoconfiguration at C-8 of 8-hydroxyoxymorphone can
be either alpha (8.alpha.) or beta (8.beta.). The 8.alpha. and
8.beta. stereoconfiguration are shown for 8-hydroxyoxymorphone in
Scheme 9. The 8-hydroxyoxymorphone may be the 8.alpha. compound, or
the 8.beta. compound, or a mixture of the
8.alpha.-hydroxyoxymorphone and the 8.beta.-hydroxyoxymorphone.
##STR00014##
[0048] Pharmaceutical compositions prepared by processes of the
present invention may be quantitatively different from
pharmaceutical compositions prepared by conventional processes
which do not utilize the hydrogenation of 14-hydroxymorphinone salt
according to the present invention, and may offer advantages over
the compositions prepared by conventional processes, e.g., in terms
of safety, efficiency and reduced manufacturing costs. For example,
these compositions may contain less by-products and/or require less
or no further processing steps after synthesis of their API.
[0049] Moreover, the hydrogenation reaction according to the
present invention may allow for a more volume efficient process, as
compared to the conventional hydrogenation reaction. The use of a
substoichiometric amount of trifluoroacetic acid (instead of, e.g.
formic acid as an excess reagent as described in conventional
hydrogenation reactions, which generally use >5 molar
equivalents of formic acid) requires the addition of less base
after the hydrogenation if the oxymorphone shall be precipitated as
its free base. This reduces the amount of base required, and also
makes the reaction more volume efficient.
[0050] Oxymorphone or an (optionally pharmaceutically acceptable)
salt or solvate thereof are also provided by the present invention.
Oxymorphone, when prepared by a process according to present
invention, may comprise only very low amounts of
8-hydroxyoxymorphone and/or 14-hydroxymorphinone. As explained
above, under the conditions described in the prior art,
14-hydroxymorphinone may be formed from 8-hydroxyoxymorphone when
preparing the oxymorphone or a salt or solvate thereof. In
particular, the oxymorphone or the pharmaceutically acceptable salt
or solvate thereof according to the present invention may comprise
an amount of 14-hydroxymorphinone which is below a desired
threshold amount, e.g., a threshold amount mandated by the
regulatory authorities for the approval of pharmaceutical
compositions for use and sale to the public, and/or it comprises an
amount of 8-hydroxyoxymorphone which is insufficient to increase
the amount of 14-hydroxymorphinone or a salt or solvate thereof,
upon further processing of the oxymorphone or a salt or solvate
thereof, above said threshold amount.
[0051] The present invention further provides pharmaceutical
compositions and dosage forms, which comprise oxymorphone or a
pharmaceutically acceptable salt or solvate thereof (e.g.,
oxymorphone hydrochloride). Said oxymorphone is preferably prepared
by the process according to the present invention. In certain
embodiments, these pharmaceutical compositions have a different
by-product profile and may have a different efficacy than
pharmaceutical compositions prepared via a different reduction
reaction, rather than via the hydrogenation reaction of the present
invention. In particular, the content of the 14-hydroxymorphinone
in these pharmaceutical compositions differs from the content of
the 14-hydroxymorphinone in pharmaceutical compositions prepared
via the free base of 14-hydroxymorphinone, rather than via the
14-hydroxymorphinone salt or a solvate thereof. This encompasses
pharmaceutical compositions comprising oxymorphone or the
pharmaceutically acceptable salt or solvate thereof and
14-hydroxymorphinone or a salt or solvate thereof in an amount
which is below a desired threshold amount, e.g., a threshold amount
mandated by the regulatory authorities for the approval of these
compositions for use and sale to the public. It also encompasses
pharmaceutical compositions comprising, in addition to the
oxymorphone or the pharmaceutically acceptable salt or solvate
thereof, 8-hydroxyoxymorphone or a salt or solvate thereof in an
amount which is insufficient to increase the levels of
14-hydroxymorphinone or a salt or solvate thereof, upon further
processing of the pharmaceutical composition, above said desired
threshold amount of the 14-hydroxymorphinone. It also encompasses
pharmaceutical compositions comprising, in addition to the
oxymorphone or the pharmaceutically acceptable salt or solvate
thereof, 14-hydroxymorphinone or a salt or solvate thereof, and
8-hydroxyoxymorphone or a salt or solvate thereof, wherein the
8-hydroxyoxymorphone is present in an amount which is insufficient
to increase the levels of the 14-hydroxymorphinone, upon further
processing as described in the prior art, above said desired
threshold amount.
[0052] The present invention is further directed to pharmaceutical
compositions and dosage forms formed as the result of carrying out
the processes of the invention, as well as methods for using these
pharmaceutical compositions and dosage forms in the treatment of
medical conditions. The immediate products formed by carrying out
the processes of the invention may be suitable as pharmaceutical
compositions themselves, without further processing steps.
[0053] These pharmaceutical compositions and dosage forms can be
used to treat or prevent one or more of the following medical
conditions: pain, addiction, cough, constipation, diarrhea,
insomnia associated with and/or caused by pain, cough or addiction,
depression associated with and/or resulting from pain, cough or
addiction, or a combination of two or more of the foregoing
conditions, etc. A method for treatment or prevention of one or
more of these conditions by administration of oxymorphone or a salt
or solvate thereof to a patient is also provided by the present
invention.
[0054] The use of a pharmaceutical composition or dosage form
according to the present invention, comprising oxymorphone or a
pharmaceutically acceptable salt or solvate thereof, in the
manufacture of a medicament for the treatment of one or more of
these medical conditions is also part of the present invention.
Certain Embodiments of the Invention
[0055] The present invention encompasses the following
embodiments:
[0056] (1) A process for preparing oxymorphone or a salt or solvate
thereof from a 14-hydroxymorphinone salt or a solvate thereof
##STR00015##
the process comprising or consisting of the steps of [0057] (a)
providing a solution or suspension of the 14-hydroxymorphinone salt
or a solvate thereof; [0058] (b) adding trifluoroacetic acid and/or
a glycol; and [0059] (c) hydrogenating the resulting mixture, thus
reducing the 14-hydroxymorphinone to the oxymorphone, wherein
[0060] X.sup.n- is an anion selected from the group consisting of
Cl.sup.-, HSO.sub.4.sup.-, SO.sub.4.sup.2-, methanesulfonate,
tosylate, trifluoroacetate, H.sub.2PO.sub.4.sup.-,
HPO.sub.4.sup.2-, PO.sub.4.sup.3-, oxalate, perchlorate, and any
mixtures thereof; and [0061] n is 1, 2, or 3. [0062] (2) The
process of (1), wherein trifluoroacetic acid and a glycol are added
in step (b). [0063] (3) The process of (1) or (2), wherein n is 2
and X is SO.sub.4.sup.2-. [0064] (4) The process of any one of (1)
to (3), wherein the amount of trifluoroacetic acid is 99 mol % or
less as compared to the molar amount of 14-hydroxymorphinone
contained in the 14-hydroxymorphinone salt. [0065] (5) The process
of (4), wherein the amount of trifluoroacetic acid is from 30 mol %
to 50 mol % as compared to the molar amount of 14-hydroxymorphinone
contained in the 14-hydroxymorphinone salt. [0066] (6) The process
of any one of (1) to (5), wherein the glycol is selected from the
group consisting of ethylene glycol, propylene glycol,
1,3-propanediol, 1,2-butanediol, 1,3-butanediol, neopentylglycol,
and mixtures thereof. [0067] (7) The process of (6), wherein the
glycol is ethylene glycol, propylene glycol, or a mixture thereof.
[0068] (8) The process of (7), wherein the glycol is ethylene
glycol. [0069] (9) The process of (7), wherein the glycol is
propylene glycol. [0070] (10) The process of any one of (1) to (9),
wherein the glycol added in step (b) is in the range of 1 to 8
volumes in mL in relation to the weight in g of the
14-hydroxymorphinone salt. [0071] (11) The process of any one of
(1) to (10), wherein the hydrogenation in step (c) is performed
with H.sub.2 and a hydrogenation catalyst. [0072] (12) The process
of (11), wherein the hydrogenation catalyst is Pd/C. [0073] (13)
The process of any one of (1) to (12), wherein a mixture of water
and the glycol is used as solvent. [0074] (14) The process of (13),
wherein the mixture is in a range from 20:80 to 45:55 glycol:water.
[0075] (15) The process of (14), wherein the mixture is about 40:60
glycol:water. [0076] (16) The process of any one of (1) to (15),
additionally comprising the step: [0077] (d) adding a base, thus
raising the pH to a pH where the oxymorphone precipitates as its
free base, and isolating the oxymorphone as its free base or a
solvate thereof. [0078] (17) The process of (16), wherein the base
added in step (d) is NaOH. [0079] (18) A process for preparing
oxymorphone or a salt or solvate thereof from oripavine, the
process comprising or consisting of the steps
[0079] ##STR00016## [0080] (aa) oxidizing the oripavine to
14-hydroxymorphinone; [0081] (bb) adding an acid
H.sup.+.sub.nX.sup.n- to the reaction mixture before, during and/or
after the oxidation reaction; [0082] (cc) optionally precipitating
the resulting 14-hydroxymorphinone as 14-hydroxymorphinone salt or
a solvate thereof; [0083] (dd) optionally isolating the
precipitated 14-hydroxymorphinone salt or solvate thereof; and
[0084] (ee) performing the process according to any one of (1) to
(17), wherein [0085] X.sup.n- is an anion selected from the group
consisting of Cl.sup.-, HSO.sub.4.sup.-, SO.sub.4.sup.2-,
methanesulfonate, tosylate, trifluoroacetate,
H.sub.2PO.sub.4.sup.-, HPO.sub.4.sup.2-, PO.sub.4.sup.3-, oxalate,
perchlorate, and any mixtures thereof; and [0086] n is 1, 2, or 3.
[0087] (19) The process of (18), wherein n is 2 and X.sup.n- is
SO.sub.4.sup.2-. [0088] (20) The process of (1), wherein said
process comprises the steps of [0089] (a) providing a solution or
suspension of the 14-hydroxymorphinone salt or a solvate thereof;
[0090] (b) adding trifluoroacetic acid and/or a glycol; and [0091]
(c) hydrogenating the resulting mixture, thus reducing the
14-hydroxymorphinone to the oxymorphone. [0092] (21) The process of
(1), wherein said process consists of the steps of [0093] (a)
providing a solution or suspension of the 14-hydroxymorphinone salt
or a solvate thereof; [0094] (b) adding trifluoroacetic acid and/or
a glycol; and [0095] (c) hydrogenating the resulting mixture, thus
reducing the 14-hydroxymorphinone to the oxymorphone. [0096] (22)
The process of (18), wherein said process comprises the steps
[0096] ##STR00017## [0097] (aa) oxidizing the oripavine to
14-hydroxymorphinone; [0098] (bb) adding an acid
H.sup.+.sub.nX.sup.n- to the reaction mixture before, during and/or
after the oxidation reaction; [0099] (cc) optionally precipitating
the resulting 14-hydroxymorphinone as 14-hydroxymorphinone salt or
a solvate thereof; [0100] (dd) optionally isolating the
precipitated 14-hydroxymorphinone salt or solvate thereof; and
[0101] (ee) performing the process according to any one of (1) to
(17). [0102] (23) The process of (18), wherein said process
consists of the steps
[0102] ##STR00018## [0103] (aa) oxidizing the oripavine to
14-hydroxymorphinone; [0104] (bb) adding an acid
H.sup.+.sub.nX.sup.n- to the reaction mixture before, during and/or
after the oxidation reaction; [0105] (cc) optionally precipitating
the resulting 14-hydroxymorphinone as 14-hydroxymorphinone salt or
a solvate thereof; [0106] (dd) optionally isolating the
precipitated 14-hydroxymorphinone salt or solvate thereof; and
[0107] (ee) performing the process according to any one of (1) to
(17). [0108] (24) Oxymorphone prepared by the process of any one of
(1) to (23). [0109] (25) The oxymorphone of (24), which contains
less than 1 ppm 8-hydroxyoxymorphone and less than 1 ppm
14-hydroxymorphinone. [0110] (26) A pharmaceutical composition
comprising the oxymorphone according to (24) or (25) and a
pharmaceutically acceptable excipient. [0111] (27) The oxymorphone
of (24) or (25), or the pharmaceutical composition of (26), for use
in the treatment of pain.
Definitions
[0112] Unless otherwise specified, the following abbreviations and
definitions are used in the context of the present invention.
[0113] The undefined article "a" or "an" is intended to mean one or
more of the species designated by the term following said article.
For example, "a compound of formula II" encompasses one or more
molecules of the compound of formula II.
[0114] The term "about" in the context of the present application
means a value within 15% (.+-.15%) of the value recited immediately
after the term "about," including any numeric value within this
range, the value equal to the upper limit (i.e., +15%) and the
value equal to the lower limit (i.e., -15%) of this range. For
example, the phrase "about 100" encompasses any numeric value that
is between 85 and 115, including 85 and 115 (with the exception of
"about 100%", which always has an upper limit of 100%). In a
preferred aspect, "about" means .+-.10%, even more preferably
.+-.5%, even more preferably .+-.1% or less than .+-.1%.
[0115] "TFA" means trifluoroacetic acid.
[0116] An "opioid" in its broadest sense encompasses all compounds
usually designated with said term in the art, including opioids
which act as an agonist on opioid receptors and opioids which act
as an antagonist on opioid receptors. Partial agonists and partial
antagonists are also known and are encompassed by the term
"opioid". Opioid agonists include, e.g., oxymorphone, oxycodone,
noroxymorphone, nalfurafine and salts and solvates of any of the
foregoing. Opioid antagonists include, e.g., naltrexone,
methylnaltrexone, naloxone, nalmefene, and salts and solvates of
any of the foregoing. In the context of the present application,
the term "opioid" shall encompass a compound having one of the
following scaffolds (which will be designated as "morphine
scaffold" in the context of present invention):
##STR00019##
The degree of unsaturation in the ring formed by atoms 5, 6, 7, 8,
14 and 13 may vary (the ring may, e.g., just contain single bonds
as in 8-hydroxyoxymorphone, contain just one double bond as in
14-hydroxymorphinone, or contain two double bonds as in
oripavine).
[0117] The "threshold amount" of 14-hydroxymorphinone in
pharmaceutical compositions and dosage forms may be set by
regulatory authorities such as the U.S. Food and Drug
Administration (FDA) and can then be learned from the latest
version of the FDA guidelines ("Guidelines") or, if not addressed
in said Guidelines, from the latest version of the ICH Guidelines.
In the context of the present invention, the threshold amount may
be 10 ppm or less.
[0118] The term "8-hydroxy compound" in the context of the present
application means a compound containing a hydroxyl group in
position 8 of the morphine scaffold. In a narrower sense, it means
8-hydroxyoxymorphone or a salt or solvate thereof. The term
"8-hydroxy compound" includes the 8.alpha.-hydroxyoxymorphone
and/or the 8.beta.-hydroxyoxymorphone.
[0119] It should be apparent to a person skilled in the art that
the terms "salt" and "solvate" in the present specification
encompass "a pharmaceutically acceptable salt" and "a
pharmaceutically acceptable solvate", respectively. The formation
of a pharmaceutically acceptable salt or solvate may be achieved
either directly or by the preparation of a pharmaceutically
unacceptable salt or solvate and a subsequent conversion to the
pharmaceutically acceptable salt or solvate. A conversion of one
pharmaceutically acceptable salt or solvate to another
pharmaceutically acceptable salt or solvate is also possible.
[0120] The term "solvate" in the context of the present application
in its broadest sense means an association product of a compound or
salt of the present invention with a solvent molecule. The molar
ratio of solvent molecule(s) per compound molecule may vary. The
molar ratio of solvent to compound/salt in the solvate may be 1
(e.g., in a monohydrate), more than 1 (e.g., 2, 3, 4, 5 or 6 in a
polyhydrate), or less than 1 (e.g., 0.5 in a hemihydrate). The
molar ratio need not be an integer ratio, it can also be, e.g., 0.5
(as in a hemihydrate) or 2.5. For example, 1 molecule water per
molecule of 14-hydroxymorphinone sulfate is bound in
14-hydroxymorphinone sulfate monohydrate. Applied to oxymorphone,
8-hydroxyoxymorphone, 14-hydroxymorphinone or, where appropriate,
to salts thereof, the solvate is in certain embodiments a hydrate,
for example a monohydrate, dihydrate, trihydrate, tetrahydrate,
pentahydrate or hexahydrate, or a hydrate wherein the ratio of
water per molecule is not necessarily an integer, but within the
range of from 0.5 to 10.0. In certain embodiments, the solvate is a
hydrate wherein the ratio of water per molecule is within the range
of from 1 to 8. In certain embodiments, the solvate is a hydrate
wherein the ratio of water per molecule is within the range of from
1 to 6, i.e. a mono- to hexahydrate. In certain embodiments, it is
a monohydrate or a pentahydrate.
[0121] The terms "precipitating"/"precipitate"/"precipitation" in
the context of the present application shall encompass
"crystallizing"/"crystallize"/"crystallization" unless stated
otherwise. In certain embodiments, the precipitate described herein
is amorphous. In certain embodiments, the precipitate is a mixture
of amorphous and crystalline components. In certain embodiments,
the precipitate described herein is crystalline. For example,
14-hydroxymorphinone sulfate may precipitate in a crystalline form,
whilst oxymorphone base typically is an amorphous precipitate.
[0122] The acronym "ppm" means parts per million. For purposes of
the present application, the numeric ppm amount values of opioids
contained in a composition containing more than one opioid are
given in relation to the amount of the opioid ("reference opioid")
constituting the majority of the opioids contained in said
composition. Such reference opioid will typically be oxymorphone
(in the final product oxymorphone of the hydrogenation reaction) or
14-hydroxymorphinone (in the starting material 14-hydroxymorphinone
salt of the hydrogenation reaction). The ppm values can be
determined by performing a chromatographic resolution of the
composition and subsequent calculation of the relative or absolute
amounts of the opioid components based on the peak area. For
purposes of the present invention, an HPLC method (e.g., as
described in Example 11 for oxymorphone and its precursors and
by-products) can be performed. The composition components can be
detected at a certain wavelength (e.g., at 292 nm for oxymorphone
and its precursors and by-products). The HPLC peak area ratio of a
certain opioid component to the reference opioid determines the ppm
value. The numeric ppm amount value of the one opioid compound
constituting the majority of the opioids in the composition (i.e.
of the reference opioid, which may be oxymorphone or
14-hydroxymorphinone) can be obtained from the percent area of the
peak of this compound in relation to the area sum of all opioid
peaks.
[0123] Under the HPLC conditions used in the context of the present
invention (e.g., the HPLC conditions as described in Example 11 for
oxymorphone and its precursors and by-products; or any other
reverse phase HPLC conditions), any salt will not be determined in
its salt form, but in a dissociated form. For example, the
14-hydroxymorphinone moiety of 14-hydroxymorphinone sulfate will be
detected and quantified in its dissolved form, i.e. as
14-hydroxymorphinone. Consequently, the HPLC peak area detectable
for an opioid salt of the present invention will be the HPLC peak
area which is detected for the opioid moiety comprised in said
salt. In case a salt contains more than one opioid moieties per
anion, the HPLC method does not detect the absolute/relative amount
of the salt itself, but of its opioid moiety. If in such a salt two
opioid moieties per anion are present (such as in
14-hydroxymorphinone sulfate wherein n is 2), the peak area
detected in the HPLC is due to the presence of the two opioid
moieties contained in said salt. In case of a 14-hydroxymorphinone
salt wherein n is 3, the peak area detected in the HPLC is due to
the presence of the three opioid moieties contained in said
14-hydroxymorphinone salt.
[0124] This has the following consequence: As defined above, the
numeric ppm value for an opioid is the ratio of peak area for said
opioid in relation to the peak area of the reference opioid. In
case the present application refers to numeric ppm values for a
ratio of 8-hydroxyoxymorphone to a 14-hydroxymorphinone salt, in
fact the ratio of the peak area for the 8-hydroxymorphone to the
peak area of the 14-hydroxymorphinone (which is contained in the
14-hydroxymorphinone salt) is provided. A 14-hydroxymorphinone salt
comprises n-times the structural unit of 14-hydroxymorphinone
(e.g., two times for a sulfate salt, three times for a phosphate
salt, etc.). All ppm values given in the description are based on
the original peak area ratio of the opioid moiety, without
adjusting them by dividing them by n. For example, if a peak area
ratio of 4 ppm is determined via HPLC for a 14-hydroxymorphinone
salt wherein n is 2, the corresponding ppm value will also be 4
(and not 2). This way of giving compound ratios in ppm will be
designated as "HPLC peak area ratio" in the following.
[0125] The opioid peaks which are typically considered in this
determination method are peaks having an UV-Vis spectrum which is
typical for an opioid. For 14-hydroxymorphinone sulfate (or another
14-hydroxymorphinone salt or solvate thereof) and for oxymorphone,
typically the peaks of oxymorphone N-oxide, pseudo-oxymorphone
(i.e., 2,2'-bisoxymorphone), 14-hydroxymorphine,
14-hydroxyisomorphine, 10-ketooxymorphone, 14-hydroxymorphinone
N-oxide, 10-hydroxyoxymorphone, 8-hydroxyoxymorphone,
14-hydroxymorphinone, hydromorphone, oxymorphone,
6.alpha.-oxymorphol, 6.beta.-oxymorphol, oripavine,
8,14-dihydrooripavine, oxycodone (see, e.g., Example 11) may be
considered (if present). However, not all of these peaks have to be
considered. It is usually sufficient to consider just some of them,
for example 8-hydroxyoxymorphone, 14-hydroxymorphinone,
oxymorphone, 6.alpha.-oxymorphol, and oripavine.
[0126] A reverse phase HPLC method may be used for determination of
ppm values.
[0127] The detection of the sample components may be performed
using a UV/VIS detector, e.g., at a wavelength of 292 nm.
[0128] Alternatively, the detection of the sample components may be
performed using a mass spectrometer. The amount of a certain
component may be determined by using a tritiated internal standard.
However, this method of detection does not require the "HPLC peak
area ratio" described above, as it uses an internal standard.
[0129] In the preferred embodiments, a HPLC method described in
Example 11 is used for determination of ppm values. In one
embodiment, the HPLC method of Example 11B is used.
[0130] "No detectable amount", "not detectable" , "not . . . in
detectable amounts" or a similar formulation means an amount of the
compound in question (e.g. 14-hydroxymorphinone or
8-hydroxyoxymorphone) below the LOD (limit of detection). In the
context of the present invention, this means an amount of less than
5 ppm, preferably less than 3 ppm, more preferably less than 1 ppm
of the compound in question (e.g. 14-hydroxymorphinone or
8-hydroxyoxymorphone in relation to oxymorphone) (HPLC peak area
ratio). In a specific aspect of the invention, this mean the
absence (i.e. 0 ppm) of the compound in question.
[0131] The term "API" in the context of the present invention means
"active pharmaceutical ingredient" (e.g., oxymorphone
hydrochloride) and shall be used in its broadest sense as a synonym
for a pharmaceutically active compound in the context of the
present invention. When an API is used in preparing a
pharmaceutical composition or dosage form, the API is the
pharmaceutically active component of said pharmaceutical
composition or dosage form. Pharmaceutical compositions or dosage
forms containing an API may be approved by a governmental agency
for sale and use in a patient (e.g., a human). Examples of APIs
described in the context of the present invention include
oxymorphone and oxymorphone hydrochloride.
[0132] The term "pharmaceutical composition" in the context of the
present application means a composition which contains an API and
is suitable for use in a patient (e.g., a human). It may be
approved by a governmental agency for sale and use in a patient.
Examples for pharmaceutical compositions described in the context
of the present invention are among the compositions containing
oxymorphone or oxymorphone hydrochloride. Pharmaceutical
compositions may be compositions prepared according to the
invention if they comply with regulatory requirements for
pharmaceutical compositions containing the same API.
[0133] The term "salt" in the context of the present application
means a compound comprising at least one cation (e.g., one or two
14-hydroxymorphinone cations resulting from protonation of
14-hydroxymorphinone (free base) by a Bronsted acid (like sulfuric
acid)) and at least one anion (e.g., a sulfate anion). A salt may
be the result of the neutralization reaction between an acid and a
base (e.g., a Bronsted acid and a Bronsted base, or a Lewis acid
and a Lewis base). In its solid form, the salt may have a
crystalline structure. The term "salt" as used in the present
application includes anhydrous, solvated, or hydrated forms of the
salt. Whenever a solution or mixture containing a salt is
mentioned, the term "salt" shall also encompass the dissolved form
of the salt. The term also encompasses pharmaceutically acceptable
salts, in particular when it refers to a salt of a compound which
can serve as API. In the context of present invention, whenever a
14-hydroxymorphinone salt is mentioned, this refers to a salt
containing a 14-hydroxymorphinone cation, resulting, e.g., from
protonation of the 14-hydroxymorphinone. The same applies to other
salts containing a cation with a morphine scaffold, e.g., a salt of
8-hydroxyoxymorphone. An example for a 14-hydroxymorphinone salt is
a salt which consists of two molecules of 14-hydroxymorphinone and
one molecule of H.sub.2SO.sub.4, i.e. which comprises two
14-hydroxymorphinone cations per sulfate anion
(14-hydroxymorphinone sulfate). In this salt, the cation results
from the protonation of two molecules of 14-hydroxymorphinone and
the anion is the resulting sulfate. In preferred embodiments of the
present invention, a salt which is a 14-hydroxymorphinone salt is
in its solid form. Another example for a salt is a salt of
oxymorphone or a solvate thereof. An example for such salt of
oxymorphone is a salt which consists of two molecules of
oxymorphone and one molecule of H.sub.2SO.sub.4, i.e. which
comprises two oxymorphone cations per sulfate anion (oxymorphone
sulfate). In this salt, the cation results from the protonation of
two molecules of oxymorphone and the anion is the resulting
sulfate. In preferred embodiments of the present invention, a salt
of oxymorphone is in its solid form.
[0134] Whenever a compound or formula mentioned herein contains an
atom or structural element which could be a stereocenter (e.g., a
chiral carbon atom or the morphine scaffold structure), it shall
cover all possible stereoisomers, unless indicated otherwise.
[0135] For compounds containing the morphine scaffold, the natural
stereoconfiguration of the morphine scaffold as shown in the
following shall be preferred:
##STR00020##
wherein the degree of unsaturation in the ring formed by atoms 5,
6, 7, 8, 14 and 13 may vary (the ring may, e.g., just contain
single bonds as in 8-hydroxyoxymorphone, or contain just one double
bond as in 14-hydroxymorphinone, or contain two double bonds as in
oripavine). At position 5, the following stereoconfiguration is
preferred (exemplified for the morphine scaffold of oripavine):
##STR00021##
[0136] For the 8-hydroxy compounds, an .alpha. or a .beta.
configuration is possible at position 8 as illustrated in the
following:
##STR00022##
[0137] In the compounds and compositions of the present invention,
either both configurations or only one configuration at position 8
may be present.
[0138] For all compounds containing a hydroxyl group at position
14, the following stereoconfiguration occurs at position 14 as
exemplified for 14-hydroxymorphinone in the following:
##STR00023##
BRIEF DESCRIPTION OF THE FIGURES
[0139] FIG. 1 shows the auto-scaled chromatograph and peak results
of the analysis of the precipitated oxymorphone of Comparative
Example 1.
[0140] FIG. 2 shows the auto-scaled chromatograph and peak results
of the analysis of the precipitated oxymorphone of Comparative
Example 2.
[0141] FIG. 3 shows the auto-scaled chromatograph and peak results
of the analysis of the isolated solid oxymorphone of Comparative
Example 10.
[0142] FIG. 4 shows a representative HPLC chromatogram for a
standard mixture of opioids resulting from the HPLC method of
Example 11A. Legend: see Example 11A.
[0143] FIG. 5 shows a representative HPLC chromatogram for a
standard mixture of opioids resulting from the HPLC method of
Example 11B. Legend: see Example 11B.
[0144] FIG. 6 shows the chromatogram of the analysis of the
isolated solid oxymorphone of Example 16 for a sample concentration
of 1 mg/mL.
[0145] FIG. 7 shows the chromatogram of the analysis of the
isolated solid oxymorphone of Example 16 for a sample concentration
of 10 mg/mL.
[0146] FIG. 8 shows the chromatogram of the analysis of the
isolated solid oxymorphone of Example 17 for a sample concentration
of 1 mg/mL.
[0147] FIG. 9 shows the chromatogram of the analysis of the
isolated solid oxymorphone of Example 17 for a sample concentration
of 10 mg/mL.
DETAILED DESCRIPTION OF THE INVENTION
I. Compounds
[0148] In the context of the present invention, compounds which are
oripavine, oxymorphone, 14-hydroxymorphinone, 8-hydroxyoxymorphone,
and salts and solvates thereof, and mixtures of two or more of any
of the foregoing compounds are described. They may be used as
starting materials, intermediates or products of the processes
according to present invention. To these compounds, the following
applies:
[0149] In all formulae containing stereocenters, any
stereoconfiguration may be present, unless indicated otherwise. If
a compound is the product of a process according to the present
invention, those stereocenters of the starting material which are
not taking part in the reaction will maintain their
stereoconfiguration. In certain embodiments, the
stereoconfiguration is as described in the Definitions section
above.
[0150] In all formulae containing X.sup.n-, X.sup.n- may be an
inorganic or organic anion wherein n is 1, 2, or 3, preferably is 1
or 2, and more preferably is 2.
[0151] X.sup.n- may be any anion of a known opioid salt, including,
but not limited to, bromide, chloride, iodide, lactate, nitrate,
acetate, tartrate, valerate, citrate, salicylate, meconate,
barbiturate, HSO.sub.4.sup.-, SO.sub.4.sup.2-, methanesulfonate,
tosylate, trifluoroacetate, H.sub.2PO.sub.4.sup.-,
HPO.sub.4.sup.2-, PO.sub.4.sup.3-, oxalate, perchlorate, and any
mixtures thereof.
[0152] Preferably, X.sup.n- is selected from the group consisting
of Cl.sup.-, HSO.sub.4.sup.-, SO.sub.4.sup.2-, methanesulfonate,
tosylate, trifluoroacetate, H.sub.2PO.sub.4.sup.-,
HPO.sub.4.sup.2-, PO.sub.4.sup.3-, oxalate, perchlorate, and any
mixtures thereof. More preferably, X.sup.n- is HSO.sub.4.sup.-,
SO.sub.4.sup.2-, methanesulfonate, tosylate, trifluoroacetate, or a
mixture thereof. Even more preferably, X.sup.n- is HSO.sub.4.sup.-,
SO.sub.4.sup.2-, methanesulfonate or trifluoroacetate. Even more
preferably, X.sup.n- is HSO.sub.4.sup.-, SO.sub.4.sup.2-, or
trifluoroacetate. Even more preferably, X.sup.n- is HSO.sub.4.sup.-
or SO.sub.4.sup.2-. Most preferably, X.sup.n- is
SO.sub.4.sup.2-.
[0153] X.sup.n- may be polymer-supported if n is 2 or 3.
[0154] Oripavine may be contained in a concentrate of a poppy straw
comprising oripavine as a main alkaloid (CPS-O), or it may be
purified oripavine, oripavine obtained from a botanical source,
synthetic oripavine, semi-synthetic oripavine, oripavine
bioengineered by, e.g., bacteria or plant cell cultures, or a
combination of two or more of any of the foregoing.
[0155] The 14-hydroxymorphinone salt is preferably
##STR00024##
or a solvate (e.g., a hydrate) thereof, respectively. As already
mentioned above, this compound will in the context of the present
invention be designated as 14-hydroxymorphinone sulfate. Because of
its stoichiometric composition, it may also be designated as
bis(14-hydroxymorphinone)sulfate. The terms 14-hydroxymorphinone
sulfate and bis(14-hydroxymorphinone)sulfate are used
interchangeably in the context of the present invention.
[0156] When a solvate of a 14-hydroxymorphinone salt is addressed,
it may be any association product of a 14-hydroxymorphinone salt
with a solvent molecule. The molar ratio of solvent molecule(s) per
molecule of 14-hydroxymorphinone salt may vary. The molar ratio of
solvent to compound/salt in the solvate may be 1 (e.g., in a
monohydrate), more than 1 (e.g., 2, 3, 4, 5 or 6 in a polyhydrate),
or less than 1 (e.g., 0.5 in a hemihydrate). The molar ratio need
not be an integer ratio, it can also be, e.g., 0.5 (as in a
hemihydrate) or 2.5. For example, 1 molecule water per molecule of
14-hydroxymorphinone sulfate is bound in 14-hydroxymorphinone
sulfate monohydrate. The solvate of the 14-hydroxymorphinone salt
is in certain embodiments a hydrate, for example a monohydrate,
dihydrate, trihydrate, tetrahydrate, pentahydrate or hexahydrate,
or a hydrate wherein the ratio of water per molecule is not
necessarily an integer, but within the range of from 0.5 to 10.0.
In certain embodiments, the solvate of the 14-hydroxymorphinone
salt is a hydrate wherein the ratio of water per molecule is within
the range of from 1 to 8. In certain embodiments, the solvate of
the 14-hydroxymorphinone salt is a hydrate wherein the ratio of
water per molecule is within the range of from 1 to 6, i.e. a mono-
to hexahydrate. In certain embodiments, the solvate of the
14-hydroxymorphinone salt is a monohydrate or a pentahydrate. The
same applies to other solvates in the context of the present
invention, e.g. solvates of oxymorphone or of a salt thereof.
II. Processes for Preparation of Oxymorphone or (Pharmaceutically
Acceptable) Salts or Solvates Thereof by Hydrogenation in the
Presence of Trifluoroacetic Acid and/or Glycol
[0157] The present invention provides a process for preparing
oxymorphone or an (optionally pharmaceutically acceptable) salt or
solvate thereof from a 14-hydroxymorphinone salt or a solvate
thereof as represented in the following Scheme 10:
##STR00025##
the process comprising or consisting of the steps of [0158] (a)
providing a solution or suspension of the 14-hydroxymorphinone salt
or a solvate thereof; [0159] (b) adding trifluoroacetic acid and/or
a glycol, preferably trifluoroacetic acid and a glycol; and [0160]
(c) hydrogenating the resulting mixture, thus reducing the
14-hydroxymorphinone to the oxymorphone, wherein X.sup.n- and n are
defined as above.
[0161] In certain embodiments, the solution or suspension
comprising the 14-hydroxymorphinone salt or the solvate thereof is
provided in step (a) by performing steps (a) to (b) of the process
described in Section II of PCT/IB2013/001541, steps (a) to (c) of
the process described in Section II of PCT/IB2013/001541, or steps
(a) to (d) of the process described in Section II of
PCT/IB2013/001541 (said steps (a) to (d) of the process described
in Section II of PCT/IB2013/001541 correspond to steps (aa) to (dd)
described herein below). When steps (a) to (d) described in Section
II of PCT/IB2013/001541 are performed, the 14-hydroxymorphinone
salt or solvate thereof isolated in step (d) thereof is dissolved
or suspended to provide the solution or suspension of said compound
in step (a) of the process according to the present invention.
[0162] In certain embodiments, the solution or suspension
comprising the 14-hydroxymorphinone salt or the solvate thereof is
the composition described in Section IV-A of PCT/IB2013/001541.
[0163] The hydrogenation of step (c) may be hydrogenation with
H.sub.2 or transfer hydrogenation. Typically, the hydrogenation is
performed in the presence of a hydrogenation catalyst. Preferably,
the hydrogenation is performed with H.sub.2 and a hydrogenation
catalyst.
[0164] An exemplary hydrogenation reaction is depicted in Scheme
11:
##STR00026##
[0165] Scheme 11 takes into account that 8-hydroxyoxymorphone or a
salt thereof may be present in the starting material in addition to
14-hydroxymorphinone sulfate (or any other 14-hydroxymorphinone
salt). Said 8-hydroxy compound may carry over during the
hydrogenation reaction. Or, as the hydrogenation is performed under
acidic conditions, said 8-hydroxy compound may be converted
partially or completely to the corresponding 14-hydroxy compound
14-hydroxymorphinone during the hydrogenation reaction. Thus,
14-hydroxymorphinone and 8-hydroxyoxymorphone may be present in the
reaction product which contains oxymorphone as main hydrogenation
product. However, typically, neither 8-hydroxyoxymorphone nor
14-hydroxymorphinone are present in the final oxymorphone when the
preferred embodiments of the hydrogenation reaction of the present
invention are performed.
[0166] In the context of the present invention, it is also
considered to precipitate and isolate the oxymorphone as its free
base. The precipitation and isolation of the free base of the
oxymorphone can result in a further purification effect, as the
precipitated base may contain less 8-hydroxyoxymorphone and/or
14-hydroxymorphinone than the mother liquor. In particular,
8-hydroxymorphone can be removed by precipitation because its
majority remains in the supernatant when oxymorphone is
precipitated as its free base.
[0167] As the hydrogenation is performed under acidic conditions,
the by-products present in the starting material and in the product
may be present in their protonated form, or as a salt or solvate
thereof.
[0168] The amount of TFA added in step (b) may be in the range from
5 to 99 mol % as compared to the molar amount of
14-hydroxymorphinone contained in the starting material.
Preferably, TFA is used in a substoichiometric amount, that is,
less TFA is added (in mol) than 14-hydroxymorphinone (in mol) which
is contained in the starting material. Thus, it is preferred that
the amount of TFA added in step (b) is 99 mol % or less (0.99
equivalents or less), more preferably from 10 to 70 mol % (0.1 to
0.7 equivalents), even more preferably from 30 to 50 mol % (0.3 to
0.5 equivalents), even more preferably from 35 to 45 mol % (0.35 to
0.45 equivalents) as compared to the molar amount of
14-hydroxymorphinone contained in the starting material. Thus, the
amount of TFA, and the total amount of acid in the reaction mixture
is lower than in conventional hydrogenation reactions leading from
14-hydroxymorphinone to oxymorphone, resulting in the advantages
described under Summary of the Invention in connection with the
substoichiometric amount of TFA.
[0169] The amount of glycol added in step (b) is typically in the
range from 1 to 8 volumes/weight (vol/w), preferably from 1.5 to 5
vol/w, more preferably from 2 to 3 vol/w, calculated for the glycol
volume in mL in relation to the weight in g of 14-hydroxymorphinone
salt (for example, in Example 16, 23 g 14-hydroxymorphinone sulfate
and 60 mL of propylene glycol are used, resulting in 2.61 vol/w
propylene glycol).
[0170] Preferably, the glycol is selected from the group consisting
of ethylene glycol, propylene glycol, 1,3-propanediol,
1,2-butanediol, 1,3-butanediol, neopentylglycol, and mixtures
thereof. More preferably, the glycol is ethylene glycol, propylene
glycol, or a mixture thereof.
[0171] A combination of TFA with glycol is especially preferred. In
said combination, the glycol is preferably selected from the group
consisting of ethylene glycol, propylene glycol, 1,3-propanediol,
1,2-butanediol, 1,3-butanediol, neopentylglycol, and mixtures
thereof. More preferably, the glycol is ethylene glycol, propylene
glycol, or a mixture thereof. In said combination, the volume ratio
of TFA to glycol is preferably from 1:15 to 1:45 (vol/vol), more
preferably from 1:20 to 1:40 (vol/vol), and even more preferably
from 1:25 to 1:35 (vol/vol). A particular embodiment is an
embodiment where said ratio is about 1:30 (vol/vol).
[0172] The hydrogenation is generally performed at a temperature of
from about 25.degree. C. to about 85.degree. C., preferably from
about 25.degree. C. to about 60.degree. C., more preferably from
about 25.degree. C. to about 50.degree. C., more preferably from
about 25.degree. C. to about 45.degree. C., more preferably from
about 25.degree. C. to about 40.degree. C., and even more
preferably from about 28.degree. C. to about 36.degree. C. (e.g.,
at 30.degree. C. as in Examples 16 and 17).
[0173] Preferably, the hydrogenation is performed with hydrogen
gas.
[0174] The hydrogenation using hydrogen gas is performed at a
suitable pressure. In certain embodiments, the hydrogenation is
performed at a pressure of from about ambient pressure (about 14.7
psia, 101.35 kPa) to about 100 psia (689.48 kPa). In certain
embodiments, it is performed at a pressure of from about 35 psia
(241.32 kPa) to about 80 psia (551.58 kPa), e.g., at about 60 psia
(413.69 kPa). In preferred embodiments, it is performed at a
pressure of from about 14.7 psia (101.35 kPa) to about 60 psia
(413.69 kPa).
[0175] The hydrogenation reaction may be run from about 0.5 minute
to about 48 hours, from about 1 minute to about 42 hours, from
about 2 minutes to about 26 hours, from about 1 minute to about 24
hours, from about 3 minutes to about 22 hours, from about 4 minutes
to about 20 hours, from about 5 minutes to about 18 hours, from
about 7 minutes to about 16 hours, from about 10 minutes to about
12 hours, from about 12 minutes to about 12 hours, from about 20
minutes to about 12 hours, from about 30 minutes to about 4 hours,
from about 2 hours to about 6 hours, or from about 3 hours to about
6 hours. In certain embodiments, the hydrogenation reaction is run
from about 1 hour to about 48 hours.
[0176] In certain embodiments, the hydrogenation reaction is run
for about 10 minutes, about 15 minutes, about 20 minutes, about 25
minutes, about 30 minutes, about 1 hour, about 1.5 hours, about 2
hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4
hours, about 4.5 hours, about 5 hours, about 5.5 hours, or about 6
hours.
[0177] In certain embodiments, the hydrogenation reaction is run
for about 8 hours, about 12 hours, about 16 hours, about 20 hours,
or about 24 hours.
[0178] In certain embodiments, the hydrogenation reaction is run
for about 26 hours, about 30 hours, about 34 hours, about 38 hours,
about 42 hours, or about 48 hours.
[0179] Generally, the hydrogenation reaction is run until
completion, i.e. until 14-hydroxymorphinone has disappeared from
the reaction mixture. This can be monitored by any suitable
detection method, e.g. by the HPLC methods described herein, in
particular the HPLC method of Example 11B.
[0180] An exemplary non-limiting list of hydrogenation catalysts
includes, e.g., Pd/C, palladium-charcoal, a combination of
diphenylsilane and Pd/C, Pd(Ph.sub.3P)/ZnCl.sub.2, a combination of
Pd/C with sodium hypophosphite (e.g., in aqueous trifluoroacetic
acid), Pt/C, Ru/C, Rh/C, PdO.sub.2, PtO.sub.2, zinc, magnesium. In
certain embodiments, the catalyst is a palladium catalyst.
Preferably, the catalyst is Pd/C, in particular Pd/C with 5%
Pd.
[0181] In certain embodiments, the hydrogenation catalyst is not a
metal, e.g., when the hydrogenation is a metal-free transfer
hydrogenation as described in Yang, J. W. et al., Angew. Chem. Int.
Ed. (2004) 43:6660-6662.
[0182] In certain embodiments, a solid support catalyst is used,
e.g., to ensure reaction completion upon contact and/or potentially
prevent or minimize the formation of any new 14-hydroxymorphinone
from 8-hydroxyoxymorphone.
[0183] Transfer hydrogenation involves the use of a hydrogen
transfer reagent.
[0184] Suitable hydrogen transfer reagents include HCO.sub.2H,
HCO.sub.2H/HCO.sub.2Na, HCO.sub.2H/NEt.sub.3, HCHO,
H.sub.2SO.sub.4, HCO.sub.2Na/NEt.sub.3, H.sub.2SO.sub.4/NEt.sub.3,
H.sub.3CSO.sub.2NHNH.sub.2/NEt.sub.3, a combination thereof, and
the like. Other hydrogen donors, like isopropanol, indoline,
cyclohexene, sodium borohydride, tetrahydroquinoline,
2,5-dihydrofuran, phosphoric acid, sodium dithionite, and
combinations thereof, might also be useful. In certain embodiments,
the hydrogen transfer reagent is a dihydropyridine, e.g., as
described in Yang, J. W. et al., Angew. Chem. Int. Ed. (2004)
43:6660-6662.
[0185] The hydrogenation may be done by a batch method or in a
continuously flowing stream.
[0186] In certain embodiments, the hydrogenation is done by a batch
method. In an exemplary batch method, a catalyst (e.g., palladium
on carbon) is charged into a batch reactor. A solution or
suspension of the 14-hydroxymorphinone salt or the solvate thereof
is added, or the 14-hydroxymorphinone salt and the solvent are
added separately. Trifluoroacetic acid and/or glycol are added. If
necessary, water is also added. The batch reactor is then sealed
and hydrogenated (e.g., at 14.7 psia (101.35 kPa), and 30.degree.
C.) for a time period sufficient to complete hydrogenation (e.g.,
for 48 hours). The catalyst is then removed by filtration.
[0187] The resulting oxymorphone may then be precipitated as its
free base by addition of a base, e.g., of sodium hydroxide or
ammonium hydroxide. Preferably, sodium hydroxide is used, because
the resulting precipitate shows a better behavior in subsequent
reactions. The precipitation may be enhanced by adding an
antisolvent. The precipitated solids are then optionally washed and
dried. The precipitation step (d) is described in more detail
below.
[0188] In certain embodiments, the hydrogenation reaction is
conducted in a continuously flowing stream. A reaction in a
continuously flowing stream of the reactants allows for the
transport of matter into and out of the reaction mixture as the
reaction is taking place. Running the reaction in a continuously
flowing stream allows, e.g., better control over reaction
conditions (including, e.g., time, temperature, equivalents of
reagents, pressure, temperature, time of exposure of reactants to
catalysts, pH, etc.), and isolation and/or removal of the
oxymorphone from the reaction mixture as it is being formed and/or
before any undesired compound is formed. In certain embodiments,
the oxymorphone is removed from the reaction mixture as it is being
formed.
[0189] In certain embodiments, conducting the reaction in a
continuously flowing stream allows for conducting the reaction at a
temperature which exceeds the boiling point of the solvent, because
the pressure can be safely maintained.
[0190] In certain embodiments, conducting the reaction in a
continuously flowing stream increases the yield of the reaction,
increases the volume efficiency of the reaction and/or decreases
the number and amounts of by-products formed during the
hydrogenation reaction, as the oxymorphone is removed before it
reacts with and/or is degraded by the remaining reactants.
[0191] The 14-hydroxymorphinone salt or solvate thereof is taken up
in a suitable solvent in step (a) of the process according to the
present invention. Thus, a suspension or solution of the
14-hydroxymorphinone salt is formed. The hydrogenation product
formed during the process typically dissolves in the solvent. In
certain embodiments, the solution or suspension of step (a) is
provided by using the glycol of step (b) as solvent. In said
embodiments, the glycol is either the sole solvent, or it is mixed
with other suitable solvents. In particular, it is preferably mixed
with water, because water is advantageous if the pH shall be raised
after the hydrogenation is complete in order to isolate the
oxymorphone as its free base. Preferably, said glycol is selected
from the group consisting of ethylene glycol, propylene glycol,
1,3-propanediol, 1,2-butanediol, 1,3-butanediol, neopentylglycol,
and mixtures thereof. More preferably, the glycol is ethylene
glycol, propylene glycol, or a mixture thereof. Other suitable
solvents for the process according to the present invention include
or consist of, e.g., methanol, tetrahydrofuran, isopropanol,
acetone, ethanol, 1-methoxy-2-propanol, 2-ethoxyethanol, tert-amyl
alcohol, isobutanol, 2-methyl-tetrahydrofuran, n-propanol,
1-butanol, 2-butanol, tert-butanol, isopropyl acetate, and
di(ethylene glycol) or a mixture of water with any one of the
foregoing, or consist of water; preferably, the other suitable
solvents include or consist of methanol, tetrahydrofuran,
isopropanol, acetone, ethanol, 1-methoxy-2-propanol,
2-ethoxyethanol, tert-amyl alcohol, or a mixture of water with any
one of the foregoing, or consist of water.
[0192] Water or a mixture of water with any of the foregoing
solvents, in particular with the foregoing glycol, is
preferred.
[0193] In certain embodiments, the suitable solvent is a 20:80
ethylene glycol:water mixture, 30:70 ethylene glycol:water mixture,
40:60 ethylene glycol:water mixture, 50:50 ethylene glycol:water
mixture, 60:40 ethylene glycol:water mixture, 70:30 ethylene
glycol:water mixture, 80:20 ethylene glycol:water mixture, 90:10
ethylene glycol:water mixture, 100:0 ethylene glycol:water mixture,
a 20:80 propylene glycol:water mixture, 30:70 propylene
glycol:water mixture, 40:60 propylene glycol:water mixture, 50:50
propylene glycol:water mixture, 60:40 propylene glycol:water
mixture, 70:30 propylene glycol:water mixture, 80:20 propylene
glycol:water mixture, 90:10 propylene glycol:water mixture, 100:0
propylene glycol:water mixture, a 50:50 methanol:water mixture,
60:40 methanol:water mixture, 70:30 methanol:water mixture, 80:20
methanol:water mixture, 90:10 methanol:water mixture, 100:0
methanol:water mixture, 50:50 ethanol:water mixture, 60:40
ethanol:water mixture, 70:30 ethanol:water mixture, 80:20
ethanol:water mixture, 90:10 ethanol:water mixture, 100:0
ethanol:water mixture, 90:10 tetrahydrofuran:water mixture, 100:0
tetrahydrofuran:water mixture, 90:10 isopropanol:water mixture,
70:30 acetone:water mixture, 80:20 acetone:water, or 90:10
acetone:water mixture. 8-Hydroxyoxymorphone is more soluble in
these mixtures than oxymorphone base and therefore may remain in
solution while the oxymorphone free base may be precipitated by
addition of a base at the end of the hydrogenation.
[0194] In certain preferred embodiments, the suitable solvent
comprises or consists of a mixture of glycol and water. Preferably,
said glycol is selected from the group consisting of ethylene
glycol, propylene glycol, 1,3-propanediol, 1,2-butanediol,
1,3-butanediol, neopentylglycol, and mixtures thereof. More
preferably, the glycol is ethylene glycol, propylene glycol, or a
mixture thereof.
[0195] In certain embodiments, the suitable solvent comprises or
consists of a mixture of ethylene glycol and water.
[0196] In certain embodiments, the suitable solvent comprises or
consists of a mixture of propylene glycol and water.
[0197] It is preferable to have more water than glycol in the
hydrogenation reaction mixture. I.e., a glycol:water mixture
containing less than 50 parts glycol per 50 parts of water is
preferred. Preferred mixtures are 30:70 glycol:water mixtures,
35:65 glycol:water mixtures, 40:60 glycol:water mixtures, and 45:55
glycol:water mixtures, and ratios between these ratios, The
preferred range is from 20:80 to less than 50:50 glycol:water
mixtures, more preferably from 30:70 to 45:55 glycol:water
mixtures, and more preferably from 35:65 to 45:55 glycol:water
mixtures. In particular, mixtures of about 40:60 glycol:water are
preferred. Especially preferred are mixtures of from 35:65 to
45:55, preferably about 40:60 ethylene glycol:water, or of from
35:65 to 45:55, preferably about 40:60 propylene glycol:water.
[0198] In certain embodiments, the suitable solvent used in step
(a) comprises or consists of water and the glycol is added in step
(b). In certain other embodiments, both glycol and water are added
simultaneously (either separately or as mixture) to the reaction
mixture at the beginning of the hydrogenation process; in said
embodiments, the solution or suspension of step (a) is provided by
using the glycol of step (b) as solvent.
[0199] Once the hydrogenation is completed, the oxymorphone may be
precipitated as its free base or a salt or solvate thereof.
[0200] In certain embodiments, the oxymorphone is precipitated as
its salt or a solvate thereof. In said salt, the anion may be
trifluoroacetate, or the same X.sup.n- as in the starting material
14-hydroxymorphinone salt, or a mixture thereof.
[0201] Preferably, the oxymorphone is precipitated as its free
base, in particular by step (d): [0202] (d) adding a base, thus
raising the pH to a pH where the oxymorphone precipitates, and
isolating the oxymorphone as its free base or a solvate
thereof.
[0203] Said step (d) is combined with steps (a) to (c) in a
preferred process according to the present invention, and said
preferred process either comprises steps (a) to (d) or consists of
steps (a) to (d). Without being bound by theory, it is assumed that
the combination of the precipitation and isolation step (d) with
the hydrogenation reaction of steps (a) to (c) gives the best
results, i.e. results in the lowest amount of 8-hydroxyoxymorphone
and 14-hydroxymorphinone in the final oxymorphone base.
[0204] The pH where the oxymorphone precipitates can be determined
by routine measures. However, it is generally in the range from 8.5
to 9.2, preferably at about 9.0.
[0205] The base added in step (d) may be any Bronsted base,
provided that its components do not form an insoluble salt with
other components of the reaction mixture. The base is preferably
selected from the group consisting of NaOH, KOH, Na.sub.2CO.sub.3,
K.sub.2CO.sub.3, NaHCO.sub.3, KHCO.sub.3, HCO.sub.2Na,
CH.sub.3CO.sub.2Na, NEt.sub.3, NH.sub.4OH or any mixtures thereof.
More preferably, it is a base containing hydroxide as anion, even
more preferably it is an alkali hydroxide or pseudo-alkali
hydroxide. Even more preferably, it is ammonium hydroxide or sodium
hydroxide, and most preferably it is sodium hydroxide. Sodium
hydroxide is preferably used, because the resulting precipitate
shows a better behavior in subsequent reactions than the
precipitate resulting from ammonium hydroxide. Ammonium hydroxide
forms ammonium sulfate or ammonium trifluoroacetate salts that
might precipitate with the oxymorphone base. These ammonium salts
can interfere, e.g., with the conversion of oxymorphone to
naloxone. It is believed that they react with N-demethylation
agents. The product resulting from sodium hydroxide has less impact
on further conversions of oxymorphone base.
[0206] The amount of base added in step (d) has to be sufficient to
achieve precipitation of the oxymorphone in its free base form.
Thus, it is preferably in the range from 0.5 to 2.0 molar
equivalents, more preferably from 0.8 to 1.7 equivalents, even more
preferably from 1.1 to 1.4 molar equivalents relative to the
oxymorphone base. From 1.2 to 1.3 molar equivalents base are
particularly preferred. Preferably, said base is sodium
hydroxide.
[0207] In certain embodiments, the precipitation of the oxymorphone
or salt or solvate thereof is enhanced by one or more of the
following: [0208] (i) adjusting (e.g., lowering) the temperature of
the reaction mixture to the precipitation temperature; [0209] (ii)
addition of an antisolvent; [0210] (iii) addition of a seed
crystal; [0211] (iv) changing the ionic strength of the reaction
mixture (e.g., by addition of a salt); [0212] (v) concentrating the
reaction mixture; [0213] (vi) reducing or stopping agitation of the
reaction mixture; or any other conventional method for initiating
or enhancing precipitation or crystallization.
[0214] When the temperature is adjusted to the precipitation
temperature, this means that the precipitation of the oxymorphone
base or salt or solvate thereof is initiated and/or enhanced by
adjusting the temperature of the reaction mixture to or beyond a
temperature at which said compound precipitates ("precipitation
temperature"). The temperature is either adjusted by performing the
reaction at the precipitation temperature, or by lowering the
temperature of the reaction mixture during the reaction or after
completion of the reaction.
[0215] In certain embodiments, the reaction mixture is adjusted to
a temperature of .ltoreq.40.degree. C. to initiate precipitation,
i.e. the precipitation temperature is .ltoreq.40.degree. C. In
certain embodiments, the precipitation is initiated at a
precipitation temperature of about -20.degree. C., about
-15.degree. C., about -10.degree. C., about -5.degree. C., about
0.degree. C., about 5.degree. C., about 10.degree. C., about
15.degree. C., about 17.degree. C., about 19.degree. C., about
21.degree. C., about 23.degree. C., about 25.degree. C., about
27.degree. C., about 29.degree. C., about 31.degree. C., about
33.degree. C., about 35.degree. C., about 37.degree. C., or about
40.degree. C.
[0216] In certain embodiments, the precipitation temperature is in
a range of from about -20.degree. C. to about 40.degree. C.,
preferably from about -10.degree. C. to about 40.degree. C., more
preferably from about -5.degree. C. to about 35.degree. C.
[0217] In certain embodiments, the precipitation temperature is in
a range of from about -10.degree. C. to about 22.degree. C.,
preferably from about -5.degree. C. to about 10.degree. C., more
preferably from about -5.degree. C. to about 5.degree. C.
[0218] In certain embodiments, an antisolvent is used in addition
to adjusting the temperature to the precipitation temperature.
Generally, however, precipitation will also occur without adding an
antisolvent.
[0219] Precipitation may also be achieved or enhanced by adding an
antisolvent to a solution of the oxymorphone or oxymorphone salt,
or by preparing a supersaturated solution (e.g. by cooling or
concentrating a reaction mixture) from which the resulting
oxymorphone or salt or solvate thereof is precipitated, e.g. by
cooling beyond the precipitation temperature or by adding a seed
crystal. The precipitated solids are then optionally washed and
dried. In one aspect, this precipitation may be achieved by adding
one or more of acetone, 1-methoxy-2-propanol, 2-butanol, and
tert-butyl methyl ether to a reaction mixture. In a specific
embodiment, tert-butyl methyl ether is added to a reaction mixture
which already may comprise water (which may be the sole solvent in
the reaction mixture). In another specific embodiment, 2-butanol is
added to a reaction mixture which already may comprise water. In
one aspect, this precipitation may be achieved by using a mixture
of water and an antisolvent, in particular a mixture of water, or a
mixture of water and tert-butyl methyl ether, or a mixture of
water, tetrahydrofuran, and tert-butyl methyl ether. Said mixture
may replace the reaction solvent after completion of the
hydrogenation reaction. The mixture can also be prepared by adding
antisolvent after completion of the hydrogenation reaction.
2-Butanol is the most preferred antisolvent.
[0220] Further suitable antisolvents may be the antisolvents
described in Section IV. I.e., a suitable antisolvent may comprise
or consist of tert-butyl methyl ether, diethyl ether, hexane(s),
tert-amyl alcohol, methanol, ethanol, n-propanol, isopropanol,
1-butanol, 2-butanol, tert-butanol, isobutanol, heptanes, xylenes,
toluene, acetone, 2-butanone, ethyl acetate, isopropyl acetate,
tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,2-dichloroethane,
chloroform, dichloromethane, 1-methoxy-2-propanol, 2-ethoxyethanol,
1,4-dioxane, methyl formate, methyl acetate, or a mixture of two or
more of any of the foregoing. The listed alcohols and ethers are
the preferred antisolvents, the alcohols being even more preferred.
In some preferred embodiments, the antisolvent is isopropanol or
2-butanol. The most preferred antisolvent is 2-butanol.
[0221] The resulting precipitate may then be isolated, thus
removing it from the mother liquor and advantageously further
purifying the free base from 8-hydroxyoxymorphone and/or
14-hydroxymorphinone which remains in the mother liquor.
[0222] Preferably, the oxymorphone is isolated as its free base.
The resulting oxymorphone in its form as free base comprises lower
amounts of 8-hydroxyoxymorphone and/or 14-hydroxymorphinone (or
salt or solvate thereof) as compared to oxymorphone made by a
process which does not involve the hydrogenation according to the
present invention.
[0223] Oxymorphone and compositions comprising said oxymorphone
which can be prepared via the process of present invention are
described, e.g., in Section VI below. The amounts of
8-hydroxyoxymorphone and 14-hydroxymorphinone which may be present
in the compositions comprising the oxymorphone are described in
Section VI below. In certain embodiments, this oxymorphone or these
compositions comprising the oxymorphone are the product of the
process described in the present section or in the subsequent
Section III.
[0224] In certain embodiments, the compositions comprising the
oxymorphone which are the product of the process described in the
present section or in the subsequent Section III can be used as
pharmaceutical compositions without further processing or
purification steps, in particular without further hydrogenation
steps.
[0225] In certain embodiments of this process, the
14-hydroxymorphinone salt is 14-hydroxymorphinone sulfate or a
solvate thereof.
[0226] In certain embodiments of this process, the
14-hydroxymorphinone salt is 14-hydroxymorphinone trifluoroacetate
or a solvate thereof.
III. Processes for Preparing Oxymorphone Starting from
Oripavine
[0227] Present invention further provides a process for preparing
oxymorphone from oripavine via a 14-hydroxymorphinone salt or a
solvate thereof. In this process, the 14-hydroxymorphinone salt or
solvate thereof serves as an intermediate. Said intermediate
14-hydroxymorphinone salt or the solvate thereof may either be
isolated or converted to oxymorphone or a salt or solvate thereof
without further isolation. In certain preferred embodiments, said
intermediate 14-hydroxymorphinone salt or the solvate thereof is
isolated before its conversion to the oxymorphone or a salt or
solvate thereof.
[0228] Thus, present invention provides a process for preparing
oxymorphone or a salt or solvate thereof from oripavine or a salt
or solvate thereof, the process comprising or consisting of (Scheme
12):
##STR00027## [0229] (aa) oxidizing the oripavine to
14-hydroxymorphinone; [0230] (bb) adding an acid
H.sup.+.sub.nX.sup.n- to the reaction mixture before, during and/or
after the oxidation reaction; [0231] (cc) optionally precipitating
the resulting 14-hydroxymorphinone as 14-hydroxymorphinone salt or
a solvate thereof; [0232] (dd) optionally isolating the
precipitated 14-hydroxymorphinone salt or solvate thereof; [0233]
(a) providing a solution or suspension of the 14-hydroxymorphinone
salt or a solvate thereof; [0234] (b) adding trifluoroacetic acid
and/or a glycol, preferably trifluoroacetic acid and a glycol; and
[0235] (c) hydrogenating the resulting mixture, thus reducing the
14-hydroxymorphinone to oxymorphone, wherein X.sup.n- and n are
defined as above.
[0236] In certain embodiments, the 14-hydroxymorphinone salt or
solvate thereof is precipitated and/or isolated in steps (cc)
and/or (dd) before the hydrogenation via steps (a) to (c).
[0237] In certain embodiments, said process will contain a further
step, namely (d) adding a base, thus raising the pH to a pH where
the oxymorphone precipitates, and isolating the oxymorphone as its
free base or a solvate thereof. See above, Section II.
[0238] In certain embodiments, step (c) of the process results in a
pharmaceutically acceptable salt or solvate of the oxymorphone. In
certain embodiments, step (c) of the process results not only in
such pharmaceutically acceptable salt or solvate of the
oxymorphone, but the complete resulting composition can be used as
pharmaceutical composition without requiring further processing
(e.g., purification). In particular, it may be used without an
additional hydrogenation to remove by-products, e.g.,
14-hydroxymorphinone. For example, the process may result in an
oxymorphone salt composition which is suitable for incorporation
into a dosage form, the oxymorphone salt composition being directly
prepared from the hydrogenation product of step (c) by a conversion
which does not include a further/additional hydrogenation step.
[0239] In certain embodiments, the salt or solvate of oxymorphone
which results from step (c) is not a pharmaceutically acceptable
salt or solvate.
[0240] In certain embodiments, the oxymorphone or salt or solvate
thereof resulting from step (c) may be converted into a
pharmaceutically acceptable salt or solvate thereof in an
additional step at the end of the process. Methods for such
conversion are known in the art (e.g., anion exchange).
[0241] In certain embodiments, the 14-hydroxymorphinone salt or
solvate thereof which is an intermediate of the process will have
the properties as described in Section IV of PCT/IB2013/001541.
[0242] All elements of steps (a) to (d) of said process and the
embodiments of said elements have already been described above. All
elements of steps (aa) to (dd) of said process and the embodiments
of said elements have already been described in PCT/IB2013/001541
(as steps (a) to (d) in Section II of PCT/IB2013/001541).
Oxymorphone which can be prepared via the process, and the amounts
of 8-hydroxyoxymorphone and 14-hydroxymorphinone which may be
present in compositions comprising said oxymorphone are described
in Section VI below. In certain embodiments, these compounds are
the product of the process described in the present section.
[0243] In the following, an exemplary embodiment of said process
will be described. Therein the starting compound for the oxidation
reaction is oripavine or a salt or solvate thereof, [0244] the
oxidation agent comprises or is performic acid formed in situ from
hydrogen peroxide and formic acid, the acid H.sup.+.sub.nX.sup.n-
in step (bb) is sulfuric acid which is added to the reaction
mixture, [0245] the 14-hydroxymorphinone salt is
14-hydroxymorphinone sulfate or a solvate thereof, and the product
is oxymorphone or a salt or solvate thereof.
[0246] In a preferred embodiment, the oxymorphone is precipitated
and isolated as its free base.
IV. Processes for Preparing a 14-Hydroxymorphinone Salt
[0247] A 14-hydroxymorphinone salt, the starting material for the
process according to the present invention, can be prepared
according to the processes for preparing a compound of formula V
described in Section II of PCT/IB2013/001541. The contents of this
Section II of PCT/IB2013/001541 are explicitly incorporated herein
by reference.
[0248] Hence, in certain embodiments, the 14-hydroxymorphinone salt
or a solvate thereof
##STR00028##
can be prepared from oripavine or a salt or solvate thereof, the
process comprising:
##STR00029## [0249] (aa) oxidizing the oripavine to
14-hydroxymorphinone; and [0250] (bb) adding an acid
H.sup.+.sub.nX.sup.n- to the reaction mixture before, during and/or
after the oxidation reaction, wherein X.sup.n- and n are defined as
above.
[0251] In a preferred embodiment, the acid H.sup.+.sub.nX.sup.n- is
added to the reaction mixture before or during the oxidation
reaction. More preferably, the acid H.sup.+.sub.nX.sup.n- is
present in the reaction mixture during the complete oxidation
reaction, i.e. it is added before the start of the oxidation
reaction, or at the start of the oxidation reaction.
[0252] In addition to the 14-hydroxymorphinone salt, the oxidation
of oripavine may generate 8-hydroxyoxymorphone or a salt or solvate
thereof. The 8-hydroxyoxymorphone may be formed as follows:
##STR00030##
[0253] The use of the 14-hydroxymorphinone salt or solvate thereof
as starting material in the hydrogenation process of the present
invention can reduce the amount of the 8-hydroxyoxymorphone which
is present at the beginning of the hydrogenation, as compared to a
process for preparation of oxymorphone without involving the
14-hydroxymorphinone salt.
[0254] The formation of a 14-hydroxymorphinone salt and the
isolation of the precipitated salt appear to prevent or reduce (i)
the formation of 8-hydroxyoxymorphone during oxidation of
oripavine, as compared to processes which do not involve the
formation of the 14-hydroxymorphinone salt, (ii) the presence of
8-hydroxyoxymorphone in a composition comprising oxymorphone base
made via a 14-hydroxymorphinone salt, and (iii) the presence of
8-hydroxyoxymorphone or a salt thereof and 14-hydroxymorphinone or
a salt thereof in an oxymorphone salt or in a pharmaceutical
composition comprising an oxymorphone salt made via a
14-hydroxymorphinone salt.
[0255] Pharmaceutical compositions prepared by processes of the
present invention may be quantitatively different from
pharmaceutical compositions prepared by conventional processes
which do not utilize the hydrogenation reaction conditions of the
present invention, and may offer advantages over the compositions
prepared by conventional processes, e.g., in terms of safety,
efficiency and reduced manufacturing costs. For example, these
compositions may contain less by-products and/or require less or no
further processing steps after synthesis of their API.
[0256] An exemplary embodiment of a process for preparing a
14-hydroxymorphinone salt is a process for preparing
14-hydroxymorphinone as its sulfate salt (or a solvate thereof),
which encompasses the oxidation of oripavine illustrated in Scheme
13:
##STR00031##
[0257] In a preferred embodiment of the present invention, the
14-hydroxymorphinone salt is
##STR00032##
(14-hydroxymorphinone sulfate) or a solvate thereof.
[0258] As described above, 8-hydroxyoxymorphone may be converted to
14-hydroxymorphinone during further processing of the
14-hydroxymorphinone salt to oxymorphone or a salt or solvate
thereof. If less 8-hydroxyoxymorphone is formed during the
oxidation reaction, less 8-hydroxyoxymorphone and ultimately less
14-hydroxymorphinone may finally be present in oxymorphone or an
(optionally pharmaceutically acceptable) salt or solvate thereof
(e.g., oxymorphone hydrochloride) made via or from the
14-hydroxymorphinone salt or a solvate thereof, as compared to
oxymorphone or a salt or solvate thereof made via a different
intermediate. Less 8-hydroxyoxymorphone and ultimately less
14-hydroxymorphinone may then also finally be present in a
pharmaceutical composition or dosage form containing said
oxymorphone or a pharmaceutically acceptable salt or solvate
thereof. Ultimately, the use of the 14-hydroxymorphinone salt as
starting material for the hydrogenation process of the present
invention may therefore contribute to the result that the amount of
8-hydroxyoxymorphone and 14-hydroxymorphinone formed during
preparation of oxymorphone or salt or solvate thereof is
insufficient to increase the total amount of the
14-hydroxymorphinone in said oxymorphone above an undesired level,
e.g., above a desired threshold amount of 14-hydroxymorphinone.
[0259] In certain embodiments, the oxidation step (aa) is partially
or completely performed in the presence of the acid
H.sup.+.sub.nX.sup.n- in the reaction mixture. That is, the acid is
added before or during the oxidation reaction, preferably before
the oxidation reaction. The acid H.sup.+.sub.nX.sup.n- is
preferably present in the reaction mixture during the complete
oxidation reaction, i.e. it is added before the start of the
oxidation reaction, or at the start of the oxidation reaction.
[0260] The 14-hydroxymorphinone salt may precipitate in certain
embodiments of the oxidation reaction.
[0261] The formation of the 14-hydroxymorphinone salt or solvate
thereof may occur via a salt formed from the oripavine, via
14-hydroxymorphinone in its free base form or in its salt or
solvate form, via both of said routes, or via a combination of one
or both of said routes with other reaction routes known to a person
skilled in the art. During this reaction, at least a part or all of
the oripavine and/or 14-hydroxymorphinone are protonated. This may
happen, e.g., under acidic reaction conditions.
[0262] In certain embodiments of the oxidation reaction, the
formation of the 14-hydroxymorphinone salt or a solvate thereof in
this process allows for a more volume efficient oxidation of the
oripavine in comparison to a process wherein no
14-hydroxymorphinone salt is formed.
[0263] In certain embodiments of the oxidation reaction, the
formation of the 14-hydroxymorphinone salt results in a lower ratio
of 8-hydroxyoxymorphone to the 14-hydroxymorphinone in the product,
as compared to a process wherein no 14-hydroxymorphinone salt or
solvate thereof is formed.
[0264] In certain embodiments of the oxidation reaction, said
result may be achieved because the formation of the
14-hydroxymorphinone salt or a solvate thereof has the effect that
less 8-hydroxy compound is formed during the oxidation reaction in
comparison to an oxidation reaction where no 14-hydroxymorphinone
salt or solvate thereof is formed. In other words, the formation of
the 14-hydroxymorphinone salt allows for an improvement of the
by-product profile of the reaction product.
[0265] In these embodiments, the oxidation reaction is typically
completely or partially performed in the presence of the acid
[0266] One example for such embodiment may be the formation of a
14-hydroxymorphinone salt, wherein n is 2 and preferably wherein
X.sup.n- is sulfate. Another example for such embodiment may be the
formation of a 14-hydroxymorphinone salt, wherein n is 1 and
preferably wherein X.sup.n- is trifluoroacetate. Another example
for such embodiment may be the formation of a 14-hydroxymorphinone
salt, wherein n is 3 and preferably wherein X is phosphate.
[0267] In certain embodiments of the oxidation reaction said result
may be achieved because the formation of the 14-hydroxymorphinone
salt or a solvate thereof has the effect that 8-hydroxyoxymorphone
can be separated from the 14-hydroxymorphinone salt or the solvate
thereof, e.g., by precipitation of the 14-hydroxymorphinone salt or
the solvate thereof from the reaction mixture. One example for such
an embodiment may be the formation of a 14-hydroxymorphinone salt
wherein X.sup.n- is sulfate.
[0268] In certain embodiments a combination of these effects takes
place, i.e., said result is achieved because both less
8-hydroxyoxymorphone is formed during the oxidation and because
said compound can be separated from the 14-hydroxymorphinone salt
or solvate thereof. One example for such an embodiment may be the
formation of a 14-hydroxymorphinone salt wherein X.sup.n- is
sulfate.
[0269] Preferably, the formation of the 14-hydroxymorphinone salt
or a solvate thereof reduces the formation of 8-hydroxy compounds
during the oxidation reaction and/or the presence of 8-hydroxy
compounds in the oxidation product, as compared to an oxidation
reaction which does not involve the step of forming the
14-hydroxymorphinone salt or a solvate thereof. The presence of
8-hydroxyoxymorphone in the product may be reduced by precipitation
of the 14-hydroxymorphinone salt. This may reduce the formation of
14-hydroxymorphinone during subsequent reactions (e.g., during
conversion of oxymorphone made from a 14-hydroxymorphinone salt to
oxymorphone hydrochloride), as compared to reactions which do not
involve the step of forming the 14-hydroxymorphinone salt or a
solvate thereof.
[0270] The process for preparing the 14-hydroxymorphinone salt or a
solvate thereof may be performed by oxidizing oripavine with an
oxidizing agent in the presence of one or more acids such that the
14-hydroxymorphinone salt is formed. An 8-hydroxy compound or a
salt or solvate thereof may be formed as by-product during the
oxidation. At the end of the preparation of the
14-hydroxymorphinone salt or a solvate thereof, said
14-hydroxymorphinone salt or solvate thereof may be provided as a
solid, a solution, or a suspension. The 14-hydroxymorphinone salt
or a solvate thereof is the starting material or intermediate for
the hydrogenation process of the present invention, i.e., the
process for preparing oxymorphone or an (optionally
pharmaceutically acceptable) salt or solvate thereof. The
14-hydroxymorphinone salt and the solvate thereof will be described
in more detail below. However, the subsequent description of the
oxidation process shall also apply to the 14-hydroxymorphinone salt
and the solvate thereof per se where applicable (e.g., when the
14-hydroxymorphinone salt is described as a reaction product of
such oxidation process).
[0271] The process step for preparing said 14-hydroxymorphinone
salt is depicted in the following Scheme 14:
##STR00033##
In certain embodiments of this process, the acid
H.sup.+.sub.nX.sup.n- is sulfuric acid.
[0272] The process for preparing a 14-hydroxymorphinone salt may be
performed as one-pot-reaction, wherein steps (aa) and (bb) are
performed concomitantly. In said one-pot-reaction, at least a part
of the acid H.sup.+.sub.nX.sup.n- is typically added before the
oxidizing agent, or concomitantly with the oxidizing agent. In
certain embodiments, all of the acid is added before the oxidizing
agent, or concomitantly with the oxidizing agent.
[0273] An exemplary one-pot reaction for forming a
14-hydroxymorphinone salt, namely 14-hydroxymorphinone sulfate, is
depicted in Scheme 15:
##STR00034##
[0274] In the oxidation reaction depicted in this Scheme, a peracid
formed from hydrogen peroxide and formic acid is used as at least
one oxidizing agent, and sulfuric acid is used as the acid
H.sup.+.sub.nX.sup.n-. It should be noted that it is not excluded
that at least part of the sulfuric acid also forms a peracid in the
presence of the hydrogen peroxide, which peroxide may also take
part in the oxidation reaction.
[0275] The reaction conditions of steps (aa) and (bb) (e.g., time,
temperature, pH, relative proportions of the reagents) will be
described in detail in the following. In a typical embodiment of
the present invention, they are adjusted such that the resulting
product containing the 14-hydroxymorphinone salt is free from, or
contains about 2500 ppm or less, about 2000 ppm or less, about 1500
ppm or less, about 1000 ppm or less, about 500 ppm or less, or
about 100 ppm or less of 8-hydroxyoxymorphone.
Oxidation Reaction
[0276] The oxidation reaction of step (aa) of the process is
represented in Scheme 16 and results in the formation of
14-hydroxymorphinone, which in turn is part of the
14-hydroxymorphinone salt:
##STR00035##
[0277] The oxidation reaction of step (aa) is generally run until
at least about 90%, about 92%, about 95%, about 97%, about 98%,
about 99% or about 100% of the oripavine is consumed by the
reaction. The amount of said compound remaining in the reaction may
be determined by any conventional determination method, e.g., by
HPLC, for example the HPLC method described in Example 11A.
[0278] The oxidizing reaction time can be anywhere from about 1
minute to about 36 hours, from about 10 minutes to about 34 hours,
from about 20 minutes to about 32 hours, from about 30 minutes to
about 30 hours, from about 45 minutes to about 28 hours, from about
1 hour to about 24 hours, from about 3 hours to about 21 hours,
from about 5 hours to about 18 hours. In certain embodiments, the
reaction time is about 30 minutes, about 1 hour, about 2 hours,
about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7
hours, about 8 hours, about 9 hours, about 10 hours, about 11
hours, about 12 hours, about 13 hours, about 14 hours, about 15
hours, about 16 hours, about 17 hours, about 18 hours, about 19
hours, about 20 hours, about 21 hours, about 22 hours, about 23
hours, or about 24 hours.
[0279] The reaction mixture may be maintained at a temperature of
from about 0.degree. C. to about 100.degree. C., from about
10.degree. C. to about 90.degree. C., from about 15.degree. C. to
about 80.degree. C., from about 20.degree. C. to about 70.degree.
C., from about 20.degree. C. to about 60.degree. C., from about
20.degree. C. to about 55.degree. C., from about 20.degree. C. to
about 45.degree. C., from about 20.degree. C. to about 40.degree.
C., or from about 20.degree. C. to about 35.degree. C.
[0280] In certain embodiments, e.g., in a reaction conducted in a
flow reactor, the reaction mixture may be maintained at a
temperature as listed in the preceding sentence, or it may be
maintained at a temperature exceeding some of the upper temperature
limits of the preceding sentence, e.g., at a temperature of from
about 40.degree. C. to about 95.degree. C.
[0281] In certain embodiments, the reaction mixture is maintained
at from about 20.degree. C. to about 45.degree. C., preferably from
about 25.degree. C. to about 40.degree. C. In certain embodiments,
the reaction mixture is maintained more preferably at from about
25.degree. C. to about 35.degree. C., even more preferably at about
30.degree. C. In certain especially preferred embodiments, the
reaction mixture is maintained more preferably at from about
30.degree. C. to about 38.degree. C., more preferably at from about
32.degree. C. to about 36.degree. C., even more preferably at about
35.degree. C. Typically, the oxidation reaction will be finished
after about 24 hours or even less hours (e.g., 16 or 20 hours) when
these preferred temperatures are used.
[0282] Typically, the oxidation of the oripavine during step (aa)
is taking place in the presence of an oxidizing agent. Said
oxidizing agent is either added to the reaction mixture, or it is
formed in situ in the reaction mixture (e.g., performic acid may be
formed in situ in a reaction mixture comprising formic acid and
hydrogen peroxide). The oripavine is then oxidized to the
14-hydroxymorphinone salt, which will result when the acid
H.sup.+.sub.nX.sup.n- is present.
[0283] The oripavine may be provided for step (aa) in a solution or
suspension comprising the oripavine and a suitable solvent. A
suitable solvent may comprise or consist of water; an alcohol
(e.g., methanol, ethanol, n-propanol, isopropanol, 1-butanol,
2-butanol, isobutanol, tert-butanol, tert-amyl alcohol,
2-ethoxyethanol, 1-methoxy-2-propanol, etc.); an aromatic
hydrocarbon (e.g., benzene, toluene, xylol, etc.); an ether (e.g.,
1,4-dioxane, tetrahydrofuran, 2-methyl-tetrahydrofuran,
diethylether, tert-butyl methyl ether, etc.); a (C.sub.1-C.sub.4)
alkyl ester of a (C.sub.1-C.sub.4) alkanoic acid (e.g., methyl
formate, methyl acetate, ethyl acetate, isopropyl acetate, etc.);
an amide (e.g., dimethylformamide, diethylformamide,
dimethylacetamide, or other N--(C.sub.1-C.sub.4) alkyl substituted
(C.sub.1-C.sub.4) alkanoic acid amides); N-methylpyrrolidone;
formylmorpholine; or any mixtures of any of the foregoing. In
certain embodiments, the reagent providing an acid for the process
(e.g., 88% formic acid in water), or the acid itself can act as
solvent. In certain embodiments, the solvent comprises or consists
of water, an ether, an alcohol, or a combination thereof. In
certain embodiments, the solvent comprises or consists of methanol,
tetrahydrofuran, n-propanol, isopropanol, 1-butanol, 2-butanol,
isobutanol, tert-butanol, acetone, ethanol, 1-methoxy-2-propanol,
2-ethoxyethanol, tert-amyl alcohol, or a mixture of water with any
one of the foregoing. In certain embodiments, the solvent comprises
or consists of tetrahydrofuran, isopropanol, methanol, ethanol,
1-butanol, 2-butanol, isobutanol, tert-butanol, tert-amyl alcohol,
n-propanol or any combination thereof. In certain embodiments, the
solvent is water or a combination of water with another solvent. In
certain embodiments, the solvent is isopropanol or a mixture of
isopropanol and water. In certain embodiments, the solvent is
2-butanol or a mixture of 2-butanol and water. In certain other
embodiments, the solvent is free or substantially free from water
(e.g., when the reaction is performed in chloroform using MCPBA as
oxidizing agent). In certain preferred embodiments, the solvent
comprises or consists of water.
[0284] The ratio of the oripavine to the solvent is selected such
that the oripavine is dissolved in the solvent, i.e. such that a
suspension or preferably a solution of the oripavine is formed. If
the oxidizing agent contains or is generated with an acid which
acts as a solvent (e.g., formic acid), or if the acid
H.sup.+.sub.nX.sup.n- acts as a solvent, said acid contributes to
the total amount of solvent in the reaction mixture or is the sole
solvent in the reaction mixture. The ratio of the oripavine (in
mmol) to the solvent (in mL) may be defined as molarity by the
following formula:
molarity=(mmol of oripavine)/(milliliters of solvent).
For example, when 33.7 mmol of oripavine and 23.6 mL water plus
formic acid are used, this results in a molarity of 1.43
(33.7/23.6). In the present process, the molarity of the oripavine
in relation to the solvent is preferably .gtoreq.0.8. In certain
embodiments, the molarity is from 0.8 to 1.8, preferably from 1.2
to 1.7, more preferably from 1.2 to 1.6 and even more preferably
from 1.3 to 1.5. In comparison, in WO 2008/130553, the molarity is
0.67 ((10 mmol oripavine)/(15 mL water plus formic acid)). The less
solvent is used, the more volume efficient steps (aa) and (bb) may
be if the process yield remains constant. Thus, this process allows
for the use of less solvent, which in turn may reduce the
environmental burden and/or production costs.
[0285] In certain embodiments, the solvent comprises or consists of
water, e.g. in the oxidation reactions described in the Examples.
The ratio of the oripavine (in mmol) to water (in mL) in said
embodiments is preferably from about 1:1 to about 5:1, more
preferably from about 1.2:1 to about 4:1, more preferably from
about 1.5:1 to about 3:1, more preferably from about 1.6:1 to about
2.4:1, even more preferably from about 1.7:1 to about 2.2:1. E.g.,
in a preferred embodiment, from about 1.5 mL to about 2.0 mL,
preferably from about 1.6 to about 1.9 mL water per g oripavine are
used. This calculation does not take into account water contained
in one of the acids or other reagents (in particular, hydrogen
peroxide) used in the oxidation reaction.
[0286] Before the oxidation reaction is initiated (e.g., by adding
or generating an oxidizing agent), the oripavine may be present in
any percentage of the reaction mixture. In certain embodiments, it
is present in a starting amount of from about 1% to about 60%, from
about 5% to about 50%, from about 10% to about 40%, from about 15%
to about 35%, from about 20 to about 33%, or from about 20% to
about 30% per weight of the complete reaction mixture. In certain
preferred embodiments, the oripavine comprises from about 20 to
about 33% of the reaction mixture by weight. In certain preferred
embodiments, the oripavine comprises from about 20% to about 30% of
the reaction mixture by weight. As the oxidation takes place, the
concentration of the oripavine decreases and may finally approach
0%.
[0287] The oxidizing agent may be a peracid, a peroxide (which
encompasses hydrogen peroxide and peroxide salts), a periodinane,
singlet oxygen or any combination thereof. For example, an
oxidizing agent may be hydrogen peroxide, potassium
peroxymonosulfate (e.g., OXONE.RTM.), performic acid, peracetic
acid (AcOOH), persulfuric acid, m-chloroperoxybenzoic acid (MCPBA),
trifluoro peracetic acid, singlet oxygen, iodosylbenzene,
K.sub.2O.sub.2, Na.sub.2O.sub.2, Li.sub.2O.sub.2, Cs.sub.2O.sub.2,
Cs.sub.2O.sub.2, K.sub.2SO.sub.5, NaSO.sub.5, or an appropriate
mixture of any two or more of the foregoing. Said oxidizing agent
may be either generated in situ in the reaction mixture (e.g.,
performic acid from hydrogen peroxide and an acid), or it may be
added to the reaction mixture (e.g., MCPBA).
[0288] In certain embodiments, the oxidizing agent is a peracid.
Said peracid may either be generated in situ in the reaction
mixture from hydrogen peroxide and an acid or from another
combination of reagents leading to the formation of a peracid
(e.g., from a peroxide salt and an acid), or it may be added to the
reaction mixture (e.g., MCPBA, or a peracid generated ex situ, i.e.
separately from the reaction mixture before its addition to the
reaction mixture). If the peracid is generated in situ, the
peroxide may be added after the acid and/or at a pH of the reaction
mixture which is less than 7.
[0289] In certain embodiments, the peracid may be performic acid,
peracetic acid, MCPBA, potassium peroxymonosulfate (which contains
one peracid group), trifluoro peracetic acid, persulfuric acid, or
a combination of any two or more thereof. When said peracid is
generated in situ, the corresponding starting acid is formic acid,
acetic acid, 3-chlorobenzoic acid, potassium monosulfate,
trifluoroacetic acid, sulfuric acid, or a mixture of any two or
more of the foregoing.
[0290] In certain embodiments, the peracid comprises or is
performic acid. When the performic acid is generated in situ or ex
situ, it is in one embodiment generated from formic acid and
hydrogen peroxide.
[0291] In certain embodiments, the peracid comprises or is a
combination of performic acid and persulfuric acid. When said
combination is generated in situ or ex situ, it is in one
embodiment generated from formic acid, sulfuric acid and hydrogen
peroxide.
[0292] In certain embodiments, the oxidizing agent is or is
generated from hydrogen peroxide (e.g., added to the reaction
mixture in 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, or 70%
aqueous solution). In certain embodiments, 35% aqueous solution of
hydrogen peroxide is added to the reaction mixture. In certain
embodiments, at the beginning of the reaction, hydrogen peroxide
may comprise about 8-10% of the reaction mixture by volume, and, as
the oxidation reaction takes place, the concentration of hydrogen
peroxide decreases and may even reach 0%.
[0293] In general, the oxidizing agent, e.g., a peracid generated
from an acid and hydrogen peroxide, is present in an amount of from
about 0.8 to about 5 moles per mole of the oripavine. In certain
embodiments, from about 1 to about 2 moles of the oxidizing agent
per 1 mole of the oripavine are utilized. In certain embodiments,
about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5,
about 1.6, about 1.8, or about 1.9 moles of the oxidizing agent per
mole of the oripavine are used. In certain embodiments, from about
1 to about 1.6 moles of the oxidizing agent per mole of the
oripavine are utilized. In certain embodiments, from about 1 to
about 1.4 moles of the oxidizing agent per mole of the oripavine
are utilized. In certain embodiments, from about 1.2 to about 1.4
moles of the oxidizing agent per mole of the oripavine are
utilized. In certain embodiments, from about 1.2 to about 1.3 moles
(e.g., 1.25 molar equivalents) of the oxidizing agent per mole of
the oripavine are utilized. In certain embodiments, from about 1 to
about 1.25 moles of the oxidizing agent per mole of the oripavine
are utilized. In certain embodiments, from about 1.05 to about 1.15
moles (e.g., 1.05 molar equivalents) of oxidizing agent per mole of
the oripavine are used. In embodiments wherein a peracid is
generated in situ, the molar amount of the starting component
containing the peroxy group (e.g., hydrogen peroxide) is deemed to
represent the molar amount of the resulting peracid in the reaction
mixture.
[0294] In those embodiments wherein the oxidizing agent is a
peracid generated in situ from hydrogen peroxide and an acid in the
reaction mixture, preferably from about 1 to about 1.6 moles of
hydrogen peroxide per mole of the oripavine are utilized. In
certain embodiments, from about 1 to about 1.5 moles of hydrogen
peroxide per mole of the oripavine are utilized. In certain
embodiments, from about 1.2 to about 1.4 moles of hydrogen peroxide
per mole of the oripavine are utilized. In certain embodiments,
from about 1.2 to about 1.3 moles (e.g., 1.25 molar equivalents) of
the oxidizing agent per mole of the oripavine are utilized. In
certain embodiments, from about 1 to about 1.25 moles of hydrogen
peroxide per mole of the oripavine are utilized. In certain
embodiments, from about 1.05 to about 1.15 moles (e.g., 1.05 molar
equivalents) of hydrogen peroxide per mole of the oripavine are
used.
[0295] In a preferred embodiment, from about 1 to about 1.5 moles
of the oxidizing agent per mole of the oripavine are utilized, and
more preferably, especially in cases where full conversion shall be
achieved within about 24 hours or less, from about 1.2 to about 1.5
moles or from about 1.2 to about 1.4 moles of the oxidizing agent
per mole of the oripavine are utilized. This means that in said
preferred embodiment, when the oxidizing agent is a peracid
generated in situ from hydrogen peroxide and an acid in the
reaction mixture, from about 1 to about 1.5 moles of hydrogen
peroxide per mole of the oripavine are utilized, and more
preferably, from about 1.2 to about 1.4 moles of hydrogen peroxide
per mole of the oripavine are utilized. In a particular aspect of
said preferred embodiment, from about 1.2 to about 1.3 moles (e.g.,
about 1.25 moles) of hydrogen peroxide per mole of the oripavine
are utilized.
[0296] In those embodiments wherein the oxidizing agent is a
peracid generated in situ from hydrogen peroxide and an acid in the
reaction mixture, the acid for generating the peracid preferably is
or comprises formic acid. This also encompasses processes wherein
the peracid is generated from a combination of formic acid and
sulfuric acid.
[0297] The molar amount of an acid used for generating a peracid in
situ may be less than, equal to, or exceeding the molar amount of
the oripavine. In certain embodiments, an excess of said acid over
the amount of the oripavine will be utilized. In certain
embodiments, said acid is used in excess over the amount of the
peroxide (e.g., hydrogen peroxide) which is used to generate the
peracid. In certain embodiments, the amount of the acid used for
generating the peracid (e.g., of formic acid) is from about 0.5 to
about 14 molar equivalents per molar equivalent of the oripavine,
preferably from about 1 to about 12 molar equivalents, more
preferably from about 1 to about 7 molar equivalents, more
preferably from about 1.5 to about 6 molar equivalents, more
preferably from about 2 to about 5 molar equivalents, more
preferably from about 2.5 to about 4.5 molar equivalents, even more
preferably from about 2.5 to 4 molar equivalents per molar
equivalent of the oripavine.
[0298] In a specific aspect of the oxidation reaction, the molar
amount of the acid used for generating the peracid in situ is from
about 2.5 to about 4.5 equivalents per molar equivalent of the
oripavine, and the molar amount of the peroxide is from about 1 to
about 1.5 moles, preferably from about 1.2 to about 1.4 moles, more
preferably from about 1.2 to about 1.3 moles per mole of the
oripavine. In said aspect, the acid is preferably formic acid, and
the peroxide is preferably hydrogen peroxide.
[0299] When an acid is used for generating the oxidizing agent in
situ, two acids may be used during a process encompassing steps
(aa) and (bb): a first acid (which is used to generate at least a
part of the peracid in situ in step (aa)), and a second acid (which
is the acid H.sup.+.sub.nX.sup.n- of step (bb), which in certain
embodiments may also generate a part of the peracid in situ in step
(aa)). The second acid may be added before, simultaneously with, or
after addition of the first acid. In certain embodiments, the acids
are pre-mixed and the pre-mixture is added to the solution or
suspension. In certain embodiments, the first acid and the second
acid may each be independently added all at once or in divided
portions. In certain embodiments, the first acid is formic acid and
the second acid is sulfuric acid.
[0300] The acid H.sup.+.sub.nX.sup.n- of step (bb) may be added as
acid H.sup.+.sub.nX.sup.n- or may be generated in situ in the
reaction mixture from a salt containing an anion X.
[0301] The acid H.sup.+.sub.nX.sup.n- may be added (or generated in
situ) before, during or after the oxidation reaction of step (aa),
or at any combination of these time points. It may be added once,
in several batches or continuously over a certain period of time.
It may be added at or during several points in time in relation to
the oxidation reaction, e.g., before, during and after the
oxidation, or before and during the oxidation reaction. If it is
added (or generated) before and/or during the oxidation reaction,
the process comprising steps (aa) and (bb) is performed as a
one-pot-reaction. Said one-pot-reaction may be more cost-, time-
and/or volume-efficient and may therefore be preferred. Especially
preferred is a process wherein the acid H.sup.+.sub.nX.sup.n- is
added to (or generated in) the reaction mixture before the
oxidation reaction of step (aa).
[0302] In certain embodiments, a portion or all of the acid
H.sup.+.sub.nX.sup.n- is added after some or substantially all of
the oripavine has been oxidized. In certain embodiments,
H.sup.+.sub.nX.sup.n- is added after substantially all of the
oripavine has been consumed.
[0303] In certain embodiments, step (bb) of the process is
performed by adding H.sup.+.sub.nX.sup.n- (e.g., H.sub.2SO.sub.4)
to the reaction mixture.
[0304] H.sup.+.sub.nX.sup.n- may be any acid containing an anion
X.sup.n- as defined herein. It may, for example, be HCl,
H.sub.2SO.sub.4 or its monosalt, methanesulfonic acid, tosylic
acid, trifluoroacetic acid, H.sub.3PO.sub.4 or one of its mono- or
disalts, oxalic acid, perchloric acid, or any mixtures thereof. In
certain embodiments, it may be HCl, H.sub.2SO.sub.4,
methanesulfonic acid, tosylic acid, trifluoroacetic acid, or a
mixture thereof. In certain embodiments, it is H.sub.2SO.sub.4,
methanesulfonic acid, or trifluoroacetic acid or a mixture thereof.
In certain embodiments, it is trifluoroacetic acid. In certain
embodiments, it is H.sub.2SO.sub.4. In certain embodiments, it is
methanesulfonic acid.
[0305] H.sup.+.sub.nX.sup.n- may in certain embodiments be polymer
supported if n is 2 or 3.
[0306] The molar amount of H.sup.+.sub.nX.sup.n- present in step
(bb) may be the same as or different from the molar amount of the
oripavine provided for step (aa). For example, in embodiments
wherein n is 2, the salt or acid added in step (bb), e.g.,
H.sub.2SO.sub.4 or a salt thereof, may be added in an amount of
from about 0.1 to about 1.5 molar equivalents, preferably of from
about 0.1 to about 1.2 molar equivalents, more preferably of from
about 0.1 to about 1 molar equivalents, even more preferably of
from about 0.25 to about 0.75 molar equivalents, even more
preferably of from about 0.4 to about 0.6 molar equivalents, even
more preferably of from about 0.45 to about 0.55 molar equivalents
or from about 0.5 to about 0.6 molar equivalents per molar
equivalent of the oripavine. In certain embodiments wherein n is 2,
the salt or acid added in step (bb), e.g., H.sub.2SO.sub.4 or a
salt thereof, is added in an amount of about 0.5 to about 0.6
equivalents, e.g. of about 0.51 to about 0.55 molar equivalents per
molar equivalent of the oripavine.
[0307] In certain embodiments, the amount of H.sup.+ provided by
H.sup.+.sub.nX.sup.n- in step (bb) is in a slight molar excess in
comparison to the oripavine. In certain embodiments, the molar
amount of H.sup.+.sub.nX.sup.n- present in step (bb) is within a
range of about 1/n+10% to about 1/n+20% molar equivalents per one
molar equivalent of the oripavine.
[0308] In certain embodiments, the acid H.sup.+.sub.nX.sup.n- is
the only acid used during the process encompassing steps (aa) and
(bb). In those embodiments where a peracid is used as oxidizing
agent, said acid H.sup.+.sub.nX.sup.n- is capable to form a peracid
and will be used for generating said peracid.
[0309] In certain other embodiments, one or more additional acids
are added to the reaction mixture. In those embodiments where a
peracid is used as oxidizing agent, there may be used an acid for
generating the peracid which is different from the acid This acid
is then an additional acid. In other embodiments, a further
additional acid may be added to the reaction mixture in addition to
the acid H.sup.+.sub.nX.sup.n- and the acid for generating the
peracid. Such further acid may be any remaining acid selected from
the acids defined as the acid H.sup.+.sub.nX.sup.n- and as the acid
for generating the peracid in the present description, or any
mixture of said remaining acids.
[0310] The total amount of acid used during steps (aa) and (bb) of
the oxidation process is important, because it may influence
whether or not the 14-hydroxymorphinone salt precipitates from the
reaction mixture during the process. It also determines the amount
of base which will be required after completion of the reaction if
a neutralization of the reaction mixture is desired. The total
amount of acid includes the acid H.sup.+.sub.nX.sup.n- and, if
present, the acid used for generating a peracid and any further
acid added to the reaction mixture during steps (aa) and (bb). The
total amount of acid may range from about 0.6 to about 14.0 molar
equivalents of total acid per molar equivalent of the
oripavine.
[0311] In certain embodiments, from about 1 to about 12 molar
equivalents of total acid per molar equivalent of the oripavine are
used. In certain embodiments, from about 1 to about 10, from about
1 to about 8, from about 1 to about 7, from about 1 to about 6.5,
from about 1 to about 6, from about 1 to about 5.5, from about 1 to
about 5, from about 1 to about 4.5, from about 1 to about 4, from
about 1 to about 3.5, or from about 1.5 to about 3.5 molar
equivalents of total acid per molar equivalent of the oripavine are
used.
[0312] In certain embodiments, from about 1 to about 8 molar
equivalents, preferably from about 1 to about 5 molar equivalents,
more preferably from about 1.5 to about 4.5 molar equivalents, even
more preferably from about 3 to about 4 molar equivalents of total
acid per molar equivalent of the oripavine are used.
[0313] In certain embodiments, from about 1.2 to about 4.5 molar
equivalents of total acid per molar equivalent of the oripavine are
used.
[0314] In certain embodiments, from about 2.5 to about 5.5 molar
equivalents, preferably from about 3 to about 5 molar equivalents
of total acid per molar equivalent of the oripavine are used.
[0315] In certain embodiments where an acid H.sup.+.sub.nX.sup.n-
and an acid used for generating the peracid (which is different
from H.sup.+.sub.nX.sup.n-) are used, the molar ratio of the acid
H.sup.+.sub.nX.sup.n- to the acid used for generating the peracid
(e.g., of sulfuric acid to formic acid) is from about 1:20 to about
1:0.5, from about 1:17 to about 1:1, from about 1:15 to about 1:1,
from about 1:14 to about 1:1, from about 1:12 to about 1:1, from
about 1:10 to about 1:1, from about 1:9 to about 1:2, from about
1:8 to about 1:3, from about 1:7 to about 1:3, from about 1:7 to
about 1:5, or a numeric value lying within these ranges. In certain
embodiments, the molar ratio of the acid H.sup.+.sub.nX.sup.n- to
the acid used for generating the peracid is from about 1:9 to about
1:4, preferably from about 1:7.5 to about 1:4, more preferably from
about 1:7 to about 1:5, or a numeric value lying within these
ranges.
[0316] In certain embodiments, from about 2.5 to about 4.5 molar
equivalents of the acid used for generating a peracid per molar
equivalent of the oripavine are used, and from about 0.1 to about
1.5, from about 0.1 to about 1, from about 0.2 to about 0.9, from
about 0.25 to about 0.75, from about 0.4 to about 0.6, or from
about 0.5 to about 0.6 molar equivalents of the acid
H.sup.+.sub.nX.sup.n- per molar equivalent of the oripavine are
used. In said embodiments, said first acid may be formic acid, and
said second acid may be sulfuric acid.
[0317] In certain embodiments, from about 0.5 to about 4 molar
equivalents of the acid used for generating a peracid per molar
equivalent of the oripavine are used, and from about 0.1 to about
1.5, from about 0.1 to about 1, from about 0.2 to about 0.9, from
about 0.25 to about 0.75, from about 0.4 to about 0.6, or from
about 0.5 to about 0.6 molar equivalents of the acid
H.sup.+.sub.nX.sup.n- per molar equivalent of the oripavine are
used. In said embodiments, said first acid may be formic acid, and
said second acid may be sulfuric acid.
[0318] In certain embodiments, from about 0.5 to about 3.5 molar
equivalents of the acid used for generating a peracid per molar
equivalent of the oripavine are used, and from about 0.1 to about
1.5, from about 0.1 to about 1, from about 0.2 to about 0.9, from
about 0.25 to about 0.75, from about 0.4 to about 0.6, or from
about 0.5 to about 0.6 molar equivalents of the acid
H.sup.+.sub.nX.sup.n- per molar equivalent of the oripavine are
used. In said embodiments, said first acid may be formic acid, and
said second acid may be sulfuric acid.
[0319] In certain embodiments, from about 1 to about 3 molar
equivalents of the acid used for generating a peracid per molar
equivalent of the oripavine are used, and from about 0.4 to about
0.6, or from about 0.5 to about 0.6 molar equivalents of the acid
per molar equivalent of the oripavine are used. In said
embodiments, said first acid may be formic acid, and said second
acid may be sulfuric acid.
[0320] In a preferred embodiment utilizing formic acid and sulfuric
acid, the oxidation is performed by oxidizing the oripavine in the
presence of about 12 molar equivalents or less, about 10 molar
equivalents or less, about 8 molar equivalents or less, about 7
molar equivalents or less, about 6 molar equivalents or less, about
5 molar equivalents or less, about 4 molar equivalents or less,
about 3 molar equivalents or less, about 2 molar equivalents or
less, or about 1 molar equivalents (e.g., 1.05 molar equivalents)
or less of total acid per one molar equivalent of the oripavine,
wherein from about 0.1 to about 1.5 molar equivalents of total acid
comes from the acid H.sup.+.sub.nX.sup.n-. In one particular
embodiment, the oripavine is oxidized to the 14-hydroxymorphinone
salt by exposing each molar equivalent of the oripavine to (i) from
about 1.0 to about 1.6, preferably from about 1.2 to about 1.4
molar equivalents of hydrogen peroxide, (ii) from about 0.3 to
about 9, from about 0.5 to about 8, from about 0.5 to about 4.5, or
from about 2.5 to about 4.5 molar equivalents of the acid used for
generating the peracid, and (iii) from about 0.1 to about 1.5, from
about 0.25 to about 0.9, or from about 0.4 to about 0.6 molar
equivalents of the acid H.sup.+.sub.nX.sup.n-. In certain
embodiments, from about 2.5 to about 4 molar equivalents of the
acid used for generating the peracid per one molar equivalent of
the oripavine are used. In certain embodiments, from about 0.4 to
about 0.6 molar equivalents of the acid H.sup.+.sub.nX.sup.n-, and
from about 2.5 to about 4 molar equivalents of the acid used for
generating the peracid are used. In certain embodiments, from about
0.4 to about 0.6 molar equivalents of the acid
H.sup.+.sub.nX.sup.n-, and from about 1 to about 3 molar
equivalents of the acid used for generating the peracid are used.
In certain embodiments, from about 0. 5 to about 0.6 molar
equivalents of the acid H.sup.+.sub.nX.sup.n-, and from about 2.5
to about 4.5 molar equivalents of the acid used for generating the
peracid are used. In certain embodiments, conducting the oxidation
reaction under these conditions may improve the volume efficiency
of the reaction and may reduce the number and amounts of
by-products formed during the oxidation reaction.
[0321] In certain embodiments, a portion or all of the
H.sup.+.sub.nX.sup.n- (e.g., H.sub.2SO.sub.4) is added to the
reaction mixture before the acid or the peroxide used for
generating the peracid is added, or at the same point in time.
[0322] In certain embodiments, H.sup.+.sub.nX.sup.n- (e.g.,
H.sub.2SO.sub.4) is added after the acid used for generating the
peracid (e.g., formic acid). In certain embodiments, the reaction
mixture may already comprise formic acid, and sulfuric acid is then
added.
[0323] In preferred embodiments, the 14-hydroxymorphinone salt is
precipitated from the reaction mixture, either because the presence
of the acid H.sup.+.sub.nX.sup.n- (e.g., H.sub.2SO.sub.4) induces
the precipitation of the 14-hydroxymorphinone salt or a solvate
thereof during the oxidation reaction, or because in addition to
said presence the precipitation is started or enhanced by other
measures, e.g., by adjusting the temperature of the solution and/or
adding a suitable antisolvent to the solution, as described in more
detail below. In certain embodiments, precipitation is achieved by
adding a suitable antisolvent. In certain embodiments,
precipitation is achieved by lowering the temperature below the
reaction temperature of the oxidation reaction.
[0324] The reaction steps (aa) and (bb) are typically performed in
a solvent. The amount of said solvent is described above with
regard to molarity.
[0325] In certain embodiments, the oxidizing agent is or comprises
performic acid generated, e.g., from hydrogen peroxide and formic
acid, and the solvent is water, an alcohol, a mixture of two or
more alcohols, or a mixture of an alcohol and water. The solvent
may be methanol or a mixture of methanol and water. The solvent may
be isopropanol or a mixture of isopropanol and water. The solvent
may be water.
[0326] In certain embodiments, the oxidizing agent is or comprises
performic acid and persulfuric acid generated, e.g., from hydrogen
peroxide and formic acid and sulfuric acid, and the solvent is
water, an alcohol, a mixture of two or more alcohols, or a mixture
of an alcohol and water. The solvent may be methanol or a mixture
of methanol and water. The solvent may be isopropanol or a mixture
of isopropanol and water. The solvent may be water.
[0327] In certain embodiments, the oxidizing agent is or comprises
peracetic acid, and the solvent is water, an alcohol, a mixture of
two or more alcohols, or a mixture of an alcohol and water.
[0328] In certain embodiments, step (aa) is performed with an
oxidizing agent formed from an acid and hydrogen peroxide. In
certain embodiments, the amount of total acid present in the
reaction mixture is about 12 molar equivalents or less, about 10
molar equivalents or less, about 8 molar equivalents or less, about
7 molar equivalents or less, about 6 molar equivalents or less,
about 5 molar equivalents or less, about 4 molar equivalents or
less, about 3 molar equivalents or less, about 2 molar equivalents
or less, or about 1 molar equivalents (e.g., 1.05 molar
equivalents) or less per molar equivalent of oripavine. In one
particular embodiment, the oripavine is oxidized to the
14-hydroxymorphinone by exposing each molar equivalent of the
oripavine to from about 1.0 to about 1.6, preferably from about 1.2
to about 1.4 molar equivalents of hydrogen peroxide, from about 0.3
to about 9 molar equivalents, from about 0.5 to about 8 molar
equivalents, or from about 2.5 to about 4.5 molar equivalents of
formic acid, and from about 0.4 to about 0.6 molar equivalents of
sulfuric acid. In certain embodiments, from about 0.5 to about 5
molar equivalents of formic acid per one molar equivalent of
oripavine are used. In certain embodiments, from about 2.5 to about
4.5 molar equivalents of formic acid per one molar equivalent of
oripavine are used. In certain embodiments, from about 2.5 to about
4 molar equivalents of formic acid per one molar equivalent of
oripavine are used.
[0329] In certain embodiments, the oxidation process is performed
by: (i) forming a solution or a suspension comprising oripavine and
from about 1.5 to about 4 molar equivalents of a first acid (e.g.,
formic acid) per molar equivalent of oripavine, (ii) adding from
about 0.4 to about 0.6 molar equivalents of the acid
H.sup.+.sub.nX.sup.n- (e.g., sulfuric acid) per molar equivalent of
oripavine to the solution or the suspension, (iii) adding from
about 1 to about 1.6 molar equivalents of hydrogen peroxide to the
solution or the suspension from (ii), and (iv) precipitating the
14-hydroxymorphinone salt from the solution or suspension (e.g., by
adjusting the temperature of the solution and/or adding a suitable
antisolvent to the solution, as described in more detail below). In
certain embodiments, precipitation is achieved by adding a suitable
antisolvent. In certain embodiments, precipitation is achieved by
lowering the temperature below the reaction temperature of the
oxidation reaction.
[0330] In certain embodiments, the oxidation process is performed
by: (i) forming a solution or a suspension comprising oripavine and
from about 2.5 to about 4.5 molar equivalents of a first acid
(e.g., formic acid) per molar equivalent of oripavine, (ii) adding
from about 0.5 to about 0.6 molar equivalents of the acid
H.sup.+.sub.nX.sup.n- (e.g., sulfuric acid) per molar equivalent of
oripavine to the solution or the suspension, (iii) adding from
about 1.0 to about 1.4 molar equivalents, preferably from about 1.2
to about 1.4 molar equivalents, and more preferably from about 1.2
to about 1.3 molar equivalents of hydrogen peroxide to the solution
or the suspension from (ii), and (iv) precipitating the
14-hydroxymorphinone salt from the solution or suspension (e.g., by
adjusting the temperature of the solution and/or adding a suitable
antisolvent to the solution, as described in more detail below). In
certain embodiments, precipitation is achieved by adding a suitable
antisolvent. In certain embodiments, precipitation is achieved by
lowering the temperature below the reaction temperature of the
oxidation reaction.
[0331] In certain embodiments, the amount of 8-hydroxyoxymorphone
in the oxidation reaction product containing the
14-hydroxymorphinone salt is less than about 2500 ppm, less than
about 2000 ppm, less than about 1500 ppm, less than about 1000 ppm,
less than about 500 ppm, less than about 100 ppm, less than about
50 ppm, less than about 10 ppm, less than about 5 ppm, or less than
about 1 ppm of the 14-hydroxymorphinone. In certain embodiments,
the amount of 8-hydroxyoxymorphone in the reaction product
containing the 14-hydroxymorphinone salt is the amount described in
Section V. In certain embodiments, the oxidation reaction product
is free from 8-hydroxyoxymorphone.
[0332] In certain embodiments, oripavine is oxidized to
14-hydroxymorphinone, wherein the reaction mixture comprises more
than one acid (e.g., two acids), and comprises less than about 14
molar equivalents of total acid per molar equivalent of oripavine
(e.g., from about 0.5 to about 11, from about 1 to about 10.5, from
about 1.5 to about 5, or from about 3 to about 5 molar equivalents
of acid per molar equivalent of oripavine).
[0333] In certain embodiments, oripavine is oxidized to
14-hydroxymorphinone, wherein the reaction mixture comprises more
than one acid (e.g., two acids), and comprises less than about 8
molar equivalents of total acid per molar equivalent of oripavine
(e.g., from about 0.5 to about 7, from about 1 to about 5, from
about 1.2 to about 4.5, from about 2.5 to about 4.5, or from about
3 to about 4 molar equivalents of total acid per molar equivalent
of oripavine).
[0334] In certain embodiments of the process, oripavine is oxidized
to 14-hydroxymorphinone in a solution or suspension containing a
mixture of formic acid and sulfuric acid, the mixture comprising
not more than about 14 molar equivalents of total acid per one
molar equivalent of oripavine (e.g., from about 0.5 to about 11,
from about 1 to about 10.5, from about 1.5 to about 5, or from
about 3 to about 5 molar equivalents of acid per one molar
equivalent of oripavine).
[0335] There are also alternative ways to perform step (bb) than by
adding H.sup.+.sub.nX.sup.n- to the reaction mixture. In step (bb)
of the process, the H.sup.+.sub.nX.sup.n- can be generated by
adding a salt containing X.sup.n-. Said salt may have the
formula
M.sup.m+(H.sup.+).sub.(n-m)X.sup.n-, or
M.sup.m+.sub.((n-l)/m)(H.sup.+).sub.lX.sup.n-, wherein [0336]
M.sup.m+ is a monovalent or polyvalent metal cation; [0337] m and n
are independently from each other an integer selected from 1, 2,
and 3, provided that m is .ltoreq.n; and [0338] l is an integer
selected from 0, 1, and 2, provided that l<n.
[0339] The metal cation may be an alkali metal cation, an alkaline
earth metal cation or a Group III cation. Exemplary cations are
Na.sup.+, K.sup.+, Ca.sup.2+. Exemplary salts are NaHSO.sub.4,
KHSO.sub.4, Na.sub.2SO.sub.4, K.sub.2SO.sub.4, NaH.sub.2PO.sub.4,
Na.sub.2HPO.sub.4, Na.sub.3PO.sub.4, KH.sub.2PO.sub.4,
K.sub.2HPO.sub.4, K.sub.3PO.sub.4.
[0340] The oxidation reaction may be prepared in any suitable
reaction vessel. In certain embodiments, the reaction vessel is a
flow reactor. In certain other embodiments, the reaction vessel is
not a flow reactor. In certain embodiments, the reaction vessel is
a continuous flow reactor. In certain other embodiments, the
reaction vessel is not a continuous flow reactor.
Precipitation and/or Isolation of the 14-Hydroxymorphinone Salt
[0341] The 14-hydroxymorphinone salt or the solvate thereof may be
provided as a solid, or in solution or suspension as a result of
the oxidation process encompassing steps (aa) and (bb). In certain
preferred embodiments, the process is performed under conditions
wherein the 14-hydroxymorphinone salt or a solvate thereof is
insoluble in the reaction mixture. In these embodiments, the
process may comprise an additional step (cc) of precipitating the
14-hydroxymorphinone salt or the solvate thereof from the reaction
mixture.
[0342] As already pointed out in the Definitions section,
"precipitating" encompasses "crystallizing" unless stated
otherwise.
[0343] The precipitation may start as soon as H.sup.+.sub.nX.sup.n-
is present in the reaction mixture (e.g., after addition of an acid
H.sup.+.sub.nX.sup.n-), or it may start at a later point in time.
In other words, it may take place during and/or after the oxidation
reaction.
[0344] The precipitation of the 14-hydroxymorphinone salt or the
solvate thereof may be caused by the presence of the acid
H.sup.+.sub.nX.sup.n- in the reaction mixture. It may be enhanced
by adding an additional amount of the acid H.sup.+.sub.nX.sup.n- or
the salt containing X.sup.n- to the reaction mixture during step
(bb).
[0345] In certain embodiments, the precipitation of the
14-hydroxymorphinone salt or the solvate thereof may require the
cooling of the reaction mixture and/or the addition of an
antisolvent.
[0346] In certain embodiments wherein the 14-hydroxymorphinone salt
or a solvate thereof precipitates from the reaction mixture, the
acid H.sup.+.sub.nX.sup.n- is H.sub.2SO.sub.4 or its monosalt,
methanesulfonic acid, tosylic acid, trifluoroacetic acid,
H.sub.3PO.sub.4 or one of its mono- or disalts, oxalic acid,
perchloric acid, or any mixtures thereof. In certain embodiments,
it may be H.sub.2SO.sub.4, methanesulfonic acid, tosylic acid,
trifluoroacetic acid, or a mixture thereof. In certain embodiments,
it is H.sub.2SO.sub.4, methanesulfonic acid, or trifluoroacetic
acid or a mixture thereof. In certain embodiments, it is
trifluoroacetic acid. In certain embodiments, it is
H.sub.2SO.sub.4. In certain embodiments, it is methanesulfonic
acid. Preferably, it is H.sub.2SO.sub.4.
[0347] The 14-hydroxymorphinone salt or the solvate thereof, once
precipitated, may either be isolated (i.e. separated from the
reaction mixture), or it may be converted without preceding
isolation to oxymorphone or a salt or solvate thereof. Preferably,
it is isolated before the hydrogenation process of the present
invention is performed.
[0348] Precipitation of the 14-hydroxymorphinone salt may be
influenced by the molar ratio of the anion X.sup.n- to the
oripavine (see above), by the amount of total acid present during
the oxidation reaction (as compared to molar equivalents of the
oripavine), by the temperature before, during or after the
oxidation reaction, by the kind and amount of solvent (e.g., water)
present in the reaction mixture, by the presence of an antisolvent
added to the reaction mixture, by the rate at which the reactants
are added during the process to the reaction mixture, or by a
combination of any of the foregoing.
[0349] In certain embodiments, the precipitation of the
14-hydroxymorphinone salt or a solvate thereof is initiated and/or
enhanced by one or more of the following: [0350] (i) adjusting
(e.g., lowering) the temperature of the reaction mixture to the
precipitation temperature; [0351] (ii) addition of an antisolvent;
[0352] (iii) addition of a seed crystal; [0353] (iv) lowering the
pH; [0354] (v) changing the ionic strength of the reaction mixture
(e.g., by addition of a salt); [0355] (vi) concentrating the
reaction mixture; [0356] (vii) reducing or stopping agitation of
the reaction mixture; or any other conventional method for
initiating or enhancing precipitation or crystallization.
[0357] When the temperature is adjusted to the precipitation
temperature, this means that the precipitation of the
14-hydroxymorphinone salt or the solvate thereof is initiated
and/or enhanced by adjusting the temperature of the reaction
mixture to or beyond a temperature at which said compound
precipitates ("precipitation temperature"). The temperature is
either adjusted by performing the oxidation reaction at the
precipitation temperature, or by lowering the temperature of the
reaction mixture during the reaction or after completion of the
reaction.
[0358] In certain embodiments, the reaction mixture is adjusted to
a temperature of .ltoreq.40.degree. C. to initiate precipitation,
i.e. the precipitation temperature is .ltoreq.40.degree. C. In
certain embodiments, the precipitation is initiated at a
precipitation temperature of about -20.degree. C., about
-15.degree. C., about -10.degree. C., about -5.degree. C., about
0.degree. C., about 5.degree. C., about 10.degree. C., about
15.degree. C., about 17.degree. C., about 19.degree. C., about
21.degree. C., about 23.degree. C., about 25.degree. C., about
27.degree. C., about 29.degree. C., about 31.degree. C., about
33.degree. C., about 35.degree. C., about 37.degree. C., or about
40.degree. C.
[0359] In certain embodiments, the precipitation temperature is in
a range of from about -20.degree. C. to about 40.degree. C.,
preferably from about 0.degree. C. to about 40.degree. C., more
preferably from about 5.degree. C. to about 35.degree. C., more
preferably from about 5.degree. C. to about 30.degree. C., even
more preferably from about 5.degree. C. to about 20.degree. C.
[0360] In certain embodiments, the precipitation temperature is in
a range of from about 5.degree. C. to about 22.degree. C.,
preferably from 5.degree. C. to about 18.degree. C., more
preferably from about 8.degree. C. to about 15.degree. C.
[0361] In certain embodiments, the precipitation temperature is in
a range of from about 5.degree. C. to about 18.degree. C.; or from
about 8.degree. C. to about 15.degree. C.
[0362] In certain embodiments, an antisolvent is used in addition
to adjusting the temperature to the precipitation temperature. In
certain embodiments, e.g., when the 14-hydroxymorphinone salt is
14-hydroxymorphinone sulfate, precipitation will also occur without
adding an antisolvent.
[0363] If an antisolvent is used for initiating precipitation, the
precipitation temperature may be in a range of from about
-20.degree. C. to about 40.degree. C., from about 0.degree. C. to
about 40.degree. C., from about 5.degree. C. to about 35.degree.
C., from about 5.degree. C. to about 22.degree. C., from about
5.degree. C. to about 18.degree. C.; or from about 8.degree. C. to
about 15.degree. C.
[0364] In certain embodiments, the reaction mixture is cooled at a
controlled rate during precipitation. In certain embodiments, the
cooling rate is about 1.degree. C., about 2.degree. C., about
3.degree. C., about 4.degree. C., or about 5.degree. C. per
hour.
[0365] An important factor influencing the precipitation of a
14-hydroxymorphinone salt or a solvate thereof in the oxidation
process may be the temperature of the reaction mixture. A further
factor influencing the precipitation appears to be the total amount
of acid in the reaction mixture. Another factor influencing the
precipitation appears to be the molarity of the reaction mixture.
The addition of an antisolvent also appears to be a factor that can
influence precipitation of a 14-hydroxymorphinone salt or a solvate
thereof. It is presently believed that the precipitation
temperature will rise when the total amount of acid is lowered.
[0366] Hence, in a process wherein the 14-hydroxymorphinone salt or
the solvate thereof is precipitated and wherein the total amount of
acid present in the reaction mixture is from about 0.6 to about
14.0 molar equivalents of total acid per molar equivalent of
oripavine, the precipitation temperature may be .ltoreq.40.degree.
C. (i.e. 40.degree. C. or less). In a process wherein the total
amount of acid present in the reaction mixture is from about 1 to
about 8 molar equivalents, preferably from about 1 to about 5 molar
equivalents of total acid per molar equivalent of the oripavine,
the precipitation temperature may be in a range of from about
0.degree. C. to about 40.degree. C., preferably from about
0.degree. C. to about 35.degree. C. In a process wherein the total
amount of acid present in the reaction mixture is from about 1 to
about 4 molar equivalents, preferably from about 1 to about 3 molar
equivalents of total acid per molar equivalent of the oripavine,
the precipitation temperature may be in a range of from about
5.degree. C. to about 22.degree. C.; preferably from about
8.degree. C. to about 20.degree. C., more preferably from about
8.degree. C. to about 15.degree. C. Further examples of such
correlations can be found in the Examples section of
PCT/IB2013/001541.
[0367] In certain embodiments, an antisolvent is added to
precipitate a 14-hydroxymorphinone salt or a solvate thereof. When
an antisolvent is added to the reaction mixture, it is added either
during or after step (bb) and in an effective amount to initiate
and/or enhance precipitation. In certain embodiments, addition of a
suitable antisolvent increases the yield of the reaction. Addition
of a suitable antisolvent may also enhance retention of
8-hydroxyoxymorphone in the supernatant. A suitable antisolvent may
comprise or consist of tert-butyl methyl ether, diethyl ether,
hexane(s), tert-amyl alcohol, methanol, ethanol, isopropanol,
2-butanol, heptanes, xylenes, toluene, acetone, 2-butanone, ethyl
acetate, tetrahydrofuran, 1,2-dichloroethane, chloroform,
dichloromethane, 1-methoxy-2-propanol, 2-ethoxyethanol, n-propanol,
1-butanol, tert-butanol, isobutanol, isopropyl acetate,
1,4-dioxane, 2-methyl-tetrahydrofuran, methyl formate, methyl
acetate, or a mixture of two or more of any of the foregoing.
14-Hydroxymorphinone sulfate has very low/no solubility in these
solvents at room temperature. The listed alcohols and ethers are
the preferred antisolvents. In some embodiments, said antisolvent
is an alcohol, e.g., methanol, isopropanol or 2-butanol. In some
embodiments, said antisolvent is an ether, e.g., tert-butyl methyl
ether and/or tetrahydrofuran. In some preferred embodiments, said
antisolvent is isopropanol or 2-butanol. In some embodiments, said
antisolvent is a mixture of an alcohol (e.g., methanol) and an
ether (e.g., tert-butyl methyl ether and/or tetrahydrofuran), for
example a mixture of methanol and tert-butyl methyl ether, or a
mixture of methanol and tetrahydrofuran, or a mixture of tert-butyl
methyl ether and tetrahydrofuran, or a mixture of methanol,
tert-butyl methyl ether, and tetrahydrofuran. When two or more
antisolvents are used (e.g., in a mixture), they can be added as a
mixture or separately.
[0368] When an antisolvent is added, it is preferably added in an
amount of from about 0.5 to about 7 mL antisolvent per 1 g
oripavine, more preferably in an amount of from about 0.5 to about
5 mL antisolvent per 1 g oripavine, more preferably in an amount of
from about 0.5 to about 4 mL antisolvent per 1 g oripavine. For
example, in a preferred embodiment, from about 1 to about 4 mL
2-butanol (e.g., 3.6 mL) per 1 g of oripavine are added. Within
these ranges, the yield is especially increased and/or the
retention of 8-hydroxyoxymorphone in the supernatant is especially
enhanced.
[0369] When a seed crystal is added, said seed crystal is a crystal
of the 14-hydroxymorphinone salt or a solvate thereof. This seed
crystal may act as crystallization nucleus if the solution of the
14-hydroxymorphinone salt resulting from step (bb) is metastable.
It may be made metastable by concentrating the reaction
mixture.
[0370] In certain embodiments, the precipitate may be isolated from
the reaction mixture (isolation step (dd)).
[0371] In said isolation step (dd), the precipitate may be
separated from the supernatant in any conventional manner, e.g., by
filtration, centrifugation, decanting, or any other conventional
method for separating a solid phase from a liquid phase. In certain
embodiments, the ratio of 8-hydroxyoxymorphone (either in its free
base form or bound in a salt or solvate) to 14-hydroxymorphinone
(which may be bound in the 14-hydroxymorphinone salt) in the
precipitate is less than the ratio of 8-hydroxyoxymorphone to
14-hydroxymorphinone in the supernatant.
[0372] In cases where the 14-hydroxymorphinone salt or a solvate
thereof is not precipitated, it may be isolated by concentrating
the reaction mixture, e.g., by drying, vacuum distillation, spray
drying or lyophilization.
Further Processing of the 14-Hydroxymorphinone Salt or the Solvate
Thereof
[0373] In certain embodiments, the precipitate containing the
14-hydroxymorphinone salt or the solvate thereof can be further
processed.
[0374] In certain embodiments, the isolated precipitate containing
the 14-hydroxymorphinone salt or solvate thereof may be washed with
and/or (re)crystallized in an organic solvent or aqueous solvent in
which 8-hydroxyoxymorphone or a salt or solvate thereof is more
soluble than the 14-hydroxymorphinone salt or solvate thereof. The
washing and/or (re)crystallization may further reduce the amount of
8-hydroxyoxymorphone in the isolated precipitate containing the
14-hydroxymorphinone salt or solvate thereof. The washing and/or
the (re)crystallization may be performed more than once, or they
may also be combined sequentially.
[0375] In certain embodiments, the isolated precipitate containing
the 14-hydroxymorphinone salt or solvate thereof is washed with
and/or is (re)crystallized in a solvent containing or consisting of
an ether, a ketone, an ester, an alcohol, water, an (optionally
halogenated) alkane, an (optionally halogenated) aromatic solvent
or any mixtures thereof. The solvent may contain or consist of one
or more of the following solvents: methanol, ethanol, isopropanol,
1-butanol, 2-butanol, isobutanol, tert-butanol, acetone,
tetrahydrofuran, ethyl acetate, heptane, tert-butyl methyl ether,
1,2-dichloroethane, toluene, 2-butanone (MEK), tert-amyl alcohol,
chloroform, xylene, and water.
[0376] In certain embodiments, the isolated precipitate containing
the 14-hydroxymorphinone salt or solvate thereof is washed and/or
(re)crystallized in a solvent consisting of an ether, an alcohol,
water, chloroform, or any mixture thereof. In certain embodiments,
said solvent may be methanol, ethanol, n-propanol, isopropanol,
1-butanol, 2-butanol, isobutanol, tert-butanol, acetone,
tetrahydrofuran, chloroform, or a mixture of water with any of the
foregoing.
[0377] In certain embodiments, the isolated precipitate containing
the 14-hydroxymorphinone salt or solvate thereof is washed and/or
(re)crystallized with a solvent which is tert-butyl methyl ether,
tetrahydrofuran, methanol, ethanol, acetone, isopropanol,
2-butanol, or a mixture of methanol:water, THF:water,
acetone:water, isopropanol:water, 2-butanol:water, or
ethanol:water. In certain embodiments, the isolated precipitate
containing the 14-hydroxymorphinone salt or solvate thereof is
washed and/or (re)crystallized with a solvent which is tert-butyl
methyl ether, tetrahydrofuran, methanol, a 2-butanol:water mixture,
or a methanol:water mixture.
[0378] In certain embodiments, preferably wherein the
14-hydroxymorphinone salt is 14-hydroxymorphinone sulfate, the
isolated precipitate containing the 14-hydroxymorphinone salt or
solvate thereof is washed with and/or (re)crystallized in a 90:10
methanol:water mixture; 80:20 methanol:water mixture, 70:30
methanol:water or 60:40 methanol:water mixture. In certain
embodiments, the isolated precipitate containing the
14-hydroxymorphinone salt or solvate thereof is washed with and/or
(re)crystallized in a 80:20 or 70:30 methanol:water mixture.
8-Hydroxyoxymorphone (and its corresponding protonated species) is
more soluble in these mixtures than 14-hydroxymorphinone sulfate
and therefore it is assumed that 8-hydroxyoxymorphone may be
removed from the isolated 14-hydroxymorphinone salt or solvate
thereof by the washing and/or (re)crystallization.
[0379] In certain embodiments, preferably wherein the
14-hydroxymorphinone salt is 14-hydroxymorphinone sulfate, the
isolated precipitate containing the 14-hydroxymorphinone salt or
solvate thereof is washed with and/or (re)crystallized in a 90:10
ethanol:water mixture, 80:20 ethanol:water mixture or 70:30
ethanol:water mixture. In certain embodiments, the isolated
precipitate containing the 14-hydroxymorphinone salt or solvate
thereof is washed with and/or (re)crystallized in 90:10
ethanol/water mixture. 8-Hydroxyoxymorphone (and its corresponding
protonated species) is more soluble in these mixtures than
14-hydroxymorphinone sulfate and therefore it is assumed that
8-hydroxyoxymorphone may be removed from the isolated
14-hydroxymorphinone salt or solvate thereof by the washing and/or
(re)crystallization.
[0380] In certain embodiments, preferably wherein the
14-hydroxymorphinone salt is 14-hydroxymorphinone sulfate, the
isolated precipitate containing the 14-hydroxymorphinone salt or
solvate thereof is washed with and/or (re)crystallized in
tetrahydrofuran or in 90:10 tetrahydrofuran:water mixture.
8-Hydroxyoxymorphone (and its corresponding protonated species) is
more soluble in these mixtures than 14-hydroxymorphinone sulfate
and therefore it is assumed that 8-hydroxyoxymorphone may be
removed from the isolated 14-hydroxymorphinone salt or solvate
thereof by the washing and/or (re)crystallization.
[0381] In certain embodiments, preferably wherein the
14-hydroxymorphinone salt is 14-hydroxymorphinone sulfate, the
isolated precipitate containing the 14-hydroxymorphinone salt or
solvate thereof is washed with and/or (re)crystallized in a 90:10
isopropanol:water mixture, 80:20 isopropanol:water mixture or 70:30
isopropanol:water mixture. In certain embodiments, the isolated
precipitate containing the 14-hydroxymorphinone salt or solvate
thereof is washed with and/or (re)crystallized in a 90:10
isopropanol:water mixture. 8-Hydroxyoxymorphone (and its
corresponding protonated species) is more soluble in these mixtures
than 14-hydroxymorphinone sulfate and therefore it is assumed that
8-hydroxyoxymorphone may be removed from the isolated
14-hydroxymorphinone salt or solvate thereof by the washing and/or
(re)crystallization.
[0382] In certain embodiments, preferably wherein the
14-hydroxymorphinone salt is 14-hydroxymorphinone sulfate, the
isolated precipitate containing the 14-hydroxymorphinone salt or
solvate thereof is washed with and/or (re)crystallized in a 90:10
2-butanol:water mixture, 80:20 2-butanol:water mixture, 70:30
2-butanol:water mixture, 60:40 2-butanol:water mixture, or 20:10
2-butanol:water mixture. In certain embodiments, the isolated
precipitate containing the 14-hydroxymorphinone salt or solvate
thereof is washed with and/or (re)crystallized in a 20:10
2-butanol:water mixture. 8-Hydroxyoxymorphone (and its
corresponding protonated species) is more soluble in these mixtures
than 14-hydroxymorphinone sulfate and therefore it is assumed that
8-hydroxyoxymorphone may be removed from the isolated
14-hydroxymorphinone salt or solvate thereof by the washing and/or
(re)crystallization.
[0383] In certain embodiments, preferably wherein the
14-hydroxymorphinone salt is 14-hydroxymorphinone sulfate, the
isolated precipitate containing the 14-hydroxymorphinone salt or
solvate thereof is washed with and/or (re)crystallized in a 70:30
acetone:water mixture or 80:20 acetone:water mixture.
8-Hydroxyoxymorphone (and its corresponding protonated species) is
more soluble in these mixtures than 14-hydroxymorphinone sulfate
and therefore it is assumed that 8-hydroxyoxymorphone may be
removed from the isolated 14-hydroxymorphinone salt or solvate
thereof by the washing and/or (re)crystallization.
[0384] The washing of the isolated precipitate containing the
14-hydroxymorphinone salt or solvate thereof may be performed in
any way conventional in the art, e.g., by forming a slurry of the
compound.
[0385] In certain embodiments, the ratio of 8-hydroxyoxymorphone to
14-hydroxymorphinone in the supernatant after the precipitation of
the 14-hydroxymorphinone salt or solvate thereof is higher than the
ratio of 8-hydroxyoxymorphone to 14-hydroxymorphinone in the
precipitate.
Preferred Process Conditions
[0386] A preferred set of reaction conditions for the oxidation
process and the subsequent isolation of the 14-hydroxymorphinone
salt is described in the following. Therein, the
14-hydroxymorphinone salt is preferably 14-hydroxymorphinone
sulfate.
[0387] The process is performed by: (i) forming a solution or a
suspension comprising the oripavine, from about 1.5 to about 2.0 mL
water per g oripavine, and from about 2.5 to about 4.5 molar
equivalents of formic acid per molar equivalent of oripavine, (ii)
adding from about 0.5 to about 0.6 molar equivalents of sulfuric
acid per molar equivalent of the oripavine to the solution or the
suspension, (iii) adding from about 1.0 to about 1.4 molar
equivalents, preferably from about 1.2 to about 1.4 molar
equivalents, more preferably from about 1.2 to about 1.3 molar
equivalents of hydrogen peroxide to the solution or the suspension
from (ii), then incubating the mixture at a temperature of from
about 30.degree. C. to about 38.degree. C., preferably of from
about 32.degree. C. to about 36.degree. C., more preferably of
about 35.degree. C., until the conversion is complete, and (iv)
precipitating the 14-hydroxymorphinone salt from the resulting
solution or suspension. Step (iv) may be performed by adding a
suitable antisolvent to the solution, as described in detail above.
A preferred antisolvent may be an alcohol, in particular
isopropanol or 2-butanol. Preferably, from about 2 to about 4 mL
antisolvent per 1 g oripavine are added.
[0388] When the 14-hydroxymorphinone salt is 14-hydroxymorphinone
sulfate, the process is preferably performed by: (i) forming a
solution or a suspension by mixing the oripavine, from about 1.5 to
about 2.0 mL water per g oripavine, and from about 2.5 to about 4.5
molar equivalents of formic acid per molar equivalent of oripavine,
(ii) adding from about 0.5 to about 0.6 molar equivalents of
sulfuric acid per molar equivalent of oripavine to the solution or
the suspension, (iii) adding from about 1.0 to about 1.4 molar
equivalents, preferably from about 1.2 to about 1.4 molar
equivalents, more preferably from about 1.2 to about 1.3 molar
equivalents of hydrogen peroxide to the solution or the suspension
from (ii), then incubating the mixture at a temperature of from
about 30.degree. C. to about 38.degree. C., preferably of from
about 32.degree. C. to about 36.degree. C., more preferably of
about 35.degree. C., until the conversion is complete, and (iv)
precipitating the 14-hydroxymorphinone sulfate from the resulting
solution or suspension. Step (iv) may be performed by adding a
suitable antisolvent to the solution, as described in detail above.
A preferred antisolvent may be an alcohol, in particular
isopropanol or 2-butanol. Preferably, from about 2 to about 4 mL
antisolvent per 1 g oripavine are added.
[0389] In the oxidation process, the formation of the
14-hydroxymorphinone salt or a solvate thereof may have the effect
that less 8-hydroxy compound is formed during the oxidation
reaction in comparison to an oxidation reaction where no
14-hydroxymorphinone salt or solvate thereof is formed. In other
words, the formation of the 14-hydroxymorphinone salt allows for an
improvement of the by-product profile of the reaction product. One
example for such oxidation reaction may be the formation of a
14-hydroxymorphinone salt wherein n is 2 and preferably wherein
X.sup.n- is sulfate. Another example for such oxidation reaction
may be the formation of a 14-hydroxymorphinone salt wherein n is 1
and preferably wherein X.sup.n- is trifluoroacetate.
[0390] The formation of the 14-hydroxymorphinone salt or a solvate
thereof may also have the effect that 8-hydroxyoxymorphone can be
separated from the 14-hydroxymorphinone salt or the solvate
thereof, e.g., by precipitation of the 14-hydroxymorphinone salt or
the solvate thereof from the reaction mixture. One example for such
an effect may be the formation of a 14-hydroxymorphinone salt
wherein X.sup.n- is sulfate. One example for such an effect may be
the use of one of the antisolvents described in the present Section
IV.
[0391] A combination of these effects may also take place. That is,
both less 8-hydroxyoxymorphone is formed during the oxidation and
said compound can be separated from the 14-hydroxymorphinone salt
or solvate thereof. One example may be the formation of a
14-hydroxymorphinone salt wherein X.sup.n- is sulfate, preferably
in combination with one of the antisolvents described in the
present Section IV.
V. 14-Hydroxymorphinone Salt
[0392] The present invention uses a 14-hydroxymorphinone salt
having the following formula or a solvate thereof
##STR00036##
wherein X.sup.n- and n are defined as above, in particular in
Section I, as starting material for the hydrogenation process
according to the invention. Present invention may use said
14-hydroxymorphinone salt or solvate thereof as a solid, in
solution or as a suspension.
[0393] The 14-hydroxymorphinone salt or solvate thereof comprises
one or more protonated molecules of 14-hydroxymorphinone and at
least one anion X.sup.n-. The anion may be an organic or inorganic
anion. The anion may be mono- or polyvalent (e.g., divalent or
trivalent). In its solid form, the components of the
14-hydroxymorphinone salt are present in stoichiometric amounts.
However, other molecular ratios may also be present either in
micro- or macrostructures of the salt, depending e.g., on the type
of the anion and valency thereof, the solvent (which might also
form part of the salt) and the ambient pH.
[0394] In certain embodiments, said 14-hydroxymorphinone salt or
solvate thereof is provided in its isolated, solid form, which in
certain embodiments is its crystalline form, as starting material
for the hydrogenation reaction.
[0395] Said 14-hydroxymorphinone salt or solvate thereof may be
obtainable or obtained by the process described in Section IV.
Preferably, it is obtained by said process.
[0396] Said 14-hydroxymorphinone salt or solvate thereof is a
starting material or intermediate for the hydrogenation reaction
according to the present invention which results in the synthesis
of oxymorphone or (pharmaceutically acceptable) salts or solvates
thereof.
[0397] In certain embodiments of the 14-hydroxymorphinone salt or
solvate thereof, n is 1 or 2, and is preferably 2.
[0398] In certain embodiments, X.sup.n- is SO.sub.4.sup.2- or
trifluoroacetate, and is preferably SO.sub.4.sup.2-.
[0399] In certain embodiments, the 14-hydroxymorphinone salt is
provided as its solvate. Said solvate may be any association
product of a 14-hydroxymorphinone salt with a solvent molecule. The
molar ratio of solvent molecule(s) per molecule of
14-hydroxymorphinone salt may vary. The molar ratio of solvent to
compound/salt in the solvate may be 1 (e.g., in a monohydrate),
more than 1 (e.g., 2, 3, 4, 5 or 6 in a polyhydrate), or less than
1 (e.g., in a hemihydrate). The molar ratio need not be an integer
ratio, it can also be, e.g., 0.5 (as in a hemihydrate) or 2.5. For
example, 1 molecule water per molecule of 14-hydroxymorphinone
sulfate is bound in 14-hydroxymorphinone sulfate monohydrate. The
solvate of the 14-hydroxymorphinone salt is in certain embodiments
a hydrate, for example a monohydrate, dihydrate, trihydrate,
tetrahydrate, pentahydrate or hexahydrate, or a hydrate wherein the
ratio of water per molecule is not necessarily an integer, but
within the range of from 0.5 to 10.0. In certain embodiments, the
solvate of the 14-hydroxymorphinone salt is a hydrate wherein the
ratio of water per molecule is within the range of from 1 to 8. In
certain embodiments, the solvate of the 14-hydroxymorphinone salt
is a hydrate wherein the ratio of water per molecule is within the
range of from 1 to 6, i.e. a mono- to hexahydrate. In certain
embodiments, the solvate of the 14-hydroxymorphinone salt is a
monohydrate or a pentahydrate.
[0400] In certain embodiments, the 14-hydroxymorphinone salt is
##STR00037##
or a solvate thereof. The solvate may be a hydrate. The molar ratio
of solvent to compound/salt in the solvate may be 1 (e.g., in a
monohydrate), more than 1 (e.g., 2, 3, 4, 5 or 6 in a polyhydrate),
or less than 1 (e.g., in a hemihydrate). The molar ratio need not
be an integer ratio, it can also be, e.g., 0.5 (as in a
hemihydrate) or 2.5. For example, 1 molecule water per molecule of
14-hydroxymorphinone sulfate is bound in 14-hydroxymorphinone
sulfate monohydrate. The solvate is in certain embodiments a
hydrate, for example a monohydrate, dihydrate, trihydrate,
tetrahydrate, pentahydrate or hexahydrate, or a hydrate wherein the
ratio of water per molecule is not necessarily an integer, but
within the range of from 0.5 to 10.0. In certain embodiments, the
solvate is a hydrate wherein the ratio of water per molecule is
within the range of from 1 to 8. In certain embodiments, the
solvate is a hydrate wherein the ratio of water per molecule is
within the range of from 1 to 6, i.e. a mono- to hexahydrate. In
certain embodiments, the solvate is a monohydrate or a
pentahydrate.
[0401] Pharmaceutical compositions and dosage forms produced from
said 14-hydroxymorphinone salt or solvate thereof, preferably,
contain less 8-hydroxyoxymorphone and/or 14-hydroxymorphinone than
pharmaceutical compositions prepared via a different intermediate,
i.e. without the 14-hydroxymorphinone salt.
[0402] In certain embodiments, the 14-hydroxymorphinone salt is
prepared as described in Section IV.
[0403] In certain embodiments, the 14-hydroxymorphinone salt or
solvate thereof additionally comprises 8-hydroxyoxymorphone.
[0404] Said 8-hydroxyoxymorphone is a by-product of the oxidation
reaction described above, as illustrated in the following reaction
Scheme 17:
##STR00038##
[0405] Said 8-hydroxyoxymorphone may be present in the form of its
free base, or in the form of its salt or solvate.
[0406] Whenever 8-hydroxyoxymorphone is comprised in the
14-hydroxymorphinone salt (thus forming a composition), it is
present in a certain amount which shall be specified in the
following.
[0407] In certain embodiments, the amount of the
8-hydroxyoxymorphone or salt or solvate thereof in the
14-hydroxymorphinone salt or solvate thereof is less than about
2500 ppm, less than about 2250 ppm, less than about 2000 ppm, less
than about 1750 ppm, less than about 1500 ppm, or less than about
1250 ppm of the 14-hydroxymorphinone salt (HPLC peak area
ratio).
[0408] In certain embodiments, the amount of the
8-hydroxyoxymorphone or salt or solvate thereof in the
14-hydroxymorphinone salt or solvate thereof is less than about
1000 ppm, less than about 750 ppm, less than about 500 ppm, or less
than about 400 ppm of the 14-hydroxymorphinone salt or solvate
thereof (HPLC peak area ratio).
[0409] In certain embodiments, the amount of the
8-hydroxyoxymorphone or salt or solvate thereof in the
14-hydroxymorphinone salt or solvate thereof is less than about 300
ppm, less than about 275 ppm, less than about 250 ppm, less than
about 225 ppm, less than about 200 ppm, less than about 175 ppm,
less than about 150 ppm, or less than about 125 ppm of the
14-hydroxymorphinone salt or solvate thereof (HPLC peak area
ratio).
[0410] In certain embodiments, the amount of the
8-hydroxyoxymorphone or salt or solvate thereof in the
14-hydroxymorphinone salt or solvate thereof is less than about 100
ppm, less than about 90 ppm, less than about 80 ppm, less than
about 70 ppm, less than about 60 ppm, less than about 50 ppm, less
than about 40 ppm, less than about 30 ppm, or less than about 20
ppm of the 14-hydroxymorphinone salt or solvate thereof (HPLC peak
area ratio).
[0411] In certain embodiments, the amount of the
8-hydroxyoxymorphone or salt or solvate thereof in the
14-hydroxymorphinone salt or solvate thereof is less than about 10
ppm, less than about 8 ppm, less than about 6 ppm, less than about
4 ppm, or less than about 2 ppm of the 14-hydroxymorphinone salt or
solvate thereof (HPLC peak area ratio).
[0412] In certain embodiments, the amount of the
8-hydroxyoxymorphone or salt or solvate thereof in the
14-hydroxymorphinone salt or solvate thereof is less than about 1
ppm, less than about 0.8 ppm, less than about 0.6 ppm, less than
about 0.4 ppm, less than about 0.3 ppm, less than about 0.2 ppm, or
less than about 0.1 ppm of the 14-hydroxymorphinone salt or solvate
thereof (e.g., the amount of 8-hydroxyoxymorphone is from about
0.05 ppm to about 0.7 ppm of the 14-hydroxymorphinone sulfate)
(HPLC peak area ratio).
[0413] In certain embodiments, the 14-hydroxymorphinone salt or
solvate thereof does not contain 8-hydroxyoxymorphone.
[0414] In certain embodiments, the 14-hydroxymorphinone salt is
14-hydroxymorphinone sulfate, and the amount of
8-hydroxyoxymorphone therein is less than about 300 ppm, less than
about 275 ppm, less than about 250 ppm, less than about 225 ppm,
less than about 200 ppm, less than about 175 ppm, less than about
150 ppm, less than about 125 ppm, less than about 100 ppm, less
than about 80 ppm, less than about 60 ppm, less than about 40 ppm,
less than about 30 ppm, or less than about 20 ppm of the
14-hydroxymorphinone sulfate (HPLC peak area ratio). In certain
embodiments, it is less than about 10 ppm, less than about 8 ppm,
less than about 6 ppm, less than about 4 ppm, less than about 2
ppm, less than about 1 ppm, less than about 0.8 ppm, less than
about 0.6 ppm, less than about 0.4 ppm, less than about 0.3 ppm,
less than about 0.2 ppm, or less than about 0.1 ppm of the
14-hydroxymorphinone sulfate (HPLC peak area ratio). In certain
embodiments, the 14-hydroxymorphinone sulfate does not contain
8-hydroxyoxymorphone.
[0415] In certain embodiments, the amount of the
8-hydroxyoxymorphone or salt or solvate thereof in the
14-hydroxymorphinone salt or solvate thereof has a lower limit of
about 0.01 ppm of the 14-hydroxymorphinone salt or solvate thereof
(HPLC peak area ratio). In certain embodiments, the lower limit is
about 0.05 ppm, 0.1 ppm, about 0.3 ppm, about 0.5 ppm, about 0.7
ppm, about 1 ppm, about 1.5 ppm, about 2 ppm, or about 3 ppm. For
example, the amount of the 8-hydroxyoxymorphone or salt or solvate
thereof in the 14-hydroxymorphinone salt or solvate thereof may
range from about 0.05 ppm to 1 ppm in a certain embodiment, and
from about 1 ppm to about 10 ppm in a certain other embodiment.
[0416] The 14-hydroxymorphinone salt or solvate thereof in certain
embodiments comprises from about 0.01 ppm to about 2500 ppm, from
about 0.05 to about 2250 ppm, from about 0.1 ppm to about 2000 ppm,
from about 0.3 to about 1750 ppm, from about 0.5 ppm to about 1500
ppm, or from about 1 ppm to about 1250 ppm 8-hydroxyoxymorphone or
a salt or solvate thereof in relation to the 14-hydroxymorphinone
salt (HPLC peak area ratio).
[0417] The 14-hydroxymorphinone salt or solvate thereof in certain
embodiments comprises from about 0.05 ppm to about 1000 ppm, from
about 0.1 ppm to about 800 ppm, from about 0.1 ppm to about 700
ppm, from about 0.2 ppm to about 600 ppm, from about 0.3 ppm to
about 500 ppm, or from about 0.5 ppm to about 400 ppm
8-hydroxyoxymorphone or salt or solvate thereof in relation to the
14-hydroxymorphinone salt.
[0418] The 14-hydroxymorphinone salt or solvate thereof in certain
embodiments comprises from about 0.05 ppm to about 350 ppm, from
about 0.1 ppm to about 300 ppm, from about 0.2 ppm to about 275
ppm, from about 0.3 ppm to about 250 ppm, from about 0.4 ppm to
about 225 ppm, or from about 0.5 ppm to about 200 ppm
8-hydroxyoxymorphone or salt or solvate thereof in relation to the
14-hydroxymorphinone salt.
[0419] The 14-hydroxymorphinone salt may comprise the
8-hydroxyoxymorphone as (i) 8.alpha. isomer, (ii) 8.beta. isomer or
(iii) a combination of 8.alpha. and 8.beta. isomer. Preferably, at
least a portion of the 8-hydroxyoxymorphone is the 8.alpha.
isomer.
[0420] Preferably, the 14-hydroxymorphinone salt is
14-hydroxymorphinone sulfate.
VI. Oxymorphone
[0421] Present invention further provides oxymorphone or a salt or
solvate thereof, which is obtainable or preferably has been
obtained by the hydrogenation process according to the present
invention.
[0422] The salt or solvate of the oxymorphone may be a
pharmaceutically acceptable salt or solvate. Such salts or solvates
are known in the art.
[0423] The oxymorphone according to the present invention is
preferably in its free base form or in the form of a solvate
thereof.
[0424] The oxymorphone according to the present invention may be
comprised in a composition, which may be a solid or a liquid. Said
composition may the product of the hydrogenation process according
to the present invention.
[0425] In certain embodiments, the oxymorphone is a solid. In
certain embodiments, it is the precipitate containing the
oxymorphone base as described as product of the hydrogenation
process described in Section II.
[0426] The oxymorphone or the (optionally pharmaceutically
acceptable) salt or solvate thereof in certain embodiments
comprises 8-hydroxyoxymorphone.
[0427] Preferably, the oxymorphone or the (optionally
pharmaceutically acceptable) salt or solvate thereof contains less
than about 5 ppm, more preferably less than about 3 ppm, even more
preferably less than about 1 ppm 8-hydroxyoxymorphone (HPLC peak
area ratio). Most preferably, it does not contain
8-hydroxyoxymorphone in detectable amounts, and even may not
contain any 8-hydroxyoxymorphone at all.
[0428] In certain embodiments, the amount of the
8-hydroxyoxymorphone or salt or solvate thereof in the oxymorphone
or the (optionally pharmaceutically acceptable) salt or solvate
thereof is less than about 2500 ppm, less than about 2250 ppm, less
than about 2000 ppm, less than about 1750 ppm, less than about 1500
ppm, or less than about 1250 ppm of the oxymorphone or salt or
solvate thereof (HPLC peak area ratio).
[0429] In certain embodiments, the amount of the
8-hydroxyoxymorphone or salt or solvate thereof in the oxymorphone
or the (optionally pharmaceutically acceptable) salt or solvate
thereof is less than about 1000 ppm, less than about 750 ppm, less
than about 500 ppm, or less than about 400 ppm of the oxymorphone
or salt or solvate thereof (HPLC peak area ratio).
[0430] In certain embodiments, the amount of the
8-hydroxyoxymorphone or salt or solvate thereof in the oxymorphone
or the (optionally pharmaceutically acceptable) salt or solvate
thereof is less than about 300 ppm, less than about 275 ppm, less
than about 250 ppm, less than about 225 ppm, less than about 200
ppm, less than about 175 ppm, less than about 150 ppm, or less than
about 125 ppm of the oxymorphone or salt or solvate thereof (HPLC
peak area ratio).
[0431] In certain embodiments, the amount of the
8-hydroxyoxymorphone or salt or solvate thereof in the oxymorphone
or the (optionally pharmaceutically acceptable) salt or solvate
thereof is less than about 100 ppm, less than about 90 ppm, less
than about 80 ppm, less than about 70 ppm, less than about 60 ppm,
less than about 50 ppm, less than about 40 ppm, less than about 30
ppm, or less than about 20 ppm of the oxymorphone or salt or
solvate thereof (HPLC peak area ratio).
[0432] In certain embodiments, the amount of the
8-hydroxyoxymorphone or salt or solvate thereof in the oxymorphone
or the (optionally pharmaceutically acceptable) salt or solvate
thereof is less than about 10 ppm, less than about 8 ppm, less than
about 6 ppm, less than about 4 ppm, or less than about 2 ppm of the
oxymorphone or salt or solvate thereof (HPLC peak area ratio).
[0433] In certain embodiments, the amount of the
8-hydroxyoxymorphone or salt or solvate thereof in the oxymorphone
or the (optionally pharmaceutically acceptable) salt or solvate
thereof is less than about 1 ppm, less than about 0.8 ppm, less
than about 0.6 ppm, less than about 0.4 ppm, less than about 0.3
ppm, less than about 0.2 ppm, or less than about 0.1 ppm of the
oxymorphone or salt or solvate thereof (e.g., the amount of
8-hydroxyoxymorphone is from about 0.1 ppm to about 0.7 ppm of the
14-hydroxymorphinone sulfate) (HPLC peak area ratio).
[0434] In certain embodiments, the oxymorphone or the (optionally
pharmaceutically acceptable) salt or solvate thereof does not
contain 8-hydroxyoxymorphone in detectable amounts, or not contain
any 8-hydroxyoxymorphone.
[0435] In certain embodiments, the amount of the
8-hydroxyoxymorphone or salt or solvate thereof in the oxymorphone
or the (optionally pharmaceutically acceptable) salt or solvate
thereof has a lower limit of about 0.05 ppm of the oxymorphone or
salt or solvate thereof (HPLC peak area ratio). In certain
embodiments, the lower limit is about 0.1 ppm, about 0.3 ppm, about
0.5 ppm, about 0.7 ppm, about 1 ppm, about 1.5 ppm, about 2 ppm, or
about 3 ppm. For example, the amount of the 8-hydroxyoxymorphone or
salt or solvate thereof in the composition may range from about
0.05 ppm to 1 ppm in a certain embodiment, and from about 1 ppm to
about 10 ppm in a certain other embodiment.
[0436] In certain embodiments, the amount of 8-hydroxyoxymorphone
or salt or solvate thereof in the oxymorphone or the salt or
solvate thereof is less than about 300 ppm, less than about 275
ppm, less than about 250 ppm, less than about 225 ppm, less than
about 200 ppm, less than about 175 ppm, less than about 150 ppm,
less than about 125 ppm, less than about 100 ppm, less than about
80 ppm, less than about 60 ppm, less than about 40 ppm, less than
about 30 ppm, or less than about 20 ppm of the oxymorphone (HPLC
peak area ratio). In certain embodiments, it is less than about 10
ppm, less than about 8 ppm, less than about 6 ppm, less than about
4 ppm, less than about 2 ppm, less than about 1 ppm, less than
about 0.8 ppm, less than about 0.6 ppm, less than about 0.4 ppm,
less than about 0.3 ppm, less than about 0.2 ppm, or less than
about 0.1 ppm of the oxymorphone (HPLC peak area ratio). In certain
embodiments, the oxymorphone does not contain
8-hydroxyoxymorphone.
[0437] In certain embodiments, the oxymorphone or the (optionally
pharmaceutically acceptable) salt or solvate thereof comprises from
about 0.05 ppm to about 2500 ppm, from about 0.05 to about 2250
ppm, from about 0.1 ppm to about 2000 ppm, from about 0.3 to about
1750 ppm, from about 0.5 ppm to about 1500 ppm, or from about 1 ppm
to about 1250 ppm 8-hydroxyoxymorphone or a salt or solvate thereof
in relation to the oxymorphone or salt or solvate thereof (HPLC
peak area ratio).
[0438] In certain embodiments, the oxymorphone or the (optionally
pharmaceutically acceptable) salt or solvate thereof comprises from
about 0.05 ppm to about 1000 ppm, from about 0.1 ppm to about 800
ppm, from about 0.1 ppm to about 700 ppm, from about 0.2 ppm to
about 600 ppm, from about 0.3 ppm to about 500 ppm, or from about
0.5 ppm to about 400 ppm 8-hydroxyoxymorphone or salt or solvate
thereof in relation to the oxymorphone or salt or solvate
thereof.
[0439] In certain embodiments, the oxymorphone or the (optionally
pharmaceutically acceptable) salt or solvate thereof comprises from
about 0.05 ppm to about 350 ppm, from about 0.1 ppm to about 300
ppm, from about 0.2 ppm to about 275 ppm, from about 0.3 ppm to
about 250 ppm, from about 0.4 ppm to about 225 ppm, or from about
0.5 ppm to about 200 ppm 8-hydroxyoxymorphone or salt or solvate
thereof in relation to compound IV or salt or solvate thereof.
[0440] Additionally, the composition comprising the oxymorphone or
the (optionally pharmaceutically acceptable) salt or solvate
thereof in certain embodiments comprises 14-hydroxymorphinone.
[0441] Preferably, the oxymorphone or the (optionally
pharmaceutically acceptable) salt or solvate thereof contains less
than about 5 ppm, more preferably less than about 3 ppm, even more
preferably less than about 1 ppm 14-hydroxymorphinone (HPLC peak
area ratio). Most preferably, it does not contain
14-hydroxymorphinone in detectable amounts, and even may not
contain any 14-hydroxymorphinone at all.
[0442] The amount of the 14-hydroxymorphinone or salt or solvate
thereof in relation to the amount of the oxymorphone or salt or
solvate thereof may in certain embodiments be less than about 500
ppm, less than about 250 ppm, less than about 200 ppm, less than
about 100 ppm, less than about 50 ppm or less than about 40 ppm
(HPLC peak area ratio). In certain embodiments, it may be less than
about 30 ppm, less than about 25 ppm, less than about 20 ppm, les
than about 15 ppm, less than about 10 ppm, less than about 5 ppm,
or less than about 2.5 ppm (HPLC peak area ratio). In certain
embodiments, it may be less than about 1 ppm, less than about 0.8
ppm, less than about 0.6 ppm, less than about 0.6 ppm, less than
about 0.4 ppm, less than about 0.2 ppm, or less than about 0.1 ppm
(HPLC peak area ratio). In certain embodiments, the oxymorphone or
the (optionally pharmaceutically acceptable) salt or solvate
thereof does not contain 14-hydroxymorphinone (in detectable
amounts).
[0443] In certain embodiments, the amount of the
14-hydroxymorphinone or salt or solvate thereof in the oxymorphone
or the (optionally pharmaceutically acceptable) salt or solvate
thereof has a lower limit of about 0.05 ppm of the oxymorphone or
salt or solvate thereof (HPLC peak area ratio). In certain
embodiments, the lower limit is about 0.1 ppm, about 0.3 ppm, about
0.5 ppm, about 0.7 ppm, about 1 ppm, about 1.5 ppm, about 2 ppm, or
about 3 ppm. For example, the amount of the 14-hydroxymorphinone or
salt or solvate thereof in the oxymorphone or the (optionally
pharmaceutically acceptable) salt or solvate thereof may range from
about 0.05 ppm to 1 ppm in a certain embodiment, and from about 1
ppm to about 10 ppm in a certain other embodiment.
[0444] The oxymorphone or the (optionally pharmaceutically
acceptable) salt or solvate thereof in certain embodiments
comprises from about 0.05 ppm to about 500 ppm, from about 0.05 ppm
to about 250 ppm, from about 0.05 ppm to about 200 ppm, from about
0.05 ppm to about 100 ppm, from about 0.05 ppm to about 50 ppm,
from about 0.05 ppm to about 25 ppm, from about 0.05 ppm to about
10 ppm, from about 0.05 ppm to about 5 ppm, or from about 0.05 ppm
to about 1 ppm 14-hydroxymorphinone or salt or solvate thereof in
relation to oxymorphone or the salt or solvate thereof.
[0445] In certain embodiments, the amount of the
14-hydroxymorphinone in relation to the amount of the oxymorphone
in the oxymorphone or the salt or solvate thereof is less than
about 200 ppm, less than about 175 ppm, less than about 150 ppm,
less than about 125 ppm, less than about 100 ppm, less than about
80 ppm, less than about 60 ppm, less than about 40 ppm, less than
about 30 ppm, less than about 20 ppm, or less than about 10 ppm, or
less than about 5 ppm of the oxymorphone (HPLC peak area ratio). In
certain embodiments, the oxymorphone or the (optionally
pharmaceutically acceptable) salt or solvate thereof does not
contain 14-hydroxymorphinone or a salt or solvate thereof.
[0446] The oxymorphone or salt or solvate thereof may also
additionally comprise a combination of 14-hydroxymorphinone with
8-hydroxyoxymorphone, preferably within the limits for the single
compounds 8-hydroxyoxymorphone and 14-hydroxymorphinone as
described in the preceding paragraphs.
[0447] In certain embodiments, the oxymorphone or the (optionally
pharmaceutically acceptable) salt or solvate thereof additionally
comprises both 14-hydroxymorphinone and 8-hydroxyoxymorphone. In
certain embodiments, the oxymorphone or the (optionally
pharmaceutically acceptable) salt or solvate thereof comprises a
combined amount of 14-hydroxymorphinone and 8-hydroxyoxymorphone
which is less than about 1000 ppm, less than about 750 ppm, less
than about 500 ppm, less than about 400 ppm, less than about 300
ppm, or less than about 275 ppm in relation to the amount of the
oxymorphone (HPLC peak area ratio).
[0448] In certain embodiments, the combined amount of the compound
14-hydroxymorphinone and 8-hydroxyoxymorphone in the oxymorphone or
the (optionally pharmaceutically acceptable) salt or solvate
thereof is less than about 250 ppm, less than about 225 ppm, less
than about 200 ppm, less than about 175 ppm, less than about 150
ppm, or less than about 125 ppm in relation to the amount of the
oxymorphone (HPLC peak area ratio).
[0449] In certain embodiments, the combined amount of the
14-hydroxymorphinone and 8-hydroxyoxymorphone in the oxymorphone or
the (optionally pharmaceutically acceptable) salt or solvate
thereof is less than about 100 ppm, less than about 90 ppm, less
than about 80 ppm, less than about 70 ppm, less than about 60 ppm,
less than about 50 ppm, less than about 40 ppm, less than about 30
ppm, or less than about 20 ppm in relation to the amount of the
oxymorphone (HPLC peak area ratio).
[0450] In certain embodiments, the combined amount of the
14-hydroxymorphinone and 8-hydroxyoxymorphone in the oxymorphone or
the (optionally pharmaceutically acceptable) salt or solvate
thereof is less than about 10 ppm, les than about 8 ppm, less than
about 6 ppm, less than about 4 ppm, or less than about 2 ppm in
relation to the amount of the oxymorphone (HPLC peak area
ratio).
[0451] In certain embodiments, the combined amount of the
14-hydroxymorphinone and 8-hydroxyoxymorphone in the oxymorphone or
the (optionally pharmaceutically acceptable) salt or solvate
thereof is less than about 1 ppm, less than about 0.8 ppm, less
than about 0.6 ppm, less than about 0.4 ppm, less than about 0.3
ppm, less than about 0.2 ppm, or less than about 0.1 ppm in
relation to the amount of the oxymorphone (HPLC peak area
ratio).
[0452] In certain embodiments, the oxymorphone or the (optionally
pharmaceutically acceptable) salt or solvate thereof does not
contain 14-hydroxymorphinone and 8-hydroxyoxymorphone (in
detectable amounts).
[0453] Preferably, the oxymorphone or the (optionally
pharmaceutically acceptable) salt or solvate thereof contains less
than about 10 ppm, more preferably less than about 6 ppm, even more
preferably less than about 4 ppm combined 14-hydroxymorphinone and
8-hydroxyoxymorphone (HPLC peak area ratio). Most preferably, it
does not contain 14-hydroxymorphinone and 8-hydroxyoxymorphone in
detectable amounts, and even may not contain any
14-hydroxymorphinone and 8-hydroxyoxymorphone at all.
[0454] In certain embodiments, the combined amount of the
14-hydroxymorphinone and 8-hydroxyoxymorphone in the oxymorphone or
the (optionally pharmaceutically acceptable) salt or solvate
thereof has a lower limit of about 0.05 ppm of the oxymorphone
(HPLC peak area ratio). In certain embodiments, the lower limit is
about 0.1 ppm, about 0.3 ppm, about 0.5 ppm, about 0.7 ppm, about 1
ppm, about 1.5 ppm, about 2 ppm, or about 3 ppm in relation to the
amount of the oxymorphone (HPLC peak area ratio).
[0455] In certain embodiments, the oxymorphone or the (optionally
pharmaceutically acceptable) salt or solvate thereof comprises less
than about 200 ppm, less than about 100 ppm, less than about 50
ppm, less than about 25 ppm, less than about 20 ppm, less than
about 15 ppm, or less than about 10 ppm of 14-hydroxymorphinone or
a salt or solvate thereof, and/or less than about 300 ppm, less
than about 200 ppm, less than about 100 ppm, less than about 50
ppm, less than about 25 ppm, or less than about 10 ppm of
8-hydroxyoxymorphone or a salt or solvate thereof.
[0456] In certain embodiments, the oxymorphone or the (optionally
pharmaceutically acceptable) salt or solvate thereof comprises less
than about 25 ppm, less than about 20 ppm, less than about 15 ppm,
less than about 10 ppm, less than about 5 ppm, or less than about 1
ppm of 14-hydroxymorphinone or a salt or solvate thereof, and/or
less than about 100 ppm, less than about 50 ppm, less than about 25
ppm, less than about 10 ppm, or less than about 5 ppm of
8-hydroxyoxymorphone or a salt or solvate thereof.
[0457] In certain embodiments, the oxymorphone or the (optionally
pharmaceutically acceptable) salt or solvate thereof comprises less
than about 10 ppm, less than about 5 ppm, less than about 4 ppm,
less than about 3 ppm, less than about 2 ppm, less than about 1
ppm, or less than about 0.5 ppm of 14-hydroxymorphinone or a salt
or solvate thereof, and/or less than about 10 ppm, less than about
5 ppm, less than about 3 ppm, less than about 2 ppm, less than
about 1 ppm, or less than about 0.5 ppm of 8-hydroxyoxymorphone or
a salt or solvate thereof.
[0458] In certain embodiments, the oxymorphone or a salt or solvate
thereof additionally comprises (i) 8-hydroxyoxymorphone or a salt
or solvate thereof, and/or (ii) 14-hydroxymorphinone or a salt or
solvate thereof, wherein the amount of the 8-hydroxyoxymorphone is
less than about 300 ppm, less than about 275 ppm, less than about
250 ppm, less than about 225 ppm, less than about 200 ppm, less
than about 175 ppm, less than about 150 ppm, less than about 125
ppm, less than about 100 ppm, less than about 80 ppm, less than
about 60 ppm, less than about 40 ppm, less than about 30 ppm, less
than about 20 ppm, less than about 10 ppm, less than about 8 ppm,
less than about 6 ppm, less than about 4 ppm, less than about 2
ppm, less than about 1 ppm, less than about 0.8 ppm, less than
about 0.6 ppm, less than about 0.4 ppm, less than about 0.3 ppm,
less than about 0.2 ppm, or less than about 0.1 ppm of the
oxymorphone (HPLC peak area ratio; e.g., from about 0.2 ppm to
about 50 ppm of the oxymorphone), and the amount of the
14-hydroxymorphinone is less than about 200 ppm, less than about
175 ppm, less than about 150 ppm, less than about 125 ppm, less
than about 100 ppm, less than about 80 ppm, less than about 60 ppm,
less than about 40 ppm, less than about 30 ppm, less than about 20
ppm, or less than about 10 ppm, or less than about 5 ppm of the
oxymorphone (HPLC peak area ratio; e.g., from about 0.1 ppm to
about 15 ppm, or from about 0.2 ppm to about 2 ppm of the
oxymorphone). In preferred embodiments, the oxymorphone is
oxymorphone free base.
[0459] In certain embodiments, the oxymorphone is oxymorphone free
base and additionally comprises (i) 8-hydroxyoxymorphone or a salt
or solvate thereof, and/or (ii) 14-hydroxymorphinone or a salt or
solvate thereof, wherein the amount of the 8-hydroxyoxymorphone is
less than about 100 ppm, less than about 80 ppm, less than about 60
ppm, less than about 40 ppm, less than about 30 ppm, less than
about 20 ppm, less than about 10 ppm, less than about 5 ppm, or
less than about 2 ppm of the oxymorphone salt (HPLC peak area
ratio; e.g., from about 0.1 ppm to about 9 ppm of the oxymorphone
salt), and the amount of the 14-hydroxymorphinone is less than
about 50 ppm, less than about 25 ppm, less than about 10 ppm, less
than about 5 ppm, or less than about 2 ppm of the oxymorphone salt
(HPLC peak area ratio).
VII. Use of the Oxymorphone
VII-A. Use in a Medicament
[0460] Oxymorphone or a pharmaceutically acceptable salt or solvate
thereof can be used as API of a medicament. To date, the API form
of oxymorphone is oxymorphone hydrochloride.
[0461] For this use, the oxymorphone or the pharmaceutically
acceptable salt or solvate thereof may be the oxymorphone as
described in Section VI.
[0462] For this use, the oxymorphone or the pharmaceutically
acceptable salt or solvate thereof may be used in a dosage form as
described in Section VIII.
[0463] In the context of the present invention, the oxymorphone is
preferably prepared as its free base according to the process of
the present invention, and then used either directly as API, or
converted into a pharmaceutically acceptable salt or solvate which
is then used as API, in particular, oxymorphone hydrochloride.
[0464] For this use, the medicament may be for treating a medical
condition selected from the group consisting of pain, addiction,
cough, constipation, diarrhea, insomnia associated with and/or
caused by pain, cough or addiction, depression associated with
and/or resulting from pain, cough or addiction, or a combination of
two or more of the foregoing conditions. In particular, said
condition may be pain.
[0465] The present invention also provides a method for treating an
animal, preferably a mammal (e.g., a human), (in the following: "a
patient") using the oxymorphone or a pharmaceutically acceptable
salt or solvate thereof. Said treatment may be of any medical
condition which is conventionally treated by administration of
oxymorphone or a pharmaceutically acceptable salt or solvate
thereof to a patient.
[0466] Said medical condition may be pain, addiction, cough,
constipation, diarrhea, insomnia associated with and/or caused by
pain, cough or addiction, depression associated with and/or
resulting from pain, cough or addiction, or a combination of two or
more of the foregoing conditions. In particular, said condition may
be pain.
[0467] For this method of treatment, the oxymorphone or the
pharmaceutically acceptable salt or solvate thereof may be the
compound as described in Section VI.
[0468] For this method of treatment, the oxymorphone or the
pharmaceutically acceptable salt or solvate thereof may be used in
a dosage form as described in Section VIII.
VII-B. Other Uses
[0469] The oxymorphone (prepared) according to the present
invention or an (optionally pharmaceutically acceptable) salt or
solvate thereof may also be used as follows:
[0470] In certain embodiments, the oxymorphone or (optionally
pharmaceutically acceptable) salt or solvate thereof is used as an
intermediate or starting material for preparing the oxymorphone in
its free base form or for preparing another salt or solvate of
oxymorphone, e.g., for preparing a(nother) pharmaceutically
acceptable salt or solvate of oxymorphone. For example, the
oxymorphone may be used for preparing oxymorphone hydrochloride.
Processes for preparing said other salt or solvate which involve a
process or compound as described above in the detailed description
are also embodiments of the present invention.
[0471] In certain embodiments, the oxymorphone or (optionally
pharmaceutically acceptable) salt or solvate thereof is used as an
intermediate or starting material for preparing another opioid or a
pharmaceutically acceptable salt or solvate thereof or a prodrug
thereof, and/or for preparing a medicament containing the
oxymorphone or a pharmaceutically acceptable salt or solvate
thereof, or containing another opioid or a pharmaceutically
acceptable salt or solvate thereof. For example, oxymorphone may be
used as starting material for preparing oxycodone, naloxone,
noroxymorphone, naltrexone, methyl naltrexone, nalmafine, or
nalfurafine. Processes for preparing said other opioids which
involve a process or compound as described above in the detailed
description are also embodiments of the present invention.
VIII. Dosage Forms
[0472] Dosage forms in accordance with the present invention
comprise one or more of the compounds described above and one or
more pharmaceutically acceptable excipients. The dosage forms may
or may not be abuse-resistant.
[0473] Those compounds, salts or solvates according to the present
invention which are or contain an active pharmaceutical ingredient,
in particular the oxymorphone which is described in Section VI, the
pharmaceutically acceptable salts and solvates thereof, can be
comprised in a pharmaceutical dosage form or medicament. Other
opioids made from compounds, salts or solvates according to the
present invention can also be comprised in a pharmaceutical dosage
form or medicament. Prodrugs of the opioids described herein can
also be comprised in a pharmaceutical dosage form or medicament.
Such dosage forms and medicaments are also an embodiment of the
present invention.
[0474] In addition to said active pharmaceutical ingredient, said
dosage forms comprise one or more pharmaceutically acceptable
excipients.
[0475] A pharmaceutical dosage form of the present invention may
comprise (i) an opioid prepared according to present invention or a
pharmaceutically acceptable salt or solvate thereof, and (ii) one
or more pharmaceutically acceptable excipients. In particular, a
pharmaceutical dosage form of the present invention may comprise
(i) oxymorphone or an oxymorphone salt or solvate as described
above, and (ii) one or more pharmaceutically acceptable
excipients.
[0476] In certain embodiments, the dosage form comprises
oxymorphone or a pharmaceutically acceptable salt or solvate
thereof, wherein said compounds have the properties as described in
Section VI and/or have been prepared according to a process of the
present invention. In one embodiment, the oxymorphone salt is
oxymorphone hydrochloride.
[0477] In certain embodiments, the dosage form comprises a
combination of oxymorphone or a salt or solvate thereof which has
the properties as described in Section VI and/or has been prepared
according to a process of the present invention, with another
opioid. In certain embodiments, the dosage form comprises a
combination of oxymorphone or a salt or solvate thereof which has
the properties as described in Section VI and/or has been prepared
according to a process of the present invention, with an opioid
receptor antagonist. For example, a dosage form of the present
invention may comprise a combination of oxymorphone or a
pharmaceutically acceptable salt or solvate thereof (such as
oxymorphone hydrochloride) and naloxone or a pharmaceutically
acceptable salt or solvate (such as naloxone hydrochloride).
[0478] In certain embodiments, the dosage form is selected from the
group consisting of oral dosage forms (e.g., tablets, capsules,
suspensions, solutions, etc.), injectable dosage forms, rectal
dosage forms (e.g., suppositories), and transdermal dosage forms
(e.g., patches).
[0479] In certain embodiments, the pharmaceutical composition or
dosage form does not contain 14-hydroxymorphinone and/or
8-hydroxyoxymorphone. Preferably, neither 14-hydroxymorphinone nor
8-hydroxyoxymorphone are contained.
[0480] In said embodiments, the dosage form may be selected from
the group consisting of oral dosage forms (e.g., tablets, capsules,
suspensions, solutions, etc.), injectable dosage forms, rectal
dosage forms (e.g., suppositories), and transdermal dosage forms
(e.g., patches). Dosage forms for oral administration may be
presented as tablets, capsules, liquid formulations, troches,
lozenges, powders, granules, microparticles (e.g., microcapsules,
microspheres and the like), or buccal tablets.
[0481] In certain embodiments, oral dosage forms of the present
invention may be in the form of tablets (sustained release and/or
immediate release), solutions, suspensions, etc.
[0482] Oral dosage forms can provide a controlled release
(sustained release or delayed release) or an immediate release of
the active pharmaceutical ingredient. One of the conventional
excipients may be a pharmaceutically acceptable carrier. Suitable
pharmaceutically acceptable carriers include but are not limited
to, e.g., alcohols, gum arabic, vegetable oils, benzyl alcohols,
polyethylene glycols, gelate, carbohydrates such as lactose,
amylose or starch, magnesium stearate, talc, silicic acid, viscous
paraffin, perfume oil, fatty acid monoglycerides and diglycerides,
pentaerythritol fatty acid esters, hydroxymethylcellulose,
polyvinylpyrrolidone, etc. The dosage form may further comprise an
inert diluent such as lactose; granulating and disintegrating
agents such as cornstarch; binding agents such as starch; and
lubricating agents such as magnesium stearate. The tablets may be
uncoated or they may be coated by known techniques for elegance or
to provide a controlled release of the drug (a sustained release, a
delayed release or a pulsatile release) of the pharmaceutical
composition.
[0483] The pharmaceutical preparations can be sterilized and if
desired mixed with auxiliary agents, e.g., lubricants,
disintegrants, preservatives, stabilizers, wetting agents,
emulsifiers, salts for influencing osmotic pressure buffers,
coloring, flavoring and/or aromatic substances and the like.
[0484] The compositions intended for oral use may be prepared
according to any method known in the art and such compositions may
contain one or more agents selected from the group consisting of
inert, non-toxic pharmaceutically acceptable excipients which are
suitable for the manufacture of the pharmaceutically acceptable
dosage forms.
[0485] In certain embodiments, the sustained release dosage form
may optionally comprise particles containing an opioid
pharmaceutical composition described above. In certain embodiments,
the particles have a diameter from about 0.1 mm to about 2.5 mm,
preferably from about 0.5 mm to about 2 mm. The particles may be
film coated with a material that permits release of the active at a
sustained rate in an aqueous medium. The film coat may be chosen so
as to achieve, in combination with the other ingredients of the
dosage form, desired release properties. The sustained release
coating formulations of the present invention should be capable of
producing a strong, continuous film that is smooth and elegant,
capable of supporting pigments and other coating additives,
non-toxic, inert, and tack-free.
Coated Beads
[0486] In certain embodiments of the present invention a
hydrophobic material is used to coat inert pharmaceutical beads
such as nu panel 18/20 beads, and a plurality of the resultant
solid sustained release beads may thereafter be placed in a gelatin
capsule in an amount sufficient to provide an effective sustained
release dose of the opioid pharmaceutical composition when ingested
and contacted by an environmental fluid, e.g., gastric fluid or
dissolution media.
[0487] The sustained release bead formulations of the present
invention slowly release the active of the present invention, e.g.,
when ingested and exposed to gastric fluids, and then to intestinal
fluids.
[0488] The sustained release profile of the formulations of the
invention can be altered, for example, by varying the amount of
overcoating with the hydrophobic material, altering the manner in
which a plasticizer is added to the hydrophobic material, by
varying the amount of plasticizer relative to hydrophobic material,
by the inclusion of additional ingredients or excipients, by
altering the method of manufacture, etc.
[0489] The dissolution profile of the ultimate product may also be
modified, for example, by increasing or decreasing the thickness of
the retardant coating.
[0490] Spheroids or beads coated with the agent(s) of the present
invention are prepared, e.g., by dissolving the pharmaceutical
compositions in water and then spraying the solution onto a
substrate, for example, nu panel 18/20 beads, using a Wurster
insert. Optionally, additional ingredients may be added prior to
coating the beads in order to assist the binding of the
pharmaceutical compositions to the beads, and/or to color the
solution, etc. For example, a product which includes
hydroxypropylmethylcellulose, etc. with or without colorant (e.g.,
Opadry.RTM., commercially available from Colorcon, Inc.) may be
added to the solution and the solution mixed (e.g., for about 1
hour) prior to application of the same onto the beads. The
resultant coated substrate, in this example beads, may then be
optionally overcoated with a barrier agent, to separate the
active(s) from the hydrophobic sustained release coating. An
example of a suitable barrier agent is one which comprises
hydroxypropylmethylcellulose. However, any film-former known in the
art may be used. It is preferred that the barrier agent does not
affect the dissolution rate of the final product.
[0491] The beads may then be overcoated with an aqueous dispersion
of the hydrophobic material. The aqueous dispersion of hydrophobic
material preferably further includes an effective amount of
plasticizer, e.g., triethyl citrate. Pre-formulated aqueous
dispersions of ethylcellulose, such as Aquacoat.RTM. or
Surelease.RTM., may be used. If Surelease.RTM. is used, it is not
necessary to separately add a plasticizer. Alternatively,
pre-formulated aqueous dispersions of acrylic polymers such as
Eudragit.RTM. can be used.
[0492] The coating solutions of the present invention preferably
contain, in addition to the film-former, plasticizer, and solvent
system (i.e., water), a colorant to provide elegance and product
distinction. Color may be added to the solution of the
therapeutically active agent instead, or in addition to the aqueous
dispersion of hydrophobic material. For example, color may be added
to Aquacoat.RTM. via the use of alcohol or propylene glycol based
color dispersions, milled aluminum lakes and opacifiers such as
titanium dioxide by adding color with shear to water soluble
polymer solution and then using low shear to the plasticized
Aquacoat.RTM.. Alternatively, any suitable method of providing
color to the formulations of the present invention may be used.
Suitable ingredients for providing color to the formulation when an
aqueous dispersion of an acrylic polymer is used include titanium
dioxide and color pigments, such as iron oxide pigments. The
incorporation of pigments, may, however, increase the retard effect
of the coating.
[0493] Plasticized hydrophobic material may be applied onto the
substrate comprising the agent(s) by spraying using any suitable
spray equipment known in the art. In a preferred method, a Wurster
fluidized-bed system is used in which an air jet, injected from
underneath, fluidizes the core material and effects drying while
the acrylic polymer coating is sprayed on. A sufficient amount of
the hydrophobic material to obtain a predetermined sustained
release of the pharmaceutical composition when the coated substrate
is exposed to aqueous solutions, e.g., gastric fluid, may be
applied. After coating with the hydrophobic material, a further
overcoat of a film-former, such as, e.g., Opadry.RTM., may be
optionally applied to the beads. This overcoat is provided, if at
all, e.g., in order to substantially reduce agglomeration of the
beads.
[0494] The release of the pharmaceutical composition(s) from the
sustained release formulation of the present invention can be
further influenced, i.e., adjusted to a desired rate, by the
addition of one or more release-modifying agents, or by providing
one or more passageways through the coating. The ratio of
hydrophobic material to water soluble material is determined by,
among other factors, the release rate required and the solubility
characteristics of the materials selected.
[0495] The release-modifying agents which function as pore-formers
may be organic or inorganic, and include materials that can be
dissolved, extracted or leached from the coating in an environment
of use. The pore-formers may comprise one or more hydrophilic
materials such as hydroxypropylmethylcellulose.
[0496] The sustained release coatings of the present invention can
also include erosion-promoting agents such as starch and gums.
[0497] The sustained release coatings of the present invention can
also include materials useful for making microporous lamina in the
environment of use, such as polycarbonates comprised of linear
polyesters of carbonic acid in which carbonate groups reoccur in
the polymer chain.
[0498] The release-modifying agent may also comprise a
semi-permeable polymer.
[0499] In certain preferred embodiments, the release-modifying
agent is selected from hydroxypropylmethylcellulose, lactose, metal
stearates, and mixtures of any of the foregoing.
[0500] The sustained release coatings of the present invention may
also include an exit means comprising at least one passageway,
orifice, or the like. The passageway may be formed by such methods
as those disclosed in U.S. Pat. Nos. 3,845,770; 3,916,899;
4,063,064; and 4,088,864.
Matrix Formulations
[0501] In other embodiments of the present invention, the sustained
release formulation is achieved via a sustained release matrix
optionally having a sustained release coating as set forth herein.
The materials suitable for inclusion in the sustained release
matrix may depend on the method used to form the matrix.
[0502] For example, a matrix in addition to the pharmaceutical
compositions described above may include hydrophilic and/or
hydrophobic materials, such as gums, cellulose ethers, acrylic
resins, protein derived materials; the list is not meant to be
exclusive, and any pharmaceutically acceptable hydrophobic material
or hydrophilic material which is capable of imparting sustained
release of the pharmaceutical composition(s) and which melts (or
softens to the extent necessary to be extruded) may be used in
accordance with the present invention.
[0503] The oral dosage form may contain between 1% and 80% (by
weight) of one or more hydrophilic or hydrophobic material(s).
[0504] The hydrophobic material is preferably selected from the
group consisting of alkylcelluloses, acrylic and methacrylic acid
polymers and copolymers, shellac, zein, hydrogenated castor oil,
hydrogenated vegetable oil, or mixtures thereof. In certain
preferred embodiments of the present invention, the hydrophobic
material is a pharmaceutically acceptable acrylic polymer,
including but not limited to acrylic acid and methacrylic acid
copolymers, methyl methacrylate, methyl methacrylate copolymers,
ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl
methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),
methacrylic acid alkylamine copolymer, poly(methyl methacrylate),
poly(methacrylic acid)(anhydride), polymethacrylate,
polyacrylamide, poly(methacrylic acid anhydride), and glycidyl
methacrylate copolymers. In other embodiments, the hydrophobic
material is selected from materials such as hydroxyalkylcelluloses
such as hydroxypropylmethylcellulose and mixtures of the foregoing.
Of these materials, acrylic polymers, e.g., Eudragit.RTM. RSPO, the
cellulose ethers, e.g., hydroxyalkylcelluloses and
carboxyalkylcelluloses are preferred.
[0505] Preferred hydrophobic materials are water-insoluble with
more or less pronounced hydrophilic and/or hydrophobic trends.
Preferably, the hydrophobic materials useful in the invention have
a melting point from about 40.degree. C. to about 200.degree. C.,
preferably from about 45.degree. C. to about 90.degree. C.
Specifically, the hydrophobic material may comprise natural or
synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl,
cetyl or preferably cetostearyl alcohol), fatty acids, including
but not limited to fatty acid esters, fatty acid glycerides (mono-,
di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal
waxes, stearic acid, stearyl alcohol and hydrophobic and
hydrophilic materials having hydrocarbon backbones. Suitable waxes
are waxes as defined in Fette, Seifen, Anstrichmittel 76, 135
(1974) and include, for example, beeswax, glycowax, castor wax and
carnauba wax.
[0506] Suitable hydrophobic materials which may be used in
accordance with the present invention include long chain
(C.sub.8-C.sub.50, especially C.sub.12-C.sub.40), substituted or
unsubstituted hydrocarbons, such as fatty acids, fatty alcohols,
glyceryl esters of fatty acids, mineral and vegetable oils and
natural and synthetic waxes. Hydrocarbons having a melting point of
between 25.degree. C. and 90.degree. C. are preferred. Of the long
chain hydrocarbon materials, fatty (aliphatic) alcohols are
preferred in certain embodiments. The oral dosage form may contain
up to 60% of at least one long chain hydrocarbon.
[0507] In certain embodiments, a combination of two or more
hydrophobic materials is included in the matrix formulations. If an
additional hydrophobic material is included, it is preferably
selected from natural and synthetic waxes, fatty acids, fatty
alcohols, and mixtures of the same. Examples include beeswax,
carnauba wax, stearic acid and stearyl alcohol. This list is not
meant to be exclusive.
[0508] One particular suitable matrix comprises at least one water
soluble hydroxyalkyl cellulose, at least one C.sub.12-C.sub.36,
preferably C.sub.14-C.sub.22, aliphatic alcohol and, optionally, at
least one polyalkylene glycol. The at least one hydroxyalkyl
cellulose is preferably a hydroxy (C.sub.1 to C.sub.6) alkyl
cellulose, such as hydroxypropylcellulose,
hydroxypropylmethylcellulose and, especially,
hydroxyethylcellulose. The amount of the at least one hydroxyalkyl
cellulose in the present oral dosage form will be determined, inter
alia, by the precise rate of API release required. The at least one
aliphatic alcohol may be, for example, lauryl alcohol, myristyl
alcohol or stearyl alcohol. In particularly preferred embodiments
of the present oral dosage form, however, the at least one
aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The
amount of the at least one aliphatic alcohol in the present oral
dosage form will be determined, as above, by the precise rate of
opioid release required. It will also depend on whether at least
one polyalkylene glycol is present in or absent from the oral
dosage form. In the absence of at least one polyalkylene glycol,
the oral dosage form preferably contains between 20% and 50% (by
weight) of the at least one aliphatic alcohol. When at least one
polyalkylene glycol is present in the oral dosage form, then the
combined weight of the at least one aliphatic alcohol and the at
least one polyalkylene glycol preferably constitutes between 20%
and 50% (by weight) of the total dosage.
[0509] In one embodiment, the ratio of, e.g., the at least one
hydroxyalkyl cellulose or acrylic resin to the at least one
aliphatic alcohol/polyalkylene glycol determines, to a (w/w) of the
at least one hydroxyalkyl cellulose to the at least one aliphatic
alcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred,
with a ratio of between 1:3 and 1:4 being particularly
preferred.
[0510] In certain embodiments, the oral dosage form contains at
least one polyalkylene glycol. The amount of the at least one
polyalkylene glycol in the oral dosage form may be up to 60%. The
at least one polyalkylene glycol may be, for example, polypropylene
glycol or, which is preferred, polyethylene glycol. The number
average molecular weight of the at least one polyalkylene glycol is
preferred between 1,000 and 15,000 especially between 1,500 and
12,000.
[0511] In certain embodiments, the sustained release matrix may
comprise polyethylene oxide. In certain embodiments polyethylene
oxide comprises from about 40% to about 95% of the dosage form. In
certain embodiments polyethylene oxide comprises from about 50% to
about 95% of the dosage form. In certain embodiments polyethylene
oxide comprises from about 55% to about 90% of the dosage form. In
certain embodiments polyethylene oxide comprises from about 60% to
about 90% of the dosage form.
[0512] Another suitable sustained release matrix would comprise an
alkylcellulose (especially ethyl cellulose), a C.sub.12 to C.sub.36
aliphatic alcohol and, optionally, a polyalkylene glycol.
[0513] In another preferred embodiment, the matrix includes a
pharmaceutically acceptable combination of at least two hydrophobic
materials.
[0514] In addition to the above ingredients, a sustained release
matrix may also contain suitable quantities of other materials,
e.g., diluents, lubricants, binders, granulating aids, colorants,
flavorants and glidants that are conventional in the pharmaceutical
art.
Matrix-Particulates
[0515] In order to facilitate the preparation of a solid, sustained
release, oral dosage form according to this invention, any method
of preparing a matrix formulation known to those skilled in the art
may be used. For example incorporation in the matrix may be
effected, for example, by (a) forming granules comprising at least
one water soluble hydroxyalkyl cellulose, and an opioid according
to present invention; (b) mixing the hydroxyalkyl cellulose
containing granules with at least one C.sub.12-C.sub.36 aliphatic
alcohol; and (c) optionally, compressing and shaping the granules.
Preferably, the granules are formed by wet granulating the
hydroxyalkyl cellulose granules with water.
[0516] In yet other alternative embodiments, a spheronizing agent,
together with the active can be spheronized to form spheroids.
Microcrystalline cellulose is a preferred spheronizing agent. A
suitable microcrystalline cellulose is, for example, the material
sold as Avicel PH 101 (Trade Mark, FMC Corporation). In such
embodiments, in addition to the active ingredient and spheronizing
agent, the spheroids may also contain a binder. Suitable binders,
such as low viscosity, water soluble polymers, will be well known
to those skilled in the pharmaceutical art. However, water soluble
hydroxy lower alkyl cellulose, such as hydroxypropylcellulose, is
preferred. Additionally (or alternatively) the spheroids may
contain a water insoluble polymer, especially an acrylic polymer,
an acrylic copolymer, such as a methacrylic acid-ethyl acrylate
copolymer, or ethyl cellulose. In such embodiments, the sustained
release coating will generally include a hydrophobic material such
as (a) a wax, either alone or in admixture with a fatty alcohol; or
(b) shellac or zein.
Melt Extrusion Matrix
[0517] Sustained release matrices can also be prepared via
melt-granulation or melt-extrusion techniques. Generally,
melt-granulation techniques involve melting a normally solid
hydrophobic material, e.g., a wax, and incorporating a powdered
drug therein. To obtain a sustained release dosage form, it may be
necessary to incorporate an additional hydrophobic substance, e.g.,
ethylcellulose or a water-insoluble acrylic polymer, into the
molten wax hydrophobic material. Examples of sustained release
formulations prepared via melt-granulation techniques are found in
U.S. Pat. No. 4,861,598.
[0518] The additional hydrophobic material may comprise one or more
water-insoluble wax-like thermoplastic substances possibly mixed
with one or more wax-like thermoplastic substances being less
hydrophobic than said one or more water-insoluble wax-like
substances. In order to achieve constant release, the individual
wax-like substances in the formulation should be substantially
non-degradable and insoluble in gastrointestinal fluids during the
initial release phases. Useful water-insoluble wax-like substances
may be those with a water-solubility that is lower than about
1:5,000 (w/w). For purposes of the present invention, a wax-like
substance is defined as any material which is normally solid at
room temperature and has a melting point of from about 25.degree.
to about 100.degree. C.
[0519] In addition to the above ingredients, a sustained release
matrix may also contain suitable quantities of other materials,
e.g., diluents, lubricants, binders, granulating aids, colorants,
flavorants and glidants that are conventional in the pharmaceutical
art. The quantities of these additional materials will be
sufficient to provide the desired effect to the desired
formulation.
[0520] In addition to the above ingredients, a sustained release
matrix incorporating melt-extruded multiparticulates may also
contain suitable quantities of other materials, e.g., diluents,
lubricants, binders, granulating aids, colorants, flavorants and
glidants that are conventional in the pharmaceutical art in amounts
up to about 50% of the particulate if desired.
[0521] Specific examples of pharmaceutically acceptable carriers
and excipients that may be used to formulate oral dosage forms are
described in the Handbook of Pharmaceutical Excipients, American
Pharmaceutical Association (1986).
Melt Extrusion Multiparticulates
[0522] The preparation of a suitable melt-extruded matrix according
to the present invention may, for example, include the steps of
blending the API together with at least one hydrophobic material
and preferably the additional hydrophobic material to obtain a
homogeneous mixture. The homogeneous mixture is then heated to a
temperature sufficient to at least soften the mixture sufficiently
to extrude the same. The resulting homogeneous mixture is then
extruded to form strands. The extrudate is preferably cooled and
cut into multiparticulates by any means known in the art. The
strands are cooled and cut into multiparticulates. The
multiparticulates are then divided into unit doses. The extrudate
preferably has a diameter of from about 0.1 to about 5 mm and
provides sustained release of the API for a time period of from
about 8 to about 24 hours.
[0523] An optional process for preparing the melt extrusions of the
present invention includes directly metering into an extruder a
hydrophobic material, the opioid API, and an optional binder;
heating the homogenous mixture; extruding the homogenous mixture to
thereby form strands; cooling the strands containing the
homogeneous mixture; cutting the strands into particles having a
size from about 0.1 mm to about 12 mm; and dividing said particles
into unit doses. In this aspect of the invention, a relatively
continuous manufacturing procedure is realized.
[0524] The diameter of the extruder aperture or exit port can also
be adjusted to vary the thickness of the extruded strands.
Furthermore, the exit part of the extruder need not be round; it
can be oblong, rectangular, etc. The exiting strands can be reduced
to particles using a hot wire cutter, guillotine, etc.
[0525] The melt extruded multiparticulate system can be, for
example, in the form of granules, spheroids or pellets depending
upon the extruder exit orifice. For purposes of the present
invention, the terms "melt-extruded multiparticulate(s)" and
"melt-extruded multiparticulate system(s)" and "melt-extruded
particles" shall refer to a plurality of units, preferably within a
range of similar size and/or shape and containing one or more
active agents and one or more excipients, preferably including a
hydrophobic material as described herein. In this regard, the
melt-extruded multiparticulates will be of a range of from about
0.1 to about 12 mm in length and have a diameter of from about 0.1
to about 5 mm. In addition, it is to be understood that the
melt-extruded multiparticulates can be any geometrical shape within
this size range. Alternatively, the extrudate may simply be cut
into desired lengths and divided into unit doses of the
therapeutically active agent without the need of a spheronization
step.
[0526] In one preferred embodiment, oral dosage forms are prepared
to include an effective amount of melt-extruded multiparticulates
within a capsule. For example, a plurality of the melt-extruded
multiparticulates may be placed in a gelatin capsule in an amount
sufficient to provide an effective sustained release dose when
ingested and contacted by gastric fluid.
[0527] In another preferred embodiment, a suitable amount of the
multiparticulate extrudate is compressed into an oral tablet using
conventional tableting equipment using standard techniques.
Techniques and compositions for making tablets (compressed and
molded), capsules (hard and soft gelatin) and pills are also
described in Remington's Pharmaceutical Sciences, (Arthur Osol,
editor), 1553-1593 (1980).
[0528] In yet another preferred embodiment, the extrudate can be
shaped into tablets as set forth in U.S. Pat. No. 4,957,681
(Klimesch, et. al.), described in additional detail above.
[0529] Optionally, the sustained release melt-extruded
multiparticulate systems or tablets can be coated, or the gelatin
capsule containing the multiparticulates can be further coated,
with a sustained release coating such as the sustained release
coatings described above. Such coatings preferably include a
sufficient amount of hydrophobic material to obtain a weight gain
level from about 2 to about 30 percent, although the overcoat may
be greater depending upon the desired release rate, among other
things.
[0530] The melt-extruded unit dosage forms of the present invention
may further include combinations of melt-extruded particles before
being encapsulated. Furthermore, the unit dosage forms can also
include an amount of an immediate release agent for prompt release.
The immediate release agent may be incorporated, e.g., as separate
pellets within a gelatin capsule, or may be coated on the surface
of the multiparticulates after preparation of the dosage forms
(e.g., sustained release coating or matrix-based). The unit dosage
forms of the present invention may also contain a combination of
sustained release beads and matrix multiparticulates to achieve a
desired effect.
[0531] The sustained release formulations of the present invention
preferably slowly release the agent(s), e.g., when ingested and
exposed to gastric fluids, and then to intestinal fluids. The
sustained release profile of the melt-extruded formulations of the
invention can be altered, for example, by varying the amount of
retardant, i.e., hydrophobic material, by varying the amount of
plasticizer relative to hydrophobic material, by the inclusion of
additional ingredients or excipients, by altering the method of
manufacture, etc.
[0532] In other embodiments of the invention, the melt extruded
material is prepared without the inclusion of the API, which can be
added thereafter to the extrudate. Such formulations typically will
have the agents blended together with the extruded matrix material,
and then the mixture would be tableted in order to provide a slow
release formulation.
Coatings
[0533] The dosage forms of the present invention may optionally be
coated with one or more materials suitable for the regulation of
release or for the protection of the formulation. In one
embodiment, coatings are provided to permit either pH-dependent or
pH-independent release. A pH-dependent coating serves to release
the active in desired areas of the gastro-intestinal (GI) tract,
e.g., the stomach or small intestine, such that an absorption
profile is provided which is capable of providing at least about
eight hours and preferably about twelve hours to up to about
twenty-four hours of the therapeutic effect (such as analgesia) to
a patient. When a pH-independent coating is desired, the coating is
designed to achieve optimal release regardless of pH-changes in the
environmental fluid, e.g., the GI tract. It is also possible to
formulate compositions which release a portion of the dose in one
desired area of the GI tract, e.g., the stomach, and release the
remainder of the dose in another area of the GI tract, e.g., the
small intestine.
[0534] Formulations according to the invention that utilize
pH-dependent coatings to obtain formulations may also impart a
repeat-action effect whereby unprotected drug is coated over the
enteric coat and is released in the stomach, while the remainder,
being protected by the enteric coating, is released further down
the gastrointestinal tract. Coatings which are pH-dependent may be
used in accordance with the present invention include shellac,
cellulose acetate phthalate (CAP), polyvinyl acetate phthalate
(PVAP), hydroxypropylmethylcellulose phthalate, and methacrylic
acid ester copolymers, zein, and the like.
[0535] In certain preferred embodiments, the substrate (e.g.,
tablet core bead, matrix particle) containing the API is coated
with a hydrophobic material selected from (i) an alkylcellulose;
(ii) an acrylic polymer; or (iii) mixtures thereof. The coating may
be applied in the form of an organic or aqueous solution or
dispersion. The coating may be applied to obtain a weight gain from
about 2 to about 25% of the substrate in order to obtain a desired
sustained release profile. Coatings derived from aqueous
dispersions are described, e.g., in detail in U.S. Pat. Nos.
5,273,760 and 5,286,493.
[0536] Other examples of sustained release formulations and
coatings which may be used in accordance with the present invention
include those described in U.S. Pat. Nos. 5,324,351; 5,356,467, and
5,472,712.
Alkylcellulose Polymers
[0537] Cellulosic materials and polymers, including
alkylcelluloses, provide hydrophobic materials well suited for
coating the beads according to the invention. Simply by way of
example, one preferred alkylcellulosic polymer is ethylcellulose,
although the artisan will appreciate that other cellulose and/or
alkylcellulose polymers may be readily employed, singly or in any
combination, as all or part of a hydrophobic coating according to
the invention.
Acrylic Polymers
[0538] In other preferred embodiments of the present invention, the
hydrophobic material comprising the sustained release coating is a
pharmaceutically acceptable acrylic polymer, including but not
limited to acrylic acid and methacrylic acid copolymers, methyl
methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl
methacrylate, poly(acrylic acid), poly(methacrylic acid),
methacrylic acid alkylamide copolymer, poly(methyl methacrylate),
polymethacrylate, poly(methyl methacrylate) copolymer,
polyacrylamide, amino alkyl methacrylate copolymer,
poly(methacrylic acid anhydride), and glycidyl methacrylate
copolymers.
[0539] In certain preferred embodiments, the acrylic polymer is
comprised of one or more ammonio methacrylate copolymers. Ammonio
methacrylate copolymers are well known in the art, and are
described in NF XVII as fully polymerized copolymers of acrylic and
methacrylic acid esters with a low content of quaternary ammonium
groups.
[0540] In order to obtain a desirable dissolution profile, it may
be necessary to incorporate two or more ammonio methacrylate
copolymers having differing physical properties, such as different
molar ratios of the quaternary ammonium groups to the neutral
(meth)acrylic esters.
[0541] Certain methacrylic acid ester-type polymers are useful for
preparing pH-dependent coatings which may be used in accordance
with the present invention. For example, there are a family of
copolymers synthesized from diethylaminoethyl methacrylate and
other neutral methacrylic esters, also known as methacrylic acid
copolymer or polymeric methacrylates, commercially available as
Eudragit.RTM. from Evonik. There are several different types of
Eudragit.RTM.. For example, Eudragit.RTM. E is an example of a
methacrylic acid copolymer which swells and dissolves in acidic
media. Eudragit.RTM. L is a methacrylic acid copolymer which does
not swell at about pH<5.7 and is soluble at about pH>6.
Eudragit.RTM. S does not swell at about pH<6.5 and is soluble at
about pH>7. Eudragit.RTM. RL and Eudragit.RTM. RS are water
swellable, and the amount of water absorbed by these polymers is
pH-dependent, however, dosage forms coated with Eudragit.RTM. RL
and RS are pH-independent.
[0542] In certain preferred embodiments, the acrylic coating
comprises a mixture of two acrylic resin lacquers commercially
available from Evonik under the trade names Eudragit.RTM. RL30D and
Eudragit.RTM. RS30D, respectively. Eudragit.RTM. RL30D and
Eudragit.RTM. RS30D are copolymers of acrylic and methacrylic
esters with a low content of quaternary ammonium groups, the molar
ratio of ammonium groups to the remaining neutral (meth)acrylic
esters being 1:20 in Eudragit.RTM. RL30D and 1:40 in Eudragit.RTM.
RS30D. The mean molecular weight is about 150,000. The code
designations RL (high permeability) and RS (low permeability) refer
to the permeability properties of these agents. Eudragit.RTM. RL/RS
mixtures are insoluble in water and in digestive fluids. However,
coatings formed from the same are swellable and permeable in
aqueous solutions and digestive fluids.
[0543] The Eudragit.RTM. RL/RS dispersions may be mixed together in
any desired ratio in order to ultimately obtain a sustained release
formulation having a desirable dissolution profile. Desirable
sustained release formulations may be obtained, for instance, from
a retardant coating derived from 100% Eudragit.RTM. RL, 50%
Eudragit.RTM. RL and 50% Eudragit.RTM. RS, and 10% Eudragit.RTM. RL
and 90% Eudragit.RTM. RS. Of course, one skilled in the art will
recognize that other acrylic polymers may also be used, such as,
for example, Eudragit.RTM. L.
Plasticizers
[0544] In embodiments of the present invention where the coating
comprises an aqueous dispersion of a hydrophobic material, the
inclusion of an effective amount of a plasticizer in the aqueous
dispersion of hydrophobic material will further improve the
physical properties of the sustained release coating. For example,
because ethyl-cellulose has a relatively high glass transition
temperature and does not form flexible films under normal coating
conditions, it is preferable to incorporate a plasticizer into an
ethylcellulose coating containing sustained release coating before
using the same as a coating material. Generally, the amount of
plasticizer included in a coating solution is based on the
concentration of the film-former, e.g., most often from about 1 to
about 50 percent of the film-former. Concentration of the
plasticizer, however, can only be properly determined after careful
experimentation with the particular coating solution and method of
application.
[0545] Examples of suitable plasticizers for ethylcellulose include
water insoluble plasticizers such as dibutyl sebacate, diethyl
phthalate, triethyl citrate, tributyl citrate, and triacetin,
although it is possible that other water-insoluble plasticizers
(such as acetylated monoglycerides, phthalate esters, castor oil,
etc.) may be used. Triethyl citrate is an especially preferred
plasticizer for the aqueous dispersions of ethyl cellulose of the
present invention.
[0546] Examples of suitable plasticizers for the acrylic polymers
of the present invention include, but are not limited to citric
acid esters such as triethyl citrate NF XVI, tributyl citrate,
dibutyl phthalate, and possibly 1,2-propylene glycol. Other
plasticizers which have proved to be suitable for enhancing the
elasticity of the films formed from acrylic films such as
Eudragit.RTM. RL/RS lacquer solutions include polyethylene glycols,
propylene glycol, diethyl phthalate, castor oil, and triacetin.
Triethyl citrate is an especially preferred plasticizer for the
aqueous dispersions of ethyl cellulose of the present
invention.
[0547] It has further been found that the addition of a small
amount of talc reduces the tendency of the aqueous dispersion to
stick during processing, and acts as a polishing agent.
Sustained Release Osmotic Dosage Form
[0548] Sustained release dosage forms according to the present
invention may also be prepared as osmotic dosage formulations. The
osmotic dosage forms preferably include a bilayer core comprising a
drug layer (e.g., containing oxymorphone or a salt or solvate
thereof as described above) and a delivery or push layer, wherein
the bilayer core is surrounded by a semipermeable wall and
optionally having at least one passageway disposed therein.
[0549] The expression "passageway" as used for the purpose of the
present description, includes aperture, orifice, bore, pore, porous
element through which an API (e.g., oxymorphone hydrochloride) may
be pumped, diffuse or migrate through a fiber, capillary tube,
porous overlay, porous insert, microporous member, or porous
composition. The passageway can also include a compound that erodes
or is leached from the wall in the fluid environment of use to
produce at least one passageway. Representative compounds for
forming a passageway include erodible poly(glycolic) acid, or
poly(lactic) acid in the wall; a gelatinous filament; a
water-removable poly(vinyl alcohol); leachable compounds such as
fluid-removable pore-forming polysaccharides, acids, salts or
oxides. A passageway can be formed by leaching a compound from the
wall, such as sorbitol, sucrose, lactose, maltose, or fructose, to
form a sustained-release dimensional pore-passageway. The dosage
form can be manufactured with one or more passageways in
spaced-apart relation on one or more surfaces of the dosage form. A
passageway and equipment for forming a passageway are disclosed in
U.S. Pat. Nos. 3,845,770; 3,916,899; 4,063,064 and 4,088,864.
Passageways comprising sustained-release dimensions sized, shaped
and adapted as a releasing-pore formed by aqueous leaching to
provide a releasing-pore of a sustained-release rate are disclosed
in U.S. Pat. Nos. 4,200,098 and 4,285,987.
[0550] In certain embodiments the drug layer may also comprise at
least one polymer hydrogel. The polymer hydrogel may have an
average molecular weight of between about 500 and about 6,000,000.
Examples of polymer hydrogels include but are not limited to a
maltodextrin polymer comprising the formula
(C.sub.6H.sub.12O.sub.5).H.sub.2O, wherein n is 3 to 7,500, and the
maltodextrin polymer comprises a 500 to 1,250,000 number-average
molecular weight; a poly(alkylene oxide) represented by, e.g., a
poly(ethylene oxide) and a poly(propylene oxide) having a 50,000 to
750,000 weight-average molecular weight, and more specifically
represented by a poly(ethylene oxide) of at least one of 100,000,
200,000, 300,000 or 400,000 weight-average molecular weights; an
alkali carboxyalkylcellulose, wherein the alkali is sodium or
potassium, the alkyl is methyl, ethyl, propyl, or butyl of 10,000
to 175,000 weight-average molecular weight; and a copolymer of
ethylene-acrylic acid, including methacrylic and ethacrylic acid of
10,000 to 500,000 number-average molecular weight.
[0551] In certain embodiments of the present invention, the
delivery or push layer comprises an osmopolymer. Examples of the
osmopolymer include but are not limited to a member selected from
the group consisting of a polyalkylene oxide and a
carboxyalkylcellulose. The polyalkylene oxide possesses a 1,000,000
to 10,000,000 weight-average molecular weight. The polyalkylene
oxide may be a member selected from the group consisting of
polymethylene oxide, polyethylene oxide, polypropylene oxide,
polyethylene oxide having a 1,000,000 average molecular weight,
polyethylene oxide comprising a 5,000,000 average molecular weight,
polyethylene oxide comprising a 7,000,000 average molecular weight,
cross-linked polymethylene oxide possessing a 1,000,000 average
molecular weight, and polypropylene oxide of 1,200,000 average
molecular weight. Typical osmopolymer carboxyalkylcellulose
comprises a member selected from the group consisting of alkali
carboxyalkylcellulose, sodium carboxymethylcellulose, potassium
carboxymethylcellulose, sodium carboxyethylcellulose, lithium
carboxymethylcellulose, sodium carboxyethylcellulose,
carboxyalkylhydroxyalkylcellulose, carboxymethylhydroxyethyl
cellulose, carboxyethylhydroxyethylcellulose and
carboxymethylhydroxypropylcellulose. The osmopolymers used for the
displacement layer exhibit an osmotic pressure gradient across the
semipermeable wall. The osmopolymers imbibe fluid into dosage form,
thereby swelling and expanding as an osmotic hydrogel (also known
as osmogel), whereby they push the active pharmaceutical ingredient
(e.g., oxymorphone hydrochloride) from the osmotic dosage form.
[0552] The push layer may also include one or more osmotically
effective compounds also known as osmagents and as osmotically
effective solutes. They imbibe an environmental fluid, for example,
from the gastrointestinal tract, into dosage form and contribute to
the delivery kinetics of the displacement layer. Examples of
osmotically active compounds comprise a member selected from the
group consisting of osmotic salts and osmotic carbohydrates.
Examples of specific osmagents include but are not limited to
sodium chloride, potassium chloride, magnesium sulfate, lithium
phosphate, lithium chloride, sodium phosphate, potassium sulfate,
sodium sulfate, potassium phosphate, glucose, fructose and
maltose.
[0553] The push layer may optionally include a
hydroxypropylalkylcellulose possessing a 9,000 to 450,000
number-average molecular weight. The hydroxypropylalkylcellulose is
represented by a member selected from the group consisting of
hydroxypropylmethylcellulose, hydroxypropylethylcellulose,
hydroxypropyl isopropyl cellulose, hydroxypropylbutylcellulose, and
hydroxypropylpentylcellulose.
[0554] The push layer optionally may comprise a nontoxic colorant
or dye. Examples of colorants or dyes include but are not limited
to Food and Drug Administration Colorant (FD&C), such as
FD&C No. 1 blue dye, FD&C No. 4 red dye, red ferric oxide,
yellow ferric oxide, titanium dioxide, carbon black, and
indigo.
[0555] The push layer may also optionally comprise an antioxidant
to inhibit the oxidation of ingredients. Some examples of
antioxidants include but are not limited to a member selected from
the group consisting of ascorbic acid, ascorbyl palmitate,
butylated hydroxyanisole, a mixture of 2 and 3
tert-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodium
isoascorbate, dihydroguaretic acid, potassium sorbate, sodium
bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate,
vitamin E, 4-chloro-2,6-di-tert butylphenol, .alpha.-tocopherol,
and propylgallate.
[0556] In certain alternative embodiments, the dosage form
comprises a homogenous core comprising an active pharmaceutical
ingredient (e.g., oxymorphone hydrochloride), a pharmaceutically
acceptable polymer (e.g., polyethylene oxide), optionally a
disintegrant (e.g., polyvinylpyrrolidone), optionally an absorption
enhancer (e.g., a fatty acid, a surfactant, a chelating agent, a
bile salt, etc.). The homogenous core is surrounded by a
semipermeable wall having a passageway (as defined above) for the
release of the opioid API.
[0557] In certain embodiments, the semipermeable wall comprises a
member selected from the group consisting of a cellulose ester
polymer, a cellulose ether polymer and a cellulose ester-ether
polymer. Representative wall polymers comprise a member selected
from the group consisting of cellulose acylate, cellulose
diacylate, cellulose triacylate, cellulose acetate, cellulose
diacetate, cellulose triacetate, mono-, di- and tricellulose
alkenylates, and mono-, di- and tricellulose alkinylates. The
poly(cellulose) used for the present invention comprises a
number-average molecular weight of 20,000 to 7,500,000.
[0558] Additional semipermeable polymers for the purpose of this
invention comprise acetaldehyde dimethycellulose acetate, cellulose
acetate ethylcarbamate, cellulose acetate methylcarbamate,
cellulose diacetate, propylcarbamate, cellulose acetate
diethylaminoacetate; semipermeable polyamide; semipermeable
polyurethane; semipermeable sulfonated polystyrene; semipermeable
cross-linked polymer formed by the coprecipitation of a polyanion
and a polycation as disclosed in U.S. Pat. Nos. 3,173,876;
3,276,586; 3,541,005; 3,541,006 and 3,546,876; semipermeable
polymers as disclosed by Loeb and Sourirajan in U.S. Pat. No.
3,133,132; semipermeable crosslinked polystyrenes; semipermeable
cross-linked poly(sodium styrene sulfonate); semipermeable
crosslinked poly(vinylbenzyltrimethyl ammonium chloride); and
semipermeable polymers possessing a fluid permeability of
2.5.times.10.sup.-8 to 2.5.times.10.sup.-2 (cm.sup.2/hr atm)
expressed per atmosphere of hydrostatic or osmotic pressure
difference across the semipermeable wall. Other polymers useful in
the present invention are known in the art in U.S. Pat. Nos.
3,845,770; 3,916,899 and 4,160,020; and in Handbook of Common
Polymers, Scott, J. R. and W. J. Roff, 1971, CRC Press, Cleveland,
Ohio.
[0559] In certain embodiments, preferably the semipermeable wall is
nontoxic, inert, and it maintains its physical and chemical
integrity during the dispensing life of the drug. In certain
embodiments, the dosage form comprises a binder. An example of a
binder includes, but is not limited to a therapeutically acceptable
vinyl polymer having a 5,000 to 350,000 viscosity-average molecular
weight, represented by a member selected from the group consisting
of poly-n-vinylamide, poly-n-vinylacetamide, poly(vinyl
pyrrolidone), also known as poly-n-vinylpyrrolidone,
poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, and
poly-n-vinyl-pyrrolidone copolymers with a member selected from the
group consisting of vinyl acetate, vinyl alcohol, vinyl chloride,
vinyl fluoride, vinyl butyrate, vinyl laureate, and vinyl stearate.
Other binders include for example, acacia, starch, gelatin, and
hydroxypropylalkylcellulose of from 9,200 to 250,000 average
molecular weight.
[0560] In certain embodiments, the dosage form comprises a
lubricant, which may be used during the manufacture of the dosage
form to prevent sticking to die wall or punch faces. Examples of
lubricants include but are not limited to magnesium stearate,
sodium stearate, stearic acid, calcium stearate, magnesium oleate,
oleic acid, potassium oleate, caprylic acid, sodium stearyl
fumarate, and magnesium palmitate.
Suppositories
[0561] The sustained release formulations of the present invention
may be formulated as a pharmaceutical suppository for rectal
administration comprising a suitable suppository base, and a
pharmaceutical opioid composition. Preparation of sustained release
suppository formulations is described in, e.g., U.S. Pat. No.
5,215,758.
[0562] Prior to absorption, the drug must be in solution. In the
case of suppositories, solution must be preceded by dissolution of
the suppository base, or the melting of the base and subsequent
partition of the drug from the suppository base into the rectal
fluid. The absorption of the drug into the body may be altered by
the suppository base. Thus, the particular suppository base to be
used in conjunction with a particular drug must be chosen giving
consideration to the physical properties of the drug. For example,
lipid-soluble drugs will not partition readily into the rectal
fluid, but drugs that are only slightly soluble in the lipid base
will partition readily into the rectal fluid.
[0563] Among the different factors affecting the dissolution time
(or release rate) of the drugs are the surface area of the drug
substance presented to the dissolution solvent medium, the pH of
the solution, the solubility of the substance in the specific
solvent medium, and the driving forces of the saturation
concentration of dissolved materials in the solvent medium.
Generally, factors affecting the absorption of drugs from
suppositories administered rectally include suppository vehicle,
absorption site pH, drug pKa, degree of ionization, and lipid
solubility.
[0564] The suppository base chosen should be compatible with the
active of the present invention. Further, the suppository base is
preferably non-toxic and nonirritating to mucous membranes, melts
or dissolves in rectal fluids, and is stable during storage.
[0565] In certain preferred embodiments of the present invention
for both water-soluble and water-insoluble drugs, the suppository
base comprises a fatty acid wax selected from the group consisting
of mono-, di- and triglycerides of saturated, natural fatty acids
of the chain length C.sub.12 to C.sub.18.
[0566] In preparing the suppositories of the present invention
other excipients may be used. For example, a wax may be used to
form the proper shape for administration via the rectal route. This
system can also be used without wax, but with the addition of
diluent filled in a gelatin capsule for both rectal and oral
administration.
[0567] Examples of suitable commercially available mono-, di- and
triglycerides include saturated natural fatty acids of the 12-18
carbon atom chain sold under the trade name Novata.TM. (types AB,
AB, B,BC, BD, BBC, E, BCF, C, D and 299), manufactured by Henkel,
and Witepsol.TM. (types H5, H12, H15, H175, H185, H19, H32, H35,
H39, H42, W25, W31, W35, W45, S55, S58, E75, E76 and E85),
manufactured by Dynamit Nobel.
[0568] Other pharmaceutically acceptable suppository bases may be
substituted in whole or in part for the above-mentioned mono-, di-
and triglycerides. The amount of base in the suppository is
determined by the size (i.e. actual weight) of the dosage form, the
amount of base (e.g., alginate) and drug used. Generally, the
amount of suppository base is from about 20 percent to about 90
percent of the total weight of the suppository. Preferably, the
amount of suppository base in the suppository is from about 65
percent to about 80 percent, of the total weight of the
suppository.
[0569] The following examples are meant to illustrate, but in no
way to limit, the present invention.
EXAMPLES
Comparative Example 1
Preparation of Oxymorphone According to Example 2 of WO
2008/130553
##STR00039##
[0571] Example 2 from WO 2008/130553 was repeated as follows.
[0572] 1. Into a 100 mL reaction vessel equipped with a temperature
probe, an overhead stirrer and a reflux condenser, oripavine (3.03
g, 10.2 mmol) was charged as a slurry in deionized water (9
mL).
[0573] 2. The reaction mixture was stirred at 300 rpm, while
maintaining an internal temperature of 20.degree. C.
[0574] 3. Formic acid (88%, 6 mL, 139.9 mmol) was added into the
reaction mixture. Upon the addition, the solids readily dissolved
into solution. During the formic acid addition, the temperature of
the reaction mixture increased to 30.degree. C.
[0575] 4. After the solution temperature had cooled to 20.degree.
C., 35% hydrogen peroxide (1.06 mL, 15.8 mmol) and sulfuric acid
(0.45 mL, 8.15 mmol) were added to the reaction.
[0576] 5. The reaction was stirred (300 rpm) at 20.degree. C. for
16 hours, until about 95% of the oripavine had been consumed
according to the HPLC analysis described in Example 11A.
[0577] 6. 0.30 g of 5% palladium on carbon was charged into the
reaction mixture, and the mixture was stirred at 20.degree. C. for
30 minutes.
[0578] 7. Sodium formate (0.60 g, 8.82 mmol) and triethylamine (7.5
mL, 53.8 mmol) were added to the reaction mixture, and the mixture
was heated to 45.degree. C. and stirred at 45.degree. C. for 2
hours.
[0579] 8. The mixture was heated to 80.degree. C. and stirred at
80.degree. C. for an additional 8 hours.
[0580] 9. The reaction was then cooled to 20.degree. C. and stirred
at 20.degree. C. for 8 hours. No precipitation was observed at this
temperature.
[0581] 10. The reaction mixture was filtered through a plug of
celite.
[0582] 11. The filtrate was basified to a pH of about 9.3 with
concentrated ammonium hydroxide, to precipitate oxymorphone free
base.
[0583] 12. The resulting mixture was stirred at room temperature
for 1 hour.
[0584] 13. The resulting mixture was then filtered, washed with
water (3.times.15 mL), and dried in a vacuum oven at 80.degree. C.
for 16 hours to yield 2.04 g of solid.
[0585] 14. Analysis of the solid by the HPLC method of Example 11A
showed an HPLC peak area ratio of
oxymorphone:14-hydroxymorphinone:8-hydroxyoxymorphone of
15,803,069:1,845:25,714. The oxymorphone base comprised 96.03% of
the composition (based on HPLC area percent), 14-hydroxymorphinone
comprised 117 ppm of the composition (based on HPLC area percent),
and 8-hydroxyoxymorphone comprised 1627 ppm of the composition
(based on HPLC area percent). The auto-scaled chromatogram and peak
results from this analysis are depicted in FIG. 1.
[0586] About 14.5 molar equivalents of total acid per molar
equivalent of oripavine were used in this example (13.7 molar
equivalents of HCO.sub.2H, 0.81 molar equivalents of
H.sub.2SO.sub.4). The molar ratio of sulfuric acid to formic acid
was about 1:17.2. No precipitation was observed up to step 11. A
molar excess of formic acid was present during the
hydrogenation.
Comparative Example 2
Preparation of Oxymorphone Free Base According to Example 3 of WO
2008/130553
##STR00040##
[0588] Example 3 from WO 2008/130553 was repeated as follows.
[0589] 1. Into a 100 mL reaction vessel equipped with a temperature
probe, overhead stirrer and reflux condenser, oripavine (3.01 g,
10.1 mmol) was charged as a slurry in deionized water (9 mL).
[0590] 2. The reaction mixture was stirred at 300 rpm, while
maintaining an internal temperature of 20.degree. C.
[0591] 3. Formic acid (88%, 6 mL, 139.9 mmol) was added into the
reaction. Upon the addition, the solids readily dissolved into
solution. During the formic acid addition, the temperature of the
reaction mixture increased to 30.degree. C.
[0592] 4. After the solution temperature had cooled to 20.degree.
C., 35% hydrogen peroxide (1.06 mL, 15.8 mmol) and sulfuric acid
(0.45 mL, 8.15 mmol) were added to the reaction.
[0593] 5. The reaction was stirred (300 rpm) at 20.degree. C. for
16 hours, until the oripavine had been consumed according to the
HPLC analysis of Example 11A.
[0594] 6. 0.30 g of 5% palladium on carbon was charged into the
reaction mixture, and the mixture was stirred at 20.degree. C. for
30 minutes.
[0595] 7. Triethylamine (8.8 mL, 63.1 mmol) was added to the
reaction mixture, and the reaction mixture was heated to 45.degree.
C. and stirred at 45.degree. C. for 2 hours.
[0596] 8. The mixture was heated to 80.degree. C. and stirred at
80.degree. C. for an additional 8 hours.
[0597] 9. The reaction was then cooled to 20.degree. C. and stirred
at 20.degree. C. for 8 hours. No solid precipitation was observed
at this temperature.
[0598] 10. The reaction mixture was filtered through a plug of
celite.
[0599] 11. The filtrate was basified to pH=9.25 with concentrated
ammonium hydroxide, and the precipitated composition was allowed to
stir at room temperature for 1 hour.
[0600] 12. The precipitated composition was then filtered, washed
with water (3.times.15 mL) and dried in a vacuum oven at 80.degree.
C. for 16 hours to yield 1.33 g of precipitate.
[0601] 13. Analysis of the precipitate by the HPLC method of
Example 11A showed an HPLC peak area ratio of
oxymorphone:14-hydroxymorphinone:8-hydroxyoxymorphone of
13,906,304:2,146:46,937. In other words, the oxymorphone base
comprised 94.94% of the composition (based on HPLC area percent),
14-hydroxymorphinone comprised 154 ppm of the composition (based on
HPLC area percent), and 8-hydroxyoxymorphone comprised 3377 ppm of
the composition (based on HPLC area percent). The auto-scaled
chromatogram and peak results from this analysis are depicted in
FIG. 2.
[0602] About 14.7 molar equivalents of total acid per molar
equivalent of oripavine were used in this example. The molar ratio
of sulfuric acid to formic acid was about 1:17.2. No precipitation
was observed up to step 11. A molar excess of formic acid was
present during the hydrogenation.
Comparative Example 3
Preparation of 14-Hydroxymorphinone from Oripavine Without Sulfuric
Acid
##STR00041##
[0604] 1. Oripavine (99.99 g, 336 mmol) was charged as a slurry in
deionized water (150 mL) into a 500 mL jacketed vessel.
[0605] 2. The slurry was stirred (250 rpm) at ambient reaction
temperature (approximately 25.degree. C.).
[0606] 3. Formic acid (100 mL, 2332 mmol, 88%) was added to the
mixture in one portion. The solids completely dissolved upon the
addition, and a slight exothermic reaction was observed
(temperature increase to approximately 34.degree. C.). The solution
was then allowed to cool back to ambient temperature (approximately
25.degree. C.).
[0607] 4. While holding the temperature at approximately 25.degree.
C., hydrogen peroxide (31.2 mL, 363 mmol, 35%, M=11.86) was added
to the solution at a controlled rate of 1.56 mL/minute (0.05
equivalents/minute).
[0608] 5. After addition was complete, the solution was allowed to
stir an additional 30 minutes at ambient temperature.
[0609] 6. The solution was then heated to 48.degree. C. and held at
this temperature for about 3.5 hours, and sampled by HPLC for
reaction completion.
[0610] 7. After approximately 3.5 hours of stirring at 48.degree.
C., the solution was cooled to 10.degree. C. over 35 minutes.
[0611] 8. The solution was held at 10.degree. C. for approximately
16 hours, and analyzed by HPLC. A sample was shown to contain
97.04% (based on HPLC area percent) 14-hydroxymorphinone, 5200 ppm
(based on HPLC area percent) oripavine, and 10900 ppm (based on
HPLC area percent) 8-hydroxyoxymorphone.
[0612] 9. The solution was then utilized for subsequent
hydrogenation in Example 4.
Comparative Example 4
Preparation of Oxymorphone from 14-Hydroxymorphinone
##STR00042##
[0614] 1. 5% Palladium on carbon (0.60 g) was charged into a 1 L
ZipperClave.RTM. autoclave high pressure reaction vessel, followed
by the solution prepared in Example 3.
[0615] 2. Deionized water (100 mL) and formic acid (100 mL, 88%,
2332 mmol) were added into the reaction solution in one
portion.
[0616] 3. The vessel was sealed and hydrogenated at 60 psia (413.69
kPa), 55.degree. C., for 3 hours and 10 minutes.
[0617] 4. The solution was vented and purged with nitrogen 3
times.
[0618] 5. A sample of the solution was analyzed by HPLC for
reaction completion.
[0619] 6. The palladium on carbon was removed from the solution by
filtration through 2 layers of filter paper and the filtrate was
stored in a refrigerator at approximately 5.degree. C.
overnight.
[0620] 7. The filtrate was transferred to a cooled 1 L jacketed
vessel (0-5.degree. C.).
[0621] 8. 50% sodium hydroxide was added into the cooled solution
at a rate such that the temperature of the solution did not exceed
20.degree. C., until a final pH in a range from 9.0 to 9.25 was
achieved.
[0622] 9. The resulting solids were stirred at 5.degree. C. for an
additional 30 minutes before being filtered by vacuum filtration
through a paper filter (Whatman#2).
[0623] 10. The resulting solid material was slurry washed with
deionized water (3.times.200 mL) and further dried by vacuum on the
filter for 1 hour, before being transferred to a vacuum oven and
dried at 40.degree. C. under house vacuum (.about.28 mmHg (3.73
kPa)). The solid material was analyzed by HPLC. The analysis showed
that the solid material contained 95.96% oxymorphone, based on HPLC
area percent, 3100 ppm 14-hydroxymorphinone, based on HPLC area
percent, and 19600 ppm 8-hydroxyoxymorphone, based on HPLC area
percent.
[0624] About 6.94 molar equivalents of formic acid per molar
equivalent of oripavine were used in Example 3, i.e. during the
oxidation. No sulfuric acid was used. No precipitation was observed
up to step 8 of Example 4. A molar excess of formic acid was
present during the hydrogenation.
Comparative Example 5
Preparation of 14-Hydroxymorphinone Sulfate
##STR00043##
[0626] 1. Oripavine (30.0 g, 101 mmol) was charged as a slurry in
deionized water (45 mL) into a 300 mL jacketed vessel, overhead
stirred and equipped with a temperature probe and an addition
funnel.
[0627] 2. The jacket temperature for the vessel was set to
22.degree. C., and the slurry was stirred at 500 rpm.
[0628] 3. Formic acid (30 mL, 700 mmol) was added into the vessel.
The solids readily dissolved into solution upon addition of formic
acid. During the formic acid addition, the temperature of the
reaction mixture increased to 30.degree. C.
[0629] 4. Sulfuric acid (2.5 mL, 45 mmol) was added to the
solution, and the solution was stirred at 500 rpm.
[0630] 5. After the solution temperature had cooled below
25.degree. C., hydrogen peroxide (10.25 mL, 119 mmol) was added to
the reaction through the addition funnel at a rate of 0.17
mL/minute.
[0631] 6. After the hydrogen peroxide addition was complete, an
additional 5 mL of deionized water was added to the reaction
through the addition funnel, and the reaction solution was allowed
to stir (500 rpm) at 22.degree. C., and the reaction progress was
monitored by HPLC. After stirring for 20 hours, approximately
15-20% of the oripavine was still present in the reaction mixture,
based on HPLC area %.
[0632] 7. The reaction mixture was heated to 30.degree. C. and an
additional 1.5 mL (17 mmol) of hydrogen peroxide was added to the
reaction in one portion, to increase conversion of oripavine
(greater than 99% conversion, as determined by HPLC).
[0633] 8. The reaction mixture was stirred (500 rpm) at 30.degree.
C. for an additional 16 hours.
[0634] 9. Sulfuric acid (0.35 mL, 6.3 mmol) was added into the
reaction, and the solution was stirred (500 rpm) for 10
minutes.
[0635] 10. Methanol (60 mL) was added into the reaction mixture,
and the rate of stirring was reduced to 200 rpm.
[0636] 11. The reaction mixture was cooled to 15.degree. C. over
2.5 hours. Upon cooling, solids precipitated out of the solution
forming a suspension.
[0637] 12. The resulting suspension was stirred (200 rpm) at
15.degree. C. for an additional 1 hour.
[0638] 13. The solids were filtered under vacuum using a Buchner
funnel, with Whatman# 1 filter paper, and the solids were collected
and washed with methanol (2.times.60 mL). A sample of the solids
was analyzed by the HPLC method of Example 11A, and was shown to
contain 14-hydroxymorphinone with 349 ppm of 8-hydroxyoxymorphone
(based on HPLC area percent).
[0639] 14. The solids were dried under vacuum on the Buchner funnel
for 30 minutes, before being transferred to a drying oven and dried
under vacuum to a constant weight. The solids contained 18.09 g (26
mmol (calculated without water of crystallization), 51.5% yield) of
14-hydroxymorphinone sulfate as fine yellow crystals, containing
349 ppm of 8-hydroxyoxymorphone (based on HPLC area percent in
relation to 14-hydroxymorphinone).
[0640] 15. To see whether the yield can be increased, the filtrate
and methanol washes were returned to the jacketed vessel and
tert-butyl methyl ether (60 mL) was added to the mixture. Upon
addition of the tert-butyl methyl ether, solids precipitated out of
the reaction mixture. The mixture was stirred at 200 rpm and heated
to 55.degree. C.
[0641] 16. After the solids had completely dissolved, the solution
was gradually cooled to 20.degree. C. over 3 hours. The mixture was
stirred (200 rpm) at 20.degree. C. for an additional 48 hours. Upon
cooling and stirring, solids precipitated.
[0642] 17. The solids were filtered under vacuum using a Buchner
funnel, with Whatman# 2 filter paper, washed with tert-butyl methyl
ether (60 mL) and dried under vacuum on the Buchner funnel for 30
minutes, before being transferred to a drying oven and dried under
vacuum to a constant weight. The solids contained 5.60g (8 mmol
(calculated without water of crystallization), 15.8% yield) of
14-hydroxymorphinone sulfate as tan crystals. The composition of
the tan crystals was substantially the same as the composition of
the yellow crystals isolated initially, except that it contained
2051 ppm, based on HPLC area percent, of 8-hydroxyoxymorphone.
[0643] About 7.4 molar equivalents of total acid per molar
equivalent of oripavine were used in this example. The molar ratio
of sulfuric acid to formic acid was about 1:13.6. Precipitation was
observed in step 11.
Comparative Example 6
Preparation of Oxymorphone Free Base
##STR00044##
[0645] 1. 14-Hydroxymorphinone sulfate (11.95 g, 17.2 mmol
(calculated without water of crystallization)) (i.e., solids from
the first isolation of Example 5 (yellow crystals)), deionized
water (120 mL) and methanol (48 mL) were charged into a 250 mL
flask equipped with a magnetic stir bar. The majority of solids did
not dissolve into solution at room temperature.
[0646] 2. Formic acid (1.50 mL, 40 mmol) was added to the mixture,
and the mixture was stirred vigorously at 22.degree. C. After 30
minutes of stirring at 22.degree. C., a large portion of the solid
material remained insoluble.
[0647] 3. The mixture was transferred from the flask to a high
pressure reaction vessel equipped with a magnetic stir bar. Into
the vessel was charged 5% palladium on carbon (0.091 g) and the
vessel was sealed.
[0648] 4. The mixture was stirred at 750 rpm and heated to
40.degree. C. The mixture was hydrogenated at 60 psia (413.69 kPa)
for 6 hours.
[0649] 5. The reaction was vented, purged with nitrogen, vented and
hydrogenated at 60 psia (413.69 kPa) for an additional 3 hours.
[0650] 6. The reaction was vented, purged with nitrogen and cooled
to 22.degree. C. over 8 hours.
[0651] 7. The reaction mixture was filtered through filter paper to
remove the palladium on carbon and the filtrate was sampled for
HPLC analysis. The solution pH was 2.75. Analysis by the HPLC
method of Example 11A showed that the sample contained oxymorphone
free base with 72 ppm of 8-hydroxyoxymorphone (based on HPLC area
percent in relation to oxymorphone free base) and 62 ppm of
14-hydroxymorphinone (based on HPLC area percent).
[0652] 8. While stirring at 200 rpm, the solution was basified by
adding 7 mL of 28% ammonium hydroxide to the filtrate solution;
solids precipitated out of solution during the ammonium hydroxide
addition and the final pH of the mixture was 9.06. Solids were
isolated, dried at room temperature under vacuum and sampled by the
HPLC method of Example 11A. Analysis by HPLC showed that the solid
sample contained oxymorphone free base with 33 ppm of
8-hydroxyoxymorphone (based on HPLC area percent) and 17 ppm of
14-hydroxymorphinone (based on HPLC area percent).
[0653] 9. The mixture was allowed to stir (200 rpm) at 22.degree.
C. for an additional 30 minutes.
[0654] 10. The solids were filtered under vacuum using a Buchner
funnel, with Whatman# 2 filter paper, washed with water (2.times.12
mL) and dried under vacuum on the Buchner funnel for 30 minutes,
before being transferred to a drying oven and dried under vacuum to
a constant weight at 80.degree. C. for 16 hours. The solids
contained 7.89 g (26.2 mmol, 76% yield) of oxymorphone (base) as a
white crystalline powder, 52 ppm of 8-hydroxyoxymorphone and 41 ppm
of 14-hydroxymorphinone, based on the HPLC method of Example
11A.
[0655] About 7.4 molar equivalents of total acid per molar
equivalent of oripavine were used in Example 5, i.e. during the
oxidation. The molar ratio of sulfuric acid to formic acid was
about 1:13.6 during oxidation. A molar excess of formic acid was
present during the hydrogenation.
Synthetic Example 7
Preparation of 14-Hydroxymorphinone Sulfate
##STR00045##
[0657] 14-Hydroxymorphinone sulfate was prepared as follows:
[0658] 1. Into a 100 mL reaction vessel equipped with a temperature
probe, overhead stirrer and reflux condenser, oripavine (3.02 g,
10.2 mmol) was charged as a slurry in deionized water (9 mL).
[0659] 2. The reaction mixture was stirred at 300 rpm, while
maintaining an internal temperature of 20.degree. C.
[0660] 3. Into the reaction was added 88% formic acid (6 mL, 139.9
mmol), and the solids readily dissolved into solution. During the
formic acid addition, the temperature of the reaction mixture
increased to 30.degree. C.
[0661] 4. After the solution temperature had cooled to 20.degree.
C., 35% hydrogen peroxide (1.06 mL, 15.8 mmol) and sulfuric acid
(0.45 mL, 8.15 mmol) were added to the reaction.
[0662] 5. The reaction was stirred (300 rpm) at 20.degree. C. for
16 hours.
[0663] 6. Stirring of the mixture was reduced to 75 rpm and the
mixture was cooled to 0.degree. C. over 1 hour. Solids began
precipitating out of solution after the temperature of the mixture
reached 15.degree. C.
[0664] 7. The mixture was stirred for an additional 1 hour at
0.degree. C. The solids were filtered under vacuum using a Buchner
funnel with Whatman #1 filter paper, and the filtered solids were
washed with tert-butyl methyl ether (3.times.15 mL).
[0665] 8. Additional solids precipitated out of the filtrate after
the tert-butyl methyl ether washes were combined with the filtrate.
These solids were also filtered under vacuum using a Buchner funnel
with Whatman #1 filter paper.
[0666] 9. The two batches of solids were dried separately under
vacuum on the Buchner funnel for 1 hour.
[0667] 10. The solids were further dried in a vacuum oven at
80.degree. C. for 16 hours.
[0668] 11. Isolated: 0.09 g of solid (14-hydroxymorphinone sulfate)
from the first filtration with an HPLC peak area ratio of
14-hydroxymorphinone:8-hydroxyoxymorphone equal to 6,340,697:312
(49.2 ppm of 8-hydroxyoxymorphone), based on the HPLC method of
Example 11A. The auto-scaled chromatograph of the sample is
depicted in FIG. 3 of PCT/IB2013/001541.
[0669] 12. Isolated: 2.33 g of solid from the second filtration
with an HPLC peak area ratio of
14-hydroxymorphinone:8-hydroxyoxymorphone equal to 5,672,733:1,561
(275 ppm 8-hydroxyoxymorphone, based on HPLC area percent), based
on the HPLC method of Example 11A. The auto-scaled chromatograph of
the sample is depicted in FIG. 4 of PCT/IB2013/001541.
[0670] About 14.5 molar equivalents of total acid per molar
equivalent of oripavine were used in this example. The molar ratio
of sulfuric acid to formic acid was about 1:17.1. Precipitation was
observed in step 6.
Synthetic Example 8
Preparation of 14-Hydroxymorphinone Sulfate
##STR00046##
[0672] 14-Hydroxymorphinone sulfate was prepared as follows:
[0673] 1. Into a 100 mL jacketed vessel equipped with a temperature
probe, overhead stirrer and an addition funnel, oripavine (20.0 g,
67.4 mmol) was charged as a slurry in deionized water (30 mL).
[0674] 2. The jacket temperature for the vessel was set to
20.degree. C. and the slurry was stirred at 300 rpm.
[0675] 3. 88% formic acid (10 mL, 232 mmol) was added into the
reaction mixture. The solids readily dissolved into solution upon
this addition. During the formic acid addition, the temperature of
the reaction mixture increased to 30.degree. C.
[0676] 4. Sulfuric acid (2.0 mL, 36 mmol) was added to the
solution, and the solution was stirred at 300 rpm.
[0677] 5. After the solution temperature had cooled below
25.degree. C., 35% hydrogen peroxide (7.00 mL, 81.4 mmol) was added
to the reaction over 15 minutes, using the addition funnel.
[0678] 6. After the peroxide addition was complete, an additional 3
mL of deionized water was added to the reaction through the
addition funnel.
[0679] 7. The reaction solution was allowed to stir (300 rpm) at
20.degree. C. for 20 minutes.
[0680] 8. The reaction was then heated to 30.degree. C. and held at
30.degree. C., while stirring at 300 rpm for 8 hours.
[0681] 9. The reaction mixture was then cooled to 20.degree. C.
over 2 hours and stirred (300 rpm) for an additional 8 hours at
this temperature. Solids precipitated out of solution during the
cooling from 30.degree. C. to 20.degree. C.
[0682] 10. The resulting suspension was treated with 20 mL of
methanol and the suspension was stirred at 20.degree. C. for 30
minutes.
[0683] 11. The solids were filtered under vacuum using a Buchner
funnel with Whatman #1 filter paper, and the solids were washed
with methanol (2.times.20 mL).
[0684] 12. The solids were dried under vacuum on the Buchner funnel
for 1 hour, before being transferred to a drying oven and dried
under vacuum at 80.degree. C. for 16 hours.
[0685] 13. 7.19 g of solid (26 mmol (calculated without water of
crystallization) 14-hydroxymorphinone sulfate (73.2% yield)) was
isolated as fine yellow-white crystals and analyzed by the HPLC
method of Example 11A. Analysis showed an HPLC area ratio of
14-hydroxymorphinone:8-hydroxyoxymorphone of 8,873,042: 623. In
other words, the composition comprised 97.88% 14-hydroxymorphinone
(based on HPLC area percent) and 70 ppm 8-hydroxyoxymorphone (based
on HPLC area percent). The auto-scaled chromatograph and peak
results from this analysis are depicted in FIG. 5 of
PCT/IB2013/001541.
[0686] About 4.66 molar equivalents of total acid per molar
equivalent of oripavine were used in this example. The molar ratio
of sulfuric acid to formic acid was about 1:6.4. Precipitation was
observed in step 9.
[0687] As compared to the previous example (Example 7), less total
acid (formic acid plus sulfuric acid) was used (4.66 equivalents
vs. 14.5 equivalents), more sulfuric acid per formic acid was used
(1:6.4 vs. 1:17.1) and the conditions of the present reaction
resulted in better yield (73.2% vs. 67% 14-hydroxymorphinone
sulfate).
Comparative Example 9
Preparation of 14-Hydroxymorphinone Sulfate
##STR00047##
[0689] 14-Hydroxymorphinone sulfate was prepared as follows.
[0690] 1. Into an 80 mL reaction vessel equipped with a temperature
probe and magnetic stirrer, oripavine (10.0 g, 33.7 mmol) was
dissolved in deionized water (20 mL) and 88% formic acid (3.60 mL,
84.0 mmol).
[0691] 2. The solution was stirred (600 rpm) at 22.degree. C. for
15 minutes.
[0692] 3. Sulfuric acid (0.94 mL, 17 mmol) was added into the
reaction mixture, and the solution was stirred at 600 rpm. After
the solution temperature had cooled below 25.degree. C., 35%
hydrogen peroxide (3.20 mL, 37.2 mmol) was added to the reaction in
one portion.
[0693] 4. After the peroxide addition was complete, an additional 1
mL of deionized water was added to the reaction. The reaction
solution was allowed to stir (600 rpm) at 22.degree. C. for 60
minutes.
[0694] 5. The reaction was then heated to 30.degree. C. over 20
minutes and held at 30.degree. C., while stirring at 600 rpm for 16
hours.
[0695] 6. Solids started to precipitate out of solution while
stirring at 30.degree. C.
[0696] 7. The reaction mixture was then cooled to 22.degree. C.
[0697] 8. The resulting suspension was treated with 20 mL of
methanol and the suspension was stirred at 22.degree. C. for 5
minutes.
[0698] 9. The solids were filtered under vacuum using a Buchner
funnel with Whatman #1 filter paper, and the solids were washed
with methanol (2.times.10 mL).
[0699] 10. The solids were dried under vacuum on the Buchner funnel
for 30 minutes, before being transferred to a drying oven and dried
under vacuum at 80.degree. C. for 16 hours.
[0700] 11. 8.08 g (11.6 mmol (calculated without water of
crystallization), 68.8% yield) of 14-hydroxymorphinone sulfate was
isolated as fine yellow-white crystals. Analysis by the HPLC method
of Example 11A showed an HPLC area ratio of
14-hydroxymorphinone:8-hydroxyoxymorphone of 8,743,438:885. In
other words, the mixture contained 101 ppm 8-hydroxyoxymorphone.
The auto-scaled chromatograph and peak results from this analysis
are depicted in FIG. 6 of PCT/IB2013/001541.
[0701] About 3 molar equivalents of total acid per molar equivalent
of oripavine were used in this example. The molar ratio of sulfuric
acid to formic acid was about 1:5. Precipitation was observed in
step 6.
[0702] The resulting 14-hydroxymorphinone sulfate was used as
starting material in the subsequent Example 10.
Comparative Example 10
Preparation of Oxymorphone from 14-Hydroxymorphinone Sulfate
##STR00048##
[0704] 1. Into a 300 mL hydrogenation vessel equipped with a
magnetic stir bar, 14-hydroxymorphinone sulfate obtained in Example
9 above (7.03 g, 10.1 mmol (calculated without water of
crystallization)), deionized water (70 mL) and methanol (28 mL)
were charged. The majority of solids dissolved into solution.
[0705] 2. Formic acid (0.935 mL, 21.8 mmol) and 5% palladium on
carbon (0.053 g) were added into the reaction mixture.
[0706] 3. The vessel was sealed, stirred at 750 rpm and heated to
40.degree. C.
[0707] 4. The mixture was then hydrogenated at 60 psia (413.69 kPa)
for 5 hours.
[0708] 5. The reaction was vented, purged with nitrogen, vented and
hydrogenated at 60 psia (413.69 kPa) for an additional 1 hour.
[0709] 6. The reaction was vented, purged with nitrogen and cooled
to 22.degree. C. over 8 hours.
[0710] 7. The reaction mixture was filtered through filter paper to
remove the palladium on carbon and the filtrate was sampled for the
HPLC analysis of Example 11A. The results showed that less than 1%
14-hydroxymorphinone (free base) remained (by HPLC area %).
[0711] 8. The filtrate was transferred to a 250 mL Erlenmeyer flask
equipped with a magnetic stir bar and pH probe. The solution pH was
2.66.
[0712] 9. While stirring at 200 rpm, the solution was basified by
adding 5 mL of 28% ammonium hydroxide; solids precipitated out of
solution during the ammonium hydroxide addition and the final pH of
the mixture was 9.13.
[0713] 10. The mixture was allowed to stir (200 rpm) at 22.degree.
C. for an additional 45 minutes.
[0714] 11. The solids were filtered under vacuum using a Buchner
funnel with Whatman# 2 filter paper, and the solids were washed
with water (2.times.10 mL).
[0715] 12. The solids were dried under vacuum on the Buchner funnel
for 2 hours, before being transferred to a drying oven and dried
under vacuum to a constant weight.
[0716] 13. Isolated: 4.58 g (15.2 mmol, 75% yield) of oxymorphone
(base) as a white crystalline powder as analyzed by the HPLC method
of Example 11A. The HPLC area ratio of oxymorphone:
14-hydroxymorphinone:8-hydroxyoxymorphone was 39,612,808:231 (6
ppm):9,518 (240 ppm). In other words, the composition contained
98.54% oxymorphone base, 6 ppm 14-hydroxymorphinone, and 240 ppm
8-hydroxyoxymorphone, based on HPLC area percent. The auto-scaled
chromatograph and peak results from this analysis are depicted in
FIG. 3.
[0717] Over all, about 3.64 molar equivalents of total acid per
molar equivalent of oripavine were used in Examples 9 and 10. A
molar excess of formic acid was present during the
hydrogenation.
Example 11
HPLC Method
Example 11A
[0718] HPLC conditions for Examples 1 to 10 and 12 to 15 were as
follows: [0719] Instrument: Waters 2695 HPLC system with Waters 966
Photodiode Array Detector [0720] Column: Waters XBridge C18
(150.times.3.0 mm; 3.5 .mu.m) [0721] Mobile phase: [0722] Solution
A: 10 mMol (pH=10.2) ammonium bicarbonate in water [0723] Solution
B: methanol [0724] Flow rate: 0.30 mL/min [0725] UV detection: 292
nm [0726] Injection volume: 10 .mu.l of a 1 mg/mL sample solution.
Samples were prepared by weighing 10.+-.0.5 mg of sample and
quantitatively transferring it to a 10 mL volumetric flask. The
solids were dissolved in a 80:20 mixture of 0.085% phosphoric acid
in water:methanol. [0727] Column temperature: 30.degree. C. [0728]
Run Time: 42 minutes
[0729] Gradient Conditions (Linear Concentration Changes):
TABLE-US-00001 TABLE 1 Time Flow % A % B initial 0.30 90.0 10.0
1.00 0.30 90.0 10.0 5.00 0.30 78.0 22.0 16.00 0.30 60.0 40.0 22.00
0.30 53.0 47.0 26.00 0.30 48.0 52.0 31.90 0.30 25.0 75.0 32.20 0.30
90.0 10.0 42.00 0.30 90.0 10.0
[0730] A representative HLPC chromatogram showing all relevant
peaks is provided in FIG. 4. The components corresponding to the
peaks are given in Table 2.
TABLE-US-00002 TABLE 2 Peak Retention Components Abbreviations Time
RRT 14-Hydroxymorphinone N-Oxide FHM-N-Oxide 3.227 0.15
10-Hydroxyoxymorphone 10OH-OMN 10.767 0.50 8-Hydroxyoxymorphone
8OH-OMN 14.641 0.68 14-Hydroxymorphinone FHM 17.544 0.82
Hydromorphone Hydromorphone 19.120 0.89 Oxymorphone OMN 21.461 1.00
6.beta.-Oxymorphol 6bOH-OMN 22.485 1.04 6.alpha.-Oxymorphol
6aOH-OMN 23.451 1.09 Oripavine ORP 23.794 1.11
8,14-Dihydrooripavine 8,14-DHO 26.385 1.23 Oxycodone OXY 31.228
1.46
The relative retention time (RRT) was calculated in relation to
oxymorphone. [0731] Estimated LOD was 1 ppm, estimated LOQ was 3 to
5 ppm.
Example 11B
[0732] HPLC conditions for Examples 16 to 17 were as follows:
[0733] HPLC unit: Agilent 1100 series HPLC [0734] Detectors:
Agilent 1100 Series DAD UV detector [0735] HP 1100 MSD mass
detector [0736] Column: Waters XSelect C18, 150.times.3.0 mm, 3.5
.mu.m [0737] Mobile phase: [0738] Solution A: 10 mMol (pH=10.2)
ammonium bicarbonate in water [0739] Solution B: methanol [0740]
Flow rate: 0.30 mL/min [0741] UV detection: 292 nm [0742] Injection
volume: 5 .mu.l of a 1 mg/mL or 10 mg/mL sample solution. Samples
were prepared by weighing 100.+-.5 mg or 10.+-.0.5 mg of sample and
quantitatively transferring it to a 10 mL volumetric flask. The
solids were dissolved in a 80:20 mixture of 0.085% phosphoric acid
in water: methanol. [0743] Column temperature: 30.degree. C. [0744]
Run Time: 37 minutes
[0745] Gradient Conditions (Linear Concentration Changes):
TABLE-US-00003 TABLE 3 Time Flow % A % B initial 0.30 90.0 10.0
1.00 0.30 90.0 10.0 5.00 0.30 78.0 22.0 16.00 0.30 60.0 40.0 22.00
0.30 53.0 47.0 26.00 0.30 48.0 52.0 31.90 0.30 25.0 75.0 37.00 0.30
25.0 75.0
[0746] A representative HLPC chromatogram showing all relevant
peaks is provided in FIG. 5. The components corresponding to the
peaks are given in Table 4.
TABLE-US-00004 TABLE 4 Peak Retention Components Abbreviations mass
Time RRT 8-Hydroxyoxymorphone 8OH-OMN 317 + 1 15.36 0.69
14-Hydroxymorphinone FHM 299 + 1 18.31 0.82 14-Hydroxymorphine
6aOH-FHM 301 + 1 19.95 0.90 Oxymorphone OMN 301 + 1 22.25 1.00
6.alpha.-Oxymorphol 6aOH-OMN 303 + 1 24.41 1.10 Oripavine ORP 297 +
1 26.59 1.20
The relative retention time (RRT) was calculated in relation to
oxymorphone. [0747] Estimated LOD was 1 ppm, estimated LOQ was 3 to
5 ppm.
Synthetic Example 12
Preparation of 14-Hydroxymorphinone Sulfate
##STR00049##
[0749] 14-Hydroxymorphinone sulfate was prepared as follows:
[0750] 1. In a 250 mL 3-necked flask equipped with a temperature
probe and magnetic stirring bar, oripavine (10.0 g; 33.6 mmol) was
dissolved in de-ionized water (18 mL) and 98% formic acid (3.88 mL,
101 mmol). The solution warmed up to 25.degree. C. The solution was
stirred (500 rpm) at 21.degree. C. for 5 minutes.
[0751] 2. Concentrated sulfuric acid (96%, 1.01 mL, 18.2 mmol) was
added. The temperature rose to 35.degree. C. The mixture was
stirred (500 rpm) at 21.degree. C. for 20 min.
[0752] 3. Hydrogen peroxide (35 wt % in H.sub.2O, 3.61 mL, 42.16
mmol) was added and the solution stirred (500 rpm) for 30 minutes
at room temperature.
[0753] 4. The mixture was then heated to 35.degree. C. over 5
minutes and held at 35.degree. C. and stirred (500 rpm) for 48
hours. Solids started to precipitate during the stirring after 10
hours.
[0754] 5. To the resulting suspension was added 2-butanol (36 mL)
and the stirring continued for 30 min. The temperature decreased
from 35.degree. C. to 26.degree. C. during this time. The resulting
slurry was cooled to 4.degree. C. and rested at this temperature
for 2 hours.
[0755] 6. Filtration, washing with water:2-butanol (1:2, 12 mL) and
thorough drying in vacuo afforded 14-hydroxymorphinone sulfate
(10.5 g, 15.1 mmol (calculated without water of crystallization)
90% yield). No oripavine or 8-hydroxyoxymorphone was detectable by
HPLC.
[0756] About 3.54 molar equivalents of total acid per molar
equivalent of oripavine were used in this example. The molar ratio
of sulfuric acid to formic acid was about 1:5.5. Precipitation was
observed in step 4.
[0757] As compared to the previous examples (Examples 7 and 8),
less total acid (formic acid plus sulfuric acid) was used (3.54
equivalents vs. 14.5 equivalents and 4.66 equivalents), more
sulfuric acid per formic acid was used (1:5.5 vs. 1:17.1 and
1:6.4), and the conditions of the present reaction resulted in
better yield (90% vs. 67% and 73.2% 14-hydroxymorphinone
sulfate).
Synthetic Example 13
Preparation of 14-Hydroxymorphinone Sulfate
##STR00050##
[0759] 14-Hydroxymorphinone sulfate was prepared as follows:
[0760] 1. In a multi-neck flask equipped with a magnetic stir bar
and temperature probe, oripavine (9.96 g, 33.5 mmol) was dissolved
in de-ionized water (18 mL) and 98% formic acid (3.88 mL, 101
mmol). The resulting solution was stirred at ambient
temperature.
[0761] 2. Concentrated sulfuric acid (96%, 0.92 mL, 16.8 mmol) was
added and the mixture stirred at 450 rpm for 10 minutes. After
addition of the sulfuric acid, the mixture heated to more than
30.degree. C., then cooled again.
[0762] 3. When the temperature of the solution had dropped below
25.degree. C., hydrogen peroxide (35 wt % in H.sub.2O, 3.8 mL, 44
mmol) was added and the solution stirred at 450 rpm for 20 minutes
at room temperature.
[0763] 4. The mixture was then stirred at 35.degree. C. internal
temperature for 48 hours.
[0764] 5. To the warm mixture was added 2-butanol (36 mL) and the
stirring continued for 30 min. The resulting slurry was cooled to
4.degree. C. and rested at this temperature for 2 hours.
[0765] 6. Filtration, washing with water: 2-butanol (1: 2, 12 mL)
and thorough drying in vacuo afforded 14-hydroxymorphinone sulfate
(9.94 g, 14.3 mmol (calculated without water of crystallization)
85.4% yield). No oripavine or 8-hydroxyoxymorphone was detectable
by HPLC.
[0766] About 3.5 molar equivalents of total acid per molar
equivalent of oripavine were used in this example. The molar ratio
of sulfuric acid to formic acid was about 1:6.
[0767] In this example, 0.5 equivalents H.sub.2SO.sub.4 were used.
As in Example 12 (where 0.55 equivalents H.sub.2SO.sub.4 were
used), compared to the previous examples (Examples 7 and 8), less
total acid (formic acid plus sulfuric acid) was used (3.5
equivalents vs. 14.5 equivalents and 4.66 equivalents), more
sulfuric acid per formic acid was used (1:6 vs. 1:17.1 and 1:6.4),
and the conditions of the present reaction resulted in better yield
(85.4% vs. 67% and 73.2% 14-hydroxymorphinone sulfate).
Synthetic Example 14
Preparation of 14-Hydroxymorphinone Sulfate
##STR00051##
[0769] 14-Hydroxymorphinone sulfate was prepared using two
different amounts of water as follows:
[0770] 1. In a multi-neck flask equipped with a magnetic stir bar
and temperature probe, oripavine (10.4 g, 35.0 mmol) was dissolved
in de-ionized water (16 or 20 mL, respectively) and 98% formic acid
(3.88 mL, 101 mmol). The resulting solution was stirred at ambient
temperature (500 rpm).
[0771] 2. Concentrated sulfuric acid (96%, 1.02 mL, 18.5 mmol) was
added and the mixture stirred at 500 rpm for 20 minutes. After
addition of the sulfuric acid, the mixture heated to more than
30.degree. C., then cooled again.
[0772] 3. When the temperature of the solution had dropped below
25.degree. C., hydrogen peroxide (35 wt % in H.sub.2O, 3.62 mL, 42
mmol) was added and the solution stirred at 500 rpm for 30 minutes
at room temperature.
[0773] 4. The mixture was then stirred (750 rpm) at 35.degree. C.
internal temperature for 48 hours.
[0774] 5. To the warm mixture was added 2-butanol (36 mL) and the
stirring continued for 30 min. The resulting slurry was cooled to
4.degree. C. and rested at this temperature for 2 hours.
[0775] 6. Filtration, washing with water:2-butanol (1:2, 12 mL) and
thorough drying in vacuo afforded 14-hydroxymorphinone sulfate
(9.90 g, 14.21 mmol (calculated without water of crystallization)
81.2% yield for 16 mL water; 10.14 g, 14.56 mmol (calculated
without water of crystallization) 83.2% yield for 20 mL water). No
oripavine or 8-hydroxyoxymorphone was detectable by HPLC.
[0776] This Example shows the same advantages as pointed out in
Example 12. Moreover, it shows that in addition to the 1.8 mL water
per g oripavine as used in Example 12, 1.5 and 1.9 mL water per g
oripavine can also advantageously be used.
Synthetic Example 15
Preparation of 14-Hydroxymorphinone Sulfate
##STR00052##
[0778] 14-Hydroxymorphinone sulfate was prepared as follows:
[0779] 1. In a multi-neck flask equipped with a magnetic stir bar
and temperature probe, oripavine (10.04 g, 33.8 mmol) was dissolved
in de-ionized water (18 mL) and 98% formic acid (3.88 mL, 101
mmol). The resulting solution was stirred (500 rpm) at ambient
temperature.
[0780] 2. Concentrated sulfuric acid (96%, 1.02 mL, 18.5 mmol) was
added and the mixture stirred for about 20 minutes. After addition
of the sulfuric acid, the mixture heated to more than 30.degree.
C., then cooled again.
[0781] 3. When the temperature of the solution had dropped below
25.degree. C., hydrogen peroxide (35 wt % in H.sub.2O, 3.46 mL,
40.1 mmol, corresponding to 1.2 eq.) was added and the solution
stirred for 30 minutes at room temperature.
[0782] 4. The mixture was then stirred at 35.degree. C. internal
temperature for 48 hours.
[0783] 5. To the warm mixture was added 2-butanol (36 mL) and the
stirring continued for 30 min. The resulting slurry was cooled to
4.degree. C. and rested at this temperature for 2 hours.
[0784] 6. Filtration, washing with water:2-butanol (1:2, 12 mL) and
thorough drying in vacuo afforded 14-hydroxymorphinone sulfate
(10.07 g, 14.5 mmol (calculated without water of crystallization)
85.8% yield). No oripavine or 8-hydroxyoxymorphone was detectable
by HPLC.
[0785] As in Example 12 (where 1.25 equivalents of hydrogen
peroxide were used), compared to the previous examples (Examples 7
and 8), less total acid (formic acid plus sulfuric acid) was used
(3.55 equivalents vs. 14.5 equivalents and 4.66 equivalents), more
sulfuric acid per formic acid was used (1:5.5 vs. 1:17.1 and
1:6.4), and the conditions of the present reaction resulted in
better yield (85.8% vs. 67% and 73.2% 14-hydroxymorphinone
sulfate).
Example 16
Hydrogenation of 14-Hydroxymorphinone Sulfate in the Presence of
Trifluoroacetic Acid and Propylene Glycol
##STR00053##
[0787] 14-hydroxymorphinone sulfate (23.05 g, 66.19 mmol free
14-hydroxymorphinone, containing 0.17% 8-hydroxyoxymorphone) and
Pd/C (70 mg, 5% Pd, 50% wet, Escat test kit 1471, Strem) were
suspended in a mixture of water (90 mL) and propylene glycol (60
mL) in a 3L flask. To this was added trifluoroacetic acid (2.0 mL,
26.12 mmol) and the mixture was hydrogenated with an overhead
mounted balloon of hydrogen (ambient pressure, 14.7 psia) for 20 h
at 34.degree. C. and 1100 rpm stirring with a stirring bar. HPLC
analysis according to Example 11B showed complete conversion. To
the mixture was added more Pd/C (70 mg, same batch as above) and
the hydrogenation was continued for 6 h at 34.degree. C. until the
result of the above mentioned HPLC analysis was known.
[0788] The mixture was filtered over Celite, washed with water (30
mL) and the filtrate basified with conc. aq. sodium hydroxide (30%
w/w, ca. 8.5 mL) to pH 9. After cooling to 5.degree. C. for 16h the
mixture was filtered and the solids washed with 65% 2-butanol/water
(2.times.30 mL), then 2-butanol (30 mL).
[0789] Drying in vacuo afforded oxymorphone (13.3 g, 67%) in 96.6%
purity (average of 3 analyses, 0.26% standard deviation). No
propylene glycol acetal, 14-hydroxymorphinone or
8-hydroxyoxymorphone were detectable in 1 mg/mL samples. Further
analysis of highly concentrated (10 mg/mL, out of linearity range)
samples detected no 8-hydroxyoxymorphone and no
14-hydroxymorphinone as well.
Example 17
Hydrogenation of 14-Hydroxymorphinone Sulfate in the Presence of
Trifluoroacetic Acid and Ethylene Glycol
##STR00054##
[0791] 14-hydroxymorphinone sulfate (4.72 g, containing 15% water,
11.51 mmol free 14-hydroxymorphinone) and Pd/C (17 mg, 5% Pd, 50%
wet, Escat test kit 1471, Strem) were suspended in a mixture of
water (17.3 mL) and ethylene glycol (11 mL) in a 250 mL flask. To
this was added trifluoroacetic acid (0.37 mL, 4.74 mmol) and the
mixture hydrogenated with an overhead mounted balloon of hydrogen
(ambient pressure, 14.7 psia) for 20 h at 30.degree. C. and 750 rpm
stirring with a stirring bar. HPLC analysis according to Example
11B showed complete conversion with 0.23% of formed ethylene glycol
acetal. The mixture was filtered over Celite, washed with water (5
mL) and the filtrate basified with conc. aq. sodium hydroxide (30%
w/w, ca. 1.5 mL) to pH 9-9.5. After cooling to 5.degree. C. for 2 h
the mixture was filtered and the solids washed with 20%
2-butanol/water (10 mL).
[0792] Drying in vacuo afforded oxymorphone (2.70 g, 8.97 mmol,
78%) in 99% purity. No ethylene glycol acetal, 14-hydroxymorphinone
or 8-hydroxyoxymorphone were detectable.
[0793] In the preceding specification, the invention has been
described with reference to specific exemplary embodiments and
examples thereof. It will, however, be evident that various
modifications and changes may be made thereto without departing
from the broader spirit and scope of the invention as set forth in
the claims that follow. The specification and drawings are
accordingly to be regarded in an illustrative manner rather than a
restrictive sense.
* * * * *