U.S. patent application number 12/916750 was filed with the patent office on 2011-02-24 for crystalline base of escitalopram and orodispersible tablets comprising escitalopram base.
This patent application is currently assigned to H. LUNDBECK A/S. Invention is credited to Robert Dancer, Helle Eliasen, Ken Liljegren, Ole Nielsen, Hans Petersen, Michael Harold Rock.
Application Number | 20110046218 12/916750 |
Document ID | / |
Family ID | 37679924 |
Filed Date | 2011-02-24 |
United States Patent
Application |
20110046218 |
Kind Code |
A1 |
Dancer; Robert ; et
al. |
February 24, 2011 |
CRYSTALLINE BASE OF ESCITALOPRAM AND ORODISPERSIBLE TABLETS
COMPRISING ESCITALOPRAM BASE
Abstract
The present invention relates to the crystalline base of the
well known antidepressant drug escitalopram,
S-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofu-
rancarbonitrile, formulations of said base, a process for the
preparation of purified salts of escitalopram, such as the oxalate,
using the base, the salts obtained by said process and formulations
containing such salts, and a process for the preparation of
purified escitalopram free base or salts of escitalopram, such as
the oxalate, using the hydrobromide, the salts obtained by said
process and formulations containing such salts. Finally the present
invention relates to an orodispersible tablet having a hardness of
at least 22 N and an oral-disintegration time of less than 120 s
and comprising an active pharmaceutical ingredient adsorbed onto a
water soluble filler wherein the active pharmaceutical ingredient
has a melting point in the range of 40-100.degree. C., as well as a
method for making such an orodispersible tablet.
Inventors: |
Dancer; Robert; (Hvidovre,
DK) ; Petersen; Hans; (Vanlose, DK) ; Nielsen;
Ole; (Valby, DK) ; Rock; Michael Harold;
(Hvidovre, DK) ; Eliasen; Helle; (Koge, DK)
; Liljegren; Ken; (Vaerlose, DK) |
Correspondence
Address: |
LUNDBECK RESEARCH USA, INC.;ATTENTION: STEPHEN G. KALINCHAK, LEGAL
215 COLLEGE ROAD
PARAMUS
NJ
07652
US
|
Assignee: |
H. LUNDBECK A/S
Valby-Copenhagen
DK
|
Family ID: |
37679924 |
Appl. No.: |
12/916750 |
Filed: |
November 1, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11425522 |
Jun 21, 2006 |
7834201 |
|
|
12916750 |
|
|
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|
60693214 |
Jun 22, 2005 |
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Current U.S.
Class: |
514/469 ;
549/467 |
Current CPC
Class: |
C07D 307/81 20130101;
A61P 25/24 20180101 |
Class at
Publication: |
514/469 ;
549/467 |
International
Class: |
A61K 31/343 20060101
A61K031/343; C07D 307/87 20060101 C07D307/87; A61P 25/24 20060101
A61P025/24 |
Claims
1. A process for the manufacture of escitalopram free base or a
salt thereof characterised in that escitalopram hydrobromide is
precipitated in crystalline form from a solvent and separated from
the solvent, optionally re-crystallised one or more times, and then
transformed into escitalopram free base or a salt thereof provided
that the escitalopram salt manufactured is not the
hydrobromide.
2. The process according to claim 1 for the manufacture of
escitalopram free base or a salt thereof characterised in that the
escitalopram hydrobromide is precipitated from a crude
escitalopram.
3. The process according to claim 1 for the manufacture of
escitalopram free base or a salt thereof characterised in that one
or more impurities of the formulas (II) or (III) ##STR00006##
wherein Z is halogen, cyano or --CONH.sub.2, R.sup.1 and R.sup.2
independently are hydrogen or methyl, provided that if both of
R.sup.1 and R.sup.2 are methyl, then Z can not be cyano, and the
bond drawn as a zigzag line in formula (III) indicates that the
configuration around the double bond may be E- or Z-; are removed
from or reduced in the escitalopram by the process.
4. The process according to claim 3, wherein the impurities are of
formula (II) wherein Z is bromo or chloro and R.sup.1 and R.sup.2
are both methyl, Z is --CONH.sub.2 and R.sup.1 and R.sup.2 are both
methyl, or Z is cyano, R.sup.1 is hydrogen and R.sup.2 is methyl;
or of the formula (III) wherein the configuration around the double
bond is Z.
5. The process according to claim 2 wherein the crude escitalopram
is subjected to initial purification before the escitalopram
hydrobromide is precipitated in crystalline form.
6. The process according to claim 1 characterised in that the
escitalopram hydrobromide is transformed into escitalopram free
base or escitalopram oxalate.
7. The crystalline base of escitalopram, or an oxalate salt of
escitalopram prepared by the process of claim 1.
8. The base or the oxalate salt of claim 7 characterised in that it
contains less than 0.20% impurities other than R-citalopram,
particularly less than 0.10%.
9. The crystalline base or oxalate salt according to claim 8
characterised in that it contains less than 0.10% of any particular
impurity other than R-citalopram.
10. An orodispersible tablet having a hardness of at least 22 N and
an oral-disintegration time of less than 120 s and comprising an
active pharmaceutical ingredient adsorbed onto a water soluble
filler, one or more disintegrants and optionally additional water
soluble filler, wherein said active pharmaceutical ingredient has a
melting point in the range of 40-100.degree. C.
11. The orodispersible tablet according to claim 10 characterised
in that the active pharmaceutical ingredient has a melting point in
the range of 40-90.degree. C.
12. The orodispersible tablet according to claim 10 characterised
in that the active pharmaceutical ingredient is selected from the
group consisting of escitalopram, ethosuximide, trimethadione,
chlorambucil, disulfuram, fenofibrate, guaifenesin, lomustine,
carisoprodol and perphenazine.
13. The orodispersible tablet according to claim 12 characterised
in that the active pharmaceutical ingredient is escitalopram.
14. The orodispersible tablet according to claim 13 characterised
in that the water-soluble filler is selected from the group
consisting of: monosaccharides, disaccharides, sugar alcohols and
polysaccharides.
15. The orodispersible tablet according to claim 14 characterised
in that the water-soluble filler is selected from the group
consisting of: mannitol, sorbitol, glucose, mannose and
lactose.
16. The orodispersible tablet according to claim 15 characterised
in that it has a hardness of at least 22 N.
17. The orodispersible tablet according to claim 16 characterised
in that it has an oral-disintegration time of less than 60 s.
18. The orodispersible tablet according to claim 17 characterised
in that the disintegrants are selected from the group consisting
of: microcrystalline cellulose, sodium starch glycolate,
croscarmellose sodium, crospovidone and povidone.
19. The orodispersible tablet according to claim 18 characterised
in that it has a friability of no more than 1%.
20. A method of manufacture of an orodispersible tablet according
to claim 10 comprising: a) mixing the water-soluble filler and the
active pharmaceutical ingredient at a temperature above, around or
slightly below the melting point of the active pharmaceutical
ingredient, whereby the active pharmaceutical ingredient is
adsorbed onto the water-soluble filler; b) followed by cooling to a
temperature below 40.degree. C.; c) mixing the mixture of the
active pharmaceutical ingredient and the water-soluble filler with
one or more disintegrants and optionally other excipients; d)
pressing the mixture into tablets with a hardness of at least 22 N.
Description
[0001] The present invention relates in a first aspect to the
crystalline base of the well known anti-depressant drug
escitalopram,
S-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofu-
rancarbonitrile, formulations of said base, processes for the
preparation of purified escitalopram free base and salts thereof,
using the crystalline base or hydrobromide of escitalopram, the
salts obtained by said process and formulations containing such
salts. In a second aspect the present invention relates to
orodispersible tablets comprising an active pharmaceutical
ingredient adsorbed onto a water-soluble filler wherein said active
pharmaceutical ingredient has a melting point in the range of
40-100.degree. C., and methods for the manufacture of such
orodispersible tablets.
BACKGROUND OF THE INVENTION
[0002] Escitalopram is a well-known antidepressant drug that has
now been on the market for some years and has the following
structure:
##STR00001##
[0003] It is a selective, centrally-acting serotonin
(5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having
antidepressant activities.
[0004] Escitalopram was first disclosed in U.S. Pat. No. 4,943,590.
The escitalopram prepared was isolated as the oxalate. Furthermore,
the escitalopram base was obtained as an oil. Escitalopram is
marketed as the oxalate.
[0005] Escitalopram my inter alia be prepared according to the
processes disclosed in WO 2003006449 and WO 2003051861.
[0006] Crystalline escitalopram hydrobromide was disclosed in WO
2004056791.
[0007] Orodispersible tablets have gained considerable attention
over the last years. Orodispersible tablets disintegrate in the
mouth and are, subsequently, swallowed. This is advantageous for
patients having difficulties swallowing conventional tablet
formulations and, consequently, orodispersible tablets increase not
only patient convenience but also patient compliance. The active
pharmaceutical ingredient that is incorporated in the fast
disintegrating tablet may partly or completely dissolve in the
mouth, thereby enabling absorption to take place from the oral
cavity.
[0008] In literature, several terms have been applied for
orodispersible tablets. Amongst these are fast dissolving tablets,
fast dispersing tablets, fast disintegrating tablets, melt tablets,
rapid dissolve tablets, rapid-melt tablets, mouth-dissolving
tablets, quick-disintegrating tablets.
[0009] Various methods have been applied to manufacture fast
disintegrating tablets. Many of the methods make use of
unconventional equipment and complicated processing techniques such
as lyophilization and foam techniques. Many of these methods result
in fast disintegrating tablets with poor tablet strength and low
friability. This may prevent the use of conventional packaging
material and conventional packaging procedures.
[0010] WO2005/018617 discloses the use of conventional melt
granulation to produce granules from a low melting point compound
that melts or soften at or below 37.degree. C., and a water-soluble
excipient. The granules were subsequently mixed with active
pharmaceutical ingredient and additional excipients and then
compressed to yield fast dissolving tablets of low hardness, 2.2 kP
or less.
[0011] Manufacturing methods that are based on the use of
conventional equipment and techniques and that result in fast
disintegrating tablets with sufficient strength are therefore
desirable.
[0012] It has now been found that the base of escitalopram may be
obtained as a very pure crystalline product, which may easily be
handled and formulated conveniently into tablets and other
pharmaceutical forms. Furthermore, it has been found that an
efficient purification of escitalopram may be obtained during
manufacture of escitalopram (e.g. of the oxalate salt) by
crystallising the base, and thereafter optionally forming a salt
from the base.
[0013] It has likewise been found that a very efficient
purification of escitalopram may be obtained during manufacture of
escitalopram (e.g. of the free base or the oxalate salt) by
crystallising the hydrobromide, and thereafter optionally forming
the base or a salt, which is not the hydrobromide, from the
base.
[0014] These purification processes are particularly useful for
removing intermediates which are structurally closely related to
escitalopram, in particular compounds which only differ from
escitalopram by the substituent situated in position 5 on the
isobenzofurane ring and/or in lacking one or both of the methyl
groups, and intermediates which have physical/chemical properties
which are close to those of escitalopram, e.g. the
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-isobe-
nzofuranes having halogen (in particular bromide and chloride), an
amide or an ester in position 5 of the isobenzofurane ring, or the
compounds of formula (III).
[0015] Furthermore, a novel type of orodispersible tablets with
high strength and low friability has been developed. These novel
orodispersible tablets can be manufactured in a melt agglomeration
process, melt coating process or melt extrusion process that can be
performed using conventional melt agglomeration equipment or melt
extrusion equipment. In the process the active pharmaceutical
ingredient is heated to a temperature above, around or slightly
below the melting point to melt agglomerate or melt coat filler
particles. The agglomerates or the coated filler particles are,
subsequently, mixed with suitable excipients and compressed into
tablets.
[0016] Escitalopram base has been found to be suitable for
formulation in such orodispersible tablets.
SUMMARY OF THE INVENTION
[0017] The present invention provides the crystalline base of
escitalopram with the formula (I):
##STR00002##
[0018] In a second aspect, the invention provides a process for the
manufacture of escitalopram free base or a salt thereof, preferably
the oxalate, in which escitalopram hydrobromide is precipitated in
crystalline form from a solvent and separated from the solvent,
optionally re-crystallised one or more times and then transformed
into escitalopram free base or a pharmaceutically acceptable salt
thereof provided that the escitalopram salt manufactured is not the
hydrobromide.
[0019] In a third aspect, the invention relates to the pure
crystalline escitalopram free base or escitalopram oxalate prepared
by the above process of the invention.
[0020] In a fourth aspect, the invention provides a process for the
manufacture of a salt of escitalopram, preferably the oxalate, in
which the free base of escitalopram is precipitated in solid form
from a solvent and separated from the solvent, optionally
re-crystallised one or more times and then transformed into a
pharmaceutically acceptable salt of escitalopram.
[0021] In a fifth aspect, the invention relates to the pure
crystalline escitalopram oxalate prepared by the above process of
the invention.
[0022] In a sixth aspect, the invention relates to a process for
the reduction of the amount of escitalopram, N-oxide
((S)-1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzof-
uran-5-carbonitrile, N-oxide) in escitalopram free base or a salt
thereof comprising dissolving escitalopram free base in
diethylether and removing escitalopram, N-oxide as a solid
material.
[0023] In a seventh aspect, the invention relates to an
orodispersible tablet having a hardness of at least 22 N and an
oral-disintegration time of less than 120 s and comprising an
active pharmaceutical ingredient adsorbed onto a water soluble
filler, one or more disintegrants and optionally additional water
soluble filler, wherein said active pharmaceutical ingredient has a
melting point in the range of 40-100.degree. C.
[0024] In an eighth aspect, the invention relates to a method of
manufacture of an orodispersible tablet as described above
comprising: [0025] a) mixing the water-soluble filler and the
active pharmaceutical ingredient at a temperature above, around or
slightly below the melting point of the active pharmaceutical
ingredient, whereby the active pharmaceutical ingredient is
adsorbed onto the water-soluble filler; [0026] b) followed by
cooling to a temperature below 40.degree. C.; [0027] c) mixing the
mixture of the active pharmaceutical ingredient and the
water-soluble filler with one or more disintegrants and optionally
other excipients; pressing the mixture into tablets with a hardness
of at least 22 N.
[0028] In a ninth aspect, the invention relates to pharmaceutical
formulations comprising escitalopram base in solid form.
DETAILED DESCRIPTION OF THE INVENTION
[0029] In one embodiment, the invention relates to escitalopram
free base in solid form, in particular in a solid form comprising
crystalline escitalopram free base, and more particularly in a
solid form that is at least 90% crystalline, even more particularly
at least 95% crystalline and most particularly at least 98%
crystalline. Specifically, the invention relates to crystalline
escitalopram free base.
[0030] In one particular embodiment, the invention relates to an
orodispersible tablet comprising escitalopram free base, whereas in
another equally particular embodiment, the invention relates to a
pharmaceutical composition containing the escitalopram free base in
solid form as disclosed above. Particularly the pharmaceutical
composition is for oral administration. The pharmaceutical
composition according to the invention may be prepared by direct
compression of escitalopram in admixture with conventional
excipients. Alternatively, a wet granulate or a melt granulate of
escitalopram, optionally in admixture with conventional excipients
may be used for compression of tablets.
[0031] In yet another embodiment, the invention relates to a method
for the manufacture of escitalopram free base or a salt thereof
characterised in that escitalopram hydrobromide is precipitated in
crystalline form from a solvent and separated from the solvent,
optionally re-crystallised one or more times, and then transformed
into escitalopram free base or a salt thereof provided that the
escitalopram salt manufactured is not the hydrobromide.
[0032] In a particular embodiment, the invention relates to such a
method wherein the escitalopram hydrobromide is precipitated from a
crude escitalopram.
[0033] In another particular embodiment, the invention relates to
such a method wherein one or more impurities of the formulas (II)
or (III)
##STR00003##
wherein Z is halogen, cyano or --CONH.sub.2, R.sup.1 and R.sup.2
independently are hydrogen or methyl, provided that if both of
R.sup.1 and R.sup.2 are methyl, then Z can not be cyano, and the
bond drawn as a zigzag line in formula (III) indicates that the
configuration around the double bond may be E- or Z-, are removed
from or reduced in the escitalopram by the process. More
particularly the invention relates to such a method, wherein the
impurities are of formula (II) wherein Z is bromo or chloro and
R.sup.1 and R.sup.2 are methyl, Z is --CONH.sub.2 and R.sup.1 and
R.sup.2 are methyl, or Z is cyano, R.sup.1 is hydrogen and R.sup.2
is methyl; or wherein the impurities are of the formula (III)
wherein the configuration around the double bond is Z.
[0034] Throughout this specification with claims, the compounds of
formula (II) may have the S-configuration, the R-configuration, be
racemic or any mixture thereof.
[0035] Throughout this specification with claims, the terms
"escitalopram oxalate" and "escitalopram hemioxalate" both refer to
the same 1:1 salt between escitalopram and oxalic acid.
[0036] In another particular embodiment, the invention relates to
such a method wherein the crude escitalopram is subjected to
initial purification before the escitalopram hydrobromide is
precipitated in crystalline form.
[0037] In yet another particular embodiment, the invention relates
to such a method wherein the escitalopram hydrobromide is
transformed into escitalopram free base or escitalopram
oxalate.
[0038] In another embodiment, the invention relates to a
crystalline base of escitalopram, or an oxalate salt of
escitalopram prepared by a process as described above; in
particular such a base or oxalate salt which contains less than
0.2% impurities other than R-citalopram, more particularly less
than 0.1%. Particularly, the invention relates to a crystalline
base or oxalate salt as disclosed above which contains less than
0.1% of any particular impurity other than R-citalopram.
[0039] In another embodiment, the invention relates to a
crystalline base of escitalopram, or an oxalate salt of
escitalopram, characterised in that it contains less than 0.2% of
impurities other than R-citalopram, particularly less than 0.1%. In
a particular embodiment, the invention relates to a crystalline
base or oxalate salt as disclosed above which contains less than
0.1% of any particular impurity other than R-citalopram.
[0040] Throughout this specification and the claims contents of
impurities are given as area % as determined by HPLC.
[0041] In yet another embodiment, the invention relates to a method
for the manufacture of a salt of escitalopram characterised in that
escitalopram free base is precipitated in solid form from a solvent
and separated from the solvent, optionally re-crystallised one or
more times, and then transformed into a salt of escitalopram.
[0042] In a particular embodiment, the invention relates to such a
method wherein the escitalopram free base is precipitated from a
crude escitalopram.
[0043] In another particular embodiment, the invention relates to
such a method wherein one or more impurities of the formula
(II)
##STR00004##
wherein Z is halogen or --CONH.sub.2 are removed from or reduced in
the escitalopram by the process; more particularly such a method
wherein Z is bromo.
[0044] In another particular embodiment, the invention relates to
such a method wherein the crude escitalopram is subjected to
initial purification before the escitalopram free base is
precipitated in solid form.
[0045] In yet another particular embodiment, the invention relates
to such a method wherein the escitalopram free base is transformed
into escitalopram oxalate.
[0046] In another embodiment the invention relates to an
orodispersible tablet having a hardness of at least 22 N and an
oral-disintegration time of less than 120 s and comprising an
active pharmaceutical ingredient adsorbed onto a water soluble
filler, one or more disintegrants and optionally additional water
soluble filler, wherein said active pharmaceutical ingredient has a
melting point in the range of 40-100.degree. C., particularly in
the range of 40-90.degree. C., more particularly 40-80.degree. C.,
and most particularly 45-70.degree. C.
[0047] In a particular embodiment the invention relates to such an
orodispersible tablet wherein the active pharmaceutical ingredient
is selected from the group consisting of escitalopram,
ethosuximide, trimethadione, chlorambucil, disulfuram, fenofibrate,
guaifenesin, lomustine, carisoprodol and perphenazine and more
particularly wherein the active pharmaceutical ingredient is
escitalopram.
[0048] In another particular embodiment the invention relates to
such an orodispersible tablet wherein the water-soluble filler is
selected from the group consisting of: monosaccharides,
disaccharides, sugar alcohols and polysaccharides; and more
particularly wherein the water-soluble filler is selected from the
group consisting of: mannitol, sorbitol, glucose, mannose and
lactose.
[0049] In another particular embodiment the invention relates to
such an orodispersible tablet comprising an antioxidant such as a
C.sub.1-6-alkyl gallate, e.g. propyl gallate, as an intra- or
extragranular excipient.
[0050] In another particular embodiment the invention relates to
such an orodispersible tablet which has a hardness of at least 22
N, particularly at least 25 N, more particularly at least 30 N,
even more particularly at least 40 N, and most particularly at
least 60 N. Suitably the tablet has a hardness in the range of
22-125 N, particularly 25-125 N, more particularly 30-125 N, even
more particularly 40-125 N, and most particularly 60-125 N. Evenly
suitably the tablet has a hardness in the range of 22-100 N,
particularly 30-100 N, more particularly 40-100 N, even more
particularly 25-60 N, and most particularly 30-60 N.
[0051] In another particular embodiment, the invention relates to
such an orodispersible tablet, which has an oral-disintegration
time of less than 60 s, particularly less than 40 s, and more
particularly less than 30 s.
[0052] In another particular embodiment, the invention relates to
such an orodispersible tablet, which has a friability of no more
than 1%, in particular no more than 0.8%.
[0053] Disintegrants suitable to be used in the orodispersible
tablets described above are selected from the group consisting of:
Microcrystalline cellulose (cellulose), sodium starch glycolate
(sodium carboxymethyl starch), croscarmellose sodium (cellulose,
carboxymethyl ether, sodium salt, crosslinked), crospovidone
(polyvinylpolypyrrolidone), povidone (polyvinyl-pyrrolidone),
natural starches such as maize starch and potato starch,
pregelatinized starch, compressible starch, alginic acid, sodium
alginate and polacrilin potassium (2-methyl-2-propenoic acid
polymer with divinylbenzene, potassium salt); and in particular
from the group consisting of: Microcrystalline cellulose, sodium
starch glycolate, croscarmellose sodium, crospovidone and povidone.
Most particularly the disintegrant is a crosscarmelose sodium
product which may provide a more stable product compared with other
disintegrants.
[0054] In yet another embodiment, the invention relates to a method
of manufacture of an orodispersible tablet as described above
wherein said method comprises: [0055] a) mixing the water-soluble
filler and the active pharmaceutical ingredient at a temperature
above, around or slightly below the melting point of the active
pharmaceutical ingredient, whereby the active pharmaceutical
ingredient is adsorbed onto the water-soluble filler; [0056] b)
followed by cooling to a temperature below 40.degree. C., in
particular below 35.degree. C. and more particularly below
30.degree. C.; [0057] c) mixing the mixture of the active
pharmaceutical ingredient and the water-soluble filler with one or
more disintegrants and optionally other excipients; pressing the
mixture into tablets with a hardness of at least 22 N.
[0058] Throughout the description and claims the term "cooling"
comprises active and passive cooling.
[0059] The use of tableting punches with a surface comprising
chromium nitride for the tableting process may be advantageous in
order to reduce adhesion to the punches. Such tableting punches may
be prepared by ion beam enhanced deposited coating available from
BeamAlloy Technologies LLC.
[0060] In a particular embodiment, the mixing in step a) above is
performed at a temperature above the melting point of the active
ingredient.
[0061] The melting point is preferably within a range from
44-49.degree. C., most preferably 45-48.degree. C. (DSC;
onset).
[0062] The terms "crude escitalopram", "crude salt" and "crude
mixture" refer to the fact that the salt and the mixture,
respectively, comprise impurities, in particular impurities of
formula (II), which must be removed or which it is desired to
remove.
[0063] The crude salt may have been separated directly from the
reaction mixture, or the crude reaction mixture may have been
subjected to some initial purification, e.g. one
re-crystallisation, and/or treatment with activated carbon and/or
silica gel, and the salt formed subsequently by treatment with an
acid using methods known in the art. The salt may be isolated by
precipitation or it may exist in a solvent, e.g. in the mixture
resulting directly from the synthesis of the salt.
[0064] Similarly, the crude mixture comprising escitalopram may be
obtained directly from the synthesis of the compound according to
any of the above mentioned processes or it may have been subjected
to some initial or simultaneous purification, e.g. one
re-crystallisation, and/or treatment with activated carbon and/or
silica gel.
[0065] The base of escitalopram may be set free from the crude salt
by dissolving the crude salt in a mixture of water and an organic
solvent and then adding a base to pH 7 or more. The organic solvent
may be toluene, ethyl acetate, diethyl ether, methyl-tert-butyl
ether, diisopropyl ether, hexane, heptane, cyclohexane,
methylcyclohexane or any other suitable solvent as well as mixtures
thereof and the base may be any convenient base, preferably NaOH or
NH.sub.3. Likewise, the base of escitalopram may, if necessary, be
set free from a crude mixture containing escitalopram by treatment
with a base.
[0066] Crude mixtures containing escitalopram base may be subjected
to further purification and extraction before the base is
precipitated in crystalline form. The base of escitalopram may be
isolated by separation of the organic phase from the aqueous phase,
evaporation of the solvent in order to obtain the base most
probably as an oil and then crystallisation of the base from a
solvent, such as an alkane, including n-heptane, hexane, isooctane,
cyclohexane and methylcyclohexane, 2-methyl-tetrahydrofuran;
1-pentanol and high and low boiling petroleum ethers or mixtures
thereof; as well as mixtures of one or more of the above mentioned
solvents with more polar solvents such as ethyl acetate,
isopropylacetate, butylacetate, acetonitrile, tetrahydrofuran and
alcohols such as 2-butanol or 2-propanol, and separating the
escitalopram base from the solvent. Crystalline escitalopram base
may be re-crystallised from the same solvents. Crystallisation may
be initiated by seeding with crystalline escitalopram oxalate or
crystalline escitalopram free base.
[0067] Pharmaceutically acceptable salts of escitalopram, such as
the oxalate, may be prepared by methods known in the art. So, the
base may be reacted with either the stoichiometric amount of acid
in a water miscible solvent, such as acetone or ethanol, with
subsequent isolation of the salt by concentration and cooling, or
with an excess of the acid in a water immiscible solvent, such as
diethyl ether, ethyl acetate or dichloromethane, with the salt
separating spontaneously. The escitalopram free base or
escitalopram oxalate obtained by the method of the invention has a
very high purity and contains less than 0.20% impurities other than
R-citalopram, particularly less than 0.10%. In particular, the
escitalopram free base or escitalopram oxalate obtained by the
method of the invention contains less than 0.10% of any particular
impurity other than R-citalopram. Other salts of escitalopram may
also be obtained in a very pure form by this process.
[0068] The compounds of formula (II) may be prepared as described
in DE 2,657,013, WO 0011926 and WO 0013648, WO 9819513, WO 9819512
and WO 9900548.
[0069] Throughout this specification with claims, the term "solid
form" refers to any solid form exemplified by crystalline form,
amorphous solid form, glassy form, foam as well as mixtures
thereof.
[0070] Throughout this specification with claims, melting points
are measured using Differential Scanning calorimetry (DSC). The
equipment used is a TA-Instruments DSC-Q1000 calibrated at
5.degree. C./min to give the melting point as onset value. About 2
mg of sample is heated 5.degree. C./min in a loosely closed pan
under nitrogen flow.
[0071] Throughout this specification with claims, halogen means
chloro, bromo or iodo.
[0072] Throughout this specification with claims, the term
"orodispersible tablets" refers to uncoated tablets intended to be
placed in the mouth where they disperse rapidly before being
swallowed. Orodispersible tablets disintegrate within 3 min when
examined by the test for disintegration of tablets and capsules
described in section 2.9.1 in European Pharmacopoeia 5.1, 5.sup.th
edition 2005.
[0073] Throughout this specification with claims, the term
"hardness" refers to the "resistance to crushing of tablets" as
defined in section 2.9.8 in European Pharmacopoeia 5.1, 5.sup.th
edition 2005. Hardness may be measured inter alia in Newton (N) or
kilopond (kP). 1 kP=9.807 N.
[0074] Throughout this specification with claims, the term
"friability" has the meaning defined in section 2.9.7 in European
Pharmacopoeia 5.1, 5.sup.th edition 2005.
[0075] Throughout this specification with claims, the term
"water-soluble" refers to substances that are soluble, freely
soluble or very soluble in water as defined in European
Pharmacopoeia 5.1, 5.sup.th edition 2005. That is "water-soluble"
refers to substances where 1 g is soluble in less than 30 ml of
water. In particular it refers to such substances that are freely
soluble or very soluble in water. That is substances where 1 g is
soluble in less than 10 ml of water.
[0076] Throughout this specification with claims, the term
"disintegrant" refers to agents added to tablet granulation for the
purpose of causing the compressed tablet to break apart
(disintegrate) when placed in an aqueous environment.
[0077] In one particular embodiment, the invention relates to an
orodispersible tablet comprising escitalopram free base, whereas in
another equally particular embodiment the pharmaceutical
compositions of the invention may be administered in any suitable
way and in any suitable form, for example orally in the form of
tablets, capsules, powders or syrups, or parenterally in the form
of usual sterile solutions for injection. Preferably the
pharmaceutical compositions of the invention are administered
orally.
[0078] In one particular embodiment, the invention relates to an
orodispersible tablet comprising escitalopram free base, whereas in
another equally particular embodiment pharmaceutical formulations
comprising escitalopram free base of the invention may be prepared
by conventional methods in the art. For example, tablets may be
prepared by mixing the active ingredient with ordinary excipients
and subsequently compressing the mixture in a conventional
tabletting machine. Examples of excipients comprise:
microcrystalline cellulose, dibasic calcium phosphate, mannitol,
maize starch, potato starch, talcum, magnesium stearate, gelatine,
lactose, gums, and the like. Any other excipients such as
colourings, aroma, preservatives etc. may be used provided that
they do not reduce the shelf life of the tablets. Preferred
excipients do not adversely affect the stability of the active
ingredients in the formulation.
[0079] In one particular embodiment, the invention relates to an
orodispersible tablet comprising escitalopram free base, whereas in
another equally particular embodiment, the formulations according
to the invention may be prepared by direct compression of
escitalopram in admixture with conventional excipients.
Alternatively, a wet granulate or a melt granulate of escitalopram,
optionally in admixture with conventional excipients may be used
for compression of tablets.
[0080] Solutions for injections may be prepared by dissolving the
active ingredient and possible additives in a part of the solvent
for injection, preferably sterile water, adjusting the solution to
the desired volume, sterilisation of the solution and filling in
suitable ampoules or vials.
[0081] Any suitable additive conventionally used in the art may be
added, such as tonicity agents, preservatives, antioxidants,
solubility enhancing agents etc.
[0082] According to the present invention, the base of escitalopram
has been found to be crystalline with stable white crystals and it
has been found that the base may be crystallised easily in a very
pure form. So for example pure escitalopram base containing less
than 0.2% of impurities different from R-citalopram, particularly
less than 0.1% was obtained by crystallisation from at least 95%
pure escitalopram hydrobromide without further purification. In a
particular embodiment, pure escitalopram base that contains less
than 0.1% of any particular impurity was obtained. Accordingly, the
process of the invention for preparing salts of escitalopram has
been found to give the salts as very pure products of
pharmaceutically acceptable quality. Accordingly, the yield may be
improved substantially during the manufacture of escitalopram.
[0083] Melt agglomeration is an agglomeration process whereby a
molten binder liquid is used. The molten binder solidifies at room
temperature. One such binder is referred to as meltable binder. In
a melt agglomeration process, the process is usually conducted at
elevated temperatures. The process temperature can be similar to
the temperature at which the binder melts, but it can also be
higher and even below the melting point. Once the process
temperature reach the level that causes melting or softening of the
binder, the binder aid the formation and growth of agglomerates.
During the agglomeration process the temperature may be non-uniform
in the mixture due to local friction forces resulting in local
friction heating. This results in that part of the binder may be
solid whereas other parts may be melted or softened. The
agglomeration process may proceed by either the distribution
mechanism, the immersion mechanism or by a combination of the two
mechanisms. When agglomerates of the desired size are formed, the
agglomerates are cooled to a temperature below 40.degree. C.
whereby the molten or softened binder congeals. The agglomerates
can, subsequently, be mixed with excipients prior to compression
into tablets.
[0084] The process may also be conducted so that agglomeration does
not take place. In that case, the process could be termed a melt
coating process. The procedure is similar to the one described for
melt agglomeration. The only difference is that the coating
material, i.e. the meltable binder, will distribute over the filler
particles resulting in a more or less homogeneous coating layer. To
avoid agglomeration, the processing conditions or the amount of
coating material, i.e. meltable binder relative to the amount of
filler particles must be controlled. The coated filler particles
can subsequently be mixed with excipients prior to compression into
tablets.
[0085] The meltable binder used in melt agglomeration is usually
polyethylene glycols, fatty acids, fatty alcohols or glycerides. It
has now been found that pharmaceutically active substances with a
suitable melting point may be used as a meltable binder in a melt
agglomeration process. Suitable melting points are in the range of
40-100.degree. C.
[0086] In one embodiment, the agglomerate or coated filler particle
is prepared by melting the active pharmaceutical ingredient and
spraying or pouring the melt on the filler. The spraying or pouring
step may be performed in accordance with known procedures.
[0087] In another embodiment all constituents of the agglomerate or
coated filler particle are added to a high shear mixer, optionally
provided with a heating jacket. By operating the high shear mixer
the friction heat and/or heat supplied by the heating jacket will
melt the active pharmaceutical ingredient which deposits onto the
filler. This method is a very attractive method for melt
agglomeration, because the method is fast and easy to perform.
[0088] Melt extrusion is a process wherein the low melting point
compound and the filler are mixed and heated in a mixer that is
usually part of the extruder. The soft mass is then fed to the
extrusion chamber and forced through small holes or orifices to
shape it into thin rods or cylinders. The melt extrusion process
may alternatively be conducted by mixing the low melting compound
and the filler in an unheated mixer. The mixture is, subsequently,
transferred to a heated extruder. In the heated extruder, the low
melting compound melts and enables the formation of soft mass in
the extrusion chamber. The soft mass is forced through small holes
or orifices to shape it into thin rods or cylinders. After the
extruded material congeals it can be milled or spheronized using
standard equipment.
[0089] Agglomerates, coated filler particles or extrudates
according to the invention may be prepared using procedures and
apparatus known within the art for melt agglomeration.
[0090] Exemplary of apparatus, which may be used are low shear
mixers, high shear mixers, fluid beds, fluid bed granulators,
rotary fluidised beds and drum granulators.
[0091] Prior to tablet production, prestart operations is required
to establish the compression force needed to compress tablets of
the desired hardness, friability etc. Those skilled in the art will
know how to adjust the compression force in order to obtain the
desired hardness and/or friability. It is, however, known for the
skilled people within the art, that the compressibility of the
formulation determines what tablet hardness can be achieved by a
given compression force.
[0092] The invention is further illustrated by the following
examples.
[0093] HPLC analyses were performed on a Luna C.sub.18, (2)
250.times.4.6 mm, ID 5 .mu.m column with gradient eluation using
mobile phase A (25 mM aqueous phosphate buffer pH 3.0/acetonitrile
(90:10)) and mobile phase B (25 mM aqueous phosphate buffer pH
3.0/acetonitrile (35:65)) with UV detection at 224 nm. A column
temperature of 45.degree. C. was used, and injection volumes were
20 pt. Runtime was 65 min with the following gradient profile:
TABLE-US-00001 Time Phase A Phase B Flow (min) (%) (%) (ml/min) 0.0
95 5 1.0 35.0 65 35 1.0 45.0 0 100 1.0 45.1 0 100 2.0 60.0 0 100
1.0 60.1 95 5 1.0 65.0 95 5 1.0
[0094] Results were reported as area %. Standards were used only
for the identification of the mentioned compounds.
Example 1
Liberation of Escitalopram Free Base from Escitalopram Oxalate
[0095] 704 g of escitalopram oxalate was placed in a 6 L
three-necked flask equipped with mechanical stirrer and
pressure-equalising funnel. 3 L of water was added followed by 600
mL of diethyl ether. pH was adjusted to 9-9.5 by addition of 27%
w/w aqueous ammonia and the mixture was stirred for 1/2 hour. The
phases were separated and the water phase was extracted once more
with 300 mL of diethyl ether. The combined organic phases were
washed twice with 300 mL water, dried over MgSO.sub.4, filtered and
evaporated under vacuum at 40.degree. C. to give a light brown
oil.
[0096] Yield: 542.5 g (98.4%)
Example 2
Precipitation of Escitalopram Hydrobromide, Liberation of the Free
Base and Crystallisation of the Base
Precipitation of the Escitalopram Hydrobromide Salt:
[0097] 3 kg of escitalopram free base (purity by HPLC: 99.16% (area
%)) as a light brown oil dissolved in 12 kg of 2-propanol was
charged into a 20 L thermostatically controlled reactor with
mechanical stirring, reflux condenser, scrubber, gas-inlet and
thermometer. The solution was heated to 40.degree. C. and HBr gas
was bubbled through the solution until pH was between 3 and 4. This
reaction was exothermic and the temperature in the reactor was kept
between 40 and 43.degree. C. A small amount of seeding crystals
(escitalopram hydrobromide, 100-200 mg) was added and
crystallisation started within 10 minutes. The mixture was then
slowly cooled to 10.degree. C. over 5 hours and kept at this
temperature for an additional 12 hours. The crystals were filtered
off, rinsed on the filter with 3.times.1 L 2-propanol and dried to
constant weight under vacuum at 60.degree. C.
[0098] Yield: 3.49 kg (93%)
[0099] Purity of the product by HPLC: 99.86% (area %)
Liberation of the Free Base:
[0100] 650 g of escitalopram hydrobromide (purity by HPLC (the
hydrobromide salt): 99.86% by area %) was placed in a 4 L
three-necked flask equipped with mechanical stirrer and
pressure-equalising funnel. 2 L of water was added followed by 1 L
of diethyl ether. pH was adjusted to 9-9.5 by addition of 27% w/w
aqueous ammonia and the mixture was stirred for 1/2 hour. The
phases were separated and the water phase was extracted once more
with 500 mL of diethyl ether. The combined organic phases were
washed twice with 300 mL water, dried over MgSO.sub.4, filtered and
evaporated under vacuum at 40.degree. C. to give a light brown
oil.
[0101] Yield: 520 g (100%)
Crystallisation of the Free Base:
[0102] The escitalopram free base was transferred to a 2 L
thermostatically controlled reactor equipped with mechanical
stirrer, reflux condenser, N.sub.2 in/out and a thermometer. 50 mL
of ethyl acetate was added followed by 1.3 L heptane. The mixture
was heated to 40.degree. C. to form a homogeneous solution.
Hereafter, a slow cooling to -5.degree. C. over 12 hours was begun
and when the temperature was about 20.degree. C. the mixture was
seeded with a small amount of escitalopram oxalate (10-20 mg).
Crystallisation of the free base started after about 1/2 hour. The
mixture was then stirred for 5 hours at -5.degree. C., the crystals
were filtered off, rinsed on the filter with 2.times.150 mL heptane
and dried under vacuum at 25.degree. C. to constant weight.
[0103] Yield: 432 g (83%)
[0104] Purity of the product by HPLC: 99.95% (area %)
[0105] Melting point (DSC, onset): 46.6.degree. C.
Example 3
Crystallisation of Escitalopram Free Base
[0106] 520 g of escitalopram free base as a light brown oil
(Purity: 99.25%; HPLC) was placed in a 2 L thermostatically
controlled reactor equipped with mechanical stirrer, reflux
condenser, N.sub.2 in/out and a thermometer. 50 mL of ethyl acetate
was added and the mixture was heated to 35.degree. C. whereupon 1.3
L heptane was added. When the solution was homogeneous a slow
cooling to -5.degree. C. over 12 hours was begun. When the
temperature was 20.degree. C., a small amount (10-20 mg) of seeding
crystals (Escitalopram base) were added. Crystallization started
around 10.degree. C. The mixture was stirred at -5.degree. C. for
an additional 5-7 hours whereafter the crystals were removed by
filtration. The crystals were washed on the filter with 2.times.150
mL of heptane and dried under vacuum at 25.degree. C. to constant
weight.
[0107] Yield: 485 g (93.3%)
[0108] Purity of product by HPLC: 99.58% (area %)
[0109] Melting point (DSC, onset): 45.8.degree. C.
Example 4
Purification of Escitalopram by Precipitation of Escitalopram Free
Base or Hydrobromide
[0110] A stock solution of escitalopram (free base, oil) in ethanol
was used. The ethanol was removed under reduced pressure, and 400 g
of the resulting oil was measured into a flask, where the following
were added: 2 g of the 5-amido analogue of citalopram
((R,S)-1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenz-
ofuran-5-carboxylic acid amide), 2 g of the 5-bromo analogue of
citalopram
((R,S)-{3-[5-bromo-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-pr-
opyl}-dimethyl-amine) and 2 g of the desmethyl analogue of
citalopram
((R,S)-1-(4-fluoro-phenyl)-1-(3-methylamino-propyl)-1,3-dihydro-isobenzof-
uran-5-carbonitrile). The resulting mixture (S0) was dissolved in
ethyl acetate to 1000 mL, and divided into 4 equal parts, and each
were evaporated separately to give an oil.
[0111] The four parts were each sequentially crystallized according
to the below scheme and procedures:
##STR00005##
Precipitation of the Crystalline Free Base:
[0112] 100 g of the free base was dissolved in 10 mL of ethyl
acetate and 240 mL of heptane at 40.degree. C. The mixture was
allowed to cool to room temperature where the mixture was seeded
with crystalline escitalopram free base. The mixture was then
cooled to ca. 0.degree. C. and stirred for ca. 2 hours, the
crystals were filtered off, rinsed on the filter with heptane and
dried under vacuum at 25.degree. C. to constant weight.
[0113] Recrystallization of the free base followed the same
procedure as precipitation of the free base.
Precipitation of the Escitalopram Hydrobromide Salt:
[0114] 100 g of the free base was dissolved in 250 mL of
2-propanol. Hydrogen bromide (anhydrous) in 2-propanol was added
until a pH of 3.5-4 was obtained and the volume was adjusted to 400
mL with 2-propanol. The crystallization started within 10 minutes.
The mixture was then allowed to cool to room temperature and was
stirred for ca. 2 hours. The crystals were filtered off, rinsed on
the filter with 2-propanol and dried to constant weight under
vacuum at 60.degree. C.
Recrystallization of the Escitalopram Hydrobromide Salt:
[0115] 100 g escitalopram hydrobromide was dissolved in 500 mL of
2-propanol at 70.degree. C. The mixture was allowed to cool to room
temperature. The crystals were filtered off, rinsed on the filter
with 2-propanol and dried to constant weight under vacuum at
60.degree. C.
Precipitation of the Escitalopram Oxalate Salt:
[0116] 100 g of the free base was dissolved in 250 mL of
2-propanol. 1 eq. of oxalic acid dihydrate was dissolved in 250 mL
of warm 2-propanol and was added at 40.degree. C. to the solution
of escitalopram base. After stirring at 40.degree. C. for 10 min
the crystallization started. The mixture was then allowed to cool
to room temperature and stirred for ca. 2 hours. The crystals were
filtered off, rinsed on the filter with 2-propanol and dried to
constant weight under vacuum at 60.degree. C.
Recrystallization of the Escitalopram Oxalate Salt:
[0117] 100 g escitalopram oxalate was dissolved in 1250 mL ethanol
at reflux. The mixture was allowed to cool to room temperature. The
crystals were filtered off, rinsed on the filter with ethanol and
dried to constant weight under vacuum at 60.degree. C.
Liberation of the Free Base:
[0118] 100 g escitalopram hydrobromide or oxalate was dissolved or
suspended in water and ethyl acetate was added. pH was adjusted to
9-9.5 by addition of 27% w/w aqueous ammonia and the mixture was
stirred for 1/2 hour. The phases were separated and the water phase
was extracted once more with ethyl acetate. The combined organic
phases were washed with water, dried over MgSO.sub.4, filtered and
evaporated under vacuum at 40.degree. C. to give a light brown
oil.
[0119] After each precipitation or crystallization a sample was
taken which was analysed for overall purity and the content of the
5-amido analogue of citalopram, the 5-bromo analogue of citalopram
and the desmethyl analogue of citalopram. The results are given in
% in table 1. All the products were crystalline unless otherwise
stated.
TABLE-US-00002 TABLE 1 5-amido 5-bromo desmethyl Sample Form Purity
analogue analogue analogue S.0 Base (Oil) 97.63 0.52 0.50 0.47
S.I.1 Base 98.51 0.48 0.44 0.13 S.I.2 HBr 99.50 0.07 0.21 0.06
S.I.3 Base 99.65 0.06 0.20 0.03 S.I.4 Oxalate 99.60 0.05 0.17 0.03
S.0 Base (Oil) 97.63 0.52 0.50 0.47 S.II.1 Base 98.55 0.42 0.42
0.14 S.II.2 Base 98.71 0.43 0.42 0.07 S.II.3 Base 98.78 0.45 0.40
0.04 S.II.4 Oxalate 98.87 0.41 0.37 0.04 S.0 Base (Oil) 97.63 0.52
0.50 0.47 S.III.1 HBr 99.34 0.10 0.23 0.16 S.III.2 HBr 99.65 0.02
0.15 0.06 S.III.3 Base 99.71 0.017 0.16 0.03 S.III.4 Oxalate 99.70
0.015 0.10 0.03 S.0 Base (Oil) 97.63 0.52 0.50 0.47 S.IV.1 Oxalate
98.06 0.45 0.42 0.48 S.IV.2 Oxalate 98.81 0.20 0.21 0.47 S.IV.3
Base 99.42 0.16 0.165 0.13 S.IV.4 Oxalate 99.34 0.15 0.15 0.13
Example 5
Purification of Escitalopram by Precipitation of Escitalopram Free
Base or Hydrobromide
TABLE-US-00003 [0120] 5-Amido Desmethyl 5-Chloro 5-Bromo Sample #
Lu 14-017 Lu 11-109 Lu 10-134 Lu 10-132 Escitalopram Enantiomer
Type (S) (S) (S) (S) LC-MS purity (%) T.0 Crude 0.73 0.753 0.165
0.291 97.59 T.I hemi-Oxalate 0.253 0.274 0.167 0.289 98.89 T.II
Recryst. ox. 0.13 0.114 0.164 0.276 99.27 T.III.1 Base 0.118 0.115
0.091 0.166 99.51 T.IV.1 hemi-Oxalate 0.078 0.059 0.069 0.133 99.66
T.0 Crude 0.73 0.753 0.165 0.291 97.59 T.I hemi-Oxalate 0.253 0.274
0.167 0.289 98.89 T.II Recryst. ox. 0.13 0.114 0.164 0.276 99.27
T.III.2 HBr salt 0.022 0.064 0.078 0.137 99.67 T.IV.2 hemi-Oxalate
0.014 0.037 0.073 0.126 99.76
[0121] Crude escitalopram base (oil, 20.7 g) (T.0) (purity: 97.59%
measured by LC-MS against standards) containing the four impurities
5-amido analogue of escitalopram
((5)-1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzof-
uran-5-carboxylic acid amide) (0.73%); desmethyl analogue of
escitalopram
((5)-1-(4-fluoro-phenyl)-1-(3-methyl-amino-propyl)-1,3-dihydro-isobenzofu-
ran-5-carbonitrile) (0.753%); 5-chloro analogue of escitalopram
((S)-{3-[5-chloro-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-pro-
pyl}-dimethyl-amine) (0.165%); 5-bromo analogue of escitalopram
((S)-{3-[5-bromo-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-1-yl]-prop-
yl}-dimethyl-amine) (0.291%)) as described in the above schemes was
purified in different ways.
[0122] A hemi-oxalate salt of escitalopram was precipitated from
IPA (2-propanol, 150 mL) and oxalic acid, 2H.sub.2O (8.0 grams)
(T.I, 26.0 g). The hemi oxalate salt (T.I, 26.0 g) was
recrystallized from IPA (250 mL) (T.II, 24.3 g)
[0123] From (T.II, 20 g) escitalopram base was liberated and
isolated as an oil (15.4 g). About half the amount of this base
(7.8 g) was precipitated as the crystalline base from
(n-heptane/ethyl:acetate (95:5), 8.5 mL) (T.III.1, 7.0 g). The
other half (7.6 g) was dissolved in IPA (60 mL) and by adding HBr
(HBr in IPA: 0.12 g HBr/mL; 16.6 mL) escitalopram hydrobromide was
precipitated and isolated in crystalline form (T.III.2, 8.53
g).
[0124] (T.III.1, 6.91 g) was dissolved in IPA (70 mL) and oxalic
acid, 2H.sub.2O (2.82 g) was added. The hemi-oxalate of
escitalopram precipitated (T.IV.1, 8.67 g). Likewise a hemi-oxalate
salt of escitalopram (T.IV.2, 8.35 g) was precipitated after
liberating and isolating the base (6.78 g) from (T.III.2) from IPA
(70 mL) and oxalic acid, 2H.sub.2O (2.77 g).
Example 6
Reduction of the Content of Escitalopram N-Oxide in
Escitalopram
[0125] Escitalopram base (51.3 grams, purity 98.60% (HPLC-area %))
containing escitalopram N-oxide (0.45% by HPLC-area %) was
dissolved in diethyl ether (250 mL) at room temperature. Almost
immediately after the crude escitalopram was dissolved, a
precipitate started to form. The suspension was stirred for three
hours at 20.degree. C. A precipitate (0.77 gram) was filtered off
and identified with LC-MS to be a mixture of escitalopram base and
escitalopram N-oxide in a ratio of about 2/1. The filtrate
contained escitalopram base (50.5 grams, purity 99.0% (HPLC-area
%)). The amount of escitalopram N-oxide in the filtrate was
measured to 0.07% (HPLC-area %) relative to escitalopram base.
Formulation Examples
Orodispersible Tablets
Example 7
TABLE-US-00004 [0126] TABLE 2 Composition mg/tablet I Escitalopram
base 4.98 II Mannitol (Pearlitol SD 100) 99.57 III Mannitol
(Pearlitol SD 100) 73.80 IV Microcrystalline cellulose 63.96
(Avicel PH 101) V Magnesium stearate 3.69
(I) Escitalopram base and (II) mannitol (Pearlitol SD 100) were
melt agglomerated in a high shear mixer. The temperature of the
heating mantle was kept at 50.degree. C. and a mixer speed of 500
rpm was applied. The resulting mixture was mixed with (III)
mannitol (extragranular filler), (IV) microcrystalline cellulose
(Avicel PH101) (extragranullar filler) and (V) magnesium stearate
(lubricant). The mixture was split into three portions. Each
portion was compressed into tablets using different compression
pressures during the tabletting process. The tablet hardnesses,
tablet friabilities and the disintegration times are shown in Table
3.
TABLE-US-00005 TABLE 3 Compression Tablet Tablet Disintegration
pressure level hardness (N) friability (%) time (Min:Sec) 1 67 0.19
00:26 2 93 0.09 00:50 3 103 0.08 01:26
Example 8
TABLE-US-00006 [0127] TABLE 4 Composition mg/tablet I Escitalopram
base 4.98 II Mannitol (Pearlitol SD 100) 99.57 III Mannitol
(Pearlitol SD 100) 61.5 IV Microcrystalline cellulose 51.66 (Avicel
PH 101) V Croscarmellose sodium (Ac-Di-Sol) 24.6 VI Magnesium
stearate 3.69
(I) Escitalopram base and (II) mannitol (Pearlitol SD 100) were
melt agglomerated in a high shear mixer. The temperature of the
heating mantle was kept at 50.degree. C. and a mixer speed of 500
rpm was applied. The resulting mixture was mixed with (III)
mannitol (extragranular filler), (IV) microcrystalline cellulose
(Avicel PH101) (extragranullar filler), (V) Ac-Di-Sol
(disintegrant) and (VI) magnesium stearate (lubricant). The mixture
was split into three portions. Each portion was compressed into
tablets using different compression pressures during the tabletting
process. The tablet hardnesses, tablet friabilities and the
disintegration times are shown in Table 5.
TABLE-US-00007 TABLE 5 Compression Tablet Tablet Disintegration
pressure level hardness (N) friability (%) time (Min:Sec) 1 56
Non-detectable 00:30 2 78 Non-detectable 00:46 3 107 Non-detectable
00:56
Example 9
TABLE-US-00008 [0128] TABLE 6 Composition mg/tablet I Escitalopram
base 5.0 II Mannitol (Pearlitol SD 100) 100.04 III Mannitol
(Pearlitol SD 100) 73.80 IV Microcrystalline cellulose 51.17
(Avicel PH 101) V Crospovidon (Kollidon CL) 12.3 VI Magnesium
stearate 3.69
(I) Escitalopram base and (II) mannitol (Pearlitol SD 100) were
melt agglomerated in a high shear mixer. The temperature of the
heating mantle was kept at 50.degree. C. and a mixer speed of 500
rpm was applied. The resulting mixture was mixed with (III)
mannitol (extragranular filler), (IV) microcrystalline cellulose
(Avicel PH101) (extragranullar filler), (V) crospovidon (Kollidon
CL) (disintegrant) and (VI) magnesium stearate (lubricant). The
mixture was split into three portions. Each portion was compressed
into tablets using different compression pressures during the
tabletting process. The tablet hardnesses, tablet friabilities and
the disintegrating times are shown in Table 7.
TABLE-US-00009 TABLE 7 Compression Tablet Tablet Disintegrating
pressure level hardness (N) friability (%) time (Min:Sec) 1 70 0.11
00:14 2 90 0.04 00:21 3 121 0.007 00:35
Example 10
TABLE-US-00010 [0129] TABLE 8 Composition mg/tablet I Escitalopram
base 5.0 II Mannitol (Pearlitol SD 100) 100.04 III Mannitol
(Pearlitol SD 100) 73.80 IV Microcrystalline cellulose 51.17
(Avicel PH 101) V Primojel 12.3 VI Magnesium stearate 3.69
(I) Escitalopram base and (II) mannitol (Pearlitol SD 100) were
melt agglomerated in a high shear mixer. The temperature of the
heating mantle was kept at 50.degree. C. and a mixer speed of 500
rpm was applied. The resulting mixture was mixed with (III)
mannitol (extragranular filler), (IV) microcrystalline cellulose
(Avicel PH101) (extragranullar filler), (V) Primojel (disintegrant)
and (VI) magnesium stearate (lubricant). The mixture was split into
three portions. Each portion was compressed into tablets using
different compression pressures during the tabletting process. The
tablet hardnesses, tablet friabilities and the disintegration times
are shown in Table 9.
TABLE-US-00011 TABLE 9 Compression Tablet Tablet Disintegration
pressure level hardness (N) friability (%) time (Min:Sec) 1 64 0.26
00:20 2 85 0.19 00:27 3 103 0.13 00:40
Example 11
TABLE-US-00012 [0130] TABLE 10 Composition mg/tablet I Escitalopram
base 5.0 II Mannitol (Pearlitol SD 100) 100.04 III Mannitol
(Pearlitol SD 100) 73.80 IV Microcrystalline cellulose 51.17
(Avicel PH 101) V Croscarmellose sodium (Ac-Di-Sol) 12.3 VI
Magnesium stearate 3.69
(I) Escitalopram base and (II) mannitol (Pearlitol SD 100) were
melt agglomerated in a high shear mixer. The temperature of the
heating mantle was kept at 50.degree. C. and a mixer speed of 500
rpm was applied. The resulting mixture was mixed with (III)
mannitol (extragranular filler), (IV) microcrystalline cellulose
(Avicel PH101) (extragranullar filler), (V) Ac-Di-Sol
(disintegrant) and (VI) Magnesium stearate (lubricant). The mixture
was split into three portions. Each portion was compressed into
tablets using different compression pressures during the tabletting
process. The tablet hardnesses, tablet friabilities and the
disintegration times are shown in Table 11.
TABLE-US-00013 TABLE 11 Compression Tablet Tablet Disintegration
pressure level hardness (N) friability (%) time (Min:Sec) 1 64 0.16
00:22 2 87 0.15 00:31 3 94 0.11 00:32
Example 12
TABLE-US-00014 [0131] TABLE 12 Composition mg/tablet I Escitalopram
base 5.01 II Mannitol (Pearlitol SD 100) 47.52 III Mannitol
(Pearlitol SD 100) 36.90 IV Microcrystalline cellulose 25.58
(Avicel PH 101) V Crospovidon (Kollidon CL) 6.15 VI Magnesium
stearate 1.85
(I) Escitalopram base and (II) mannitol (Pearlitol SD 100) were
melt agglomerated in a high shear mixer. The temperature of the
heating mantle was kept at 50.degree. C. and a mixer speed of 500
rpm was applied. The resulting mixture was mixed with (III)
mannitol (extragranular filler), (IV) microcrystalline cellulose
(Avicel PH101) (extragranullar filler), (V) Crospovidon (Kollidon
CL) (disintegrant) and (VI) magnesium stearate (lubricant). The
mixture was split into three portions. Each portion was compressed
into tablets using different compression pressures during the
tabletting process. The tablet hardnesses, tablet friabilities and
the disintegration times are shown in Table 13.
TABLE-US-00015 TABLE 13 Compression Tablet Tablet Disintegration
pressure level hardness (N) friability (%) time (Min:Sec) 1 35 0.6
00:14 2 58 0.6 00:30 3 86 0.62 01:22
Example 13
TABLE-US-00016 [0132] TABLE 14 Composition mg/tablet I Escitalopram
base 5.02 II Crystalline Maltitol (Maltisorb P 90) 100.46 III
Mannitol (Pearlitol SD 100) 36.00 IV Microcrystalline cellulose
25.02 (Avicel PH 102) V Croscarmellose sodium (Ac-Di-Sol) 9.00 VI
Magnesium stearate 4.5
(I) Escitalopram base and (II) crystalline maltitol (Maltisorb P
90) were melt agglomerated in a high shear mixer. The temperature
of the heating mantle was kept at 80.degree. C. and a mixer speed
of 800 rpm was applied. The resulting mixture was mixed with (III)
mannitol (extragranular filler), (IV) microcrystalline cellulose
(Avicel PH102) (extragranullar filler), (V) Ac-Di-Sol
(disintegrant) and (VI) magnesium stearate (lubricant). The mixture
was compressed into tablets. The tablet hardnesses, tablet
friabilities and the disintegration times are shown in Table
15.
TABLE-US-00017 TABLE 15 Compression Tablet Tablet Disintegration
pressure level hardness (N) friability (%) time (Min:Sec) 1 24.6
Not measured 01:09
Example 14
TABLE-US-00018 [0133] TABLE 16 Composition mg/tablet I Escitalopram
base 5.02 II Crystalline Dextrose monohydrate SF 100.46 III
Mannitol (Pearlitol SD 100) 36.00 IV Microcrystalline cellulose
25.02 (Avicel PH 102) V Croscarmellose sodium (Ac-Di-Sol) 9.00 VI
Magnesium stearate 4.5
(I) Escitalopram base and (II) crystalline dextrose monohydrate SF
(particle size approx. 50 .mu.m) were melt agglomerated in a high
shear mixer. The temperature of the heating mantle was kept at
80.degree. C. and a mixer speed of 800 rpm was applied. The
resulting mixture was mixed with (III) mannitol (extragranular
filler), (IV) microcrystalline cellulose (Avicel PH102)
(extragranullar filler), (V) Ac-Di-Sol (disintegrant) and (VI)
magnesium stearate (lubricant). The mixture was compressed into
tablet. The tablet hardnesses, tablet friabilities and the
disintegration times are shown in Table 17.
TABLE-US-00019 TABLE 17 Compression Tablet Tablet Disintegration
pressure level hardness (N) friability (%) time (Min:Sec) 1 30.5
0.6 01:11
Example 15
TABLE-US-00020 [0134] TABLE 18 Composition mg/tablet I Escitalopram
base 5.02 II Crystalline Lactose 100.46 III Mannitol (Pearlitol SD
100) 36.00 IV Microcrystalline cellulose 25.02 (Avicel PH 102) V
Croscarmellose sodium (Ac-Di-Sol) 9.00 VI Magnesium stearate
4.5
(I) Escitalopram base and (II) crystalline lactose (Pharmatose 125
M. Particle size approx. 55 .mu.m) were melt agglomerated in a high
shear mixer. The temperature of the heating mantle was kept at
80.degree. C. and a mixer speed of 800 rpm was applied. The
resulting mixture was mixed with (III) mannitol (extragranular
filler), (IV) microcrystalline cellulose (Avicel PH102)
(extragranullar filler), (V) Ac-Di-Sol (disintegrant) and (VI)
magnesium stearate (lubricant). The mixture was split into two
portions. Each portion was compressed into tablets using different
compression pressures during the tabletting process. The tablet
hardnesses, tablet friabilities and the disintegration times are
shown in Table 19.
TABLE-US-00021 TABLE 19 Compression Tablet Tablet Disintegration
pressure level hardness (N) friability (%) time (Min:Sec) 1 33.5
0.5 00:37 2 41.7 0.5 00:34
Example 16
TABLE-US-00022 [0135] TABLE 20 Composition mg/tablet I Escitalopram
base 5.02 II Crystalline Lactose 100.46 III Mannitol (Pearlitol SD
100) 36.00 IV Microcrystalline cellulose 25.02 (Avicel PH 102) V
Croscarmellose sodium (Ac-Di-Sol) 9.00 VI Magnesium stearate
4.5
(I) Escitalopram base and (II) crystalline lactose (Pharmatose 110
M. Particle size approx. 105 .mu.m) were melt agglomerated in a
high shear mixer. The temperature of the heating mantle was kept at
80.degree. C. and a mixer speed of 800 rpm was applied. The
resulting mixture was mixed with (III) mannitol (extragranular
filler), (IV) microcrystalline cellulose (Avicel PH102)
(extragranullar filler), (V) Ac-Di-Sol (disintegrant) and (VI)
magnesium stearate (lubricant). The mixture was split into three
portions. Each portion was compressed into tablets using different
compression pressures during the tabletting process. The tablet
hardnesses, tablet friabilities and the disintegration times are
shown in Table 21.
TABLE-US-00023 TABLE 21 Compression Tablet Tablet Disintegration
pressure level hardness (N) friability (%) time (Min:Sec) 1 33.3
0.5 00:38 2 36.3 0.6 01:03 3 40.4 0.6 01:20
Example 17
TABLE-US-00024 [0136] TABLE 22 Composition mg/tablet I Escitalopram
base 5.02 II Crystalline Lactose 100.46 III Mannitol (Pearlitol SD
100) 36.00 IV Microcrystalline cellulose 25.02 (Avicel PH 102) V
Croscarmellose sodium (Ac-Di-Sol) 9.00 VI Magnesium stearate
4.5
(I) Escitalopram base and (II) crystalline lactose (Pharmatose 90
M. Particle size approx. 135 .mu.m) were melt agglomerated in a
high shear mixer. The temperature of the heating mantle was kept at
80.degree. C. and a mixer speed of 800 rpm was applied. The
resulting mixture was mixed with (III) mannitol (extragranular
filler), (IV) microcrystalline cellulose (Avicel PH102)
(extragranullar filler), (V) Ac-Di-Sol (disintegrant) and (VI)
magnesium stearate (lubricant). The mixture was compressed into
tablets. The tablet hardnesses, tablet friabilities and the
disintegration times are shown in Table 23.
TABLE-US-00025 TABLE 23 Compression Tablet Tablet Disintegration
pressure level hardness (N) friability (%) time (Min:Sec) 1 30.6
0.8 00:53
Example 18
TABLE-US-00026 [0137] TABLE 24 Composition mg/tablet I Escitalopram
base 5.02 II Spraydried Lactose 100.46 III Mannitol (Pearlitol SD
100) 36.00 IV Microcrystalline cellulose 25.02 (Avicel PH 102) V
Croscarmellose sodium (Ac-Di-Sol) 9.00 VI Magnesium stearate
4.5
(I) Escitalopram base and (II) spraydried lactose (Pharmatose DCL
11. Particle size approx. 110 .mu.m) were melt agglomerated in a
high shear mixer. The temperature of the heating mantle was kept at
80.degree. C. and a mixer speed of 800 rpm was applied. The
resulting mixture was mixed with (III) mannitol (extragranular
filler), (IV) microcrystalline cellulose (Avicel PH102)
(extragranullar filler), (V) Ac-Di-Sol (disintegrant) and (VI)
magnesium stearate (lubricant). The mixture was compressed into
tablets. The tablet hardnesses, tablet friabilities and the
disintegration times are shown in Table 25.
TABLE-US-00027 TABLE 25 Compression Tablet Tablet Disintegration
pressure level hardness (N) friability (%) time (Min:Sec) 1 25.1
0.9 00:49
Example 19
TABLE-US-00028 [0138] TABLE 26 Composition mg/tablet I Escitalopram
base 5.02 II Spraydried lactose 100.46 III Mannitol (Pearlitol SD
100) 36.00 IV Microcrystalline cellulose 25.02 (Avicel PH 102) V
Croscarmellose sodium (Ac-Di-Sol) 9.00 VI Magnesium stearate
4.5
(I) Escitalopram base and (II) spraydried lactose (Pharmatose DCL
14. Particle size approx. 110 .mu.m) were melt agglomerated in a
high shear mixer. The temperature of the heating mantle was kept at
80.degree. C. and a mixer speed of 800 rpm was applied. The
resulting mixture was mixed with (III) mannitol (extragranular
filler), (IV) microcrystalline cellulose (Avicel PH102)
(extragranullar filler), (V) Ac-Di-Sol (disintegrant) and (VI)
magnesium stearate (lubricant). The mixture was compressed into
tablets. The tablet hardnesses, tablet friabilities and the
disintegration times are shown in Table 27.
TABLE-US-00029 TABLE 27 Compression Tablet Tablet Disintegration
pressure level hardness (N) friability (%) time (Min:Sec) 1 24.3
0.8 01:01
Example 20
TABLE-US-00030 [0139] TABLE 28 Composition mg/tablet I Fenofibrate
5.02 II Mannitol (Pearlitol SD 100) 100.46 III Mannitol (Pearlitol
SD 100) 36.00 IV Microcrystalline cellulose 25.02 (Avicel PH 102) V
Croscarmellose sodium (Ac-Di-Sol) 9.00 VI Magnesium stearate
4.5
(I) Fenofibrate and (II) mannitol (Pearlitol SD 100) were melt
agglomerated in a high shear mixer. The temperature of the heating
mantle was kept at 80.degree. C. The resulting mixture was mixed
with (III) mannitol (extragranular filler), (IV) microcrystalline
cellulose (Avicel PH102) (extragranullar filler), (V) Ac-Di-Sol
(disintegrant) and (VI) magnesium stearate (lubricant). The mixture
was split into two portions. Each portion was compressed into
tablets using different compression pressures during the tabletting
process. The tablet hardnesses, tablet friabilities and the
disintegration times are shown in Table 29.
TABLE-US-00031 TABLE 29 Compression Tablet Tablet Disintegration
pressure level hardness (N) friability (%) time (Min:Sec) 1 33.2
0.6 00:28 2 56.3 0.7 00:30
Example 21
TABLE-US-00032 [0140] TABLE 30 Composition mg/tablet I Escitalopram
base 4.99 II Mannitol (Pearlitol 160C) 99.84 III Mannitol
(Pearlitol 160C) 36.40 IV Microcrystalline cellulose 25.30 (Avicel
PH 102) V Crospovidon (Kollidon CL) 9.10 VI Magnesium stearate
6.37
(I) Escitalopram base and (II) mannitol (Pearlitol 160C. Particle
size approx. 160 .mu.m) were melt agglomerated in a high shear
mixer. The temperature of the heating mantle was kept at 65.degree.
C. and a mixer speed of 500 rpm was applied. The resulting mixture
was mixed with (III) mannitol (Pearlitol 160C) (extragranular
filler), (IV) microcrystalline cellulose (Avicel PH101)
(extragranullar filler), (V) Crospovidon (disintegrant) and (VI)
magnesium stearate (lubricant). The mixture was compressed into
tablets. The tablet hardnesses, tablet friabilities and the
disintegration times are shown in Table 31.
TABLE-US-00033 TABLE 31 Compression Tablet Tablet Disintegration
pressure level hardness (N) friability (%) time (Min:Sec) 1 24.1
0.7 00:18
Example 22
TABLE-US-00034 [0141] TABLE 32 Composition mg/tablet I Escitalopram
base 4.99 II Mannitol (Pearlitol 300DC) 99.84 III Mannitol
(Pearlitol 300DC) 36.40 IV Microcrystalline cellulose 25.30 (Avicel
PH 102) V Crospovidon (Kollidon CL) 9.10 VI Magnesium stearate
6.37
(I) Escitalopram base and (II) mannitol (Pearlitol 300DC. Particle
size approx. 300 .mu.m) were melt agglomerated in a high shear
mixer. The temperature of the heating mantle was kept at 65.degree.
C. and a mixer speed of 500 rpm was applied. The resulting mixture
was mixed with (III) mannitol (Pearlitol 300DC) (extragranular
filler), (IV) microcrystalline cellulose (Avicel PH101)
(extragranullar filler), (V) Crospovidon (disintegrant) and (VI)
magnesium stearate (lubricant). The mixture was compressed into
tablets. The tablet hardnesses, tablet friabilities and the
disintegration times are shown in Table 33.
TABLE-US-00035 TABLE 33 Compression Tablet Tablet Disintegration
pressure level hardness (N) friability (%) time (Min:Sec) 1 27 0.33
00:30
* * * * *