U.S. patent application number 16/352125 was filed with the patent office on 2019-08-22 for pharmaceutically acceptable salts and polymorphic forms of hydrocodone benzoic acid enol ester and processes for making same.
The applicant listed for this patent is KemPharm, Inc.. Invention is credited to Bindu Bera, Guochen Chi, Sven Guenther, Jaroslaw Kanski, Andrea K. Martin, Christal Mickle, Travis Mickle.
Application Number | 20190256522 16/352125 |
Document ID | / |
Family ID | 51492046 |
Filed Date | 2019-08-22 |
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United States Patent
Application |
20190256522 |
Kind Code |
A1 |
Mickle; Travis ; et
al. |
August 22, 2019 |
PHARMACEUTICALLY ACCEPTABLE SALTS AND POLYMORPHIC FORMS OF
HYDROCODONE BENZOIC ACID ENOL ESTER AND PROCESSES FOR MAKING
SAME
Abstract
Compositions comprising hydrocodone benzoic acid enol ester to
form novel prodrugs including hydrocodone benzoic acid enol ester
salts, and various polymorphs. Also provided are processes for the
preparation of hydrocodone benzoic acid enol ester salts, and
various polymorphs.
Inventors: |
Mickle; Travis; (Kissimmee,
FL) ; Guenther; Sven; (Coralville, IA) ;
Mickle; Christal; (Kissimmee, FL) ; Chi; Guochen;
(Coralville, IA) ; Kanski; Jaroslaw; (Blacksburg,
VA) ; Martin; Andrea K.; (Fincastle, VA) ;
Bera; Bindu; (Blacksburg, VA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
KemPharm, Inc. |
Celebration |
FL |
US |
|
|
Family ID: |
51492046 |
Appl. No.: |
16/352125 |
Filed: |
March 13, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15730885 |
Oct 12, 2017 |
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16352125 |
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14773628 |
Sep 8, 2015 |
9815844 |
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PCT/US2014/022716 |
Mar 10, 2014 |
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15730885 |
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61774756 |
Mar 8, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 489/04 20130101;
C07B 2200/13 20130101; A61K 31/485 20130101; C07D 489/02
20130101 |
International
Class: |
C07D 489/04 20060101
C07D489/04; C07D 489/02 20060101 C07D489/02; A61K 31/485 20060101
A61K031/485 |
Claims
1-83. (canceled)
84. A process for the preparation of benzhydrocodone enol ester
comprising the steps of: (a) preparing a mixture comprising
hydrocodone free base and a benzoylating reagent, and, (b) heating
the mixture to a temperature in the range of about 80.degree. C. to
about 160.degree. C.
85. The process of claim 84, wherein the benzoylating reagent is
selected from the group consisting of benzoic anhydride or benzoyl
chloride.
86. The process of claim 84, wherein the mixture further comprises
a suitable organic solvent.
87. The process of claim 86, wherein the suitable organic solvent
is selected from the group consisting of toluene,
dimethylformamide, N-methyl-2-pyrrolidinone, and xylenes.
88. The process of claim 87, wherein the suitable organic solvent
is toluene.
89. A process for the preparation of benzhydrocodone comprising the
steps of: (a) preparing a mixture comprising hydrocodone free base,
benzoic anhydride, and toluene and, (b) heating the mixture to a
temperature in the range of about 80.degree. C. to about
160.degree. C.
90. The process of claim 88 or 89, wherein the toluene is
substantially removed from the mixture via step b.
91. The process of claim 84, 88, or 89, wherein the temperature of
step (b) is in the range of about 126.degree. C. to about
132.degree. C.
92. The process of claim 84, 88, or 89 wherein the mixture further
comprises a suitable base.
93. The process of claim 92, wherein the suitable base is selected
from the group consisting of pyridine, N,N-diisopropylethylamine,
diazabicycloundecene, trimethylamine, and potassium benzoate.
94. The process of claim 84, 88, or 89 further comprising adding
concentrated hydrochloric acid to the mixture.
95. A pharmaceutical composition comprising a therapeutically
effective amount of a benzhydrocodone enol ester prepared according
to the process of claim 84, 88, or 89 and a pharmaceutically
acceptable excipient.
Description
FIELD OF THE INVENTION
[0001] The present disclosure relates to pharmaceutically
acceptable salts and polymorphic forms of hydrocodone benzoic acid
enol ester. The disclosure further relates to processes for making
the salts and polymorphic forms of hydrocodone benzoic acid enol
ester,
BACKGROUND OF THE INVENTION
[0002] Hydrocodone benzoic acid enol ester is an opiate prodrug
that is useful for overdose prevention. Previous processes for the
preparation of hydrocodone benzoic acid enol esters require the
isolation of pure hydrocodone from hydrocodone bitartrate before
preparation of the benzoic acid enol ester. Such processes are
inefficient and expensive. Another drawback to prior art processes
is th difficulty in preparing a high quality product. Thus, there
remains a need for new processes for making hydrocodone benzoic
acid enol esters.
SUMMARY OF THE INVENTION
[0003] In one embodiment, the present disclosure provides a
substantially pure compound comprising hydrocodone benzoic acid
enol ester having a level of impurities less than about 10% to
0.1%. For example, the impurities can be, for example, less than
10% (purity of 90%), less than 5% (purity of 95%), less than 2,0%
(purity of 98%), less than 1.0% (purity of 99%), less than 0.5%
(purity of 99.5%), less than 0.1% (purity of 99.9%). In one aspect
of this embodiment, the level of impurities is less than 0.1%. In
another aspect of this embodiment, the impurities include
hydrocodone and benzoic acid.
[0004] In another embodiment, the compound may be part of a
pharmaceutical composition, such as but not limited to any
pharmaceutically acceptable salt of hydrocodone benzoic acid enol
ester. According to this aspect, the pharmaceutically acceptable
salt may be selected from the group consisting of hydrochloride,
hydrobromide, hydrogensulphate, sulphate, malcate, fumarate,
oxalate, methanesulfonate, succinate, ascorbate, and tartrate.
However, other suitable salts can be used as would be known by one
of ordinary skill in the art. Other embodiments of the invention
further include polymorphic forms of hydrocodone benzoic acid enol
ester hydrochloride such as Forms I, II, III, IV, V, or a
combination thereof. In yet another embodiment, a pharmaceutical
composition may comprise a polymorphic form of hydrocodone benzoic
acid enol ester hydrochloride, such as Form I, II, III, IV, V, or a
combination thereof.
[0005] In accordance with other embodiments, various polymorphic
forms of hydrocodone benzoic acid enol ester hydrochloride are
described. The polymorphic form may be one of Form I, II, III, IV,
or V, or alternatively may be a combination thereof.
[0006] In some embodiments, polymorphic Form I can have an XRPD
pattern having XRPD peaks at about the following 2.theta. values:
6.16, 9.05,10.95, 11.91, 12.32, 13.16, 14.60, 14.94, 17.04, 17.23,
17.80, 18.57, 19.18, 20.66, 21.10, 22.15, 23.50, 26.07, and 28.39.
Polymorphic Form II can have an XRPD pattern having XRPD peaks at
about the following 2.theta. values: 4.31, 8.62, 12.95, 13.19,
13.42, 14.33, 14.97, 15.72, 17.48, 18.47, 21.73, 22.92, 24.15,
24.98, 26.41, 26.53, 26.62, 27.93, and 30.46, Polymorphic Form III
can have an XRPD pattern having XRPD peaks at about the following
2.theta. values: 4.35, 8.68, 13.01, 13.27, 13.86, 14.06, 15.05,
16.02, 18.40, 21.72, 22.38, and 26,14, Polymorphic Form IV can have
an XRPD pattern having XRPD peaks at about the following 2.theta.
values: 7.87, 10.27, 11.87, 12.56, 13.18, 14.19, 15.34, 16.77,
17.67, 18.58, 19.50, 20.30, and 21.31. Polymorphic Form V can have
an XRPD pattern having XRPD peaks at about the following 2.theta.
values: 6.17, 7,50, 9.04, 10.96, 11.93, 12.34, 12.64, 13.13, 14.34,
14.62, 14.93, 16.73, 17.04, 17.22, 17.81, 18.59, 18.98, 19.19,
19.52, 20.67, 21.10, 21.91, 22.15, 22.82, 23.49, 25.03, 25.37,
26.09, and 26.43.
[0007] In another aspect, a solid pharmaceutical composition
comprising a therapeutically effective amount of one or more
polymorphic forms of hydrocodone benzoic acid enol ester
hydrochloride and a pharmaceutically acceptable excipient in a
formulation for administration is provided. In one embodiment, the
formulation can be designed for oral administration. Accordingly,
the solid pharmaceutical composition can be a coated or uncoated
tablet, a hard or soft gelatin capsule, a sugar-coated pill, a
lozenge, a wafer sheet, a pellet, or a powder. As would be
appreciated by one of ordinary skill in the art, however,
formulations comprising therapeutically effective amounts of the
polymorphic forms disclosed herein may also be designed for other
routes of administration. In one aspect of this embodiment, the
composition may consist of a pure polymorphic form.
[0008] In another aspect, the disclosed subject matter is directed
to a process for preparing polymorphic forms of hydrocodone benzoic
acid enol ester hydrochloride. In one embodiment, hydrocodone
benzoic acid enol ester hydrochloride is prepared by
recrystallizing hydrocodone benzoic acid enol ester hydrochloride
from an organic solvent in the presence of water. In one
embodiment, the process produces polymorphic Form I. For example,
polymorphic Form I is formed in instances where the molar ratio of
water to hydrocodone benzoic acid enol ester hydrochloride is at
least about 0.5, such as about 0.5, 1.0, or more.
[0009] In accordance with the process, the organic solvent may be
alcohol, an ether, or ester. For example, the solvent can be
selected from ethanol, tert-butyl methyl ether, or ethyl acetate,
or a combination thereof.
[0010] In another embodiment, the hydrocodone benzoic acid enol
ester hydrochloride is recrystallized in an organic solvent
containing less than 0.2% water to form polymorphic Form II. The
organic solvent may be anhydrous. For example, the solvent may be
isopropanol, isopropyl acetate, or a mixture of the two.
[0011] In yet another embodiment, polymorphic Form II can be
employed to form polymorphic forms III, IV, and V. For example,
hydrocodone benzoic acid enol ester hydrochloride Form II can be
heated at a temperature of between about 210.degree. C. and about
230.degree. C. to create polymorphic Form III. In another
embodiment, hydrocodone benzoic acid enol ester hydrochloride Form
II can be exposed to a high relative humidity for a period of time
to create Form IV. In one embodiment, the relative humidity is from
about 75% to about 100%. Hydrocodone benzoic acid enol ester
hydrochloride Form III can be exposed to a high relative humidity
for a period of time to create Form V. The relative humidity may be
between about 75% and about 100%.
[0012] In yet another aspect of the present embodiment, hydrocodone
benzoic acid enol ester hydrochloride is prepared in an amorphous
form. This form may be prepared by dissolving the hydrocodone
benzoic acid enol ester hydrochloride in an organic solvent, then
evaporating the solvent.
[0013] In another embodiment, a process of preparing hydrocodone
benzoic acid enol ester is provided. The process includes heating
hydrocodone free base with a benzoylating reagent with or without
the presence of a base to form hydrocodone benzoic acid enol ester.
The reaction may be heated to between about 80.degree. C. and about
160.degree. C.
[0014] In one aspect of this embodiment, the reaction takes place
in an organic solvent. Some suitable organic solvents include but
are not limited to toluene, dimethylformamide,
N-methyl-2-pyrrolidinone, or xylenes. However, other suitable
organic solvents can be used as would be known in the art.
Alternatively, the reaction proceeds without solvent when using a
base capable of at least partially dissolving hydrocodone free base
and the benzoylating reagent. The base may be, for example,
pyridine, N,N-diisopropylethylamine, diazacycloundecene,
triethylamine, or potassium benzoate. Various benzoylating agents
may be employed. Some non-limiting examples include benzoic
anhydride, benzoyl chloride, benzoyl bromide,
N-benzoyloxysuccinimide.
[0015] According to another aspect, the hydrocodone benzoic acid
enol ester may be converted to its hydrochloric acid salt.
According to this embodiment, the hydrocodone benzoic acid enol
ester is crystallized from an organic solvent in the presence of
approximately 1.1. equivalents of hydrochloric acid.
[0016] According to another aspect, a process for making
hydrocodone benzoic acid enol ester is provided in which
hydrocodone benzoic acid enol ester can be created from hydrocodone
and a benzoylating reagent in one step. The possibility to perform
this reaction in one step provides an advantage over prior art
methods such as U.S. patent application Ser. No. 12/826,381, which
discloses a two-step addition process. The present one-step method
is also robust enough to use crude hydrocodone as a starting
material, which provides an advantage over prior art methods
requiring pure hydrocodone as a starting material.
BRIEF DESCRIPTION OF DRAWINGS
[0017] FIG. 1 is a chart depicting the inter-relation of
hydrocodone benzoic acid enol ester HCl salt crystal forms.
[0018] FIG. 2 shows XRPD patterns of pure hydrocodone benzoic acid
enol ester HCl salt--(a) Form I and (b) mixture of Forms I and
II.
[0019] FIG. 3 Shows an XRPD pattern of pure hydrocodone benzoic
acid enol ester HCl salt Form I.
[0020] FIG. 4 shows a DSC of pure hydrocodone benzoic acid enol
ester HCl salt Form I.
[0021] FIG. 5 shows an XRPD pattern of pure hydrocodone benzoic
acid enol ester HCl salt Form II.
[0022] FIG. 6 shows a DSC of pure hydrocodone benzoic acid enol
ester HCl salt Form II.
[0023] FIG. 7 shows an XRPD pattern of pure hydrocodone benzoic
acid enol ester HCl salt Form III.
[0024] FIG. 8 shows a DSC of pure hydrocodone benzoic acid enol
ester HCl salt Form III.
[0025] FIG. 9 shows an XRPD pattern of pure hydrocodone benzoic
acid enol ester HCl salt Form IV.
[0026] FIG. 10 shows a DSC of pure hydrocodone benzoic; acid enol
ester HCl salt Form IV.
[0027] FIG. 11 shows an XRPD pattern of pure hydrocodone benzoic
acid enol ester HCl salt Form V.
[0028] FIG. 12 shows a DSC of pure hydrocodone benzoic acid enol
ester HCl salt Form V.
[0029] FIG. 13 shows an XRPD pattern of pure amorphous hydrocodone
benzoic acid enol ester HCl salt.
[0030] FIG. 14 shows a DSC of pure amorphous hydrocodone benzoic
acid enol e HCl salt.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0031] In a first aspect, the present disclosure provides a
pharmaceutically acceptable salt of hydrocodone benzoic acid enol
ester, and processes for making the pharmaceutically acceptable
hydrocodone benzoic acid enol ester salt. Prior methods for making
hydrocodone benzoic acid enol ester required the isolation of pure
hydrocodone (through the bitartrate) before preparation of the
benzoic acid enol ester. It has been found that this purification
step is not required. Advantageously, the process of the present
disclosure eliminates the purification step thereby providing a
more efficient process of making hydrocodone benzoic acid enol
ester, it salts, and various polymorphic forms. Moreover, the
presently described process provides a pure hydrocodone benzoic
acid enol ester. For example, a hydrocodone benzoic acid enol ester
compound with high purity. For the purpose of illustration, the
hydrocodone benzoic acid enol ester can have a level of impurities
less than about 10% to 0.1%. For example, the impurities can be,
less than 10% (purity of 90%), less than 5% (purity of 95%), less
than 2.0% (purity of 98%), less than 1.0% (purity of 99%), less
than 0.5% (purity of 99.5%), less than 0.1% (purity of 99.9%).
##STR00001##
[0032] Synthesis. Hydrocodone benzoic acid enol ester hydrochloride
may be prepared by direct atrent of hydrocodone freebase with any
benzoylating reagent, while heating the mixture, preferably in the
presence of any suitable base. Hydrocodone benzoic acid enol ester
hydrochloride may also be prepared by treatment of hydrocodone HX
(X=Cl, Br, HSO.sub.4) salts with any benzoylating reagent, while
heating the mixture in any suitable solvent and any suitable base.
The Hydrocodone benzoic acid enol ester HCl salt may then be formed
and recrystallized. More specifically, hydrocodone or its salts may
be heated in the presence of any benzoylating reagent and any
suitable base. Suitable bases include pyridine,
N,N-diisopropylethylamine, diazabicycloundecene, triethylamine and
potassium benzoate. Some suitable solvents include toluene,
dimethylformamide, N-methyl-2-pyrrolidinone, and xylenes. However,
when using pyridine or another base capable of at least partially
dissolving both hydrocodone and the benzoylating reagent, the
reaction may be performed without an additional solvent. Any
benzoylating reagent may be used, for example benzoic anhydride or
benzoyl chloride.
[0033] In one embodiment, the process includes heating crude
hydrocodone with benzoic anhydride and potassium benzoate in
toluene or xylenes between about 80.degree. C. and about
160.degree. C. Once complete, the reaction may be worked up using
an aqueous extraction to remove excess reagents and salts. In an
alternative aspect of this embodiment, when the appropriate
reaction solvent and anti-solvent are selected according to methods
known in the art, the reaction may be cooled and filtered to remove
most of the byproducts and reagents. Hydrocodone benzoic acid enol
ester free base may be isolated in high purity at this stage.
[0034] The HCl salt may also be prepared from the filtrate solution
and isolated in good purity. Optimally, an anti-solvent is added to
the filtrate. Upon salt formation, hydrocodone benzoic acid enol
ester crystallizes from the solution. More specifically, acetone
may be used to dilute the toluene or xylenes filtrate and upon the
addition of HCl, crystals of hydrocodone benzoic acid enol ester
hydrochloride are obtained. Recrystallization of hydrocodone
benzoic acid enol ester HCl can be accomplished from many solvents
and solvent/anti-solvent combinations. Some ideal solvents are
isopropyl alcohol, acetone and ethanol, with or without the
addition of suitable anti-solvents.
[0035] Hydrocodone benzoic acid enol ester HCl exists in at least 6
distinct solid forms, designated herein as Forms I-V and amorphous.
FIG. 1 is a scheme that depicts the general processes for
converting hydrocodone benzoic acid enol ester HCl between its
polymorphic forms I-V. Each polymorph has different
characteristics, including solubility and stability. For example,
the water solubility of Form I at 37.degree. C. was about 24 mg/mL
while Form II had water solubility of >200 mg/mL--9 times higher
than the solubility of Form I. Significant water solubility
differences between polymorphs could result in variation in
bioavailability if mixtures are produced. Therefore, it is
important to consistently produce one polymorph, preferably the one
that is more stable.
[0036] Recrystallization of hydrocodone benzoic acid enol ester HCl
by common procedures may produce inconsistencies in the polymorphs
produced. For example, as shown in FIG. 2, crystallization of
Hydrocodone benzoic acid enol ester HCl using anhydrous isopropanol
and isopropyl acetate results in a mixture comprising a mixture of
polymorphs I and II.
[0037] The present disclosure describes methods of producing each
polymorph in substantially pure form. Substantially pure means a
minimum of 95% of the desired polymorph, preferably 98%, and more
preferably 99%.
[0038] Form I. A polymorph, designated herein as Form I, may be
prepares substantially pure form by crystallizing hydrocodone
benzoic acid enol ester HCl from an organic solvent in the presence
of water co-dissolved in the solvent. The water content of the
solvent may vary from traces to 100%. More specifically, ethanol
containing 1% water may be used as a solvent, with the addition of
n-heptane as anti-solvent. Alternative solvents include but are not
limited to alcohols, ethyl acetate, tBME, acetonitrile and acetone.
The required water content depends on the properties of the organic
solvent employed.
[0039] The XRPD pattern of Form I is presented FIG. 3. The water
content of Form I is approximately 2% by weight. This corresponds
to a hemi-hydrate stoichiometry. The DSC of Form I is presented in
FIG. 4. Table 1 presents selected peak positions from the XRPD and
their intensity relative to the largest peak. A characteristic peak
of Form is at 2.theta. of 9.05.degree.. One skilled in the art
would realize that the peak position could be altered as much as
.+-.0.2.degree. depending on sample preparation method and XRPD
instrument used for data collection.
TABLE-US-00001 TABLE 1 Form I XRPD peaks with intensity >10% of
the largest peak 2.theta. d spacing, A Intensity, % 6.16 14.34 38
9.05 9.77 100 10.95 8.07 31.1 11.91 7.42 18.8 12.32 7.18 47.7 13.16
6.72 81.8 14.60 6.06 15.6 14.94 5.92 54.9 17.04 5.20 31.3 17.23
5.14 13.5 17.80 4.98 13.5 18.57 4.77 48.6 19.18 4.62 22.4 20.66
4.30 23.9 21.10 4.21 26.6 22.15 4.01 15 23.50 3.78 15.7 26.07 3.41
20.5 28.39 3.14 10.4
[0040] Form II. A polymorph, designated herein as Form II, may be
produced in substantially pure form by crystallizing any other form
of hydrocodone benzoic acid enol ester HCl from an organic solvent
system that is substantially free of water. Substantially free of
water means a water content of less than 0.2 percent by volume and
more preferably less than 0.1 by volume. Substantially pure Form II
means a minimum of 95% of Form II, or preferably 98% and more
preferably 99%.
[0041] The XRPD pattern of Form Il is presented in FIG. 5. The DSC
of Form II is presented in FIG. 6. Table 2 presents selected peak
positions from the XRPD and their intensity relative to the biggest
peak. A characteristic peak of Form II is at 2.theta. of
4.31.degree.. One skilled in the art will realize that the peak
position may be altered as much as .+-.0.2.degree. depending on
sample preparation method and XRPD instrument used for data
collection.
TABLE-US-00002 TABLE 2 Form II XRPD peaks with intensity >1% of
the largest peak 2.theta. d spacing, A Intensity, % 4.31 20.48 20.6
8.62 10.25 100 12.95 6.83 4.6 13.19 6.71 4.4 13.42 6.59 2.8 14.33
6.17 2 14.97 5.91 2.4 15.72 5.63 6.6 17.48 5.07 2.4 18.47 4.80 1.2
21.73 4.09 3.4 22.92 3.88 2.1 24.15 3.68 2 24.98 3.56 1 26.41 3.37
1.3 26.53 3.36 1.4 26.62 3.34 1.3 27.93 3.19 1.1 30.46 2.93
1.17
[0042] Form III. A novel polymorph, designated as Form III, may be
prepared in substantially pure form by heating Form I to any
temperature between 210.degree. C. to 230.degree. C. preferably
215-225.degree. C. and more preferably 217.degree. C. One skilled
in the art could perform this heating operation in a different
equipment, e.g. a heating cell, while giving enough time at the
high temperature to achieve complete formation of Form III.
Substantially pure Form III means a minimum of 95% of Form III, or
preferably 98% and more preferably 99%.
[0043] The XRPD pattern of Form III is presented in FIG. 7. The DSC
of Form III is presented in FIG. 8. Table 3 presents selected peak
positions from the XRPD and their intensity relative to the largest
peak. A characteristic peak of Form III is at 2.theta. of
13.01.degree.. One skilled in the art will realize that the peak
position may differ from the listed positions by as much as
.+-.0.2.degree. depending on sample preparation method and XRPD
instrument used for data collection.
TABLE-US-00003 TABLE 3 Form III XRPD peaks with intensity >3% of
the largest peak 2.theta. d spacing, A Intensity, % 4.35 20.28 21.1
8.68 10.18 100 13.01 6.80 8.6 13.27 6.67 4.7 13.86 6.39 4.1 14.06
6.29 4.5 15.05 5.88 5.6 16.02 5.53 4.8 18.40 4.82 4.8 21.72 4.09
3.5 22.38 3.97 3.4 26.14 3.41 3.6
[0044] Form IV. A novel polymorph, designated as Form IV, may be
prepared in substantially pure form by exposing Form II to a
relative humidity of 75-100% for a period of two weeks. Preferably,
the relative humidity is in the range of 75-100%, more preferably
it is in the range 85-95% and most preferably the relative humidity
is 90%. Substantially pure Form IV means a minimum of 95% of Form
IV, or preferably 98% and more preferably 99%.
[0045] The XPRD pattern of Form IV is presented in FIG. 9. The DSC
of Form IV is presented in FIG. 10. Table 4 presents selected peak
positions in the XRPD and their intensity relative to the largest
peak. A characteristic peak of Form IV is at 2.theta. of
7.87.degree.. One skilled in the art will realize that he peak
position could be altered as much as .+-.0.2.degree. depending on
sample preparation method and XRPD instrument used for data
collection.
TABLE-US-00004 TABLE 4 Form IV XRPD peaks with intensity >4% of
the largest peak 2.theta. d spacing, A Intensity, % 7.87 11.23 100
10.27 8.61 12.1 11.82 7.48 8.1 12.56 7.04 7.5 13.18 6.71 22.6 14.19
6.24 10.8 14.65 6.04 17.6 15.34 5.77 5.8 16.77 5.28 6.2 17.67 5.01
4.4 18.58 4.77 9.9 19.50 4.55 5.2 20.30 4.37 6.2 21.31 4.17 4
[0046] Form V. A novel polymorph, designated as Form V, may be
prepared in substantially pure form by exposing Form III to a
relative humidity of 75-100% for a period of two weeks. Preferably,
the relative humidity is in the range of 75-100%, more preferably
it is in the range 85-95% and most preferably the relative humidity
is 90%. Substantially pure Form II means a minimum of 95% of Form
II, or preferably 98% and more preferably 99%.
[0047] The XRPD pattern of Form V is presented in FIG. 11. The DSC
is presented in FIG. 12. Table 5 presents selected peak position
from the XRPD and their intensity relative to the largest peak. A
characteristic peak of Form V is at 2.theta. of 7.50.degree.. One
skilled in the art will realize that the peak position could be
altered as much as .+-.0.2.degree. depending on sample preparation
method and XRPD instrument used for data collection.
TABLE-US-00005 TABLE 5 Form V XRPD peaks with intensity >10% of
the largest peak 2.theta. d spacing, A Intensity, % 6.17 14.31 21.4
7.50 11.78 100 9.04 9.77 44.2 10.96 8.07 10.3 11.93 7.42 22.3 12.34
7.17 47 12.64 6.99 12.8 13.13 6.74 60.8 14.34 6.17 10.6 14.62 6.05
31.1 14.93 5.93 25 16.73 5.29 17.3 17.04 5.20 29.8 17.22 5.15 18.6
17.81 4.98 22.4 18.59 4.77 26.4 18.98 4.67 13.2 19.19 4.62 18 19.52
4.55 12.4 20.67 4.29 23.4 21.10 4.21 30.6 21.91 4.05 10.1 22.15
4.01 20.1 22.82 3.89 11.7 23.49 3.78 15.2 25.03 3.56 12.5 25.37
3.51 21.9 26.09 3.41 14.6 26.43 3.37 13.8
[0048] Amorphous form. An amorphous form of hydrocodone benzoic
acid enol ester may be prepared in substantially pure form by
dissolving the hydrocodone benzoic acid enol ester in an organic
solvent, then evaporating the solvent in an oven. The solvent may
be any organic solvent that dissolves hydrocodone benzoic acid enol
ester, including methanol, trifluoroethanol, and acetic acid.
[0049] The XRPD pattern of the amorphous form is presented in FIG.
13. The DSC of the amorphous form is presented in FIG. 14. Upon
heating of amorphous solid in DSC, an endothermic peak with maximum
at about 216.degree. C. was observed.
EXAMPLES
Example 1
Synthesis of Hydrocodone Benzoic Acid Enol Ester Hydrochloride Free
Base
[0050] A mixture of crude hydrocodone freebase (1 eq.), benzoic
anhydride (2.5 eq.), and potassium benzoate (1.0 eq.) in toluene
(1.8 vol. to hydrocodone) was stirred and heated at
129.+-.3.degree. C. until >98% conversion of hydrocodone to
hydrocodone benzoic acid enol ester by HPLC was achieved (.about.24
hr.). The mixture was cooled to room temperature and diluted with
toluene (0.8 vol.) then further cooled to 5.degree. C. The
resulting mixture was filtered to remove potassium benzoate and
benzoic acid. The cake was washed with toluene (2.times.0.75 vol.).
The filtrate was washed with NaHCO.sub.3 solution (5%, 4 vol.) and
brine (10%, 2 vol.). The organic layer was dried with sodium
sulfate (2.times.). The mixture was filtered and the cake was
washed with toluene. The filtrate was concentrated to give oily
residue of hydrocodone benzoic acid enol ester.
Example 2
Synthesis of Hydrocodone Benzoic Acid Enol Ester Hydrochloride
[0051] A mixture of crude hydrocodone freebase (1 eq.), benzoic
anhydride (2.5 eq.), and potassium benzoate (1.0 eq.) in toluene
(1.8 vol. to hydrocodone) was stirred and heated at
129.+-.3.degree. C. until >98% conversion of hydrocodone to
hydrocodone benzoic acid enol ester by HPLC (.about.24 hr.). The
mixture was cooled to room temperature and diluted with toluene
(0.8 vol.) then further cooled to 5.degree. C. The resulting
mixture was filtered to remove potassium benzoate and benzoic acid.
The cake was washed with toluene (2.times.0.75 vol.). The filtrate
was diluted with acetone (6 vol.) and cooled to 5.+-.2.5.degree. C.
with agitation. Concentrated HCl (1.1.+-.0.05 equivalents) was
added and the resulting mixture was stirred at 5.+-.2.5.degree. C.
for 2 hr. The solid suspension was filtered and the cake was washed
with acetone (2.times.1 vol.). The solid was dried on the filter to
give crude hydrocodone benzoic acid enol ester hydrochloride in 88%
yield and 98.9% AUC purity. Crude hydrocodone benzoic acid enol
ester was dissolved in ethanol (6.0 vol.) at 65 to 70.degree. C. DI
water (1% v/v with respect to total amount of EtOH) was added and
the mixture was allowed to cool to 50.+-.5.degree. C. and held for
30 to 60 minutes after crystal growth was noticed. n-Heptane (3
vol.) was added at 50.+-.5.degree. C. The mixture was cooled to
room temperature over approximately 1 hr. and then further cooled
to 5.+-.2.5.degree. C. and stirred for 1.5 hr. The solid mixture
was filtered and the crystalline product cake was rinsed with a
mixture of ethanol and n-heptane. The cake was dried under to give
hydrocodone benzoic acid enol ester hydrochloride as Form I in
93.5% recovery, >99.9% AUC purity, 82.5% overall yield from
hydrocodone.
Example 3
Synthesis of Hydrocodone Benzoic Acid Enol Ester HCl Salt (Form I)
from the Corresponding Free Base
[0052] To 475 mg of hydrocodone benzoic acid enol ester were added
4.75 mL of Acetone:Toluene (1.5:1 vol ratio) at room temperature,
which resulted in a solution. Then, 1.03 eq. of concentrated HCl
(37.5 wt %) were slowly added to the freebase solution.
Precipitation started during the addition. After completion of acid
addition, the slurry was stirred for about 30 minutes and filtered.
The cake was washed with about 0.5 mL acetone and then dried. The
dry solid was substantially pure Form I.
[0053] In example 3, other organic solvents such as but not limited
to alcohols, tBME and ethyl acetate could be used. Instead of
adding solvent to freebase, the freebase could he added to solvent.
The temperature of acid addition could be in the range of 0.degree.
C. to 60.degree. C., preferably 10.degree. C. to 40.degree. C. and
more preferably 20.degree. C. to 30.degree. C.
Example 4
Form I Recrystallization
[0054] To 158 mg of HCl salt Form I was added 7.8 volumes of
Ethanol and the mixture heated to 65.degree. C. to achieve
dissolution. The solution was then cooled to 50.degree. C. followed
by addition of 12.2 .mu.L, water. When a crystal bed was achieved,
2.7 volumes of heptane were added over about 30 minutes followed by
cooling to 20-25.degree. C. Filtration and drying resulted in Form
I (84% yield) with a chemical purity of 99+%.
[0055] In example 4, ethanol could be replaced with other organic
solvents such as but not limited to other alcohols and acetone.
Instead of adding solvent to the salt, the salt could be added to
the solvent. The temperature of water addition could be in the
range of 0.degree. C. to 60.degree. C., preferably 30.degree. C. to
55.degree. C. and more preferably 45.degree. C. to 50.degree. C.
The water quantity could be in the range of 0.2% to 15 vol % with
respect to organic solvent, preferably 0.3-5% and more preferably
0.8-1.2%. Alternatively, seeds of Form I could be added to promote
crystallization after water addition. Heptane volume could be in
the range of 0-15 volumes, preferably 1-5 volumes and more
preferably 2-3 volumes. The starting solid of this example could be
Form 1 or any other polymorphs of hydrocodone benzoic acid enol
ester HCl.
Example 5
Form I Recrystallization
[0056] To 130 mg of HCl salt Form I were added 7.8 volumes of
Ethanol and heated to 65.degree. C. to achieve dissolution. The
solution was then cooled to 50.degree. C. followed by addition of
10 .mu.L water. Within 30 minutes a crystal bed was achieved. The
mixture was cooled to 20.degree. C. to 25.degree. C., filtered, and
dried which resulted in Form I (80% yield) and a chemical purity of
99+%.
[0057] In example 5, ethanol could be replaced with other organic
solvents such as but not limited to other alcohols and acetone.
Instead of adding solvent to the salt, the salt could be added to
the solvent. The temperature of water addition could be in the
range of 0.degree. C. to 60.degree. C., preferably 30.degree. C. to
55.degree. C. and more preferably 45.degree. C. to 50.degree. C.
The water quantity could be in the range of 0.2% to 15 vol % with
respect to organic solvent, preferably 0.3-5% and more preferably
0.8-1.2%. Alternatively, seeds of Form I could be added to promote
crystallization after water addition. The starting solid of this
example could be Form I or any other polymorphs of hydrocodone
benzoic acid enol ester HCl.
Example 6
Synthesis of Hydrocodone Benzoic Acid Enol Ester HCl Salt (Form
II)
[0058] To about 118 mg of Form I were added 12.3 volumes of
anhydrous isopropanol and 13.4 volumes of anhydrous isopropyl
acetate added and the slurry was heated to reflux to achieve
complete dissolution. The solution was cooled to about 20.degree.
C. over about 3 hrs. Nucleation was observed at about 60.degree. C.
The slurry was filtered at about 20.degree. C. and the product was
dried. The resulting solid was substantially pure Form II with 67%
yield.
Example 7
Synthesis of Hydrocodone Benzoic Acid Enol Ester HCl Salt (Form
III)
[0059] Hydrocodone benzoic acid enol ester HCl salt (Form I) was
heated to 217.degree. C. in DSC followed by cooling to room
temperature which resulted in substantially pure Form III by XRPD
analysis.
Example 8
Synthesis of Hydrocodone Benzoic Acid Enol Ester HCl Salt (Form
IV)
[0060] Hydrocodone benzoic acid enol ester HCl salt (Form II) was
exposed to humidity of more than 90% at room temperature for two
weeks, which resulted in Form IV confirmed by XRPD.
Example 9
Synthesis of Hydrocodone Benzoic Acid Enol ester HCl Salt (Form
V)
[0061] Hydrocodone benzoic acid enol ester HCl salt (Form III) was
exposed to humidity of more than 90% at room temperature for two
weeks, which resulted in Form V confirmed by XRPD.
Example 10
Synthesis of Hydrocodone Benzoic Acid Enol Ester HCl Salt
(Amorphous Form)
[0062] 64 mg of Hydrocodone benzoic acid enol ester HCl salt was
dissolved in 1 mL of methanol. The solvent was evaporated in the
oven temperature of 50.degree. C. and under vacuum. The resulting
solid was amorphous by XRPD.
Example 11
Slurry Stability Studies
[0063] A number of experiments were performed to map out the
relative stability of Forms I to V. Prior to the relative stability
tests, the solids of Forms I, II and III were dried in the oven to
remove surface water. Table 6 shows the results of these slurries.
It was found that Form I is always the most stable in water or
organic solvents that contain water. However, in anhydrous organic
solvents, Form II is the more stable one, especially at higher
temperatures. Therefore, Form I was selected as the most viable
form for development.
TABLE-US-00006 TABLE 6 Relative stability of various forms After
Starting After 1 day slurry 10 days slurry Solvent Form 25.degree.
C. 50.degree. C. 25.degree. C. 50.degree. C. Water I + II + III I I
I I Water I + IV + V I I I I IPA I + II + III I + II I + II I II
Acetonitrile I + II + III I + traces of II II I I
Example 12
Grinding Stability Studies
[0064] Form I was exposed to dry and solvent drop grinding using
mortar and pestle. This test mimics shear stresses that a crystal
polymorph could be exposed to during commercial formulation. Table
7 illustrates the grinding results.
TABLE-US-00007 TABLE 7 Wet and dry grinding of Form I - 5 minutes
of manual grinding Starting Form Conditions Resulting Form I Dry
grinding I I Wet grinding- ~0.3X vol I water I Wet grinding- ~0.5X
vol IPA I
Example 13
Humidity Stability Studies
[0065] The stability of various forms of hydrocodone benzoic acid
enol ester hydrochloride was evaluated under high humidity
(RH>90% at room temperature) conditions. Form I was stable for
at least two weeks. Form H was hygroscopic and unstable, and
converted to Form IV. Form III was hygroscopic and unstable, and
converted to Form V.
* * * * *