U.S. patent application number 12/591787 was filed with the patent office on 2010-04-01 for processes for the preparation of different forms of (s)-(+)-clopidogrel besylate.
This patent application is currently assigned to CADILA HEALTHCARE LIMITED. Invention is credited to Mayank Ghanshyambhai Dave, Parind Narendra Dholakia, Braj Bhushan Lohray, Vidya Bhushan Lohray, Bipin Pandey.
Application Number | 20100081824 12/591787 |
Document ID | / |
Family ID | 37898811 |
Filed Date | 2010-04-01 |
United States Patent
Application |
20100081824 |
Kind Code |
A1 |
Lohray; Braj Bhushan ; et
al. |
April 1, 2010 |
Processes For the preparation of different forms of
(S)-(+)-Clopidogrel besylate
Abstract
Improved processes for the preparation of different forms of
(S)-(+)-Clopidogrel besylate, pharmaceutical compositions
containing them and their use in medicine.
Inventors: |
Lohray; Braj Bhushan;
(Ahmedabad, IN) ; Lohray; Vidya Bhushan;
(Ahmedabad, IN) ; Pandey; Bipin; (Ahmedabad,
IN) ; Dave; Mayank Ghanshyambhai; (Ahmedabad, IN)
; Dholakia; Parind Narendra; (Ahmedabad, IN) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON
VA
22203
US
|
Assignee: |
CADILA HEALTHCARE LIMITED
Ahmedabad
IN
|
Family ID: |
37898811 |
Appl. No.: |
12/591787 |
Filed: |
December 1, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12065386 |
Aug 11, 2008 |
|
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PCT/IN2006/000322 |
Aug 28, 2006 |
|
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12591787 |
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Current U.S.
Class: |
546/114 |
Current CPC
Class: |
C07D 495/04
20130101 |
Class at
Publication: |
546/114 |
International
Class: |
C07D 495/04 20060101
C07D495/04 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 5, 2005 |
IN |
1072/MUM/2005 |
Claims
1. A process for the preparation of amorphous form of
(S)-(+)-Clopidogrel besylate comprising: i. treating Clopidogrel
base with benzene sulfonic acid in suitable solvent(s) selected
from tetrahydrofuran, methyl isobutyl ketone, or their suitable
mixtures; and ii. removing the solvent to obtain the amorphous
form.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of co-pending U.S. Ser. No.
12/065,386 filed Feb. 29, 2008, which was the U.S. national phase
of International Application No. PCT/IN2006/000322, filed 28 Aug.
2006, which designated the U.S. and claimed priority based on IN
1072/MUM/2005, filed 5 Sep. 2005, the entire contents of all of
which are hereby incorporated by reference.
BACKGROUND
[0002] 1. Technical Field
[0003] The present invention relates to an improved processes for
the preparation of different forms of (S)-(+)-Clopidogrel besylate,
pharmaceutical compositions containing them and their use in
medicine.
[0004] Clopidogrel has the following structure (1):
##STR00001##
[0005] It is available in the market as its bisulfate salt and is
marketed by Sanofi-Synthelabo as "Plavix" having the general
formula (II):
##STR00002##
[0006] Clopidogrel is an inhibitor of platelet aggregation and is
marketed as an anti-anginal agent and an anti-platelet agent, and
is found to decrease morbid events in people with established
atherosclerotic cardiovascular disease and cerebrovascular
diseases.
[0007] 2. Related Art
[0008] The therapeutic application of Clopidogrel as a
blood-platelet aggregation inhibiting agent and an anti-thrombotic
agent, and its preparation is disclosed in U.S. Pat. No. 4,529,596.
U.S. Pat. No. 4,847,265 describes the process for the preparation
of the hydrogen sulfate salt of Clopidogrel.
[0009] Polymorphs of Clopidogrel bisulfate has been described in
U.S. Pat. Nos. 6,504,040 and 6,429,210. We have disclosed novel
polymorphs of Clopidogrel bisulfate in our published International
Application No. WO2004/081016.
[0010] U.S. Pat. No. 4,847,265 discloses that the dextrorotatory
enantiomer of formula (I) of Clopidogrel has an excellent
anti-aggregant platelet activity, whereas the corresponding
levorotatory enantiomer of (I) is less tolerated of the two
enantiomers and is less active. U.S. Pat. No. 4,847,265 also
describes various other salts of Clopidogrel base, as well as of
the dextrorotatory isomer like its hydrochloride, carboxylic acid
and sulfonic acids salts. Specifically salts of acetic, benzoic,
fumaric, maleic, citric, tartaric, gentisic, methanesulfonic,
ethanesulfonic, benzenesulfonic and lauryl sulfonic acids were
prepared. However, according to the patent, these salts usually
precipitated in amorphous form and/or they were hygroscopic, making
them difficult to handle on an industrial scale. Also, no process
and no data corresponding to any of these salts are reported. The
specification also describes salts of dobesilic acid
(M.P.=70.degree. C.) and para-toluenesulfonic acid, having a
melting point of 51.degree. C., the purification of which, as
disclosed in the patent, proved to be difficult.
[0011] Clopidogrel besylate which is at least partly in crystalline
(solvated) forms has been disclosed by Helm in published
International Application Nos. WO2004/072084 (US2005/0256152, EP
1480985 B1) and WO2004/072085. Subsequently, Helm disclosed
non-solvated forms in published U.S. Application No.
US2005/0203122.
[0012] We disclosed new polymorphic forms of Clopidogrel mesylate,
Clopidogrel besylate and Clopidogrel tosylate in our published
International Application No. WO 2004/106344, which are stable,
free flowing, scalable, useful industrially and have important
pharmacological properties. We herein disclose improved processes
for preparing different forms of (S)-(+)-Clopidogrel besylate.
EXEMPLARY EMBODIMENTS OF THE INVENTION
[0013] In an exemplary embodiment of the present invention are
disclosed improved processes for the preparation of different forms
of (S)-(+)-Clopidogrel besylate.
[0014] In a further exemplary embodiment of the present invention
are provided improved processes for the preparation of crystalline
(S)-(+)-Clopidogrel besylate.
[0015] In a still further exemplary embodiment are provided
improved processes for the preparation of amorphous
(S)-(+)-Clopidogrel besylate.
[0016] As a further exemplary embodiment of the present invention
are provided pharmaceutical compositions containing and the use of
the various forms of (S)-(+)-Clopidogrel besylate prepared
according to the processes described herein.
[0017] These processes are easy to scale up, commercially viable,
safe, easy to handle and provide operational simplicity.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The present invention discloses improved processes for the
preparation of different forms (both amorphous and crystalline) of
(S)-(+)-Clopidogrel besylate.
[0019] The terms Clopidogrel base, Clopidogrel besylate used in the
specification mean (S)-(+)-Clopidogrel base and (S)-(+)-Clopidogrel
besylate, respectively.
[0020] The amorphous form described in the specification is
prepared by the process described below.
[0021] Clopidogrel base in suitable solvents is treated with
benzene sulfonic acid, the solvent is evaporated to dryness and the
amorphous form is separated. Suitable solvents are selected from
tetrahydrofuran (THF), methyl isobutyl ketone and the like or
mixtures thereof.
[0022] The crystalline form of (S)-(+)-Clopidogrel besylate is
prepared by any of the processes described below, or suitable
combinations of one or more of any of the processes described
below: [0023] i) Clopidogrel base in suitable solvents is treated
with benzene sulfonic acid and the solvent is removed to obtain the
crystalline form. Suitable solvent(s) may be selected from methyl
tertiary butyl ether, or suitable alcohols selected from
C.sub.2-C.sub.12 alcohols which may be linear or branched, primary,
secondary or tertiary alcohols such as ethanol, propanol,
isopropanol, 1-butanol, 2-butanol, isobutanol, t-butanol,
1-pentanol, 1-hexanol, 2-hexanol, 3-hexanol, isohexanol,
1-heptanol, 2-heptanol, 3-heptanol, 4-heptanol, octanol,
isooctanol, decanol, dodecanol and the like or mixtures thereof.
[0024] ii) Amorphous (S)-(+)-Clopidogrel besylate is dissolved in
suitable solvents and the solvent is removed to obtain the
crystalline form. Suitable solvent(s) may be selected from methyl
tertiary butyl ether or suitable alcohols selected from
C.sub.2-C.sub.12 alcohols which may be linear or branched, primary,
secondary or tertiary alcohols such as ethanol, propanol,
isopropanol, 1-butanol, 2-butanol, isobutanol, t-butanol,
1-pentanol, 1-hexanol, 2-hexanol, 3-hexanol, isohexanol,
1-heptanol, 2-heptanol, 3-heptanol, 4-heptanol, octanol,
isooctanol, decanol, dodecanol and the like or mixtures thereof.
[0025] iii) Clopidogrel base in suitable solvents is treated with
benzene sulfonic acid, the solution is seeded with crystals of
(S)-(+)-Clopidogrel besylate and the solvent is removed to obtain
the crystalline form. Suitable solvent(s) may be selected from
methyl tertiary butyl ether or suitable alcohols selected from
C.sub.2-C.sub.12 alcohols which may be linear or branched, primary,
secondary or tertiary alcohols such as ethanol, propanol,
isopropanol, 1-butanol, 2-butanol, isobutanol, t-butanol,
1-pentanol, 1-hexanol, 2-hexanol, 3-hexanol, isohexanol,
1-heptanol, 2-heptanol, 3-heptanol, 4-heptanol, octanol,
isooctanol, decanol, dodecanol and the like or mixtures thereof.
[0026] iv) Amorphous (S)-(+)-Clopidogrel besylate is dissolved in
suitable solvent(s) and the solution is seeded with crystals of
(S)-(+)-Clopidogrel besylate. The solvent is removed to obtain the
crystalline form. Suitable solvent(s) may be selected from methyl
tertiary butyl ether or suitable alcohols selected from
C.sub.2-C.sub.12 alcohols which may be linear or branched, primary,
secondary or tertiary alcohols such as ethanol, propanol,
isopropanol, 1-butanol, 2-butanol, isobutanol, t-butanol,
1-pentanol, 1-hexanol, 2-hexanol, 3-hexanol, isohexanol, is
1-heptanol, 2-heptanol, 3-heptanol, 4-heptanol, octanol,
isooctanol, decanol, dodecanol and the like or mixtures
thereof.
[0027] Alternatively, the processes described above can be repeated
by using the Clopidogrel base prepared according to the improved
processes described by the applicants in U.S. Pat. No.
6,635,763.
[0028] The amorphous Clopidogrel benzene sulfonate (Clopidogrel
besylate) prepared according to the process of the present
invention has a melting point (M.P.) in the range of 85.degree.
C.-95.degree. C.
[0029] The crystalline Clopidogrel benzene sulfonate (Clopidogrel
besylate) prepared according to the process of the present
invention has a melting point in the range of 130.degree.
C.-135.degree. C.
[0030] The following non-limiting examples illustrate the
inventors' improved processes for the preparation of different
forms of (S)-(+)-Clopidogrel besylate discussed in the invention
and should not be construed to limit the scope of the invention in
any way.
Example 1
Preparation of Amorphous Clopidogrel Besylate
[0031] Clopidogrel base was dissolved in THF, to which benzene
sulfonic acid was added at 20.degree. C., and the reaction mixture
was heated to reflux temperature for 2 to 10 hr. The solvent was
evaporated to dryness under reduced pressure to obtain Clopidogrel
besylate, which on characterization showed to be the amorphous
form.
[0032] The above process for preparing amorphous Clopidogrel
besylate is carried out using methyl isobutyl ketone and the like
or a mixture of THF and methyl isobutyl ketone as a solvent.
Example 2
Preparation of Crystalline Clopidogrel Besylate
[0033] Clopidogrel base (10 g) was dissolved in decan-1-ol at
50-55.degree. C., to which benzene sulfonic acid (5 g) was added at
50-55.degree. C. and the reaction mixture was stirred for about 20
hr. The solid was filtered and washed with methyl tertiary butyl
ether and dried in a vacuum oven for at least 20 hr. to give
Clopidogrel besylate, which on characterization was found to be
crystalline form. M.P. 130-135.degree. C.
Example 3
Preparation of Crystalline Clopidogrel Besylate
[0034] Clopidogrel base (10 g) was dissolved in decan-1-ol at
50-55.degree. C., to which benzene sulfonic acid (5 g) was added at
50-55.degree. C. The reaction mixture was seeded with crystalline
Clopidogrel besylate and the reaction mixture was stirred for about
10 hr. The solid was filtered and washed with methyl tertiary butyl
ether dried in a vacuum oven for at least 20 hr. to give
Clopidogrel besylate, which on characterization was found to be
crystalline form. M.P. 130-135.degree. C.
Example 4
Preparation of Crystalline Clopidogrel Besylate
[0035] Clopidogrel base (60 g) was dissolved in isopropanol at
50-55.degree. C., to which was added benzene sulfonic acid (30 g)
dissolved in isopropanol at 50-55.degree. C. The reaction mixture
was stirred for 20 hr. The solid was filtered and washed with
isopropanol and dried in a vacuum oven for at least 20 hr. to give
Clopidogrel besylate, which on characterization was found to be
crystalline form. M.P. 130-135.degree. C.
Example 5
Preparation of Crystalline Clopidogrel Besylate
[0036] Clopidogrel base (30 g) was dissolved in isopropanol at
50-55.degree. C., to which mixture benzene sulphonic acid (15 g)
was added at 50-55.degree. C. The reaction mixture was stirred for
20 hr. The solid was filtered and washed with cold isopropanol and
dried in a vacuum oven for at least 20 hr. to give Clopidogrel
besylate, which on characterization was found to be crystalline
form. M.P. 130-135.degree. C.
Example 6
Preparation of Crystalline Clopidogrel Besylate
[0037] Clopidogrel base (10 g) was dissolved in decan-1-ol at
50-55.degree. C., to which benzene sulfonic acid (5 g) dissolved in
decan-1-ol was added at 50-55.degree. C. The reaction mixture was
seeded with crystalline Clopidogrel besylate and the reaction
mixture was stirred for about 20 hr. The solid was filtered and
washed with methyl tertiary butyl ether and dried in a vacuum oven
for at least 20 hr. to give Clopidogrel besylate, which on
characterization was found to be crystalline form. M.P.
130-135.degree. C.
Example 7
Preparation of Crystalline Clopidogrel Besylate
[0038] Clopidogrel base (100 g) was dissolved in decan-1-ol at
50-55.degree. C., to which benzenesulfonic acid (50 g) dissolved in
decan-1-ol was added at 50-55.degree. C. The reaction mixture was
seeded with crystalline Clopidogrel besylate (1 g) and the reaction
mixture was stirred for about 10 hr. The solid was filtered and
washed with methyl tertiary butyl ether and dried in a vacuum oven
for at least 20 hr. to give Clopidogrel besylate, which on
characterization was found to be crystalline form. M.P.
130-135.degree. C.
Example 8
Preparation of Crystalline Clopidogrel Besylate
[0039] Clopidogrel base (5 g) was dissolved in methyl tertiary
butyl ether, to which benzene sulfonic acid (2.5 g) dissolved in
methyl tertiary butyl ether was added at 50-55.degree. C. The
reaction mixture was seeded with crystalline Clopidogrel besylate
(50 mg) and the reaction mixture was stirred for at least 24 hr.
The solid was filtered and washed with methyl tertiary butyl ether
and dried in a vacuum oven for at least 20 hr. to give Clopidogrel
besylate, which on characterization was found to be crystalline
form. M.P. 130-135.degree. C.
Example 9
Preparation of Crystalline Clopidogrel Besylate
[0040] Clopidogrel base (100 g) was dissolved in isopropanol at
50-55.degree. C., to which benzene sulfonic acid (50 g) dissolved
in isopropanol was added at 50-55.degree. C. The reaction mixture
was seeded with crystalline Clopidogrel besylate (1 g) and the
reaction mixture was stirred for about 10 hr. The solid was
filtered and washed with isopropanol and dried in a vacuum oven for
at least 20 hr. to give Clopidogrel besylate, which on
characterization was found to be crystalline form. M.P.
130-135.degree. C.
Example 10
Preparation of Crystalline Clopidogrel Besylate
[0041] Clopidogrel base (100 g) was dissolved in isopropanol at
50-55.degree. C., to which benzene sulfonic acid (50 g) was added
at 50-55.degree. C. The reaction mixture was seeded with
crystalline Clopidogrel besylate (1 g) and the reaction mixture was
stirred for about 10 hr. The solid was filtered and washed with
isopropanol and dried in a vacuum oven for about 20 hr. to give
Clopidogrel besylate, which on characterization was found to be
crystalline form. M.P. 130-135.degree. C.
Example 11
Preparation of Crystalline Clopidogrel Besylate
[0042] Clopidogrel base (30 g) was dissolved in hexan-1-ol at
50-55.degree. C., to which benzene sulfonic acid (15 g) dissolved
in hexan-1-ol was added at 50-55.degree. C. The reaction mixture
was seeded with crystalline Clopidogrel besylate (1 g) and the
reaction mixture was stirred for about 10 hr. The solid was
filtered and washed with methyl tertiary butyl ether and dried in
vacuum oven for at least 20 hr. to give Clopidogrel besylate, which
on characterization was found to be crystalline form. M.P.
130-135.degree. C.
[0043] The besylate salts of Clopidogrel prepared according to the
processes of the present invention can be administered to a person
in need thereof, either without further formulation or formulated
into suitable formulations and dosage forms as are well known.
[0044] Some of the advantages of the processes for preparation of
different forms of Clopidogrel besylate according to the present
invention are:
[0045] scalable at plant level and industrially useful
[0046] easy to operate
[0047] good recovery of solvents
[0048] gives high yield.
* * * * *