WO2011125069A1

WO2011125069A1 - A process for preparation of crystalline form i of clopidogrel bisulfate

Info

Publication number: WO2011125069A1
Application number: PCT/IN2011/000179
Authority: WO
Inventors: Anita Ranjan Srivastava; Yuvraj Suresh Sonar; Ranjan Prasad Srivastava; Krishna Anand Poojari
Original assignee: Rpg Life Sciences Limited
Priority date: 2010-03-22
Filing date: 2011-03-18
Publication date: 2011-10-13

Abstract

The present invention relates to process for preparation of crystalline Form I of clopidogrel bisulfate comprising steps of preparing clear solution of clopidogrel free base in ethyl acetate, which is cooled to a temperature varying from about -7 to about - 10°C and reacted with concentrated sulphuric acid while maintaining said temperature, thereafter slowly warmed to room temperature, and then heated to reflux, which on cooling to room temperature, filtration, washing and vacuum drying results in crystalline Form 1 of clopidogrel bisulfate.

Description

A PROCESS FOR PREPARATION OF CRYSTALLINE FORM I OF CLOPIDOGREL BISULFATE

Field of the Invention :-

5 The present invention relates to a process for preparation of crystalline Form I of clopidogrel bisulfate also known as clopidogrel hydrogen sulfate or hydrogen sulfate of methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetate and crystalline Form I of clopidogrel bisulfate produced thereby.

Particularly, the present invention relates to a process for preparation of highly0 pure crystalline Form I of clopidogrel bisulfate having melting point of 180 to 185°C, chiral purity of >99% by HPLC, preferably 99.5% by HPLC with optical rotation ([ ]_D ²⁰) of +55° to 56°, preferably +55.4° (1.89 g/100 ml; Methanol) and crystalline Form I of clopidogrel bisulfate produced thereby.

Background of the Invention :-5 The clopidogrel bisulfate also known as bisulfate of methyl (+)-(S)- a-(2- chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetate in crystalline Form I is known to be platelet aggregation inhibitor.

The clopidogrel bisulfate was first described in European patent no. EP0281459 and its equivalent US patent no. 4,847,265 [US'265].

0 As per US'265 [equivalent of EP0281459], clopidogrel bisulfate was prepared by precipitation by action of corresponding acid on the base either in a solution of a solvent from which it could be precipitated spontaneously or by addition of non-solvent (anti-solvent), and the ideal solvent suggested was acetone. No further details of process were described, except that in its example 1(e), it is stated that by mere addition5 of concentrated sulfuric acid over solution of residue from saturated solution of sodium bicarbonate and camphor-10-sulfonic acid salt of methyl-a-5-(4,5,6,7-tetrahydro(3,2- c)thieno pyridyl) (2-chlorophenyl)-acetate in ice cold acetone will result in precipitates of "hydrogen sulfate of dextrorotatory methyl- -5(4,5,6,7-tetrahydro(3,2-c)thieno pyridyl) (2-chlorophenyl)-acetate" (which required recrystallization) having melting0 point of 184°C and optical rotation of [a]_D ²⁰ = + 55.10 (c = 1.891 g/100 ml; in methanol). This patent was merely aimed to identify dextrorotatory isomer which was found to have better therapeutic index than salt of the racemic mixture. In fact as per this patent, levorotatory isomer exhibited no platelet aggregation inhibiting activity and its toxicity was found to markedly higher than of its dextrorotatory homologue.

Further, US'265 [equivalent of EP0281459] did not make any suggestion that clopidogrel hydrogen sulfate could exist in polymorphic forms Form I and Form II.

It was only in subsequent US patent No. 6,429,210 [US'210], which was national phase of PCT application No. PCT/FR99/01371 , PCT publication No. W099/65915, confirmed that synthesis described in US'265 leads to the preparation of hydrogen sulfate of the polymorph of clopidogrel Form I.

However, the US'210 taught that reaction in acetone solvent, which was also the ideal solvent as per US'265, is to be carried out at room temperature (at 20°C), which is contrary to previous teachings of US'265, wherein reaction in acetone is to be carried out under ice cold conditions. As per US'210, the reaction at room temperature on addition of about 80% H₂S0₄ results in formation of Form I of clopidogrel hydrogen sulfate. Therefore, a person reading these patents will only be motivated to react selected acid salt of US'210 in acetone solvent at room temperature and not at ice cold temperature.

Further, as per US'210, the process described in US'265 leads only to formation of Form I of clopidogrel hydrogen sulfate, however, the inventors of present invention have found that it results in formation of Form 1, but contaminated with Form II.

The US'210 discloses process to prepare clopidogrel hydrogen sulfate Form II, but simultaneously clopidogrel hydrogen sulfate Form I is also formed.

The US'210 confirms that Form II is thermodynamically more stable as compared to Form I of clopidogrel hydrogen sulfate, which means that over a period of time, Form I is more likely to be converted to Form II of clopidogrel hydrogen sulfate, and/or at least the process to prepare Form I is less likely to be reproducible and/or at least the process to prepare Form I is likely to result in Form I, but to be contaminated with Form II.

Further, the US'210 also confirms that any attempt of crystallization of clopidogrel hydrogen sulfate from a solvent may result in formation of Form I as per US'265 or in formation of Form II. Therefore, from teachings of US'210, it may be concluded that if crystalline form of Form I of clopidogrel hydrogen sulfate is not formed "directly" during the process of its preparation, then any attempt to crystallize these is more likely to result in formation of Form II as well, meaning thereby, Form I prepared by process of preparation of clopidogrel hydrogen sulfate involving crystallization step is more likely to be contaminated by its Form II, because of its greater thermodynamic stability, and hence, resulting in rejection thereof.

Further, the Form I prepared in accordance with methods of US'210 was found to have a melting point varying from 181°C to 187°C (184±3°C), which itself indicates that Form I formed even by methods of US'210 is not pure.

Further, due to possibility of formation of Form II of clopidogrel hydrogen sulfate, the yield of Form I by either process of US'265 and US'210 is very low. meaning thereby these processes, in-addition to above drawbacks, also suffer for being highly un-economical.

Even, when inventors of present invention have made an attempt to prepare

Form I of clopidogrel hydrogen sulfate as per method of US'210, they found that Form I is contaminated with Form II as the compound prepared was found to have melting point varying from 176-177°C for product prepared as per Experiment I B, and varying from 177-178°C for product prepared as per Experiment 1C.

From the foregoing description, it is understood that processes of US'265 and subsequent patent US'210 are not acceptable if one is aiming to prepare crystalline Form I of clopidogrel hydrogen sulfate without contamination of Form II, that is of high chiral purity at least of 99% or more by HPLC.

It was noted that as per US'210, crystalline form of Form II of clopidogrel hydrogen sulfate was prepared by seeding (crystallization) with crystals of Form II, but this may not have adversely effected the desired results of US'210 to form pure Form II, because it is Form II which is thermodynamically more stable, and hence, while preparing Form II question of contamination did not arise. However, the same may not be true when one is aiming at preparation of crystalline form of pure Form I.

The PCT application no. PCT/CZ2003/000049, PCT publication no.

WO2004/020443 [PCT'49], made an attempt to overcome above problems of prior art by proposing a process to prepare crystalline Form I of clopidogrel hydrogen sulfate without detectable impurity of Form II. This application proposes crystallization of Form I from solvents selected from C 1 -C5 alcohols, particularly iso-propanol, or their esters, particularly n-butyl acetate, optionally combination thereof, particularly combination of iso-propanol and n-butyl acetate.

As per teachings of PCT'49, one can obtain Form I of clopidogrel hydrogen sulfate without detectable impurity of Form II by dissolving clopidogrel base in iso- propanol then cooling to 0 to -5°C or only upto 0°C followed by addition of concentrated sulphuric acid while stirring for about 2.5 hours.

However, these methods require pre-condition of inoculation with crystals of Form I, which in fact is required to be carried out twice - once after addition of concentrated sulphuric acid then after heating the solution.

Further, above methods of PCT'49 also require that solution, after addition of concentrated sulphuric acid, heated to a temperature of 15°C is cooled down once again to a temperature of -5°C or -1°C and maintained for 8 hours.

It may be noted that in method of Example 2 of PCT'49, neither yield nor purity of Form I has been reported. The inventors of present invention, when repeated the method of Example 2 of PCT'49 found that yield is of about 70% indicating less economical process and the optical rotation is of about 53.0° indicating poor chiral purity of the product produced.

As per teachings of PCT'49, one can also obtain Form I of clopidogrel hydrogen sulfate without detectable impurity of Form II by dissolving clopidogrel base in n-butyl acetate then cooling to 0 to +5°C in a water-and-ice bath followed by addition of concentrated sulphuric acid by allowing temperature to rise upto +5°C.

However, these methods also require pre-condition of inoculation with crystals of Form I, which is carried out before addition of concentrated sulphuric acid that is when even clopidogrel hydrogen sulfate has not been formed.

These methods do not require that solution, after addition of concentrated sulphuric acid, heated to a temperature of 10°C is to be cooled down once again to a temperature of -5°C or -1°C, but the reported yield is of 84.8%, which, without defining any reasons therein even goes down to 78.0%.

Accordingly, it is understood that pre-condition of inoculation, that's too twice with crystals of Form I not only elongates overall duration of process, that is makes it highly time consuming, but also adds-on additional steps, and hence, makes it more complex process.

Further, as stated herein above, if crystalline form of Form I of clopidogrel hydrogen sulfate is not formed "directly" during the process of its preparation, then any attempt to crystallize these is more likely to result in formation of Form II as well, meaning thereby, Form I prepared is more likely to be contaminated by its Form II, because of its greater thermodynamic stability, and hence, resulting in its rejection. The PCT'49 discloses an alternative method to prepare Form I of clopidogrel hydrogen sulfate without step(s) of inoculation, but the solvent selected is mixture of iso-propanol and butyl ester, and there is no mention of yield and purity of Form I. Therefore, as per PCT'49, a person skilled in the art, attempting to crystallize Form I of clopidogrel hydrogen sulfate either from iso-propanol or from butyl ester, will have to perform step(s) of inoculation. As stated herein, even with inoculation, the yield and purity of Form I are not satisfactory.

The recent US patents 7,291 ,735 [US'735] and 7,482,453 [US'453] both national phase of PCT application No. PCT/IB2003/003104 (PCT Publication No. WO 2005/012300) [PCT'3104] tried to overcome above problems by use of ethyl acetate, but at room temperature and by requiring seeding with crystals of Form I of clopidogrel hydrogen sulfate, but could only produce Form I of clopidogrel hydrogen sulfate having increased melting point of 198 to 200°C. The Form I with such an increased melting point will have reduced optical rotation as it is also reported to be [α]ο^{20 =} + 51.16° at a concentration of 1.61 gm/100 ml methanol in its Example (b) and claimed in claim of PCT'3104 meaning thereby the Form I produced is not likely to be acceptable as platelet aggregation inhibitor. These patents do state that specific optical rotation [α]ο²⁰ of Form I produced is + 55.16° at concentration of 1.61 g/100 ml methanol, but as evidenced from the actual product produced, the [α]ο²⁰ is + 51.16° at a concentration of 1.61 gm/100 ml methanol.

It may be noted that the US'735 and US'453 confirm that alcoholic solvents result in mixture of Form I and Form II of clopidogrel hydrogen sulfate and not in pure Form I of clopidogrel hydrogen sulfate.

It may also be noted that the US'735 and US'453 also confirm that even using seeded crystals of pure Form I in acetone could only afford Form II of clopidogrel hydrogen sulfate.

The inventors of present invention have found that when an attempt to prepare Form I of clopidogrel hydrogen sulfate was made in accordance with method of US'735 and US'453 by dissolving the clopidogrel base in ethyl acetate at room temperature and seeding with crystals of Form I of clopidogrel hydrogen sulfate followed by addition of concentrated sulfuric acid at room temperature a sticky mass is formed which makes it very difficult not only to stir the reacting mixture, but also makes it difficult to crystallize and separate Form I of clopidogrel hydrogen sulfate. As stated herein, the step of seeding with crystals of Form I of clopidogrel hydrogen sulfate is not only expected to increase process step and cost of process but is also expected to formation of Form II of clopidogrel hydrogen sulfate due to its greater thermodynamical stability.

Need of the Invention:

Therefore, still there is a need to have further improved process which is simpler, time saving and comprising minimum number of steps, and does not require step of seeding (inoculation) with crystals of Form I of clopidogrel hydrogen sulfate, and can still produce crystalline Form I of clopidogrel hydrogen sulfate without contamination of Form II or at least with substantially reduced impurity of Form II, and having chiral purity of 99.0% or more, preferably 99.5% by HPLC, and thereby meeting the requirements of United States Pharmacopoeia [USP] specifications.

Problem to be solved:-

Accordingly, the present invention aims to solve above-described problems of prior art by providing a simpler process without involving step of seeding (inoculation) with crystals of Form I of clopidogrel hydrogen sulfate, and being less time consuming, and suitable and economical for large scale production, and still being capable of producing crystalline Form I of clopidogrel hydrogen sulfate without contamination of Form II or at least with substantially reduced impurity of Form II and having chiral purity of 99.0% or more, preferably 99.5% by HPLC, and having melting point of 180 to 185°C, specific optical rotation of [a]_D ²⁰ = +55° to 56°, preferably of + 55.4° at concentration of 1.89 g/100 ml; methanol, so that Form I of clopidogrel hydrogen sulfate produced can be used as per US pharmacopoeia as platelet aggregation inhibitor.

Objects of the Invention:-

Accordingly, the main object of present invention is to provide a simpler process without involving step of seeding (inoculation) with crystals of Form I of clopidogrel hydrogen sulfate, and being less time consuming, and suitable and economical for large scale production, and still being capable of producing crystalline Form I of clopidogrel hydrogen sulfate without contamination of Form II or at least with substantially reduced impurity of Form II and having chiral purity of 99.0% or more, preferably 99.5% by HPLC, and having melting point of 180 to 185°C, specific optical rotation of [a]_D ²⁰ = +55° to 56°, preferably of + 55.4° at concentration of 1.89 g/100 ml methanol, so that the Form I of clopidogrel hydrogen sulfate produced can be used as per US pharmacopoeia as platelet aggregation inhibitor.

The another object of present invention is to provide a process to prepare dextrorotatory crystalline Form I of clopidogrel hydrogen sulfate without contamination of Form II.

This is also an object of present invention to provide a reproducible process which is capable of producing stable crystalline Form I of clopidogrel hydrogen sulfate in about less than 6 hrs, preferably less than 4 hrs after completion of addition of sulphuric acid vis-a-vis of about 10 hrs or more of conventional processes rendering the process of present invention highly time saving.

This is also an object of present invention to provide a reproducible process which is capable of producing stable crystalline Form I of clopidogrel hydrogen sulfate which does not get converted to any other form including Form II.

This is also an object of present invention to provide a process to prepare stable crystalline Form I of clopidogrel hydrogen sulfate, wherein no additional crystallization step is required, thereby possibility of formation of Form II of clopidogrel hydrogen sulfate is ruled out, and hence, probability of contamination of Form I with its Form II is ruled out or at least minimized to maximum possible extent.

This is also an object of present invention to provide a process to prepare stable crystalline Form I of clopidogrel hydrogen sulfate having melting point varying only from 180 to 185°C, indicating that Form I formed is highly pure.

This is also an object of present invention to provide a process to prepare stable crystalline Form I of clopidogrel hydrogen sulfate wherein yield of Form I is more than 87% molar, preferably 89% molar or more confirming that process is highly time saving, economical and suitable for industrial production.

This is also an object of present invention to provide a process to prepare stable crystalline Form I of clopidogrel hydrogen sulfate requiring no pre-condition or condition of inoculation with crystals of Form I of clopidogrel hydrogen sulfate, and hence, it not only avoids associated drawbacks of inoculation, but is also independent of requirement of product which is yet to be produced by the process.

This is also an object of present invention to provide a process to prepare stable crystalline Form I of clopidogrel hydrogen sulfate wherein repeated heating and cooling steps are avoided, thereby resulting in advantages of substantial saving of process time and energy, and still being capable of producing Form I in yield of more than 87% molar, preferably 89% molar or more, and hence, making the process more economical and suitable for industrial production.

This is also an object of present invention to provide a process to prepare stable crystalline Form I of clopidogrel hydrogen sulfate wherein recovery of Form I of clopidogrel hydrogen sulfate is easy and convenient.

Other objects and advantages of present invention will become more apparent from following description when read in conjunction with accompanying figures, which are not intended to limit scope of present invention.

Brief Description of Accompanying Figures:

Figure 1 illustrates Fourier Transform Infrared (FTIR) Spectra of crystalline

Form I of clopidogrel bisuifate as prepared in accordance with present invention.

Figure 2 illustrates Powder X Ray Diffractogram (PXRD) of crystalline Form I of clopidogrel bisuifate as prepared in accordance with present invention.

Figure 3 illustrates Differential Scanning Calorimetry (DSC) spectra of crystalline Form I of clopidogrel bisuifate as prepared in accordance with present invention.

Description and Preferred Embodiments of the Invention:

With aim to provide an improved process for preparation of crystalline Form I of clopidogrel bisuifate without requiring step of seeding (inoculation) with crystals of Form I of clopidogrel hydrogen sulfate, and still being less time consuming, and suitable and economical for large scale production, and capable of producing crystalline Form I of clopidogrel hydrogen sulfate without contamination of its Form II or at least with substantially reduced impurity of its Form II and having chiral purity of 99.0% or more, preferably 99.5% by HPLC, and having melting point of 180 to 185°C, specific optical rotation of [a]_D ²⁰ = +55° to 56°, preferably of + 55.4° at concentration of 1.89 g/100 ml methanol, the inventors have found that if solution of clopidogrel free base in ethyl acetate is cooled down to a temperature varying from -7 to -10°C and thereafter concentrated sulphuric acid is gradually added to this cooled solution while maintaining the said temperature varying from -7 to -10°C, and a care is taken that the said temperature of reacting mass does not go beyond -7°C, it surprisingly results in formation of soft precipitates of clopidogrel bisuifate which get uniformly dispersed in the solution medium and which on slow increase of temperature results in crystalline Form 1 of clopidogrel bisuifate, which has been found to have above-described characteristics and suitable for use as per US pharmacopoeia as platelet aggregation inhibitor.

Accordingly, the present invention relates to process for preparation of crystalline Form I of clopidogrel bisulfate comprising steps of:- a) preparing clear solution of clopidogrel free base in ethyl acetate at room temperature;

b) cooling clear solution of step - a) to a temperature varying from about -7 to about -10°C;

c) adding concentrated sulphuric acid to cooled solution of step - b) while maintaining said temperature varying from about -7 to about -10°C while stirring it for additional about 30 min to 1 hr, and a care is taken that said temperature of reacting mass does not go beyond about -7°C;

d) slowly warming the reaction mass of step - c) to room temperature;

e) heating to reflux the reaction mass of step - d) to a temperature of about 70 to 80°C under constant stirring and maintained at this temperature for upto about 2 hr; and

f) cooling the reaction mass of step - e) to room temperature while stirring, which is continued upto about 1 hr, and which on filtration, washing and vacuum drying results in crystalline Form 1 of clopidogrel bisulfate.

In accordance with present invention, the step - d) of slowly warming the reaction mass of step - c) to room temperature is completed in about 1 hr.

In accordance with present invention, the step - e) of heating to reflux the reaction mass of step - d) to a temperature of about 70 to 80°C under constant stirring is completed in about 2 hrs, preferably in about 1 hr.

In accordance with present invention, the step - f) of cooling the reaction mass of step - e) to room temperature is completed in about 1 hr.

The crystalline Form 1 of clopidogrel bisulfate produced by method of present invention has been found to be substantially free of contamination of Form II and having chiral purity of 99.0% or more, preferably 99.5% by HPLC, and melting point of 180 to 185°C, and specific optical rotation of [a]_D ²⁰ = +55° to 56°, preferably of + 55.4° at concentration of 1.89 g/100 ml methanol, which confirm that Form I formed is highly pure. The crystalline Form 1 of clopidogrel bisulfate produced by method of present invention has been found to have FTIR spectrum as illustrated in accompanying Figure 1, which was recorded on a Perkin-Elmer Paragon- 1000 FTIR using a KBr pellet. The characteristic peaks of the FTIR are described in following Table 1 , wherein following peaks in Table - 1 in FTIR confirm that Form I of clopidogrel bisulfate is formed, and absence of peaks at 2551 , 1497, 1 189, and 1029 (cm^'1) confirms absence of Form II of clopidogrel bisulfate.

Table - 1

The crystalline Form 1 of clopidogrel bisulfate produced by method of present invention has been found to have PXRD as illustrated in accompanying Figure 2, which was recorded on SHIMADZU model XRD 6000 defractometer with Cu k alpha Radiation source. The characteristic peaks with 2 Theta (2Θ), d spacing and Intensity (I/Io) values are described in following Table - 2.

Table - 2

Differection Pattern of crystalline Form I of Clopidogrel Bisulfate

The enclosed PXRD having above peaks confirms formation of Form I of clopidogrel bisulfate having polymorphic purity of more than 99%. The absence of peaks at 2Theta 8.797 and 12.89 confirms the absence of Form II of clopidogrel bisulfate.

The crystalline Form 1 of clopidogrel bisulfate produced by method of present invention has been found to have DSC spectra as illustrated in accompanying Figure 3, which was recorded on Mettler Toledo, DSC 822. The onset and main peak were observed at 180.24°C and 184.62°C respectively, which confirms formation of Form I of clopidogrel bisulfate having melting point varying from 180°C to 185°C.

In accordance with present invention, it has been observed that when solution of clopidogrel free base in ethyl acetate is cooled down to a temperature varying from -7 to -10°C and concentrated sulphuric acid is gradually added to this cooled solution while maintaining the said temperature varying from -7 to -10°C, and taking care that said temperature of reacting mass does not go beyond -7°C, it surprisingly results in formation of soft precipitates (not crystals) of clopidogrel bisulfate which get uniformly dispersed in the solution medium, and surprisingly no hindrance is observed in stirring pattern, and these soft precipitates of clopidogrel bisulfate result in crystalline Form 1 of clopidogrel bisulfate of high purity in high yield on slow increase of temperature and the produced crystalline Form 1 of clopidogrel bisulfate has been found suitable for use as per US pharmacopoeia as platelet aggregation inhibitor.

The inventors have observed that when process of present invention is performed as per above described process steps it, surprisingly and unexpectedly, results in production of crystalline Form 1 of clopidogrel bisulfate in less than 6 hrs, preferably less than 4 hrs after completion of addition of sulphuric acid vis-a-vis of about 10 hrs or more of conventional processes rendering the process of present invention highly time saving

The inventors have also observed that when sulphuric acid is added in the manner as described, no sticky mass is formed, and hence, neither stirring problem is observed nor uneven dispersion of formed soft precipitates of clopidogrel bisulfate is observed.

Further, the inventors have also observed that when sulphuric acid is added in the manner as described, no unwanted polymorphic forms including Form II of clopidogrel bisulfate are formed in the isolated product of present invention, which is also confirmed by its melting point, PXRD, IR and DSC and chiral purity of 99% or more as measured by HPLC.

The inventors have also observed that when solution after complete addition of sulphuric acid is maintained at said temperature varying from -7 to -10°C for about 30 min to 1 hr, it results in complete conversion of clopidogrel base to Form 1 of clopidogrel bisulfate and clopidogrel bisulfate formed is in the form of precipitates (not crystals). The higher yield of more than 87% molar, preferably 89% molar or moreconfirms substantial conversion in step-c), and therefore, process has been found to be highly economical and suitable for industrial production.

The inventors have also observed that when solution after complete addition of sulphuric acid and stirring for about 30 min to 1 hr is gradually, first, warmed to room temperature, which is, then, heated to reflux to a temperature of about 70 to 80°C under constant stirring and maintained at this temperature for about 1 to 2 hr surprisingly results in separation of crystalline Form I of clopidogrei bisulfate with ease and convenience, and without step of seeding (inoculation) with crystals of Form I of clopidogrei hydrogen sulfate or additional step of crystallization.

In accordance with present invention, the step of heating to reflux is performed immediately after warming the reaction mixture to room temperature as otherwise the clopidogrei bisulfate produced gets contaminated with its Form II.

The inventors have also observed that when solution after complete addition of sulphuric acid and stirring for about 30 min to 1 hr at said temperature of about -7 to about -10°C is gradually warmed to room temperature it does not disturb soft precipitates formed on addition of concentrated sulphuric acid and the precipitates were found to remain intact, which on heating to reflux results in crystal formation of Form I of clopidogrei bisulfate with ease, and without step of seeding (inoculation).

The inventors of present invention have found that if temperature of cooled solution of step - b) during addition of concentrated sulphuric acid is increased beyond about -7°C, not only the isolation of crystalline Form I of clopidogrei bisulfate becomes difficult due to formation of a sticky mass, but its yield also reduces substantially, and the clopidogrei bisulfate produced is also substantially contaminated with its Form II or other forms of clopidogrei bisulfate.

In accordance with present invention, the concentrated sulphuric acid is 98% or more pure. The inventors of present invention have observed that if concentrated sulphuric acid is less than 98%, the clopidogrei bisulfate produced is substantially contaminated with its Form II.

Accordingly, from the foregoing description it is understood that process of present invention, in addition to above-described advantages, is not only simpler, but is also less time consuming, and suitable and economical for large scale production, and also results in formation of crystalline Form I of clopidogrei bisulfate without involving step of seeding (inoculation) with crystals of Form I of clopidogrei hydrogen sulfate or additional step of crystallization, meaning thereby it not only avoids associated drawbacks of inoculation, but is also independent of requirement of product which is yet to be produced by the process, and possibility of formation of Form II of clopidogrel bisulfate is also ruled out, and hence, probability of contamination of Form I with its Form II or other forms of clopidogrel bisulfate is ruled out or at least has been minimized to maximum possible extent.

The crystalline Form I of clopidogrel bisulfate as produced by present invention has also been found to be stable as it did not convert to any other form including Form II even in six months from date of its preparation.

In accordance with process of present invention repeated requirements of heating and cooling steps have been avoided, meaning thereby process time and energy are saved which makes the process even more economical.

In accordance with present invention, the clopidogrel free base used in preparation of crystalline Form I of clopidogrel bisulfate of present invention is chemically and optically highly pure having chemical purity of more than 99.0% and optical purity of more than 99.0% and can be prepared by any method.

However, in accordance with one of the preferred embodiments of present invention, the chemically and optically pure (+)clopidogrel free base is prepared as follows:- a) preparing a clear solution of optically impure (+) clopidogrel free base in acetone;

b) treating clear solution of step-a) with L (-) camphorsulphonic acid by heating to reflux, which on cooling, filtration, washing and drying results in S(+) clopidogrel camphor- 10-sulphonate salt;

c) treating S(+) clopidogrel camphor- 10-sulphonate salt of step-b) with aqueous ammonia solution in presence of an organic solvent, preferably n-hexane till pH of 7 is achieved; and

d) separating organic (n-hexane) layers of mixture of step-c), which on concentration, drying result in chemically and optically pure (+) clopdigrel base.

In accordance with present invention, to clear solution of step-1 ), L (-) camphorsulphonic acid is added at room temperature of about 25 to 30°C. In accordance with present invention, after complete addition of L (-) camphorsulphonic acid, the clear solution is heated to reflux at a temperature of about 54 to 56°C for about 2 to about 3 hours under constant stirring.

In accordance with present invention, the S(+) clopidogrel camphor- 10- sulphonate salt in step-2) is obtained in substantially higher yield of about 82% Molar or more having high chiral purity, as confirmed by optical rotation of [ ]ο²⁰ = +24.8° [1.68 gm/100 ml; Methanol].

In accordance with present invention, the organic (n-hexane) layers of mixture of step-3) are collected after repeated treatments of aqueous layer with organic solvent (n-hexane), which on concentration, drying result in chemically and optically pure (+) clopdigrel base as a colourless oil in substantially higher yield of about 90% or more, preferably of about 94% or more, and purity as accessed by Gas Chromatography (GC) of 99% or more.

In accordance with another preferred embodiment of the present invention, the chemically and optically pure (+)clopidogrel free base is prepared by a process comprising steps of:- a) treating chemically and optically pure pharmaceutically acceptable acid addition salt of (+) Clopidogrel with water and n-hexane at about 25 - 30°C under constant stirring;

b) treating the reaction mixture of sep-a) with aqueous ammonia solution till pH of about 7 is achieved;

c) separating the organic and aqueous layers;

d) treating the separated aqueous layers with n-hexane;

e) concentrating the combined organic layers to dryness under vacuum to generate (+) clopidogrel free base as colourless oil.

In accordance with preferred embodiment of the present invention, the pharmaceutically acceptable acid addition salt of (+) Clopidogrel is bisulfate salt.

In accordance with present invention, the water and n-hexane are taken in equal amounts by volume.

In accordance with present invention, the aqueous ammonia solution is about 20 to 30% aqueous ammonia solution. It has been found that this method produces about 97.86 % Molar yield of chemically and optically pure (+) clopidogrel free base with purity of about 99.0% by Gas Chromatography.

Examples:

The present invention is now described with help of following example, which is not intended to limit its scope.

Example- 1 - Preparation of crystalline Form I of clopidogrel bisulfate:

Clopidogrel free base (800 gm) is taken with 9.6 L of ethyl acetate at room temperature (25 - 30°C) in a cylindrical glass vessel under nitrogen atmosphere and stirred to obtain a clear solution. The clear solution is gradually cooled to a temperature of -8 to -9°C and 248.8 gm of concentrated sulphuric acid (98%) is added slowly at said temperature of -8 to -9°C with agitation at preferred rate. The reaction mixture is continuously stirred at said temperature of -8 to -9°C for 45 minutes, and then warmed to room temperature (25 to 30°C), and then heated to reflux at about 75°C under constant stirring and maintained at this temperature for 1 hr, and the reaction mixture is then cooled to 25 to 30°C with continuous stirring for one hour. The solid thus obtained is filtered, washed with ethyl acetate (800 ml) twice and dried under vacuum to give highly pure crystalline Form I of clopidogrel bisulfate in higher yield (934 gm; 89.5% Molar) which was evaluated by melting point, Assay by HPLC, chiral purity by optical rotation and chiral HPLC as given below and by IR, PXRD and DSC as illustrated in accompanying Figures 1 to 3 respectively. The polymorphic purity was found to be more than 99% as confirmed by melting point, IR, PXRD and DSC.

Melting Point 181 to 184 °C

Chiral Purity by HPLC 99.5%

Optical Rotation [oc]_D ²⁰ +55.4° (1.89 g/100 ml; Methanol) Assay by HPLC (on anhydrous basis) 99.57%

The Form I Clopidogrel bisulfate as prepared meets the USP specification.

Example-2 - Preparation of chemically and optically pure (+) clopidogrel base to be used for preparation of crystalline Form I of clopidogrel bisulfate: A] Preparing S(+) clopidogrel camphor-10-sulphonate salt:-

Optically impure (+) clopidogrel base (600 gm) is taken with 1.8 L of acetone at 25 - 30°C in a cylindrical glass vessel and stirred to obtain a clear solution to which 420 gm of L (-) camphorsulphonic acid is added in portion wise at 25 - 30°C, and after complete addition, the reaction mixture is heated to reflux at 54-56°C for 2.5 hours under constant stirring, which on cooling to room temperature while stirring for one hour results in a solid mass, which is filtered, washed with acetone 600 ml and dried under vacuum to give highly pure S(+) clopidogrel camphor- 10-sulphonate salt in high yield (810 gm; 85.25% Molar) with high chiral purity, as confirmed by optical rotation [<x]_D ²⁰ of +24.8° [1.68 gm/100 ml; Methanol].

B] Preparing chemically and optically pure (+) clopidogrel base:-

S(+) clopidogrel camphor- 10-sulphonate salt (810 gm), prepared in section A, is taken with 4.0 Liter of water at 25 - 30°C in a cylindrical glass vessel and 4.8 L of n- hexane is added under constant stirring, and to this stirred solution, 22% aqueous ammonia solution (250-260 ml) is added drop wise till pH 7 is obtained. The n-hexane layer is separated and the aqueous layer is again extracted with 1.6 L of n-hexane. The combined hexane layers are concentrated to dryness under vacuum to generate chemically and optically pure (+) clopidogrel base colourless oil in high yield [445 gm (94.5 % Molar)] and purity of >99.0% as checked by GC.

Example-3 - Preparation of chemically and optically pure (+) clopidogrel free base to be used for preparation of crystalline Form I of clopidogrel bisulfate (Alternate route):

The chemically and optically pure pharmaceutically acceptable acid addition salt of (+) Clopidogrel, preferably bisulfate salt (1 Kg), is taken with 6.0 liter of water at about 25 - 30°C in a glass vessel and about 6.0 L of n-hexane is added under constant stirring, and to this stirred solution, about 22% aqueous ammonia solution (390-400 ml) is added drop wise till pH 7 is obtained. The n-hexane layer is separated and the aqueous layer is again extracted with about 2.0 L of n-hexane. The combined hexane layers are concentrated to dryness under vacuum to generate (+) clopidogrel base as colourless oil. This method has been found to produce 0.750 Kg (97.86 % Molar yield) of chemically and optically pure (+) clopidogrel free base with purity of about 99.0% by Gas Chromatography.

It may be noted that word "about" as used herein is not intended to extend scope of range referred thereto, but is intended to include experimental errors as may be allowable in field of invention.

Claims

A process for preparation of crystalline Form I of clopidogrel bisulfate comprising steps of:- a) preparing clear solution of clopidogrel free base in ethyl acetate at room temperature;

c) adding concentrated sulphuric acid to cooled solution of step - b) while maintaining said temperature varying from about -7 to about -10°C while stirring it for additional about 30 min to 1 hr, and taking care that said temperature of reacting mass does not go beyond about -7°C;

d) warming the reaction mass of step - c) to room temperature;

e) heating to reflux the reaction mass of step - d) to a temperature of about 70 to 80°C under constant stirring and maintained at this temperature upto about 2 hr;

f) cooling the reaction mass of step - e) to room temperature while stirring, which is continued upto about 1 hr; and which on filtration, washing and vacuum drying results in crystalline Form 1 of clopidogrel bisulfate.

A process as claimed in claim 1, wherein step - d) of warming the reaction mass of step - c) to room temperature is completed in about 1 hr.

A process as claimed in any one of claims 1 or 2, wherein step - e) of heating to reflux the reaction mass of step - d) is completed in about 2 hrs.

A process as claimed in any one of claims 1 to 3, wherein step - f) of cooling the reaction mass of step - e) to room temperature is completed in about 1 hr.

A process as claimed in any one of claims 1 to 4, wherein crystalline Form 1 of clopidogrel bisulfate produced has chiral purity of 99.0% or more by HPLC, and melting point of 180 to 185°C, and specific optical rotation of [a]_D ²⁰ = +55° to 56° at concentration of 1.89 g/100 ml methanol.

A process as claimed in any one of claims 1 to 5, wherein crystalline Form 1 of clopidogrel bisulfate produced has polymorphic purity of more than 99%.

A process as claimed in any one of claims 1 to 6, wherein addition of concentrated sulphuric acid in step-c) results in substantia] conversion of clopidogrel base to Form 1 of clopidogrel bisulfate. A process as claimed in claim 7, wherein clopidogrel bisulfate is in the form soft precipitates.

A process as claimed in any one of claims 1 to 8, wherein crystalline Form 1 of clopidogrel bisulfate is separated without step of seeding (inoculation) with crystals of Form I of clopidogrel hydrogen sulfate or additional step of crystallization.

A process as claimed in any one of claims 1 to 9, wherein clopidogrel free base is chemically and optically pure having chemical purity of more than 99.0% and optical purity of 99.0%.

A process as claimed in any one of claims 1 to 10, wherein step - e) of heating to reflux is performed immediately after the reaction mixture attains room temperature in step - d).

A process as claimed in any one of claims 1 to 1 1, wherein concentrated sulphuric acid is 98% or more pure.

A process as claimed in any one of claims 1 to 12, wherein clopidogrel free base is chemically and optically pure (+)clopidogrel free base and is prepared by a process comprising steps of:- a) preparing a clear solution of optically impure (+) clopidogrel free base in acetone;

c) treating S(+) clopidogrel camphor- 10-sulphonate salt of step-b) with aqueous ammonia solution in presence of an organic solvent till pH of 7 is achieved; and

d) separating organic layers of mixture of step-c), which on concentration, drying result in chemically and optically pure (+) clopdigrel base.

A process as claimed in claim 13, wherein organic solvent is n-hexane.

A process as claimed in claim 13 or 14, wherein after complete addition of L (-) camphorsulphonic acid, the clear solution is heated to reflux at a temperature of about 54 to 56°C for about 2 to about 3 hours under constant stirring. A process as claimed in any one of claims 1 to 12, wherein clopidogrel free base is chemically and optically pure (+)clopidogrel free base and is prepared by a process comprising steps of:- a) treating chemically and optically pure pharmaceutically acceptable acid addition salt of (+) Clopidogrel with water and n-hexane at about 25 - 30°C under constant stirring;

c) separating the organic and aqueous layers;

d) treating the separated aqueous layers with n-hexane;

A process as claimed in claim 16, wherein pharmaceutically acceptable acid addition salt of (+) Clopidogrel is bisulfate salt.

A process as claimed in claim 16 or 17, wherein water and n-hexane are taken in equal amounts by volume.

A process as claimed in any one of claims 16 to 18, wherein aqueous ammonia solution is about 20 to 30% aqueous ammonia solution.

A process for preparation of crystalline Form I of clopidogrel bisulfate substantially as herein described with reference to foregoing examples and as illustrated in the accompanying figures.