U.S. patent application number 12/764945 was filed with the patent office on 2010-08-12 for processes for preparing different forms of (s)-(+)-clopidogrel bisulfate.
This patent application is currently assigned to CADILA HEALTHCARE LIMITED. Invention is credited to Mayank Ghanshyambhai DAVE, Parind DHOLAKIA, Braj Bhushan LOHRAY, Vidya Bhushan LOHRAY, Bipin PANDEY.
Application Number | 20100204268 12/764945 |
Document ID | / |
Family ID | 34740781 |
Filed Date | 2010-08-12 |
United States Patent
Application |
20100204268 |
Kind Code |
A1 |
LOHRAY; Braj Bhushan ; et
al. |
August 12, 2010 |
PROCESSES FOR PREPARING DIFFERENT FORMS OF (S)-(+)-CLOPIDOGREL
BISULFATE
Abstract
The invention provides improved processes for the preparation of
hydrated form of (S)-(+)-Clopidogrel bisulfate as well as improved
processes for the preparation of form-I and form-II of
(S)-(+)-Clopidogrel bisulfate.
Inventors: |
LOHRAY; Braj Bhushan;
(Gujarat, IN) ; LOHRAY; Vidya Bhushan; (Gujarat,
IN) ; PANDEY; Bipin; (Gujarat, IN) ; DAVE;
Mayank Ghanshyambhai; (Gujarat, IN) ; DHOLAKIA;
Parind; (Gujarat, IN) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON
VA
22203
US
|
Assignee: |
CADILA HEALTHCARE LIMITED
Ahmedabad
IN
|
Family ID: |
34740781 |
Appl. No.: |
12/764945 |
Filed: |
April 21, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10577940 |
Jul 12, 2006 |
|
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PCT/IN2004/000341 |
Nov 2, 2004 |
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12764945 |
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Current U.S.
Class: |
514/301 ;
546/114 |
Current CPC
Class: |
A61P 7/02 20180101; C07D
495/04 20130101; A61P 9/10 20180101; A61P 9/00 20180101 |
Class at
Publication: |
514/301 ;
546/114 |
International
Class: |
A61K 31/4365 20060101
A61K031/4365; C07D 513/04 20060101 C07D513/04; A61P 9/00 20060101
A61P009/00; A61P 9/10 20060101 A61P009/10 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 3, 2003 |
IN |
1154/MUM/2003 |
Nov 25, 2003 |
IN |
1217/MUM/2003 |
Claims
1. A process for the preparation of hydrated form of
amorphous(S)-(+)-Clopidogrel bisulfate comprising i. treating
Clopidogrel base with dil. H.sub.2SO.sub.4 in one or more suitable
solvent(s); ii. removing the solvent and isolating amorphous form
by addition of one or more suitable antisolvent(s).
2. A process for the preparation of hydrated form of
amorphous(S)-(+)-Clopidogrel bisulfate comprising i. treating
Clopidogrel base in one or more suitable solvent(s) and water with
concentrated H.sub.2SO.sub.4; ii. removing the solvent and
isolating the amorphous form by addition of one or more suitable
antisolvent(s).
3. A process for the preparation of hydrated form of
amorphous(S)-(+)-Clopidogrel bisulfate comprising i. treating
Clopidogrel bisulfate in dichloromethane-water with one or more
suitable base(s), to obtain Clopidogrel base; ii. treating the
Clopidogrel base(s) with dil. H.sub.2SO.sub.4 in one or more
suitable solvent(s); iii. removal of the solvent(s) and isolating
the amorphous form by addition of suitable one or more
antisolvent(s).
4. A process for the preparation of hydrated form of
amorphous(S)-(+)-Clopidogrel bisulfate comprising i. treating
Clopidogrel bisulfate in dichloromethane-water with one or more
suitable base(s), to obtain Clopidogrel base; ii. treating
Clopidogrel base with concentrated H.sub.2SO.sub.4 in a mixture of
suitable solvent(s) and water, iii. removing the solvent and
isolating the amorphous form by addition of one or more suitable
antisolvent(s).
5. A process for the preparation of hydrated form of amorphous
(S)-(+)-Clopidogrel bisulfate comprising i. treating (S)-(+)
Clopidogrel camphor-sulfonate in one or more suitable solvent(s)
with a suitable base(s) to obtain Clopidogrel base wherein the
suitable solvent is selected from ethyl acetate, dichloromethane,
dichloroethane, chloroform or mixtures thereof ii. treating the
Clopidogrel base with concentrated H.sub.2SO.sub.4 in a mixture of
one or more suitable solvent(s) and water, iii. removing the
solvent(s) and isolating the amorphous form by addition of suitable
one or more antisolvent(s).
6. A process for the preparation of hydrated form of
amorphous(S)-(+)-Clopidogrel bisulfate comprising i. treating
(S)-(+) Clopidogrel camphor-sulfonate in one or more suitable a
solvent(s) with one or more suitable base(s), to obtain Clopidogrel
base wherein the suitable solvent is selected from ethyl acetate,
dichloromethane, dichloroethane, chloroform, or mixture thereof;
ii. treating the Clopidogrel base with dilute H2SO4 in one or more
suitable solvent(s); iii. removing the solvent and isolating the
amorphous form by addition of one or more suitable
antisolvent(s).
7. A process as claimed claim 1, wherein the solvent is selected
from the group consisting of methanol, ethanol, propanol,
isopropanol, 1-butanol, 2-butanol, dichloromethane, dimethyl
formamide, dimethyl acetamide, 1,4-dioxane, tetrahydrofuran, and
mixtures thereof.
8. A process as claimed in claim 1, wherein the antisolvent is
selected from the group consisting of pentane, n-hexane, heptane,
cyclohexane, pet ether, and mixtures thereof.
9. A process as claimed in claim 1, wherein the base is selected
from the group consisting of NaOH, KOH, LiOH, NaHCO.sub.3,
Na.sub.2CO.sub.3, K.sub.2CO.sub.3, and tertiary alkyl amines.
10-21. (canceled)
22. A process for the preparation of form II of (S)-(+)-Clopidogrel
bisulfate comprising stirring the different amorphous forms in
Methyl-tert-butyl ether and subsequent removal of the solvent.
23. A method of treating cardiovascular and related diseases by
providing a patient in need thereof, the various forms of
(S)-(+)-Clopidogrel bisulfate prepared according to the present
invention or pharmaceutical compositions containing the same.
24. (canceled)
Description
FIELD OF INVENTION
[0001] The present invention relates to improved processes for the
preparation of different forms of clopidogrel bisulfate. The
present invention particularly describes improved processes for the
preparation of amorphous (S)-(+)-Clopidogrel bisulfate and Form I
of (S)-(+)-Clopidogrel bisulfate. More particularly, in a preferred
embodiment, the present invention discloses improved processes for
the preparation of amorphous form of (S)-(+)-Clopidogrel bisulfate
as hydrates, solvates and various pharmaceutical compositions
containing the amorphous forms prepared according to the present
invention.
[0002] In another preferred embodiment, this invention describes
improved processes for the preparation of Form I, Form II
polymorphs of S-(+)-Clopidogrel bisulfate and pharmaceutical
compositions containing them. (S)-(+)-Clopidogrel bisulfate an
antiplatelet drug is currently being marketed for the treatment of
atherosclerosis, myocardial infraction, strokes and vascular death.
The present invention also describes a method of treatment of such
cardiovascular disorders using the different forms of Clopidogrel
bisulfate or mixtures thereof prepared according to the present
invention, and pharmaceutical compositions containing them. The
present invention further relates to the use of the different forms
of (S)-(+)-Clopidogrel bisulfate prepared according to the
processes disclosed herein and pharmaceutical compositions
containing them for the treatment of cardiovascular disorders.
BACKGROUND OF THE INVENTION
[0003] Clopidogrel bisulfate corresponds to the empirical formula
C.sub.16H.sub.16ClNO.sub.2S.H.sub.2SO.sub.4. Chemically it is
methyl
(+)-(S)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-ace-
tate sulfate (1:1), having the following structural formula.
##STR00001##
[0004] Clopidogrel is an inhibitor of platelet aggregation and is
marketed as an antianginal agent, antiplatelet agent and is found
to decrease morbid events in people with established
atherosclerotic cardiovascular disease and cerebrovascular
diseases.
[0005] The therapeutic application of Clopidogrel as blood-platelet
aggregation inhibiting agents and antithrombotic agent and its
preparation is disclosed in U.S. Pat. No. 4,529,596.
[0006] U.S. Pat. No. 4,847,265 describes the process for the
preparation of the hydrogen sulfate salt of Clopidogrel.
[0007] Various other strategies to prepare Clopidogrel are
disclosed in WO 98/51681, WO 98/51682, WO 98/51689, WO 99/18110,
U.S. Pat. No. 5,036,156, U.S. Pat. No. 5,132,435, U.S. Pat. No.
5,139,170, U.S. Pat. No. 5,204,469 and U.S. Pat. No. 6,080,875.
[0008] U.S. Pat. No. 4,847,265 discloses that the dextrorotatory
enantiomer of formula (I) of Clopidogrel has an excellent
antiaggregant platelet activity, whereas the corresponding
levorotatory enantiomer is less tolerated and is less active. U.S.
Pat. No. 4,847,265 relates to the dextrorotatory enantiomer and its
pharmaceutically acceptable salts with platelet aggregation
inhibiting activity.
[0009] Subsequently filed Patent Application WO 99/65915 (U.S. Pat.
No. 6,429,210) titled "Polymorphic Clopidogrel hydrogen sulfate
form", which is herein incorporated by reference, discloses the
existence of a specific polymorphic Form II of the hydrogen sulfate
of (S)-(+)-Clopidogrel (m.p.=176.+-.3.degree. C.). It is also
disclosed in this patent application that the earlier processes
described in the U.S. Pat. No. 4,847,265 gives Form I (m.p.
184.+-.3.degree. C.). These two crystalline polymorphic forms I and
II differed in their stability, physical properties, spectral
characteristics and their method of preparation. However, both the
polymorphs have similar bioavailability, as shown in their
bioequivalence in healthy human volunteers.
[0010] Although, U.S. Pat. No. 4,847,265 reports the formation of
(S)-(+)-Clopidogrel bisulfate salt with m.p. 184.degree. C., it was
disclosed as Form I only in patent application WO 99/65915.
However, a reproducible and consistent method for the preparation
of Form I with chirally pure material (ee>99%) was in doubt
since chiral purity of the material (Clopidogrel bisulfate) with
m.p. 184.+-.3.degree. C., disclosed in U.S. Pat. No. 4,847,265 was
not precisely known.
[0011] In fact, we have observed that formation of Form I of
(S)-(+)-Clopidogrel bisulfate with chiral purity >99% e.e. is
inconsistent and difficult to reproduce using the procedures
reported in U.S. Pat. No. 4,847,265 and WO 99/65915 whereas the
formation of Form II is extremely facile and consistent with
optically pure (S)-(+)-Clopidogrel free base.
[0012] We have earlier disclosed improved processes for the
manufacture of (S)-(+)-Clopidogrel bisulfate & its
intermediates [Indian Patent Applications 84/MUM/2001 (WO
02059128/U.S. Pat. No. 6,635,763), & 335/MUM/2001] which are
cited herein in their entirety as reference.
[0013] We have also disclosed hydrated form of amorphous
Clopidogrel bisulfate as well as methanolates, ethanolates and
containing different form stabilizers [Indian patent application
1154/MUM/2003 and 413/MUM/2003], which are also incorporated as
reference.
[0014] Amorphous Clopidogrel bisulfate and other solvated forms
(1-butanol, 2-butanol, isopropanol, 1-propanol) as well mixtures of
amorphous form with Form I and Form II and processes for preparing
them have been disclosed in Teva's application no. WO 03/051362 A2,
which is cited herein as reference. However, this application does
not disclose amorphous Clopidogrel bisulfate hydrate.
[0015] Teva's application also discloses processes for preparing
Form I and Form II of Clopidogrel bisulfate. The Form I is prepared
by contacting the amorphous form disclosed therein in ethers
preferably diethyl ether or MTBE. These processes have the
following disadvantages: [0016] i. diethyl ether and MTBE are very
volatile and inflammable hence are hazardous to work with; [0017]
ii. the process is difficult to be scaled up to plant scale; [0018]
iii. problem of recovery of antisolvents further making the process
economically unfeasible.
[0019] We herein disclose improved processes for preparing
amorphous Clopidogrel bisulfate, amorphous Clopidogrel bisulfate
hydrate, amorphous Clopidogrel bisulfate solvates, with high
optical purity (ee>99%).
[0020] We also disclose improved processes for preparing Form I and
Form II of Clopidogrel bisulfate. Also disclosed are amorphous
Clopidogrel bisulfate, Form I and Form II of Clopidogrel bisulfate
with characteristic impurity profile.
OBJECTS OF THE INVENTION
[0021] It is an object of the present invention to provide an
improved processes for preparation of amorphous (S)-(+)-Clopidogrel
bisulfate in hydrate form containing from about 1-4% water.
[0022] Yet another object of the present invention is to provide
improved processes for the preparation of amorphous Clopidogrel
bisulfate solvates.
[0023] A still further object of the present invention is to
provide improved processes for the preparation of Form I of
Clopidogrel bisulfate.
[0024] A still further object of the present invention is to
provide improved processes for the preparation of Form II of
Clopidogrel bisulfate.
[0025] As an embodiment of the present invention pharmaceutical
compositions containing the various amorphous forms of Clopidogrel
bisulfate, Form I and Form II described herein and prepared
according to the present invention are provided.
[0026] Also is provided a method of treatment and use of the
various amorphous forms of Clopidogrel bisulfate, Form I and Form
II described herein and prepared according to the present invention
for the treatment of cardiovascular disorders, comprising
administering, for example, orally a composition of the invention
in a therapeutically effective amount.
[0027] These processes are easy to scale up, commercially viable,
safe, easy to handle and provides operational simplicity.
DESCRIPTION OF INVENTION
[0028] The present invention discloses improved processes for the
preparation of different forms of clopidogrel bisulfate.
[0029] The present invention provides improved processes for the
preparation of different amorphous forms of Clopidogrel bisulfate
as described else where in the specification. The term "amorphous",
as used herein, relates to solid material which lacks a regular
crystalline structure. In a powder X-ray diffractogram such
material gives no good intensity peaks. Whenever sulfuric acid is
being used for preparing the bisulfate salt as disclosed in the
specification, it is used in the range of 0.95-1.25 mole
equivalent. The term Clopidogrel base, Clopidogrel bisulfate used
in the specification means (S)-(+)-Clopidogrel base and
(S)-(+)-Clopidogrel bisulfate respectively.
[0030] The various amorphous forms (hydrates, solvates, amorphous
form containing form stabilizers) described in the specification
can be prepared by any of the processes described below or used in
combination. [0031] i) clopidogrel base in suitable solvents is
treated with dil. H.sub.2SO.sub.4, the solvent is evaporated and
amorphous form is precipitated by addition of a suitable
antisolvent(s). Suitable solvents can be selected from methanol,
ethanol, propanol, isopropanol, 1-butanol, 2-butanol,
dichloromethane, dimethyl formamide, dimethyl acetamide,
1,4-dioxane, tetrahydrofuran and the like or mixtures thereof.
Suitable antisolvents may be selected from pentane, n-hexane,
heptane, cyclohexane, pet ethers and the like or mixtures thereof.
[0032] ii) clopidogrel base in suitable solvents and water is
treated with concentrated H.sub.2SO.sub.4, the solvent is
evaporated and amorphous form is precipitated by addition of a
suitable antisolvent(s). Suitable solvents can be selected from
methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol,
dichloromethane, dimethyl formamide, dimethyl acetamide,
1,4-dioxane, tetrahydrofuran and the like or mixtures thereof.
Suitable antisolvents may be to selected from pentane, n-hexane,
heptane, cyclohexane, pet ethers and the like or mixtures thereof
[0033] iii) clopidogrel bisulfate in dichloromethane-water is
treated with suitable bases, to obtain Clopidogrel base which is
then treated with dil. H.sub.2SO.sub.4 in suitable solvents, the
solvent is evaporated and the amorphous form is precipitated by
addition of a suitable antisolvent(s). Suitable bases can be
selected from NaOH, KOH, LiOH, NaHCO.sub.3, Na.sub.2CO.sub.3,
K.sub.2CO.sub.3 and the like. Suitable solvents can be selected
from methanol, ethanol, propanol, isopropanol, 1-butanol,
2-butanol, dichloromethane, dimethyl formamide, dimethyl acetamide,
1,4-dioxane, tetrahydrofuran and the like or mixtures thereof.
Suitable antisolvents may be selected pentane, n-hexane, heptane,
cyclohexane, pet ethers and the like or mixtures thereof [0034] iv)
clopidogrel bisulfate in dichloromethane--water is treated with
suitable bases, to obtain Clopidogrel base which is then treated
with concentrated H.sub.2SO.sub.4 in a mixture of suitable solvents
and water, the solvent is evaporated and amorphous form
precipitated by addition of suitable antisolvent(s). Suitable bases
can be selected from NaOH, KOH, LiOH, NaHCO.sub.3,
Na.sub.2CO.sub.3, K.sub.2CO.sub.3, organic bases like tertiary
alkyl amines and the like. Suitable solvents can be selected from
methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol,
dichloromethane, dimethyl formamide, dimethyl acetamide,
1,4-dioxane, tetrahydrofuran and the like or mixtures thereof.
Suitable antisolvents may be selected pentane, n-hexane, heptane,
cyclohexane, pet ethers and the like or mixtures thereof [0035] v)
(S)-(+) Clopidogrel camphor-sulfonate in suitable solvents like
ethyl acetate, dichloromethane, dichloroethane, chloroform and the
like and water is treated with a suitable base, to obtain
Clopidogrel base which is then treated with dil. H.sub.2SO.sub.4 in
suitable solvents. The solvent is evaporated and amorphous form is
precipitated by addition of suitable antisolvent(s). Suitable bases
can be selected from NaOH, KOH, LiOH, NaHCO.sub.3,
Na.sub.2CO.sub.3, K.sub.2CO.sub.3, organic bases like tertiary
alkyl amines and the like. Suitable solvents can be selected from
methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol,
dichloromethane, dimethyl formamide, dimethyl acetamide,
1,4-dioxane, tetrahydrofuran and the like or mixtures thereof.
Suitable antisolvents may be selected from pentane, n-hexane,
heptane, cyclohexane, pet ethers and the like or mixtures thereof.
[0036] vi) (S)-(+) Clopidogrel camphor-sulfonate in suitable
solvents like ethyl acetate, dichloromethane, dichloroethane,
chloroform and the like and water is treated with a suitable base,
to obtain Clopidogrel base which is then treated with concentrated
H.sub.2SO.sub.4 in a mixture of suitable solvent(s) and water. The
solvent is evaporated and amorphous form precipitated by addition
of suitable antisolvent. Suitable bases can be selected from NaOH,
KOH, LiOH, NaHCO.sub.3, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, organic
bases like tertiary alkyl amines and the like. Suitable solvents
can be selected from methanol, ethanol, propanol, isopropanol,
1-butanol, 2-butanol, dichloromethane, dimethyl formamide, dimethyl
acetamide, 1,4-dioxane, tetrahydrofuran and mixtures thereof.
Suitable antisolvents may be selected from pentane, n-hexane,
heptane, cyclohexane, pet ethers and the like or mixtures
thereof.
[0037] Various polyethylene glycols (PEG) 200, 400, 800, 900, 1000,
1200, 2000 and 4000 can also be used as amorphous form stabilizers
in any of the processes described above.
[0038] Alternatively, the processes [(i)-(vi)] described above can
be repeated by using the Clopidogrel base, (S)-(+) Clopidogrel
bisulfate and (S)-(+) Clopidogrel camphor-sulfonate prepared
according to the improved processes described by the applicant in
WO 02059128/U.S. Pat. No. 6,635,763.
[0039] The present invention also describes improved processes for
the preparation of Form I of Clopidogrel bisulfate from the
different amorphous forms prepared according to any of the
processes of the present invention. The Form I is obtained by
treating the above amorphous forms in a mixture of diethyl
ether-heptane, diethyl ether-hexane, diethyl ether-pet ethers in
various combination and proportion, with a view to enhance
operational safety, scalability and simplicity.
[0040] The Form I can also be prepared by any of the processes
described below either alone or used in combination: [0041] (i)
clopidogrel base in suitable solvent(s) selected from
C.sub.6-C.sub.12 alcohols is treated with dil. H.sub.2SO.sub.4, to
obtain Form I of (S)-(+)-Clopidogrel bisulfate. Suitable solvents
can be selected from C.sub.6-C.sub.12 alcohols which may be linear
or branched, primary, secondary or tertiary alcohols such as
1-hexanol, 2-hexanol, 3-hexanol, isohexanol, 1-heptanol,
2-heptanol, 3-heptanol, 4-heptanol, octanol, isooctanol, decanol,
and the like or mixtures thereof. [0042] (ii) clopidogrel base in
suitable solvent(s) selected from C.sub.6-C.sub.12 alcohols and a
trace of water is treated with concentrated H.sub.2SO.sub.4, to
obtain Form I of (S)-(+)-Clopidogrel bisulfate. Suitable solvents
may be selected from C.sub.6-C.sub.12 alcohols which may be linear
or branched, primary, secondary or tertiary alcohols such as
hexanol, 2-hexanol, 3-hexanol, isohexanol, 1-heptanol, 2-heptanol,
3-heptanol, 4-heptanol, octanol, isooctanol, decanol, and the like
or mixtures thereof. [0043] (iii) clopidogrel bisulfate in any form
including different crystalline forms such as Forms II, III, IV, V,
VI etc. or amorphous form or in the form of oil is
dissolved/contacted with suitable solvent(s) selected from
C.sub.6-C.sub.12 alcohols to obtain Form I of (S)-(+)-Clopidogrel
bisulfate. Suitable solvents can be selected from C.sub.6-C.sub.12
alcohols which may be linear or branched, primary, secondary or
tertiary alcohols such as 1-hexanol, 2-hexanol, 3-hexanol,
isohexanol, 1-heptanol, 2-heptanol, 3-heptanol, 4-heptanol,
octanol, isooctanol, decanol, and the like or mixtures thereof.
[0044] (iv) clopidogrel bisulfate in any form including crystalline
forms II, III, IV, V, VI etc. or amorphous form or in the form of
oil is dissolved/contacted with suitable solvent(s) selected from
C.sub.6-C.sub.12 alcohols and a trace of water, to obtain Form I of
(S)-(+)-Clopidogrel bisulfate. Suitable solvent(s) can be selected
from C.sub.6-C.sub.12 alcohols which may be linear or branched,
primary, secondary or tertiary alcohols such as 1-hexanol,
2-hexanol, 3-hexanol, isohexanol, 1-heptanol, 2-heptanol,
3-heptanol, 4-heptanol, octanol, isooctanol, decanol, and the like
or mixtures thereof. [0045] (v) (S)-(+) Clopidogrel
camphor-sulfonate in suitable solvent(s) like ethyl acetate,
dichloromethane, dichloroethane, chloroform and the like and water
is treated with suitable base(s), to obtain Clopidogrel base which
is then treated with dil. H.sub.2SO.sub.4 in suitable solvent(s),
selected from C.sub.6-C.sub.12 alcohols to obtain Form I of
(S)-(+)-Clopidogrel bisulfate. Suitable bases can be selected from
NaOH, KOH, LiOH, NaHCO.sub.3, Na.sub.2CO.sub.3, K.sub.2CO.sub.3,
organic bases like tertiary alkyl amines and the like. Suitable
solvents can be selected from C.sub.6-C.sub.12 alcohols which may
be linear or branched, primary, secondary or tertiary alcohols such
as 1-hexanol, 2-hexanol, 3-hexanol, isohexanol, 1-heptanol,
2-heptanol, 3-heptanol, 4-heptanol, octanol, isooctanol, decanol,
and the like or mixtures thereof [0046] (vi) clopidogrel
camphor-sulfonate in suitable solvent(s) like ethyl acetate,
dichloromethane, dichloroethane, chloroform and the like and water
is treated with suitable base(s), to obtain Clopidogrel base which
is then treated with concentrated H.sub.2SO.sub.4 in suitable
solvent(s), selected from C.sub.6-C.sub.12 alcohols and a trace of
water to obtain Form I of (S)-(+)-Clopidogrel bisulfate. Suitable
bases can be selected from NaOH, KOH, LiOH, NaHCO.sub.3,
Na.sub.2CO.sub.3, K.sub.2CO.sub.3, organic bases like tertiary
alkyl amines and the like. Suitable solvents can be selected from
C.sub.6-C.sub.12 alcohols which may be linear or branched, primary,
secondary or tertiary alcohols such 1-hexanol, 2-hexanol,
3-hexanol, isohexanol, 1-heptanol, 2-heptanol, 3-heptanol,
4-heptanol, octanol, isooctanol, decanol, and the like or mixtures
thereof.
[0047] Alternatively, the processes [(i)-(vi)] described above can
be repeated by using the Clopidogrel base, Clopidogrel bisulfate
and (S)-(+) Clopidogrel camphor-sulfonate prepared according to the
improved processes described by the applicant in U.S. Pat. No.
6,635,763.
[0048] The present invention also describes improved process for
the preparation of Form II of Clopidogrel bisulfate from the
different amorphous forms prepared according to any of the
processes of the present invention. Form II is obtained by stirring
the different amorphous forms in solvents like, MTBE and the like
or their mixtures.
[0049] The amorphous forms of (S)-(+)-Clopidogrel bisulfate
including hydrates/solvates (methanolates, ethanolates and the
like), Form I and Form II of (S)-(+)-Clopidogrel bisulfate prepared
according to the processes of the present invention may be
characterized by their melting point, physical characteristics,
X-ray powder diffraction pattern, DSC, thermogravimetric analysis,
differential scanning calorimetry, diffused reflection IR
absorption and/or by its solid state nuclear magnetic resonance
spectrum and % content of water, methanol, ethanol and other
solvates mentioned in processes described elsewhere in the
specification, including form stabilizers like various PEGs.
[0050] The advantages of the processes for preparation of different
forms of clopidogrel bisulfate according to the present
[0051] not hazardous as it does not use volatile chemicals like
ethers.
[0052] scalable at plant level and so industrially useful
[0053] easy to operate
[0054] good recovery of solvents
[0055] gives high yield
[0056] The different forms of amorphous (S)-(+)-Clopidogrel
bisulfate hydrates/solvates (methanolates, ethanolates and the
like), Form I and Form II of (S)-(+)-Clopidogrel bisulfate prepared
according to the processes of the present invention may be
administered orally, parenterally or rectally without further
formulation, or any pharmaceutically acceptable liquid carrier. The
drug substance of the present invention may also be filled in a
capsule directly for oral administration. However, it is preferred
that the drug substance is formulated with one or more excipients
to prepare a pharmaceutical composition, for example, an oral
dosage form.
[0057] Another aspect of the present invention aims at providing
the various pharmaceutical compositions of the different amorphous
forms of (S)-(+)-Clopidogrel bisulfate, Form I and Form II of
(S)-(+)-Clopidogrel bisulfate prepared according to the present
invention.
[0058] According to the present invention, the various amorphous
forms of (S)-(+)-Clopidogrel bisulfate, Form I and Form II prepared
according to the processes of the present invention is formulated
into pharmaceutical compositions for oral use containing required
amount of the active ingredient per unit of dosage, in combination
with at least one pharmaceutical excipient in the form of tablets,
sugar coated tablets, capsules, injectable solutions, granules or a
syrup. They can also be administered rectally in the form of
suppositories or can be parentally administered in the form of an
injectable solution.
[0059] In another embodiment of the present invention a method of
treatment and use of the different amorphous forms of
(S)-(+)-Clopidogrel bisulfate, Form I and Form II prepared
according to the present invention, for the treatment of
cardiovascular disorders is provided, comprising administering, for
example, orally or in any other suitable dosage forms, a
composition of the invention in a therapeutically effective
amount.
[0060] The following non-limiting examples illustrate the
inventor's preferred methods for preparing the amorphous forms as
well as Form I & Form II of (S)-(+)-Clopidogrel bisulfate
discussed in the invention and should not be construed as limiting
the scope of the invention in any way.
Example 1
Preparation of Clopidogrel Hydrogen Sulfate Hydrated Amorphous
Form
[0061] Clopidogrel base (444.18 gms) was dissolved in methanol
(4.136 L) with stirring at 25 to 30.degree. C. Dilute sulfuric acid
was added to the solution dropwise in about 15 minutes of time at 5
to 10.degree. C. The reaction mixture was stirred for 30 minutes.
Then the solvent was evaporated under reduced pressure at 50 to
55.degree. C. Cyclohexane (2 L) was added to reaction mixture and
the same was stirred, filtered and dried at 45 to 50.degree. C. in
a vacuum oven for 8 hours to obtain powder (493 gms, 85%) whose
characterization data showed to be the hydrated amorphous form. KF
value is found in the range from 1 to 3% water (in different
batches) and powder XRD data indicated to be amorphous with no
peaks due to crystalline form.
Example 2
Preparation of Clopidogrel Hydrogen Sulfate Hydrated Amorphous
Form
[0062] Clopidogrel base (500 gms) was dissolved in methanol (4.65
L) and water (65 ml) with stirring at 25 to 30.degree. C.
Concentrated sulfuric acid was added to the solution dropwise in
about 15 minutes of time at 5 to 10.degree. C. The reaction mixture
was stirred for 30 minutes. Then the solvent was evaporated under
reduced pressure at 50 to 55.degree. C. Cyclohexane (2 L) was added
to the reaction mixture. The reaction mixture was stirred, filtered
and dried at 45 to 50.degree. C. in a vacuum oven for 8 hours to
obtain powder (600 gms, 92%) whose characterization data showed to
be the hydrated amorphous form. KF value is found in the range from
1 to 3% (in different batches) and powder XRD data indicated to be
amorphous with no peaks due to crystalline form.
Example 3
Preparation of Clopidogrel Hydrogen Sulfate Hydrated Amorphous
Form
[0063] Suspension of Clopidogrel hydrogen sulfate (50 gms) was
stirred in dichloromethane (300 ml) and subsequently basified by
adding NaHCO.sub.3 solution (10%, 500 ml) in it. The mixture was
stirred at 25 to 30.degree. C. for about 10 minutes. The layers
were separated and the aqueous layer was extracted with
dichloromethane (50 ml.) and washed with water (100 ml.). It was
then dried over Na.sub.2SO.sub.4 and the solvent was distilled off
on a water bath at 50 to 55.degree. C. to obtain Clopidogrel free
base (39.5 gms).
[0064] The Clopidogrel base (38.3 gms) obtained above was dissolved
in methanol (356 mL) and water (5 ml) at 25 to 30.degree. C.
Concentrated sulfuric acid was added to the solution dropwise in
about 15 minutes of time at 5 to 10.degree. C. The reaction mixture
was stirred for 30 minutes. The solvent was evaporated under
reduced pressure at 50 to 55.degree. C. Cyclohexane (175 mL) was
added to the reaction mixture and stirred for approximately 10
minutes and filtered, dried at temperature in the range from 45 to
50.degree. C. in a vacuum oven for approximately 8 hours to obtain
powder (46 gms, 92%) whose characterization data showed to be the
hydrated amorphous form a KF value is found in the range from 1 to
3% (in different batches) and powder XRD data indicated to be
amorphous with no peaks due to crystalline form.
Example 4
Preparation of Clopidogrel Hydrogen Sulfate Hydrated Amorphous
Form
[0065] Suspension of Clopidogrel hydrogen sulfate (61 gms) was
stirred in dichloromethane (360 ml) and subsequently basified with
NaHCO.sub.3 solution (10%, 600 ml). The mixture was stirred at 25
to 30.degree. C. for about 10 minutes. The layers were separated
and the aqueous layer was extracted with dichloromethane (60 ml.)
and washed with water (120 ml.). It was then dried over
Na.sub.2SO.sub.4 and the solvent was distilled off on a water bath
at a temperature in the range from 50 to 55.degree. C. to obtain
Clopidogrel free base (46.0 gms)
[0066] Clopidogrel base (46 gms) obtained above was dissolved in
methanol (427 mL) at 25 to 30.degree. C. Dilute sulfuric acid was
added to the solution dropwise in about 15 minutes at 5 to
10.degree. C. The reaction mixture was stirred for 30 minutes. The
solvent was evaporated under reduced pressure at 50 to 55.degree.
C. Cyclohexane (190 mL) was added to the reaction mixture and
stirred for approximately 10 minutes and filtered, and dried at
temperature in the range from 45 to 50.degree. C. in a vacuum oven
for approximately 8 hours to obtain powder (54 gms, 90%) whose
characterization data showed to be the hydrated amorphous form. KF
value is found in the range from 1 to 3% (in different batches) and
powder XRD data indicated to be amorphous with no peaks due to
crystalline form.
Example 5
Preparation of Clopidogrel Hydrogen Sulfate Hydrated Amorphous
Form
[0067] A suspension of (S)-(+) Clopidogrel camphor sulphonate (66
gms) was stirred in dichloromethane (300 ml) and subsequently
basified with NaHCO.sub.3 solution (10%, 500 ml). The mixture was
stirred at 25 to 30.degree. C. for about 10 minutes. The layers
were separated and the aqueous layer was extracted with
dichloromethane (50 ml.) and washed with water (100 ml.). It was
then dried over Na.sub.2SO.sub.4 and the solvent was distilled off
on a water bath at a temperature in the range from 50 to 55.degree.
C. to obtain Clopidogrel free base (39.5 gms)
[0068] Clopidogrel base (38.3 gms) obtained above was dissolved in
methanol (356 mL) at 25 to 30.degree. C. Dilute sulfuric acid was
added to the solution dropwise in about 15 minutes of time at 5 to
10.degree. C. The reaction mixture was stirred for 30 minutes. Then
the solvent was evaporated under reduced pressure at 50 to
55.degree. C. Cyclohexane (175 mL) was added to the reaction
mixture and stirred for approximately 10 minutes and filtered,
dried at 45 to 50.degree. C. in a vacuum oven for approximately 8
hours to obtain powder (46 gms, 92%) whose characterization data
showed to be the hydrated amorphous form. KF value is found in the
range from 1 to 3% (in different batches) and powder XRD data
indicated to be amorphous with no peaks due to crystalline
form.
Example 6
Preparation of Clopidogrel Hydrogen Sulfate Hydrated Amorphous
Form
[0069] A suspension of (S)-(+) Clopidogrel camphor sulphonate (132
gms) was stirred in dichloromethane (600 ml) and subsequently
basified with NaHCO.sub.3 solution (10%, 1000 ml). The mixture was
stirred at a temperature in the range from 25 to 30.degree. C. for
about 10 minutes. The layers were separated and aqueous layer was
extracted with dichloromethane (100 ml.) and washed with water (200
ml.). The organic layer was then dried over Na.sub.2SO.sub.4 and
solvent was distilled off on a water bath at a temperature in the
range from 50 to 55.degree. C. to obtain Clopidogrel free base (79
gms)
[0070] Clopidogrel base (76.6 gms) obtained above was dissolved in
methanol (712 mL) and water (10 ml) at 25 to 30.degree. C.
Concentrated sulfuric acid was added to the solution dropwise in
about 15 minutes of time at 5 to 10.degree. C. The reaction mixture
was stirred for 30 minutes. The solvent was evaporated under
reduced pressure at 50 to 55.degree. C. Cyclohexane (350 mL) was
added to the reaction mixture and stirred for approximately 10
minutes, filtered and dried at 45 to 50.degree. C. in a vacuum oven
for approximately 8 hours to obtain powder (90 gms, 90%) whose
characterization data showed to be the hydrated amorphous form. KF
value is found in the range from 1 to 3% (in different batches) and
powder XRD data indicated to be amorphous with no peaks due to
crystalline form.
Example 7
Preparation of Clopidogrel Hydrogen Sulfate Hydrated Amorphous
Form
[0071] A suspension of (S)-(+) Clopidogrel hydrogen sulfate (110
gms) was stirred in dichloromethane (1.1 L) The solution was
stirred at 25 to 30.degree. C. Water (132 ml) was added and the
reaction mixture was stirred for approximately 10 minutes. The
reaction mixture was distilled at atmospheric pressure, on a water
bath at a temperature in the range from 50 to 55.degree. C. and
high vacuum was applied. Dichloromethane (500 ml) was again added
to it, excess solvent was distilled off applying high vacuum at 50
to 55.degree. C. The operation was repeated with 500 ml
dichloromethane. Finally 250 ml dichloromethane was charged to the
mixture and subsequently the solvent was distilled off using high
vacuum at a temperature 50 to 55.degree. C., and a solid was
obtained as a free flowing solid. It was scratched and vacuum was
reapplied for 10 to 15 minutes. Solid was transferred in to a drier
in a dry area, dried at 50-53.degree. C. for 8 hrs. to obtain
powder (100 gms) whose characterization data showed to be the
hydrated amorphous form.
Example 8
Preparation of Clopidogrel Hydrogen Sulfate Form I
[0072] Clopidogrel base (925 gms) was dissolved in n-hexanol (4.6
L) with stirring at 25 to 30.degree. C. Dilute sulfuric acid was
added to the reaction mixture at 10 to 15.degree. C. The mixture
was seeded with form-I crystal at 20 to 25.degree. C. The reaction
mixture was stirred for approximately 8 to 10 hours &
subsequently further stirred for 8-10 hrs at 22 to 25.degree. C.
with low agitation. The solid was then filtered and washed with
methyl tert butyl ether (1875 ml) and subsequently dried at 30 to
35.degree. C. on a drier, to get 1095 g of clopidogrel bisulfate
salt as crystals. Subsequent analysis confirmed that the crystals
were clopidogrel hydrogen sulfate Form-I.
Example 9
Preparation of Clopidogrel Hydrogen Sulfate Form I
[0073] Clopidogrel base (500 gms) was dissolved in n-hexanol (2.5
L) with stirring at 25 to 30.degree. C. and water (10.3 ml) was
added to it. Concentrated H.sub.2SO.sub.4 was added at
10-15.degree. C. The reaction mixture was seeded with form-I
crystal at 20-25.degree. C. The mixture was stirred at room
temperature for 10-12 hrs and subsequently it was stirred at 22 to
25.degree. C., for 1-2 hours with high agitation. The mixture was
further stirred for 5-8 hours at room temperature with low
agitation. It was filtered, washed with methyl tert butyl ether
(1500 ml) and dried at a temperature in the range from 30 to
35.degree. C. in a drier, to get 525 g of salt as crystals.
Subsequent analysis confirmed that the crystals were clopidogrel
hydrogen sulfate Form-I.
Example 10
Preparation of Clopidogrel Hydrogen Sulfate Form
[0074] Suspension of Clopidogrel hydrogen sulfate (660 gms) was
stirred in dichloromethane (3900 ml) & subsequently basified
with NaHCO.sub.3 solution (10%, 6500 ml). The reaction mixture was
stirred at 25 to 30.degree. C. for about 10 minutes. The layers
were separated and the aqueous layer was extracted with
dichloromethane (650 ml.) and washed with water (1300 ml.). It was
then dried over Na.sub.2SO.sub.4 and the solvent was distilled off
on a water bath at 50 to 55.degree. C. to obtain Clopidogrel free
base (505 gms).
[0075] Clopidogrel base (500 gms) obtained above was dissolved in
n-hexanol (2.5 L) with stirring at 25 to 30.degree. C. and water
(10.3 ml) was added to it. Concentrated sulfuric acid was added at
10 to 15.degree. C. The reaction mixture was seeded with form-I
crystals at a temperature in the range from 20 to 25.degree. C. The
mixture was stirred at 25 to 30.degree. C. for 10-12 hrs &
subsequently it was stirred at high agitation, at a temperature in
the range from 22 to 25.degree. C. for 1-2 hrs. The reaction
mixture was further stirred for 5-8 hrs at 22 to 25.degree. C., at
low agitation. The mixture was then filtered, washed with methyl
tert butyl ether (1500 ml) and dried at 30-35.degree. C. in a
drier, to obtain 561 g clopidogrel bisulfate salt. Subsequent
analysis confirmed that the crystals were clopidogrel hydrogen
sulfate Form-I.
Example 11
Preparation of Clopidogrel Hydrogen Sulfate Form I
[0076] A suspension of Clopidogrel hydrogen sulfate (330 gms) was
stirred in dichloromethane (1950 ml) and subsequently with
NaHCO.sub.3 solution (10%, 3300 ml). The mixture was stirred at 25
to 30.degree. C. for about 10 minutes. The layers were separated
and aqueous layer was extracted with dichloromethane (325 ml.) and
washed with water (1300 ml,). It was then dried over
Na.sub.2SO.sub.4 and the solvent was distilled off on a water bath
at a temperature in the range from 50 to 55.degree. C. to obtain
Clopidogrel free base (250 gms).
[0077] Clopidogrel base (250 gms) obtained above was dissolved in
n-hexanol (1.25 L) with stirring at 25 to 30.degree. C. Dilute
sulfuric acid was added to it at 10 to 15.degree. C. The reaction
mixture was seeded with form-I crystal at 20 to 25.degree. C. The
mixture was stirred at room temperature, for 10-12 hrs and
subsequently it was stirred at 22 to 25.degree. C., for 1-2 hours
at high agitation. The reaction mixture was further stirred for 5-8
hours at room temperature at low agitation. The mixture was then
filtered, washed with methyl tert butyl ether (750 ml) and dried at
30 to 35.degree. C. in a drier, to get 260 g of salt as crystals.
Subsequent analysis confirmed that the crystals were clopidogrel
hydrogen sulfate Form-I.
Example 12
Preparation of Clopidogrel Hydrogen Sulfate Form I
[0078] A suspension of (S)-(+) Clopidogrel camphor sulphonate
(861.3 gms) was stirred in dichloromethane (450 ml), and
subsequently basified with NaHCO.sub.3 solution (10%, 6500 ml). The
mixture was stirred at 25 to 30.degree. C. for about 10 minutes.
The layers were separated and the aqueous layer was extracted with
dichloromethane (900 ml.) and washed with water (1800 ml.). It was
then dried over Na.sub.2SO.sub.4 and solvent was distilled off on a
water bath at a temperature in the range from 50 to 55.degree. C.
to obtain Clopidogrel free base (500 gms).
[0079] Clopidogrel base (500 gms) obtained above was dissolved in
n-hexanol (2.5 L) with stirring at 25 to 30.degree. C. and water
(10.3 ml) was added to it. Concentrated sulfuric acid was added to
it at 10 to 15.degree. C. The reaction mixture was seeded with
form-I crystal at 20 to 25.degree. C. The reaction mixture was
stirred at room temperature for 10-12 hrs and subsequently it was
stirred at 22 to 25.degree. C., for 1-3 hours at high agitation.
The reaction mixture was further stirred for 5-8 hours at room
temperature at low agitation. Then, the reaction mixture was
filtered, washed with methyl tert butyl ether (1500 ml) and dried
at 30 to 35.degree. C. in drier, to obtain 561 g of Clopidogrel
bisulfate salt. Subsequent analysis confirmed that the crystals
were clopidogrel hydrogen sulfate Form-I.
Example 13
Preparation of Clopidogrel Hydrogen Sulfate Form I
[0080] A suspension of (S)-(+) Clopidogrel camphor sulphonate
(430.65 gms) was stirred in dichloromethane (225 ml), and
subsequently basified with NaHCO.sub.3 solution (10%, 3250 ml).
Stirred at 25 to 30.degree. C. for about 10 minutes. The layers
were separated and the aqueous layer was extracted with
dichloromethane (450 ml.) and washed with water (900 ml.). It was
then dried over Na.sub.2SO.sub.4 and distilled on a water bath at a
temperature in the range from 50 to 55.degree. C. to obtain
Clopidogrel free base (250 gms).
[0081] Clopidogrel base (250 gms) was dissolved in n-hexanol (1.25
L) with stirring at 25 to 30.degree. C. Dilute sulfuric acid was
added at 10 to 15.degree. C. The reaction mixture was seeded with
form-I crystals at 20 to 25.degree. C. The reaction mixture was
stirred at room temperature, for 10-12 hrs and subsequently it was
stirred at 22 to 25.degree. C., for 1-3 hours at high agitation.
The reaction mixture was further stirred for 5-8 hours at a room
temperature at low agitation. It was then filtered, washed with
methyl tert butyl ether (750 ml) and dried at 30 to 35.degree. C.
in a drier, to obtain 240 g of clopidogrel bisulfate salt.
Subsequent analysis confirmed that the crystals were clopidogrel
hydrogen sulfate Form-I.
Example 14
Preparation of Clopidogrel Hydrogen Sulfate Form I
[0082] The amorphous form of Clopidogrel bisulfate (50 g) by any
process mentioned above was dissolved in n-hexanol (250 mL) at 25
to 30.degree. C. The reaction mixture was stirred for 12 hours. The
precipitated solid was filtered, washed with methyl tert butyl
ether (50 ml), and dried at 30 to 35.degree. C. in a drier, to
obtain 50 g of clopidogrel bisulfate salt. Subsequent analysis
confirmed that the crystals were clopidogrel hydrogen sulfate
Form-I.
Example 15
Preparation of Clopidogrel Hydrogen Sulfate Form I
[0083] A suspension of Clopidogrel hydrogen sulfate (330 gms) was
stirred in dichloromethane (1950 ml) and subsequently with
NaHCO.sub.3 solution (10%, 3300 ml). The mixture was stirred at 25
to 30.degree. C. for about 10 minutes. The organic layer was
separated and aqueous layer was extracted with dichloromethane (325
ml.) and washed with water (1300 ml.). It was then dried over
Na.sub.2SO.sub.4 and the solvent was distilled off on a water bath
at a temperature in the range from 50 to 55.degree. C. to obtain
Clopidogrel free base (250 gms).
[0084] Clopidogrel base (250 gms) was dissolved in n-hexanol (1.25
L) with stirring at 25 to 30.degree. C. Dilute sulfuric acid was
added to it at 10 to 15.degree. C. The mixture was stirred at room
temperature, for 6 hrs and subsequently it was stirred at 22 to
25.degree. C., for 5 hours at high agitation. The reaction mixture
was further stirred for 4-5 hours at room temperature at low
agitation. The mixture was then filtered, washed with methyl tert
butyl ether (750 ml) and dried at 30 to 35.degree. C. in a drier,
to get 280 g of salt as crystals. Subsequent analysis confirmed
that the crystals were Clopidogrel hydrogen sulfate Form-I.
Example 16
Preparation of Clopidogrel Hydrogen Sulfate Form I
[0085] A suspension of Clopidogrel hydrogen sulfate (330 gms) was
stirred in dichloromethane (1950 ml) and subsequently basified with
NaRCO.sub.3 solution (10%, 3300 ml). The mixture was stirred at 25
to 30.degree. C. for about 10 minutes. The layers were separated
and the aqueous layer was extracted with dichloromethane (325 ml.)
and washed with water (1300 ml.). It was then dried over
Na.sub.2SO.sub.4 and distilled off on a water bath at a temperature
in the range from 50 to 55.degree. C. to obtain Clopidogrel free
base (250 gms).
[0086] Clopidogrel base (250 gms) was dissolved in n-hexanol (1.25
L) with stirring at 25 to 30.degree. C. and water (5 ml) was added
to it. To the mixture was added concentrated sulfuric acid at 10 to
15.degree. C. The mixture was stirred at room temperature for 6 hrs
and subsequently it was stirred at 22 to 25.degree. C., for 5 hours
at high agitation. The reaction mixture was further stirred for 4
hours at room temperature at low agitation. The mixture was then
filtered, washed with methyl tert butyl ether (750 ml) and dried at
30 to 35.degree. C. in a drier, to get 270 g of Clopidogrel
bisulfate salt as crystals. Subsequent analysis confirmed that the
crystals were Clopidogrel hydrogen sulfate Form-I.
Example 17
Preparation of Clopidogrel Hydrogen Sulfate Form I
[0087] A suspension of Clopidogrel camphor sulphonate (430.65 gms)
was stirred in dichloromethane (225 ml), and subsequently basified
with NaHCO.sub.3 solution (10%, 3300 ml). The mixture was stirred
at 25 to 30.degree. C. for about 10 minutes. The layers were
separated and the aqueous layer was extracted with dichloromethane
(450 ml.) and washed with water (900 ml.). It was then dried over
Na.sub.2SO.sub.4 and the solvent was distilled off on a water bath
at a temperature in the range from 50 to 55.degree. C. to obtain
Clopidogrel free base (250 gms).
[0088] Clopidogrel base (250 gms) was dissolved in n-hexanol (1.25
L) with stirring at 25 to 30.degree. C. Dilute sulfuric acid was
added to it at 10 to 15.degree. C. The mixture was stirred at room
temperature for 6 hrs and subsequently it was stirred at 22 to
25.degree. C., for 5 hours at high agitation. The reaction mixture
was further stirred for 4 hours at room temperature at low
agitation. The mixture was then filtered, washed with methyl tert
butyl ether (750 ml) and dried at 30 to 35.degree. C. in a drier to
get 250 g of Clopidogrel bisulfate salt as crystals. Subsequent
analysis confirmed that the crystals were Clopidogrel hydrogen
sulfate Form-I.
Example 18
Preparation of Clopidogrel Hydrogen Sulfate Form I
[0089] A suspension of Clopidogrel camphor sulphonate (430.65 gms)
was stirred in dichloromethane (225 ml), and subsequently basified
with NaHCO.sub.3 solution (10%, 3300 ml). The reaction mixture was
stirred at 25 to 30.degree. C. for about 10 minutes. The layers
were separated and the aqueous layer was extracted with
dichloromethane (450 ml.) and washed with water (900 ml.). It was
then dried over Na.sub.2SO.sub.4 and the solvent was distilled off
on a water bath at a temperature in the range from 50 to 55.degree.
C. to obtain Clopidogrel free base (250 gms).
[0090] Clopidogrel base (250 gms) was dissolved in n-hexanol (1.25
L) with stirring at 25 to 30.degree. C. and water (5 ml) was added
followed by addition of concentrated sulfuric acid at 10 to
15.degree. C. The mixture was stirred at room temperature, for 6
hrs and subsequently it was stirred at 22 to 25.degree. C., for 5
hours at high agitation. The reaction mixture was further stirred
for 4 hours at room temperature at low agitation. The mixture was
then filtered, washed with methyl tent-butyl ether (750 ml) and
dried at 30 to 35.degree. C. in a drier, to get 280 g of
Clopidogrel bisulfate salt as crystals. Subsequent analysis
confirmed that the crystals were Clopidogrel hydrogen sulfate
Form-4.
Example 19
Preparation of Clopidogrel Hydrogen Sulfate Form I
[0091] Clopidogrel base (39 gms) was dissolved in n-heptanal (154
mL) with stirring at 25 to 30.degree. C. and water (0.8 ml) was
added to it. Concentrated H.sub.2SO.sub.4 was added at
10-15.degree. C. The reaction mixture was seeded with form-I
crystal at 20-25.degree. C. The reaction mixture was stirred at
room temperature, for 21 hrs. It was filtered, washed with methyl
tert-butyl ether (50 ml) and dried at a temperature in the range
from 30 to 35.degree. C. in a drier, to get 42 g of salt as
crystals. Subsequent analysis confirmed that the crystals were
Clopidogrel hydrogen sulfate Form-I.
Example 20
Preparation of Clopidogrel Hydrogen Sulfate Form I
[0092] Clopidogrel base (50 gms) was dissolved in n-heptanol (154
mL) with stirring at 25 to 30.degree. C. and dilute H.sub.2SO.sub.4
was added at 10-15.degree. C. The reaction mixture was seeded with
form-I crystal at 20-25.degree. T. The reaction mixture was stirred
at room temperature, for 20-24 hrs, filtered, washed with methyl
tert-butyl ether (50 ml) and dried at temperature in the range from
30 to 35.degree. C. in a drier, to get 50 g of Clopidogrel
bisulfate salt as crystals. Subsequent analysis confirmed that the
crystals were Clopidogrel hydrogen sulfate Form-I.
Example 21
Preparation of Clopidogrel Hydrogen Sulfate Form I
[0093] Clopidogrel base (10 gms) was dissolved in decan-1-ol (50
mL) with stirring at 25 to 30.degree. C. and water (0.2 ml) was
added to it. Concentrated H.sub.2SO.sub.4 was added at
10-15.degree. C. Solid material precipitated. The mixture was
stirred at room temperature, for 24 hrs. It was filtered, washed
with methyl tert-butyl ether (30 ml) and dried at temperature in
the range from 30 to 35.degree. C. in a drier, to get 7 g of
Clopidogrel bisulfate salt as crystals. Subsequent analysis
confirmed that the crystals were clopidogrel hydrogen sulfate
Form-I.
Example 22
Preparation of Clopidogrel Hydrogen Sulfate Form
[0094] Clopidogrel base (10 gms) was dissolved in decan-1-ol (50
mL) with stirring at 25 to 30.degree. C. Dilute H.sub.2SO.sub.4 was
added at 10-15.degree. C. when the solid material precipitated. The
reaction mixture was stirred at room temperature, for 24 hrs. Then
the mixture was filtered, washed with methyl tert butyl ether (30
ml) and dried at a temperature in the range from 30 to 35.degree.
C. in a drier, to get 8 g of Clopidogrel bisulfate salt as
crystals. Subsequent analysis confirmed that the crystals were of
Clopidogrel hydrogen sulfate Form-I.
Example 23
Preparation of Clopidogrel Hydrogen Sulfate Form II
[0095] The amorphous Clopidogrel bisulfate (50 g) was dissolved in
methyl-tert-butyl ether (500 mL) at 25 to 30.degree. C. The
reaction mixture was stirred for 24 hours. Then the reaction
mixture was filtered, washed with methyl tert-butyl ether (50 ml),
and dried at 30 to 35.degree. C. in a drier, to obtain 49 g of
clopidogrel bisulfate salt Form-II. Subsequent analysis confirmed
that the crystals were of Clopidogrel hydrogen sulfate Form-II.
* * * * *