U.S. patent application number 12/760542 was filed with the patent office on 2011-01-06 for polymorph and amorphous form of (s)-(+)-clopidogrel bisulfate.
This patent application is currently assigned to Cadila Healthcare Limited. Invention is credited to Mayank G. Dave, Braj B. LOHRAY, Vidya B. Lohray, Bipin Pandey.
Application Number | 20110003846 12/760542 |
Document ID | / |
Family ID | 32982877 |
Filed Date | 2011-01-06 |
United States Patent
Application |
20110003846 |
Kind Code |
A1 |
LOHRAY; Braj B. ; et
al. |
January 6, 2011 |
POLYMORPH AND AMORPHOUS FORM OF (S)-(+)-CLOPIDOGREL BISULFATE
Abstract
The present invention relates to new polymorphs of
S-(+)-Clopidogrel bisulfate and a process for preparing the
same.
Inventors: |
LOHRAY; Braj B.; (Gujarat,
IN) ; Lohray; Vidya B.; (Gujarat, IN) ;
Pandey; Bipin; (Gujarat, IN) ; Dave; Mayank G.;
(Gujarat, IN) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON
VA
22203
US
|
Assignee: |
Cadila Healthcare Limited
Gujarat
IN
|
Family ID: |
32982877 |
Appl. No.: |
12/760542 |
Filed: |
April 14, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10548712 |
Aug 14, 2006 |
|
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PCT/IN2003/000053 |
Mar 12, 2003 |
|
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12760542 |
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Current U.S.
Class: |
514/301 ;
546/114 |
Current CPC
Class: |
C07D 495/04 20130101;
A61P 7/02 20180101 |
Class at
Publication: |
514/301 ;
546/114 |
International
Class: |
A61K 31/4365 20060101
A61K031/4365; C07D 471/04 20060101 C07D471/04 |
Claims
1. Amorphous S-(+) Clopidogrel bisulfate having a powder X-ray
diffraction pattern substantially as depicted in FIG. 1.
2-36. (canceled)
37. Amorphous S-(+) Clopidogrel bisulfate as claimed in claim 1 in
anhydrous form.
38. Amorphous S-(+) Clopidogrel bisulfate as claimed in claim 1 in
hydrated form.
39. A pharmaceutical composition comprising amorphous S-(+)
Clopidogrel bisulfate as claimed in claim 1.
40. A pharmaceutical dosage form comprising a pharmaceutical
composition of amorphous S-(+) Clopidogrel bisulfate having a
powder X-ray diffraction pattern substantially as depicted in FIG.
1.
41. A method of treatment comprising administering a composition of
amorphous S-(+) Clopidogrel bisulfate having a powder X-ray
diffraction pattern substantially as depicted in FIG. 1 in a
therapeutically effective amount for the treatment of a
cardiovascular disorder.
42. The method as claimed in claim 40, wherein the amorphous S-(+)
Clopidogrel bisulfate is in anhydrous form.
43. The method as claimed in claim 40, wherein the amorphous S-(+)
Clopidogrel bisulfate is in hydrated form.
Description
FIELD OF INVENTION
[0001] The present invention describes new forms of
(S)-(+)-Clopidogrel bisulfate; processes for their preparation and
pharmaceutical compositions containing them. More particularly, the
present invention reveals new amorphous polymorphs of
(S)-(+)-Clopidogrel bisulfate, processes to prepare amorphous forms
of (S)-(+)-Clopidogrel to bisulfate and various pharmaceutical
compositions containing amorphous form of (S)-(+)-Clopidogrel
bisulfate. This invention further describes processes for the
preparation of other crystalline polymorphs of S-(+)-Clopidogrel
bisulfate, Form I, Form II and mixtures of amorphous and Form I and
Form II and pharmaceutical compositions containing them.
(S)-(+)-Clopidogrel bisulfate an antiplatelet drug is currently
being marketed for the treatment of atherosclerosis, mycocardial
infarcation, strokes and vascular death. The present invention also
describes the method of treatment of such cardiovascular disorders
using new polymorphs or mixtures thereof, of (S)-(+)-Clopidogrel
bisulfate and pharmaceutical compositions containing them. The
present invention relates to the use of new polymorphs of
(S)-(+)-Clopidogrel bisulfate disclosed herein and pharmaceutical
compositions containing them for the treatment of cardiovascular
disorders.
BACKGROUND TO THE INVENTION
[0002] The compound of the invention referred herein by its generic
name Clopidogrel bisulfate corresponds to the empirical formula
C.sub.16H.sub.16ClNO.sub.2S.H.sub.2SO.sub.4 and has a molecular
weight 419.9. 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##
[0003] 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.
[0004] 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.
[0005] U.S. Pat. No. 4,847,265 describes the process for the
preparation of the hydrogen sulfate salt of Clopidogrel.
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.
[0006] We have recently disclosed novel processes for the
manufacture of (S)-(+)-Clopidogrel bisulfate (Indian Patent
Applications 335/MUM/2001 and 630/MUM/2001).
[0007] U.S. Pat. No. 4,847,265 discloses that the dextrorotatory
enantiomer of formula (I) of Clopidogrel has an excellent
antiagregant 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 relates to
the dextrorotatory enantiomer and its pharmaceutically acceptable
salts with platelet aggregation inhibiting activity. However, the
precision of determination of laevoenantiomer in dextrorotatory
enantiomer was not less than 4%, implying thereby that the method
used by the inventors cannot distinguish precisely a sample of S:R
ratio 96:4 from a sample having the two enantiomers in the ratio
99.5:0.5 (refer page 5, line 35-50, U.S. Pat. No. 4,847,265).
Current regulatory requirements, however, require a high chiral
purity (ee not less than 99%) for chiral drugs.
[0008] Subsequently filed Patent Application WO 99/65915 (U.S. Pat.
No. 6,429,210) titled "Polymorphic Clopidogrel hydrogensulfate
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 bioavailabilty, as shown in their
bioequivalence in healthy human volunteers.
[0009] 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 (degree of imprecision 4% as discussed
above.).
[0010] In fact, we have observed that formation of Form I of
(S)-(+)-Clopidogrel bisulfate with chiral purity >99% ee) 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.
[0011] Therefore it is very essential to find an alternate
polymorphic form which can be consistently produced with high
optical purity (ee >99%).
[0012] In the present invention, we wish to disclose that formation
of form I of Clopidogrel bisulfate is quite reproducible and
consistent, if the optical purity is low (S:R=96:4) as reported in
U.S. Pat. No. 4,847,265. Therefore, it is imperative to prepare
another polymorph of Clopidogrel bisulfate with high optical purity
(>99% ee). The present invention describes a new amorphous form
of (S)-(+)-Clopidogrel bisulfate having optical purity greater than
99% (ee).
[0013] Crystalline solids normally require a significant amount of
energy for dissolution due to their highly organized, lattice like
structures. For example, the energy required for a drug molecule to
escape from a crystal is more than from an amorphous or a
non-crystalline form. It is known that the amorphous forms in a
number of drugs exhibit different dissolution characteristics and
in some cases different bioavailability patterns compared to the
crystalline form (Konno T., Chem. Pharm. Bull., 1990; 38:
2003-2007). For some therapeutic indications, one bioavailability
pattern may be favoured over another. Therefore, it is desirable to
have amorphous forms of drugs and a highly reproducible processes
for their preparation.
SUMMARY OF THE INVENTION
[0014] Accordingly, the present invention provides new amorphous
form of Clopidogrel bisulfate, Another objective of the present
invention is to develop a process for the preparation of amorphous
polymorphs of (S)-(+)-Clopidogrel bisulfate.
[0015] Yet another object is to develop a process for the
preparation of a mixture of the new polymorphs described herein
with Form I.
[0016] Yet another object is to develop a process for the
preparation of a mixture of the new polymorphs described herein
with Form II.
[0017] As an embodiment of the present invention pharmaceutical
compositions containing the new forms described in the present
invention is provided. There is also provided a composition
comprising a Clopidogrel bisulfate crystallization inhibitor
composite.
[0018] Also is provided a method of treatment and use of the new
polymorphs of Clopidogrel for the treatment of cardiovascular
disorders, comprising administering, for example, orally a
composition of the invention in a therapeutically effective
amount.
[0019] The main objective of the present invention is to disclose a
novel amorphous form of (S)-(+)-Clopidogrel bisulfate.
[0020] The amorphous form presented in this invention is
non-sticky, free flowing, pharmaceutically processable and stable
with distinct physico-chemical properties.
[0021] In an embodiment of the present invention processes to
manufacture amorphous (S)-(+) Clopidogrel bisulfate, disclosed in
the specification is provided.
[0022] In another embodiment of the invention process to
manufacture a mixture of Form I enriched with amorphous
S-(+)-Clopidogrel bisulfate is disclosed.
[0023] Another object of the present invention is to disclose
processes which may lead to the mixture of amorphous and Form I in
the ratio ranging from 0:100 to 100:0.
[0024] Still another object of the present invention is to disclose
processes, which may lead to the mixture of amorphous and Form II
in the ratio ranging from 0:100 to 100:0.
[0025] Still another aspect of the present invention, involves the
conversion of amorphous (S)-(+)-Clopidogrel bisulfate to Form
I.
[0026] Yet another object of the invention involves conversion of
amorphous (S)-(+) Clopidogrel bisulfate to Form II.
DESCRIPTION OF INVENTION
[0027] The present invention provides a novel amorphous form of
(S)-(+)-Clopidogrel bisulfate. 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. Without being bound by theory, it is believed
and also observed that the amorphous solids offer the advantages of
faster dissolution due to reduced dissolution energy requirement.
Rapid dissolution is important for poorly soluble compounds
administered orally, since there is a direct correlation between
dissolution rate and bioavailability. Numerous instances have been
recorded where only the amorphous form has adequate
bioavailability.
[0028] Amorphous (S)-(+)-Clopidogrel bisulfate of the present
invention can be prepared by any suitable process, not limited to
processes described herein.
[0029] Amorphous drug substance of the present invention can be
precipitated from solution or obtained from melt of compound by
carrying out the solidification in such a way, so as to avoid the
thermodynamically preferred crystallization process. Such
interferences in the process can be brought about by freeze-drying,
spray drying and various other processes discussed below.
[0030] Amorphous forms can also be prepared by disrupting an
existing crystal structure e.g. Form I of (S)-(+)-Clopidogrel
bisulfate. This leads to excess free energy and entropy into
amorphous solids, since they do not reach their lowest energy state
during crystallization.
[0031] Amorphous form of (S)-(+)-Clopidogrel bisulfate can be
prepared by reacting (S)-(+) Clopidogrel free base in suitable
solvents with concentrated sulfuric acid (80% to 98%) with molar
ratio of 0.98 to 1.2 between -30.degree. C. to 50.degree. C. and
applying vacuum for slow removal of solvents. The suitable solvents
can be water, methanol, ethanol, propanol, n-butanol,
dichloromethane, dimethyl formamide, dimethyl acetamide,
1,4-Dioxane, tetrahydrofuran and mixtures thereof. Removal of
solvent(s) under vacuum leads to amorphous form of clopidogrel
bisulfate as a powder or a brittle foam, which on mechanical
agitation and subsequent drying gives processable dry amorphous
solid.
[0032] Alternatively, amorphous form of (S)-(+)-Clopidogrel
bisulfate can be prepared by reacting (S)-(+) Clopidogrel free base
in suitable solvents with potassium hydrogen sulfate or sodium
hydrogen sulfate with molar ratio of 1 to 4 between 20.degree. C.
to 35.degree. C. and applying vacuum for slow removal of solvents.
The suitable solvents can be water, methanol, ethanol, benzene,
propanol, isopropanol, n-butanol, dichloromethane, dichloroethane,
acetone, cyclohexane, dimethyl formamide, dimethyl acetamide,
1,4-Dioxane, tetrahydrofuran or a mixture thereof.
[0033] The process of manufacture of amorphous form of
(S)-(+)-Clopidogrel bisulfate involves using a (S)-(+) Clopidogrel
free base (% ee >99%), suitably employed solvent selected from
ethanol, methanol, propanol, isopropanol, butanol, 1,4-dioxane,
tetrahydrofuran, DMF, DMA, dichloromethane, acetone, cyclohexane,
water and the like and cone, H.sub.2SO.sub.4 (80 to 98%) or
potassium hydrogen sulfate (1-4 moles) in a suitable solvent, with
or without inert atmosphere.
[0034] In a preferred embodiment of the present invention, the
suitable solvents are ethanol, 1,4-dioxane, acetone, cyclohexane,
THF, dichloromethane, water or a mixture thereof, which is removed
under vacuum.
[0035] It is more preferred to use ethanol, acetone,
dichloromethane, cyclohexane or water as a solvent, which is
removed under reduced pressure.
[0036] Various processes employed to obtain the amorphous
(S)-(+)-Clopidogrel bisulfate includes, solidification of the melt,
spray drying, freeze drying, reduction of the particle size,
lyophilization, removal of solvent from solvate or hydrates, rapid
freezing, milling, grinding and cogrinding. Amorphous solid may
also be prepared by the use of solvates and anti-solvents. Some of
the typical antisolvents can be pet-ether, ether, t-butyl methyl
ether, diisopropyl ether, toluene, n-hexane, cyclohexane,
n-heptane, hexane fraction, heptane fraction and such other
non-polar solvents.
[0037] Amorphous (S)-(+)-Clopidogrel bisulfate can exist in
anhydrous form as well as hydrated form or solvated form. In
general, the hydrated forms are therapeutically equivalent to
anhydrous forms and intended to be encompassed within the scope of
the present invention.
[0038] Seeding with Form I at a suitable stage of solvate
formation, more particularly in a highly concentrated state, gives
a material enriched with Form I with partial amorphous form. Use of
85% H.sub.2SO.sub.4, 90% H.sub.2SO.sub.4, 95% H.sub.2SO.sub.4 and
98% H.sub.2SO.sub.4, was found to be advantageous. Various
polyethylene glycols (PEG) 200, 400, 800, 900, 1000, 1200, 2000 and
4000 were used as amorphous form stabilizer. The concentration of
PEG's wt/wt, w.r.t. Clopidogrel free base was between 0.1 to 5%.
Scratching of the supersaturated solution also results in the
formation of Form I enriched amorphous (S)-(+)-Clopidogrel
bisulfate. Seeding with Form II at a suitable stage of solvate
formation, more particularly in a highly concentrated state, gives
a material enriched with Form II with partial amorphous form.
Scratching of the supersaturated solution also results in the
formation of Form II enriched amorphous (S)-(+)-Clopidogrel
bisulfate.
[0039] Alternatively, it has been found that the sequence of
addition of the reagents and its various permutations and
combinations in the reaction conditions can be altered by people
skilled in the art to obtain the desired result. It has also been
envisaged that the product can be achieved with/without an inert
atmosphere of nitrogen, argon or helium. All the above processes
are incorporated in the scope of the current invention for
manufacturing of amorphous (S)-(+)-Clopidogrel bisulfate.
[0040] An alternate process to produce amorphous Clopidogrel
bisulfate comprises: 1) melting of solid form of Clopidogrel
bisulfate, 2) cooling the melt rapidly to get a solid, and if
required, 3) grinding or milling of the solid drug substance
produced in step (2) above to get a powder.
[0041] Another alternate process for the preparation of amorphous
Clopidogrel bisulfate involves reacting (S)-(+) Clopidogrel free
base in suitable solvents with aqueous dilute sulfuric acid (15% to
35%) between 20.degree. C. to 40.degree. C. and applying vacuum for
slow removal of solvents. The suitable solvents can be water,
methanol, ethanol, propanol, n-butanol, benzene, dichloromethane,
dichloroethane, acetone, cyclohexane, dimethyl formamide, dimethyl
acetamide, 1,4-Dioxane, tetrahydrofuran or mixtures thereof.
[0042] Melting of the solid form of the drug substance may be done
by techniques known in the art such as heating in an oven or
heating in a reactor with heated jacket and the like. Cooling can
be achieved by cooling the reactor vessel jacket to required
temperature or floating the melt containing container over a cold
bath or liquid nitrogen and the like.
[0043] Grinding may be performed by any suitable method such as
grinding in a pestle and mortar or in a suitable mill to get the
powder of required consistency.
Characterization of Amorphous Form
[0044] The amorphous form of (S)-(+)-Clopidogrel bisulfate so
obtained can be characterized by its 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. Some of the key representative data
are attached herewith.
The following nonlimiting examples illustrate the inventor's
preferred methods for preparing the amorphous S(+) clopidogrel
bisulfate and related compounds discussed in the invention.
Example 1
[0045] Crystalline S(+) Clopidogrel bisulfate 100 g was dissolved
in 700 ml of ethanol with agitation at ambient temp. under nitrogen
atmosphere and a clear solution was obtained. Subsequently solvent
was removed slowly under vacuum with rotavapor at approx. 30 to
50.degree. C. Foaming was observed during solvent removal. During
the removal of last traces of solvent, a brittle glossy foam is
obtained, which is broken mechanically into free flowing powder.
The powder is further dried at 60-65.degree. C. for 3 to 4 hours in
the rotavapar and amorphous S(+) clopidogrel bisulfate (98 g, 98%)
is obtained. The amorphous form was characterized by XRD, DSC, IR,
SOR (1% MeOH)+54.degree., chemical purity (HPLC) 99.95% and chiral
purity 99.7% (S-Isomer), m.p. 68 to 72%.
Example 2
[0046] Above experiment was repeated in the same manner except the
removal of solvent at rotavapor was replaced by concentrating
ethanolic solution under vacuum and mechanical stirrer under above
conditions. The product was found to be identical as in Ex. 1.
Example 3
[0047] 508 g of (+) clopidogrel (-) camphor sulfate
(diastereoisomer salt) prepared as per WO 02/059128 Ex. 51/52/53,
was dissolved into 200 ml of dichloromethane and the mixture is
agitated for complete dissolution. Then a solution of 91 g of
potassium carbonate in 700 ml of deionized water was introduced and
vigorously agitated, so that pH of aqueous layer was .about.8. The
organic layer was separated and dried over anhydrous sodium
sulfate, filtered and further concentrated to give 280 g of S(+)
clopidogrel free base. Subsequently 1680 ml of ethanol was added
and the mixture was stirred until a clear homogeneous solution was
obtained. This solution was cooled externally 0 to 5.degree. C. and
1 equivalent of 98% conc. H.sub.2SO.sub.4 was added slowly.
Simultaneously vacuum was applied and the solution was concentrated
initially at .about.25.degree. C. and subsequently at 40-50.degree.
C. under mild mechanical stirring. Once again, foam formation
occurred, which was broken with mechanical agitation, Finally, the
last traces of solvents were removed at 60-65.degree. C. under high
vacuum and 347 g (95%) amorphous S(+) clopidogrel bisulfate was
obtained. The product was identical to the product obtained in Ex.
1.
Example 4
[0048] S(+) Clopidogrel free base (2 g) was generated as per Ex. 3,
and was dissolved in 20 ml of n-propanol at 80-85.degree. C. and 1
eq. of 98% concen. H.sub.2SO.sub.4 was added. The solvent was
distilled under vacuum and final traces of solvents were removed
under 1-2 mm, vacuum at 60.degree. C. (.+-.5.degree. C.) for 2 h,
to give 2 g of amorphous S(+) clopidogrel bisulfate (77%). The
product was identical to the product obtained in Ex. 1, except
presence of residual OVI. (Organic Volatile Impurities)
Similar experiments were repeated with tert-butanol, n-butanol,
1,4-Dioxane, tetrahydrofuran, isopropyl alcohol, dichloromethane
and mixtures thereof.
Example 5
[0049] 114 g of (+) clopidogrel (-) camphor sulfate
(diastereoisomeric salt prepared as per WO 02/059128 Ex. 51/52/53)
was dissolved into 450 ml of dichloromethane and aqueous layer was
basified with sodium bicarbonate until basic pH .about.8. Organic
layer was extracted and washed twice with 2.times.100 ml deionized
water. Subsequently organic layer was collected and dried over
anhydrous sodium sulfate, filtered and the aerate was concentrated
to give 63 g (95%) of S(+) Clopidogrel free base. Acetone 380 ml
was added to it at ambient temp. and stirred until a clear solution
was obtained. 1.26 g of polyethylene glycol-200 (PEG-200), as
amorphous form stabilizer or as crystallization inhibitor, was
added to the reaction mixture and the whole solution was cooled
externally to -5 to 0.degree. C., to which 1 eq. of 98% of
concentration H.sub.2SO.sub.4 was added in 5 to 7 min. This
solution was immediately rotavapored under mild vacuum and the
solution was concentrated. Once again, glossy brittle foams were
observed during the final stages of drying. The final traces of
solvent was removed by drying the powder at 55-60.degree. C. under
vacuum 1 mm for 3 h, to give 79.5 g (96%) of amorphous (+)
clopidogrel bisulfate. The drug substance was identical to the
product obtained in Ex. 1, except residual OVI (Organic volatile
impurities).
Example 6
Includes Variations of Several Examples
[0050] The experiment was repeated in a similar manner as described
in Ex. 5, except the fact that PEG 200 was changed to PEG-400 (2%
w/w w.r.t. S(+) clopidogrel free base) and Similarly, several
experiments were conducted with PEG-600, PEG-800, PEG-900,
PEG-1000, PEG-1200, PEG-2000, PEG-4000 and PEG-6000. The
concentration of PEG'S wt/wt-w.r.t. free base was varied between
0.1% to 5%.
Similarly, another variations to above experiments was used of 90%
H.sub.2SO.sub.4, 95% H.sub.2SO.sub.4 and 85% H.sub.2SO.sub.4,
instead of 98% H.sub.2SO.sub.4, to make amorphous S(+) clopidogrel
bisulfate with various other PEG's already mentioned above, gave
invariably pharmaceutically processable amorphous material.
However, the mol. ratio of above H.sub.2SO.sub.4 w.r.t. free base
was always between 0.95 to 1.2. In quality terms i.e., XRD, DSC,
chiral purity, chemical purity, IR, the product obtained via above
methods was always amorphous free flowing processable solid.
Example 7
[0051] Polymorph I of (+)-Methyl
(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate
bisulfate salt (I)
[0052] 2.1 g (+)-Methyl
(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate
was added 7.6 mL of acetone to obtain a clear solution. To this
solution, 0.887 g of H.sub.2SO.sub.4 (80%) was added slowly and
temperature was maintained around 20.degree. C. under nitrogen
atmosphere. Later the reaction mixture was cooled up to -20.degree.
C. for 2 hrs and then the temperature was brought to room
temperature (20.degree. C.). The reaction mixture was stirred at
20-25.degree. C. Precipitate was isolated (600 mg), dried under
vacuum at temperature not exceeding 50.degree. C.
[0053] The product obtained was characterized by different
physico-chemical characteristics and was found identical to Form I
as described in the literature, having characteristics as given
below;
[0054] SOR (.alpha..sup.D): +54.03.degree. (C=1.89, MeOH)
[0055] Melting point: 185.degree. C..+-.1.degree. C.
[0056] Chiral Purity: 99.63% (ee)
IR and XRD were found matching to that reported in the
literature.
Example 8
[0057] Polymorph I of (+)-Methyl
(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate
bisulfate salt (I)
[0058] To 2 g (+)-Methyl
(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate
was added 5 mL of acetone and stirred at 25-30.degree. C. The
temperature of the reaction mixture was raised from 25 to
65.degree. C. and then kept at 65.degree. C. for 5 min. At
temperature 50-52.degree. C. 0.676 g of concentrated
H.sub.2SO.sub.4 was added. The reaction mixture was cooled from
52.degree. C. to 5.degree. C., and additional acetone was added and
stirred for 5 min. Later the reaction mixture was stirred at
25-30.degree. C. for 12 hrs, the thick precipitate obtained was
filtered, washed with 5 mL of acetone and the residue was dried in
a vacuum oven. The yield of titled product obtained was 1.27 g
(47%).
[0059] The product obtained was characterized by different
physico-chemical characteristics and was found identical to Form I
as described in the literature, having characteristics, as given
below;
[0060] SOR (.alpha..sup.D): +54.03.degree. (C=1.89, MeOH)
[0061] Melting point: 185.degree. C..+-.1.degree. C.
[0062] Chiral Purity: 99.80% (ee)
IR and XRD were found matching to that reported in the
literature.
Example 9
[0063] Polymorph I of (+)-Methyl
(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate
bisulfate salt (I)
[0064] To 1.98 g (+)-Methyl
(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate
was added 5 mL of acetone and stirred at 25-30.degree. C. The
temperature of the reaction mixture was raised from 25 to
50-52.degree. C. and within one lot 0.7 g of concentrated
H.sub.2SO.sub.4 (95%) was added with constant stirring and the
reaction mixture was suddenly cooled to 0.degree. C. to -5.degree.
C. for 10 min, Later the reaction mixture was stirred at
25-30.degree. C. for 12 hrs, the thick precipitate obtained was
filtered, washed with 5 mL of acetone and the residue (1.6 g, 62%)
was dried in a vacuum oven.
[0065] The product obtained was characterized by different
physico-chemical characteristics and was found identical to Form I
as described in the literature, having characteristics as given
below;
[0066] SOR (.alpha..sup.D): +55.96.degree. (C=1.89, MeOH)
[0067] Melting point: 185.degree. C..+-.1.degree. C.
[0068] Chiral Purity: 99.85% (ee)
IR and XRD were found matching to that reported in the
literature.
Example 10
[0069] Crystalline S(+) clopidogrel bisulfate 10 g was dissolved
into 100 ml of ethanol at ambient temp. until a clear solution was
obtained. Vacuum was applied and the solution was concentrated at
50-55.degree. C., until a dense thick liquid is obtained. In the
presence of ethanol, the brittle foam collapses into dense thick
liquid. To this, 5% by wt, i.e. 500 mg of S (+) clopidogrel
bisulfate Form I (see Ex. 7/8/9) was added as a seed and
subsequently the concentrated heterogenous thick liquid is
concentrated at 55.degree. C. under high vacuum. Once again glossy
brittle foam is observed during the drying of final traces of
solvents and after breaking the foam mechanically, the solid was
further dried for 3 h at 60-65.degree. C. to give amorphous
S(+)clopidogrel with impurities of Form I (9.5 gm 95%), m.p.
160-168.degree. C.
Example 11
[0070] Crystalline S(+) Clopidogrel bisulfate 10 g was dissolved
into 100 ml of ethanol at ambient temp. until a clear solution was
obtained. Vacuum was applied and the solution was concentrated at
50-55.degree. C., until a dense thick liquid is obtained, In the
presence of ethanol, the brittle foam collapses into dense thick
liquid. To this, 10% by wt. i.e. 1000 mg of S(+) clopidogrel
bisulfate Form I (see Ex. 7/8/9) was added as a seed and
subsequently the concentrated heterogenous thick liquid is
concentrated at 55.degree. C. under high vacuum. Once again glossy
brittle foam is observed during the drying of final traces of
solvents and after breaking the foam mechanically, the solid was
further dried for 3 h at 60-65.degree. C. to give amorphous
S(+)clopidogrel with impurities of Form I (9.5 gm 95%), m.p.
160-168.degree. C.
Example 12
[0071] A solution of 10 g of S(+) Clopidogrel free base in 50 ml of
ethanol was cooled to -5 to 0.degree. C. and conc. H.sub.2SO.sub.4
1 eq. was added to it which was spray dried in a spray Dryer (Jay
Instruments & Systems, LSD-48) with 45-50 mm of water aspirator
with a flow rate of 10-10.5 ml/min. with inlet temp. 60.degree. C.
and outlet temp. 35-40.degree. C. and 5 g of amorphous Clopidogre
bisulphate was obtained. This substance was identical in every
respect.
Example 13
Molt+Form I
[0072] To a molt of 10 g of amorphous S(+) Clopidogrel bisulfate as
prepared in previous examples at 100.degree. C.(.+-.10.degree. C.),
seed of 1 g of Form I of Clopidogrel bisulfate is added and the
seeded molt is cooled slowly to room temperature with vigorous
stirring. 10.5 g of amorphous Clopidogrel with impurities of Form I
is obtained.
Example 14
Includes Variations of Several Examples
[0073] To 10 g of S(+) Clopidogrel free base, 5-6 volume of acetone
is added. The mixture is cooled to 0 to 5.degree. C. and 1 eq. of
98% conc. H.sub.2SO.sub.4 and then PEG-200 (Form stabilizer) was
added. The solution was concentrated to approximately 15 g. and 5%
wt/wt of Form I (Ex. 7/8/9) was added as seed.
[0074] Similarly, several experiments were conducted with PEG-400,
PEG-1000, PEG-2000 and PEG-4000. The concentration of PEG wt/wt
w.r.t. free base was varied between 0.2% to 5%. Similarly, another
variation to above experiments was the use of 10% and 20% of Form I
as seed along with various other PEG's mentioned above, This gave
amorphous and Form I in 10 g to 12 g yield depending on amount of
Form I used. Mixture of amorphous and Form I is prepared in varied
proportions.
Example 15
[0075] Crystalline Form II of S (+) Clopidogrel hydrogen sulfate
(110 g, 0.262 mole) was dissolved in a mixture of dichloromethane
(1.1 L) and water (132 mL) under stirring at 25-30.degree. C., and
then evaporated to dryness. The operation of addition of
dichloromethane to the reaction mixture and evaporation was
repeated to remove most of the water and then traces of water was
removed under reduced pressure (10-15 mm) at 50-55.degree. C. The
solid obtained was dried at 50-55.degree. C. for 8 hours to get
amorphous Clopidogrel bisulfate (111.6 g). The amorphous faith was
characterized by XRD, DSC, IR, chemical purity (HPLC) >99% and
chiral purity 99.38% (S-Isomer), % water 1.47, m.p. 122-126.degree.
C. (softens).
Example 16
[0076] S (+) Clopidogrel hydrogen sulfate (Form I) (25 g, 0.059
mole) was similarly treated as described in Experiment 15 above to
give 26 g amorphous clopidogrel hydrogen sulfate. The amorphous
form was similarly characterized by XRD, DSC, IR, chemical purity
(HPLC) >99% and chiral purity (chiral HPLC) 99.84% (e.e.), %
water 1.5, m.p. 124-126.degree. C. (softens).
Example 17
[0077] To a stirred suspension of clopidogrel base (38.31 g, 0.119
mole) in water (30 mL), was added potassium hydrogen sulfate (32.3
g, 0.237 mole) at 25-30.degree. C. The reaction mixture was stirred
for 15 minutes and acetone (250 mL) was added, stirred further for
30 minutes and filtered. Insoluble solid was filtered. The filtrate
was distilled at 50-55.degree. C. under reduced pressure (5-10 mm).
Dichloromethane (380 mL) was added and distilled at 50-55.degree.
C. This operation was repeated twice by adding dichloromethane (350
mL), and finally traces of water was removed under reduce pressure
(5-10 mm) to give amorphous clopidogrel hydrogen sulfate (46 g).
The amorphous form was similarly characterized by XRD, DSC, IR,
chemical purity (HPLC) >99% and chiral purity (chiral HPLC)
99.8% (e.e.), % water 1.91, m.p, 132-135.degree. C. (softens).
Example 18
[0078] To a stirred suspension of clopidogrel base (3.83 g, 0.0119
mole) in water (3 mL) was added potassium hydrogen sulfate (1.62 g,
0.0119 mole) at 25-30.degree. C. The reaction mixture was stirred
for 15 minutes and acetone (25 mL) was added, further stirred for
30 minutes and filtered. The filtrate was distilled at
50-55.degree. C. under reduce pressure (5-10 mm). Benzene (10 mL)
was added to the reaction mixture and distilled at 90-95.degree.
C., di-isopropyl ether (20 mL) was added and stirred at
25-30.degree. C. for 1 hour and filtered. The semi sold material
was dissolved in dichloromethane (25 mL) and distilled under
reduced pressure (5-10 mm) to give clopidogrel hydrogen sulfate
(2.1 g). The amorphous form was similarly characterized by XRD,
DSC, IR, chemical purity (HPLC) >99% and chiral purity (chiral
HPLC) 99.5% (e.e.), % water 3.0, m.p. 94-98.degree. C.
(softens).
Example 19
[0079] Amorphous Clopidogrel hydrogen sulfate (23 g, m.p,
132-35.degree. C.) was melted under reduced pressure (2-5 mm). The
molten mass was cooled to 25-30.degree. C. at reduced pressure.
Subsequently, the vacuum was released under nitrogen atmosphere and
the amorphous Clopidogrel bisulfate was isolated (21 g). The
amorphous form was similarly characterized by XRD, DSC, IR,
chemical purity (HPLC) >99% and chiral purity (chiral HPLC) 99%
(e.e.), % water 0.34, m.p. 88-90.degree. C. (softens).
Example 20
[0080] To a solution of Clopidogrel free base (13 g, 0.04 moles) in
acetone (85 ml) at 25-30.degree. C. was added dropwise dilute
aqueous sulfuric acid (3.56 g, 0.036 mole). The solution was
stirred for 15 minutes, distilled at 50-55.degree. C. under reduced
pressure (5-10 mm). Dichloromethane (130 ml) was added and
distilled, the operation was repeated using dichloromethane (130
ml). Finally traces of water was removed under reduced pressure
(5-10 mm) to give amorphous clopidogrel hydrogen sulfate (16.4 g).
The amorphous form was similarly characterized by XRD, DSC, IR,
chemical purity (HPLC) >99% and chiral purity (chiral HPLC)
99.4% (e.e.), % water 3.37, m.p. 128-130.degree. C. (softens).
Example 21
[0081] To a solution of Clopidogrel free base (10 g, 0.031 moles)
in acetone (65 ml) and water (13 ml), was added dropwise sulfuric
acid (3.0 g, 0.33 mole) at 25-30.degree. C. The solution was
stirred for 15 minutes, distilled at 50-55.degree. C. under reduced
pressure (5-10 mm). Dichloromethane (100 ml) was added and
distilled, the operation was repeated twice using dichloromethane
(100 ml). Finally traces of water was removed under reduced
pressure (5-10 mm) to give amorphous clopidogrel hydrogen sulfate
(13.7 g). The amorphous form was similarly characterized by XRD,
DSC, IR, chemical purity (HPLC) >99% and chiral purity (chiral
HPLC) 99.8% (e.e.), % water 1.95, m.p. 110-120.degree. C.
(softens).
Example 22
[0082] Amorphous Clopidogrel hydrogen sulfate prepared above (1.2
g) was stirred in ethyl acetate (36 ml) for 30-45 minutes and
distilled to dryness (oily residue). The oily residue was stirred
in ethyl acetate (36 ml) at 20-25.degree. C. and filtered to give
Form II of S-(+) Clopidogrel hydrogen sulfate (0.5 g, m.p.
169-175.degree. C., chemical purity (HPLC) 98% and chiral purity
(chiral HPLC) 99.8% (e.e.))
Example 23
[0083] Amorphous Clopidogrel hydrogen sulfate prepared above (0.2
g) was stirred in acetone (3 ml) for 16 hours and filtered, washed
with acetone and dried, to give Form II of S-(+) Clopidogrel
hydrogen sulfate (0.12 g, m.p. 174-177.degree. C.).
Description of Attachments
[0084] 1. FIG. 1 XRD of amorphous (S)-(+)-Clopidogrel bisulfate. 2.
FIG. 2 IR of amorphous (S)-(+)-Clopidogrel bisulfate. 3. FIG. 3 XRD
of Form I (chirally pure ee 99.7%). 4. FIG. 4 XRD of Form II
(chirally pure ee 99.5%). 5. FIG. 5 XRD of Form I enriched
amorphous solid 6. FIG. 6 IR of Form I enriched amorphous
Solid.
[0085] XRD represents X-ray diffractogram. The horizontal axis
represents 2.theta. and the vertical axis represents the peak
intensity.
[0086] The powder X-ray diffraction pattern of the amorphous form
of the present invention shows no peaks (FIG. 1) which are
characteristic of the crystalline forms of the Clopidogrel
bisulfate (FIG. 3 and FIG. 4), thus demonstrating the amorphous
nature of the drug substance.
[0087] The amorphous S-(+) Clopidogrel bisulfate of the present
invention is water soluble. The amorphous S-(+) Clopidogrel
bisulfate of the present invention is also easy to handle and
formulate into various pharmaceutical compositions.
Formulation
[0088] The amorphous Clopidogrel drug substance of the present
invention prepared according any process described above or any
other process can be administered orally, parenterally or rectally
without further formulation, or as a simple solution in water 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.
[0089] Another aspect of the present invention aims at providing
the various pharmaceutical compositions of amorphous
(S)-(+)-Clopidogrel bisulfate containing active ingredients.
[0090] According to the present invention, amorphous
(S)-(+)-Clopidogrel bisulfate is formulated in 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. It
can also be administered rectally in the form of suppositories or
can be parentally administered in the form of an injectable
solution.
[0091] In the form of tablets, it can be administered in a solid
composition by mixing the principal active ingredient with a
pharmaceutical vehicle, such as gelatin, lactose magnesium
stearate, talc, Arabic gum or amidon, and can be coated with
saccharose or other appropriate materials or can be treated so as
to ensure prolonged activity and controlled or sustained release in
a continuous manner by predetermining the quantity of the principal
active ingredient.
[0092] In the case of powders or granules, an active ingredient
mixed with some dispersion agents or dampening agents, or
suspending agents like polyvinylpyrrolidone, along with some
sweetening substances or taste correctors are employed.
[0093] The capsule form can be easily attained by mixing the active
ingredient with a dilutant and by pouring the mixture obtained in
soft or hard capsules. The active ingredient can be formulated in
the form of microcapsules, possibly with one or more supports or
additives.
[0094] In an embodiment of the present invention, there is provided
a Clopidogrel bisufate-crystallization inhibitor composite which
comprises of the amorphous drug substance along with at least one
crystallization inhibitor in an intimate association.
Crystallization inhibitors include any material which reduces the
conversion of the amorphous Clopidogrel bisulfate to crystalline
form, such as, polymers, carbohydrates, lipids and the like. Some
examples are polyvinylpyrrolidone, hydroxypropylmethylcellulose
(HPMC), ethyl cellulose, sodium or calcium carboxymethylcellulose,
hydroxyethylcellulose, HPMC phthalate, dextran,
.beta.-cyclodextrin, polyvinyl alcohol, polyethylene glycol, block
copolymers of ethylene oxide or propylene oxide, acacia, starch and
the like. It is understood that the stability of the amorphous
composite is influenced by the crystallization inhibitor(s) as well
as the quantity used. The drug-crystallization inhibitor composite
of the present invention can be prepared by any suitable process
but not limited to the ones known in the art. Aqueous suspensions,
saline solutions or sterile and injectable solutions can be
employed for parental administration.
[0095] For rectal administration the formulation would constitute
the use of suppositors as the principal active ingredient, which
can be prepared with binders melting at the rectal temperature, for
example cocoa butter or polyethylene glycols.
[0096] In another embodiment of the present invention a method of
treatment and use of the new polymorphs of Clopidogrel 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.
* * * * *