Title of Invention

PROCESS FOR PREPARATION OF CRYSTALLINE CLOPIDOGREL HYDROGEN SULPHATE FORM I

Abstract

The present invention describes an improved industrial process for crystallizing out polymorph ‘Form I’ of (+) clopidogrel hydrogen sulphate (also called clopidogrel hydrogen sulphate) in solvent selected from methylethyl ketone, tertiarybutyl methylether, cyclopentylmethyl ether, dipropylglycolether, dibutylglycol ether, propylmethyl cellosolve, butylmethylcellosolve, propylethylellosolve, butylethylcellosolve or their mixtures, in a reproducible manner without detectable contamination of form II.

Full Text

FORM 2 THE PATENT ACT 1970 (39 of l970)&The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule l3) 1. TITLE OF THE INVENTION: “Process for preparation of crystalline clopidogrel hydrogen sulphate FORM I” 2. APPLICANT(S): (a) NAME: IPC A LABORATORIES LIMITED (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West), Mumbai-400 067, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION: The following specification describes the nature of this invention and the manner in which it is to be performed: Technical Field of Invention: The present invention relates to a process for manufacturing (+)-(S)-alpha-2-(chlorophenyl)-6,7-dihydrothieno [3,2-C] pyridine-5-(4-H)-acetic acid methyl ester hydrogen sulphate of Formula I, commonly known as Clopidogrel bisulphate in “Form-I” crystalline form. Background of the invention: (+)-(S)-alpha-2-(chlorphenyl)-6,7-dihydrothieno-[3,2-C]-pyridine-5-(4-H)-acetic acid methyl ester known as clopidogrel under the International Non-Proprietary Name is marketed as hydrogen sulphate salt. Clopidogrel is known for its platelet aggregating and anti-thrombotic properties and finds medicinal applications in this field. It can be represented by Formula-I, and was disclosed in Patent US 4529596 (hereinafter referred as '596' patent) in its racemic form for the first time. The pure enantiomeric forms of clopidogrel (dextro and levo isomers) were disclosed in EP 281459 which teaches the isolation of the dextro rotatory isomer of Clopidogrel by diasteriomeric salt formation of racemic Clopidogrel base using an optically active acid such as 10-L-camphor sulfonic acid. The Clopidogrel free base was then converted into its hydrogen sulfate salt by dissolving in acetone, cooling and mixing with concentrated sulfuric acid to precipitation. The precipitate thus obtained is then isolated by filtration, washed and dried to give Clopidogrel hydrogen sulfate in the form of white crystals whose melting point was 184°C and optical rotation was +55.1° (c = 1.891 / CH30H). But '459 patent did not characterize or suggest any name to this crystals (polymorph) of Clopidogrel hydrogen sulfate. Subsequently International patent publication, WO 99/65915 (herein after referred as '915 patent), disclosed two polymorphic forms of Clopidogrel hydrogen sulfate referred to as Form-1 and Form-II. The '915 patent identified that the precipitation method 2 described in ‘459 patent had led to crystalline Form-I. The ‘915 also deals with a new crystalline form called Form-II of Clopidogrel hydrogen sulfate. The latter is suggested to be thermodynamically most stable crystalline form. According to '915 patent both polymorphs, namely Form I and Form II, were prepared from the same solvent viz; acetone. The process for obtaining crystalline Form-II of Clopidogrel hydrogen sulfate according to example 1A of the '915 patent describes the introduction of Clopidogrel camphor sulfate in methylene dichloride (MDC) and transformation of salt into the base with potassium carbonate solution. Clopidogrel base is extracted in MDC and solvent is evaporated. Residue obtained is dissolved in acetone and cooled. Addition of sulfuric acid precipitated out Clopidogrel hydrogen sulfate. Also in the same application it was described to get Form-II either by keeping mother liquor of Form-I or by heating acetone solution containing the base after addition of sulfuric acid to reflux or by subjecting the suspension to mechanical shearing using a shearing device or by inoculation. However, this process was not found to be suitable for the production of Form I of clopidogrel hydrogen sulphate on an industrial scale owing to its thermodynamic instability in solvents like acetone and invariably yielded Form II without having the need of keeping for longer periods (ref. '915 patent). This problem became the subject of many latter patent applications and a detailed study of the various publications clearly indicates that manufacture of Form I of clopidogrel hydrogen sulphate poses a well known technical challenge to the process chemist. Although most of the general class of organic solvents are said to be used for preparation of Form I polymorph, it appears both from the latest literature and from the experimental studies on this polymorph by the present authors, most of these solvents gives only Form II or contaminated Form I. Moreover, among all these, most processes are not reliably reproducible on large scale. The present inventors are also noted that, since the Form 1 is thermodynamically unstable, the process variants of dissolving clopidogrel hydrogen sulphate salt in conventional solvents at higher temperature and cooling to precipitate Form I resulted in Form II or its mixture with Form I. Moreover, the poor solubility of clopidogrel salt 3 (whereas the free base possess good solubility) in most of the non-polar conventional solvents does not allow to use this crystallization process variant to be practiced. There are ample literatures available for preparation of Form I, such as US2006074242, US20060205766, WO2005117866, WO2005100364, US2005059696, WO2005063708, WO2005016931, WO2005003139, SK12852002, PL355514, WO2004026879, WO2004081015, WO2004020443, WO2004081016, WO2004048385, WO2004081016, WO20040024012, WO2006087226, US20030114479, US2003225129, & WO2002059128 a few to name, but it is also clear from these literature that same solvent unarguably gives two different crystalline forms in different hands, which is surprising, for example, the US2003225129 patent (herein after referred as '129 patent) describes process for the preparation of Form-II from solvents selected from dichloromethane, 1,4-dioxane, toluene, chloroform, ethyl acetate, methyl ethyl ketone and t-butyl methyl ether. The '129 patent, for the first time, claimed to produce Form II from ethyl acetate which was the main subject of '443 patent application for Form I preparation. A cursory review of the prior art indicates that almost all classes of solvents covering ethers, diethers, esters, alcohols, nitriles, ketones etc. are disclosed for use in the preparation of Form I, but those solvents are disclosed also taught to give Form II in the same or different publication. WO2005003139 patent discusses combination of polar and non-polar solvent combinations for obtaining Form I, however, the present inventors have found that the adjustment of specific proportion of two or more solvents are rather difficult and does not give consistent & reproducible results while adjusting the polarity of mixtures. So, it is evident from the prior art that the methods to produce Form-I of clopidogrel hydrogen sulphate from different solvents are poorly reproducible, necessitating the optimization of experimental conditions and the selection of suitable solvents. Since Form-I is kinetically controlled and Form-II is thermodynamically controlled form, they require very specific temperature range and specific conditions for getting reproducible results in conventional solvents. Also, a minor variation in condition appears to give Form-II instead of expected Form-I or a mixture of Form-I & Form-II. Since, Form I of clopidogrel hydrogen sulphate is used for pharmaceutical formulation, the importance of a rugged method that gives Form I consistently doesn't require any emphasis. 4 Thus there is a need in the art to get industrially reliable process for the preparation of Form-I without contamination of Form II or other polymorphs. This forms the subject of the present invention. Objectives of the present invention: An objective of the present invention is to provide solvent systems where the Form I crystals of clopidogrel hydrogen sulphate can be efficiently and reproducibly formed and easily maneuvered at large scale operations. Summary of the invention: The present inventors had identified that the prior art processes present substantial difficulties in producing Form I polymorph of chlopidogrel hydrogen sulphate in a consistent manner. The invention, therefore, aims to provide an improved process for making Form 1 clopidogrel hydrogen sulphate (Formula IB) The present invention provides an improved industrial process for crystallizing out polymorph ‘Form I’ of (+) clopidogrel hydrogen sulphate (also called clopidogrel hydrogen sulphate) from an organic solvent selected from a ketoalkyl ester, in a reproducible manner without detectable contamination of form II. Especially preferred ketoester solvents possess carbon atoms ranging from C4 to C12 atoms, preferrably betaketo esters of lower aliphatic alcohols, specific examples of such solvents are ethyl acetoacetate, methyl acetoacetate, chloroethylacetoacetate etc. In a preferred embodiment of the present invention, the process for preparation of 'Form I' comprises dissolving the clopidogrel base in suitable ketoester solvent as discussed above; cooling the obtained clopidogrel base solution to a temperature of-20 5 to 30° C; adding concentrated sulphuric acid (98%, d= 1.84) while maintaining the temperature in the above range to obtain chlopidogrel hydrogen sulphate salt; optionally further maintaining the salt at a temperature of about 10 to 30 ° C and filtering the crystals of Form I obtained. Brief description of Figures: Figure 1 represents Powder X-Ray diffraction pattern (PXRD) of clopidogrel hydrogen sulphate Form I prepared according to example 1 of the present invention. Figure 2 represents Differential Scanning Calorimetry record of Form I of clopidogrel hydrogen sulphate prepared according to example 1 of the present invention. Figure 3 represents Powder X-Ray diffraction pattern (PXRD) of clopidogrel hydrogen sulphate Form I standard as given in '915 patent. Figure 4 represents the spectrogram obtained by Fourier Transform Infra Red spectrometry (FTIR) of clopidogrel hydrogen sulphate Form I prepared according to example 1 of the present invention. Figure 5 represents an overlay of powder x-ray diffraction pattern (PXRD) of clopidogrel hydrogen sulphate crystalline Form I and Form II. Detailed description of the invention: Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows. Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters 6 immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. The term "isolating" is used to indicate separation or collection or recovery of the compound being isolated in the specified crystalline form. The term "separating from a solvent" with respect to the crystalline solids described herein means obtaining a solid of specified characteristics from a solution or a partial solution. The term "treating" means adding or combining or mixing the stated reagent or materials to the things being treated. The term "forming a solution" means obtaining a solution of a substance in a solvent in any manner. The term "inoculating" has the same meaning as the term "seeding," and means adding previously obtained solid to facilitate crystallization. Thus, the term "seeding crystals" with respect to claimed process means crystals/powder of previously obtained crystalline Form 1 of clopidogrel hydrogen sulphate. It should be understood that there exists equilibrium between a free species and salt form of a compound capable of forming salt with bases/acids (e.g., by virtue of having an amino-functionality in the molecule). For the purposes of this description and claims of the present invention, the term "crystalline Form I" of clopidogrel hydrogen sulphate is the polymorphic form denoted as Form I and having characteristics as given in US6429210 patent. Identification of solids obtained by the process of the invention can be made by comparing with the reference analytical information provided in the US6429210 patent. Of course, it should be understood that operator, instrument and other similar variables may result in some margin of error with respect to analytical characterization of the solid. 7 Large scale production of Form 1 according to the process described in the ‘915 patent or ‘210 patent resulted in Form II or a mixture with Form I or contaminated with other forms at a higher percentage. This lead us to find suitable solvents or conditions where these problems are minimized and ensure reproducibility of Form I, without contamination of other forms, especially Form II. This research has led to an efficient process where Form I can be produced reliably from a single solvent or mixture of solvents. Thus the present inventors, on exploring various process alternatives, for a reliable process solution have found that the use of organic solvent selected from keto esters of alphatic alcohols or mixtures of such solvents for crystallization permits reliable preparation of Form I of clopidogrel hydrogen sulphate. Especially preferred ketoesters are beta and gamma keto esters of lower aliphatic alcohols, preferably beta-keto esters. Especially preferred keto ester consists of carbon atoms ranging from C4 to C12 in the molecule. The preferred ketoesters are ethyl acetoacetate, methyl acetatoacetate, and 4-chloroethylacetoacetate etc. It has also been observed that presence of other conventional solvent(s) in the novel solvent(s) of the present invention does not alter results of the present process. Thus a solvent selected from the group of esters, C3-C6 aliphatic or alicylcic ketones, C3-C6 chain or branched chain alcohols, and ethers in about 1 to 20 weight percent in the solvents of the present invention gives Form I consistently. The weight percent will depend upon the choice of the individual solvent from the above class of solvents, but can be determined by routine experimentation. Especially preferred solvents for making mixtures are acetone, methylpropyl ketone, methylisopropyl ketone, isobutyl ketone among ketones; propylacetate and butyl acetate among esters; butanol and pentanol among alcohols; and tertiary butyl methyl ether and cyclopentyl methyl ether among ethers. The presence of these solvents in the process of the present invention are especially useful in removing the ketoester used in the invention to keep those solvent level in the final product as low as" possible to meet the pharmacopoeias specifications. It is very surprising to note that the reactive compounds like ethyl acetoacetate is inert through out the crystallization process of the present invention and does not participate 8 in any chemical change or impurity formation as against the expected reactivity of such solvents. Accordingly, in one embodiment, the present invention provides a process for preparing polymorph Form I of clopidogrel hydrogen sulphate comprising dissolving the (+) clopidogrel base in an organic solvent selected from ketoesters, for example ethyl acetoacetate; cooling the solution to a temperature of -25° C to 30° C; adding concentrated sulphuric acid (98%, d= 1.84) by maintaining the temperature at in the range of-20 to 20°C; and maintaining for a period of 5 to 10 hours to crystallize out the Form 1 clopidogrel hydrogen sulphate. The precipitated crystals may be collected by conventional methods like filtration or centrifugation. In the process for preparation of Form I, the preferred concentration of sulphuric acid is in the range of 80% to 98% and the molar ratios are in the range of 1 to 1.1 with respect to the (+) clopidogrel base. The most preferred concentration of sulphuric acid used in the salt formation is 90-98%. The sulphuric acid may be employed directly in the salt formation or may be employed as a solution in a carrier solvent. Especially preferred carrier solvents, although not limited to, are those selected from the above described group of solvents or ketoesters. In a preferred embodiment of the process, the exotherm of sulphuric acid addition is controlled by cooling and maintaining the temperature in between-10 to 10°C. The Form 1 so obtained was characterized by PXRD, DSC and FTIR without any detectable quantity of Form II or other polymorphic Forms with respect to the standard PXRD pattern of Form I as described in '915 patent. In the process, the clopidogrel free base solution may be formed by dissolving clopidogrel free base in the ketoester solvent at any temperature at or below the reflux temperature of the solvent and the solution may then be filtered to remove any particulate matter. Once the solution of the clopidogrel free base is obtained in the solvents of the present invention, the solution is cooled to a temperature below 25 degree, more particularly below 10 degrees and sulpuric acid is incorporated to form the clopidogrel hydrogen sulphate salt. The mass is then cooled or maintained at this 9 temperature until crystallization of the solid is complete. The solid is filtered, washed, and dried. In the process, optionally, either before or after sulphuric acid addition, the solution may be seeded with previously obtained crystals of the Form I. The seed crystals may be obtained by performing the present invention at a lower scale or by methods known in the art. The process conditions are further illustrated in the Examples. The starting material, clopidogrel free base may be obtained by following any known process disclosed in the literature. The present inventors used samples obtained as per the process disclosed in EP1723141. Analytical characterization of the solid(s) obtained in accordance with the process of the invention was carried out by using X-ray powder diffraction using a PANALYTICAL XpertPRO X-Ray machine of Philips make. The X-ray powder diffraction patterns were recorded with Cu K alpha-1 radiation source (voltage of 50 kV; current: 25 mA). The following examples further illustrate the present invention but are not construed by limiting in any manner the scope of the invention as substantially described herein. Examples: Example 1. (Form I clopidogrel hydrogen sulphate): Clopidogrel base (100 gm) was dissolved in ethyl acetoacetate (600 ml) at room temperature. This mixture was cooled to -10° C and concentrated sulphuric acid ( 98%, density = 1.83 ) was added (15.5 gm) maintaining temperature -10° to 0° C while addition. The reaction mass was stirred for 1.0 hour and warmed slowly to 10 to 15° C in 30 to 45 minute. The formed crystals were stirred for 10 hours. The reaction mass temperature was further raised to 28 to 30°C and maintained for 2 hours. The solid obtained was filtered under suction and washed with acetone, and dried in oven at 48°C for 3 hours. The solid after drying weighed 96 gm, was Form I clopidogrel hydrogen sulphate (PXRD pattern incorporated: figure 1). Example 2. (Form 1 clopidogrel hydrogen sulphate): Clopidogrel base (100 gm) was dissolved in 4-chloro-ethyl acetoacetate (600 ml) at room temperature. This mixture was cooled to -10° C and concentrated sulphuric acid ( 98%, density = 1.83 ) was added (15.5 gm) maintaining temperature -10° to 0° C while 10 addition. The reaction mass was stirred for 1.0 hour and warmed slowly to 10 to 15° C in 30 to 45 minute. The formed crystals were stirred for 10 hours. The reaction mass temperature was further raised to 28 to 30°C and maintained for 2 hours. The solid obtained was filtered under suction and washed with acetone, and dried in oven at 48°C for 3 hours. The solid after drying weighed 95 gm, was Form 1 clopidogrel hydrogen sulphate (PXRD pattern incorporated: figure 1). Example 3. (Form I clopidogrel hydrogen sulphate): Clopidogrel base (100 gm) was dissolved in a mixture of ethyl acetoacetate (500 ml) and acetone (100 ml) at room temperature. This mixture was cooled to -10° C and concentrated sulphuric acid ( 98%, density =1.83 ) was added (15.5 gm) maintaining temperature -10° to 0° C while addition. The reaction mass was stirred for 1.0 hour and warmed slowly to 10 to 15° C in 30 to 45 minute. The formed crystals were stirred for 10 hours. The reaction mass temperature was further raised to 28 to 30°C and maintained for 2 hours. The solid obtained was filtered under suction and washed with acetone, and dried in oven at 48°C for 3 hours. The solid after drying weighed 97 gm, was Form I clopidogrel hydrogen sulphate (PXRD pattern incorporated: figure 1). It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. 11 We claim, 1. A process for preparation of ‘Form I’ crystals of (+)-(S)-clopidogrel hydrogen sulphate of Formula IB comprising: isolating clopidogrel hydrogen sulphate Form I from a ketoester class of solvent.. 2. The process as claimed in claim 1, wherein the keto functional group is at beta or gamma position to the ester functionality. 3. The process as claimed in claim 1 to 2, wherein the solvent comprises 4 to 12 carbons. 4. The process as claimed in claim 1-3, wherein the organic solvents are ethyl acetoacetate, methyl acetoacetate, and 4-chloroethylacetoacetate. 5. The process as claimed in claim 1 to 4, wherein said isolation step comprises dissolving methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-5-acetate [i.e., (+)-(S)-clopidogrel base] in said keto-ester solvent or mixtures thereof; cooling said clopidogrel base solution; adding sulphuric acid to said cooled solution to form hydrogen sulphate salt; allowing said salt mixture to precipitate (+)-(S)-clopidogrel hydrogen sulphate in Form I and recovering said crystals of Form I. 6. The process as claimed in claim 5, wherein said solvent is ethyl acetoacetate, methyl acetoacetate, 4-chloroethylacetoacetate. 7. The process as claimed in claim 1 to 5, wherein said ketoester solvent further comprises one or more other solvent selected from the class of esters, C3-C8 12 aliphatic or alicylcic ketones, C3-C6 chain or branched chain alcohols solvent or an ether. 8. The process as claimed in claims 7, wherein said other solvent is not more that 25 weight percent. 9. The process as claimed in claim 7-8, wherein the esters class of solvent is propylacetate and butyl acetate. 10. The process as claimed in claim 7-8, wherein the ketone class of solvent is acetone, methyl ethyl ketone, methylisopropyl ketone, methylpropyl ketone, methylisobutylketone. 11. The process as claimed in claim 7 to 8, wherein the alcohol class of solvent is butanol or pentanol. 12. The process as claimed in claim 7 to 8, wherein the ether class of solvent is tertiary butyl methyl ether and cyclopentyl methyl ether. 13. The process as claimed in claims 5, wherein the solution of clopidogrel base in said solvents cooled to a temperature range of below 20 °C before adding sulphuric acid. 14. The process as claimed in claims 5 or 15, wherein the addition of said concentrated sulphuric acid is carried out while maintaining reaction solution temperature between -20 to 10° C. 15. The process as claimed in claims 1 to 5, wherein the clopidogrel base solution in said solvents seeded with Form I prior to addition of sulphuric acid. 16. The process as claimed in claims 1 to 5, wherein said sulphuric acid salt mixture is maintained at a temperature range of 0 ° to 30 ° C. 13 17. The process as claimed in claim 5, wherein said reaction mixture is maintained at 10° to 30° C for 8 to 15 hours. 18. The process as claimed in claim 1 to 15, wherein the strength of said sulphuric acid is about 80 to 98 %. 19. The process as claimed in claim 18, wherein the molar ratio of sulphuric acid used is 1.02 to 1.1 relative to (+)-(S)-clopidogrel base. 20. The process as claimed in claims 1 to 19, wherein the sulphuric acid is incorporated as a solution in a carrier solvent. 21. Clopidogrel Form I prepared according to any one of the preceding claim and having the Powder X-ray diffraction pattern as substantially given in figure 1. 22. A pharmaceutical composition characterized in that the clopidogrel prepared according to any one of the preceding claim and having the Powder X-ray diffraction pattern as substantially given in figure 1 is put into a pharmaceutically acceptable dosage form. 23. A process for preparation of crystalline clopidogrel hydrogen sulphate Form I as substantially described herein with reference to the examples 1 to 3. Dated this 13th day of February 2007 Dr. Gopakumar G. Nair Agent for the Applicant 14 ABSTRACT The present invention describes an improved industrial process for crystallizing out polymorph ‘Form I’ of (+) clopidogrel hydrogen sulphate (also called clopidogrel hydrogen sulphate) in solvent selected from methylethyl ketone, tertiarybutyl methylether, cyclopentylmethyl ether, dipropylglycolether, dibutylglycol ether, propylmethyl cellosolve, butylmethylcellosolve, propylethylellosolve, butylethylcellosolve or their mixtures, in a reproducible manner without detectable contamination of form II.

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292-mum-2007-claims.doc

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292-mum-2007-correspondance-received.pdf

292-mum-2007-correspondence(8-9-2009).pdf

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292-mum-2007-description (complete).pdf

292-MUM-2007-DESCRIPTION(GRANTED)-(28-6-2012).pdf

292-MUM-2007-DRAWING(29-7-2010).pdf

292-MUM-2007-DRAWING(GRANTED)-(28-6-2012).pdf

292-mum-2007-drawings.pdf

292-mum-2007-form 1(13-2-2007).pdf

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292-MUM-2007-FORM 2(GRANTED)-(28-6-2012).pdf

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292-mum-2007-form 3(8-9-2009).pdf

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292-MUM-2007-REPLY TO EXAMINATION REPORT(30-3-2011).pdf

292-MUM-2007-REPLY TO HEARING(30-5-2012).pdf

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