Indian Patents. 224934:AN IMPROVED PROCESS FOR MANUFACTURE OF CRYSTALLINE FORMS OF METHYL (+)-(S)-α-(2-CHLOROPHENYL)-4,5,6,7-TETRAHYDROTHIENO[3,2-C] PYRIDINE-5-ACETATE HYDROGEN SULPHATE SALT

Title of Invention	AN IMPROVED PROCESS FOR MANUFACTURE OF CRYSTALLINE FORMS OF METHYL (+)-(S)-α-(2-CHLOROPHENYL)-4,5,6,7-TETRAHYDROTHIENO[3,2-C] PYRIDINE-5-ACETATE HYDROGEN SULPHATE SALT
Abstract	An improved process for manufacturing hydrogen sulfate salt of (+)-(S)-alpha-2-(chlorphenyl)-6,7-dihydrothieno [3,2-C] pyridine-5 (4-H)-acetic acid methyl ester, commonly known as Clopidogrel hydrogen sulphate, in two crystalline forms viz: Form-I and Form-II is disclosed herein.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; Rule 13] "An improved process for manufacture of crystalline Forms of methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno [3,2-C] pyridine-5- acetate hydrogen sulphate salt" (a) IPCA LABORATORIES LIMITED (b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of this invention and the manner in which it is to be performed: Technical Field: The invention relates to an improved process for manufacturing hydrogen sulfate salt of (+)-(S)-alpha-2-(chlorphenyl)-6,7-dihydrothieno [3,2-C] pyridine-5 (4-H)-acetic acid methyl ester of Formula I, commonly known as Clopidogrel hydrogen sulphate, in two crystalline forms viz: Form-I and Form-II. Background and Prior Art: Clopidogrel hydrogen sulfate [Formula-I, which is known as hydrogen sulfate of methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno [3,2-C] pyridine-5-acetate)] is an antithrombotic agent that was disclosed in Patent EP 281459 (herein after referred as '459 patent.) in its pure enantiomeric form for the first time. Formula -1 The '459 patent teaches the isolation of the dextro rotatory isomer of Clopidogrel by diasteriomeric salt formation of racemic base of Clopidogrel using an optically active acid such as 10-L-camphor sulfonic acid in solvents like acetone, followed by successive recrystallization of the salt until a product with constant rotatory power was obtained. The pure dextrorotatory isomer of clopidogrel was released from the respective diasteriomeric salt by reaction with a base. Clopidogrel freebase 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 2 184°C and optical rotation was +55.1° (c = 1.891 / CH30H). But '459 patent did not suggest any name to this polymorph of Clopidogrel hydrogen sulfate. Subsequently International patent publication, WO 99/65915 (herein after referred as '915 patent), disclosed two polymorph forms of Clopidogrel hydrogen sulfate referred to as Form-I and Form-II. The '915 patent identified that the precipitation method 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 MDC and transformation of salt into the base with potassium carbonate solution. Clopidogrel base is extracted in MDC and 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 suitable for the production of the 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 the patent application WO 2004020443 (herein after referred as '443 patent). According to the '443 patent application, a process was claimed to produce Form I consistently by forming hydrogen sulphate salt of clopidogrel from a solvent selected from the series of C1-C5 alcohols or their esters with C1-C4 acids, optionally of mixture of 3 alcohols and esters. The process involves dissolving clopidogrel base in solvents like isopropyl alcohol and/or butyl acetate, cooling the mixture, adding sulfuric acid and inoculating the mixture with Form-I of Clopidogrel hydrogen sulfate. Stirring the crystallized mixture precisely at a temperature between -5 and +15°C to get crystals of clopidogrel in Form-I. In another process variant, the subject of '443 patent, the clopidogrel hydrogen sulphate was directly dissolved at reflux in the above mentioned solvents and crystallized under cooling. Although the process mentioned in the '443 patent application works in butyl acetate, which is a hazardous solvent (affects central nervous system and exposure limit is 150 ppm), but fails to give pure Form I in other industrially friendly solvents like ethyl acetate under the specified conditions. As the Form I is thermodynamically unstable, the process variant of dissolving clopidogrel hydrogen sulphate salt in solvents at higher temperature and cooling to precipitate Form I resulted in Form II or Form IV or their mixture with Form I. This finding is in agreement with the prior art disclosed in United States patent application 2003/0225129 A2 (herein after referred as '129 patent), where isopropanol was used to produce Form-IV crystals ( Form IV of clopidogrel hydrogen sulphate is known to be its isopropyl alcohol solvate) by a process comprising the steps of preparing solution of Clopidogrel hydrogen sulfate either by using Clopidogrel base or its hydrogen sulfate salt in isopropyl alcohol at reflux and cooling to precipitate Clopidogrel hydrogen sulfate and separating the mentioned polymorph, i.e. Form IV. The '129 patent also 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. 4 Moreover, in our hands under the specified conditions at lower temperature of-5° to 15 ° C, as claimed in the '443 patent, we found the crystals formed in ethyl acetate is Form II of clopidogrel hydrogen sulphate. It is clear from above embodiments that same solvent gives two different crystalline forms under different experimental conditions. So, it is evident from the prior art that methods to produce Form-I of clopidogrel hydrogen sulphate from different solvents are poorly reproducible, necessitating the optimization of experimental conditions other than of the selection of 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. 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, only 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. Apart from the inconsistency of the process in solvents like ethyl acetate, the process given in the '443 patent application also suffers from operational problems from an industrial scale-up point of view as follows; 1. During the salt formation in solvents like ethyl acetate at lower temperature, the product forms a sticky & lumpy mass that sticks to the stirrer and difficult to disperse due to the lowered solubility at this condition, 2. The workability of the process found limit to single solvent mainly butyl acetate which is a hazardous and industrial unfriendly solvent, 3. The crystallization from comparatively high boiling solvent like butyl acetate (124° to 128 ° C) suffers from the problem of removal of solvent from the precipitate during drying, which is difficult on large scale as Form I crystals may convert to the undesirable Form II because that is the thermodynamically stable form, and 4. The crystal form obtained by performing the salt formation between 5° to 15° C in ethyl acetate is Form II of clopidogrel hydrogen sulphate. This may be due to the non- 5 dispersability of the sticky mass obtained under these conditions and the fast/prolonged stirring performed for dispersion, allows the crystals to grow and rearranges to the most stable form. Thus there is a need to get industrially reliable process for the preparation of Form-I and Form-II without contamination of one into other Form. So it was of interest to find a suitable solvent where the crystallization can be performed at a temperature near to ambient temperature, for solving the inconsistency/operational problems in the prior art, yielding clopidogrel Form I in its pure state. Also of interest was to see its workability at higher temperature to affect a fast and easily dispersible crystallization conditions, an important factor for operations. Another objective of the present invention was to find solvent systems where the Form I crystals of clopidogrel hydrogen sulphate can be efficiently and reproducibly formed on inductrial scale. Yet another area of interest was to find the conditions, where the transformation of Form I to Form II is taking place in the same solvent. These objectives become the subject of the present invention. Summary of the invention: The present invention provides an improved process for preparing and crystallizing out compound of formula (I) in solvents such as methyl propyl ketone, methyl isopropyl ketone, diethyl ketone or their mixture thereof, ethyl acetate, mixture of ethyl acetate and methyl propyl ketone, mixture of ethyl acetate and methyl isopropyl ketone, mixture of ethyl acetate and diethyl ketone, in its crystalline Form I in a reproducible manner without detectable contamination of form II. In one aspect of the present invention the process comprises dissolving the clopidogrel base in solvent such as methyl propyl ketone or methyl isopropyl ketone or diethyl ketone or mixture of ethyl acetate and methyl propyl ketone or mixture of ethyl acetate and methyl isopropyl ketone, mixture of ethyl acetate and diethyl ketone at room temperature 6 (20 to 30° C), then cooling the obtained clopidogrel base solution to a temperature of-10 to 10° C, adding concentrated sulphuric acid (98%, d= 1.84) while maintaining the temperature in the range -10 to 20° C, further maintaining the temperature at about 10 to 30 ° C for about 12 to 17 hours and filtering the crystals of Form I obtained. In another aspect of the present invention there is provided an improved manufacturing process for preparing compound of Formula (I) in ethyl acetate, in its crystalline Form-I in a reproducible manner without detectable contamination of Form-II at a temperature ranging from 18° to 30°C in optimum duration of 8 to 10 hours. The present invention also provides process for the formation of clopidogrel Form II from ethyl acetate at a temperature of 45°C to 50°C without detectable contamination of Form I. The present invention also provides process for preparation of both Form-I and Form-II from the same solvent, i.e. ethyl acetate, at different experimental condition, which gives operation-wise flexibility and excellent reproducibility, making the process practical and plant friendly. In another aspect, the present invention provides process for the preparation of Form II clopidogrel hydrogen sulphate from a commonly used solvent like isopropanol and tetrahydrofuran. The present invention also proves that not only the solvent but also the operational conditions are important to get different polymorphs of Clopidogrel hydrogen sulphate. 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 Powder X-Ray diffraction pattern (PXRD) of clopidogrel hydrogen sulphate Form II prepared according to example 4 of the present invention. Figure 3 represents Differential Scanning Calorimetry record of Form I of clopidogrel hydrogen sulphate prepared according to example 1 of the present invention. 7 Figure 4 represents Differential Scanning Calorimetry record of Form II of clopidogrel hydrogen sulphate prepared according to example 4 of the present invention. Figure 5 represents Powder X-Ray diffraction pattern (PXRD) of clopidogrel hydrogen sulphate Form I standard as given in '915 patent. Figure 6 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 7 represents spectrogram obtained by Fourier Transform Infra Red spectrometry (FTIR) of clopidogrel hydrogen sulphate Form II prepared according to example 4 of the present invention. Fig 8 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 This invention relates to the improved process for the preparation of Form I and II of Clopidogrel hydrogen sulphate on large scale. Large scale production of these two crystalline Forms according to the process described in the '915 patent resulted in Form II or a mixture or contaminated with either forms at a higher percentage. Also the improved process of '443 patent application resulted in scale-up problems on large scale due to lump formation and semi-solid/sticky nature of the product at lower temperature. Also encountered problems in maintaining precise control of temperature at different set points as stated in the '443 patent on large scale production. This lead us to find a flexible temperature range where these problems are minimized and ensure reproducibility of Form I and II, particularly Form I. This research has led to a process where Form I and Form II can be produced reliably from a single solvent. 8 In one aspect, the present invention provides a process for preparing polymorph Form I of clopidogrel hydrogen sulphate comprising dissolving the clopidogrel base in solvents like methyl propyl ketone, methyl isopropyl ketone, diethyl ketone or mixture thereof, or mixture of ethyl acetate and methyl propyl ketone or mixture of ethyl acetate and methyl isopropyl ketone, or mixture of ethyl acetate and diethyl ketone; cooling to a temperature of-10° C to 10° C; adding concentrated sulphuric acid (98%, d= 1.84) by maintaining the temperature at in the range of-10 to 20°C; raising to a temperature of 10° C to 15° C and maintaining for 5 to 7 hours; further raising to a temperature of 28° to 30° C and maintaining for a period of 7 to 10 hours and filtering the crystals obtained. The mixture of ketone solvents include mixture of methyl propyl ketone and methyl isopropyl ketone, mixture of methyl propyl ketone and diethyl ketone, mixture of methyl isopropyl ketone and diethyl ketone, in all proportions. In another aspect, the present invention provides a process for preparing polymorph Form I of clopidogrel hydrogen sulphate comprising steps of dissolving the clopidogrel base in ethyl acetate, cooling to a temperature of 18°C, adding concentrated sulphuric acid with or without maintaining temperature at 18°, raising to a temperature of 28° to 30° C and maintaining for a period of 7 to 10 hours and filtering the crystals obtained. In the process, the temperature range of 18° to 30°C gave Form I reproducibly on a large scale. Within this temperature range an easily dispersible solid is obtained and slight imbalance of temperature is well tolerated to give Form I consistently. In both the cases, in the process, the preferred concentration of sulphuric acid was in the range of 90% to 98% and the molar ratios were 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 was 96%. In a preferred embodiment the exotherm of sulphuric acid addition is controlled by cooling and maintaining the temperature in between 18° to 24°C in case of solvent ethyl 9 acetate; and cooling and maintaining the temperature in between -10 to 10°C in case of solvents methyl propyl ketone, methyl isopropyl ketone, diethyl ketone or their mixture thereof, or mixture of ethyl acetate and methyl propyl ketone or mixture of ethyl acetate and methyl isopropyl ketone, or mixture of ethyl acetate and diethyl ketone. The Form I so obtained was confirmed by PXRD, DSC and FTIR without any detectable quantity of Form II or other polymorphic Forms with respect to the standard Form I PXRD pattern as described in '915 patent. In another aspect, Form II crystals of clopidogrel hydrogen sulphate is prepared from the same solvent ethyl acetate comprising steps of dissolving clopidogrel base in the solvent, heating to a temperature of 45° C, adding concentrated sulphuric acid, stirring the reaction mixture at 45° C to 50° C for a period of 1 hour, cooling to 30° C and continue stirring for a period of 4 to 7 hours to effect the complete crystallization. In the process, the preferred concentration of sulphuric acid was in the range of 90 % to 98% and the molar ratios were in the range of 1.0 to 1.1 with respect to clopidogrel base. The most preferred concentration of sulphuric acid used in the salt formation was 96%. The Form II obtained by the process of the invention was confirmed by PXRD, DSC and FTIR and found to be identical with it disclosed in the '915 patent without any detectable contamination of Form I. In yet another aspect, Form II of clopidogrel is prepared from ethyl acetate at a lower temperature of 5° to 15° C comprising the steps of dissolving clopidogrel base in ethyl acetate at 25° to 30° C, cool to 5° to 15° C and mixing with cone, sulphuric acid at the said temperature, maintaining the mass under stirring for a period of 8 to 10 hours at 5 to 15 ° C to yield crystals of clopidogrel Form II. The crystals obtained are filtered and dried and is identified as Form II by PXRD, FTIR and DSC without detectable contamination of Form I. 10 To our surprise the crystal form obtained at temperature below 15° C and above 40° C process conditions are the stable Form II crystals, while the temperature range of 18° to 30° C processing conditions invariably yielded crystal Form I of clopidogrel hydrogen sulphate. In another embodiment, the present invention provides a process for the preparation of Form II crystals of clopidogrel hydrogen sulphate from isopropyl alcohol comprising steps of dissolving clopidogrel base in solvent, adding concentrated sulphuric acid at a temperature of 28° to 30° C, stirring to effect complete crystallization for a period of 12 to 15 hours, filter and dry the crystals. The crystal form is identified equivalent to Form II. This solvent system (isopropyl alcohol) is, however, known to give Form IV. In a preferred embodiment of the process the concentrated sulphuric acid is added as a solution in isopropyl alcohol. The present invention also provides a process for the preparation of Form II of clopidogrel hydrogen sulphate from tetrahydrofuran comprising steps of dissolving clopidogrel base in solvent, cooling the reaction mass to a temperature of 10° to 15° C; adding concentrated sulphuric acid at a temperature of 10° to 15° C, stirring to effect complete crystallization for a period of 6 to 8 hours, filter and dry the crystals. The crystal form is identified equivalent to Form II. The following actual examples further illustrate the present invention without limiting the scope of the invention substantially described. Examples: 1) Clopidogrel base (5.79 kg) was dissolved in methyl propyl ketone (37 liter) at room temperature. This mixture was cooled to -10° C and concentrated sulphuric acid ( 96%, density =1.83 ) was added (1.02 liter) 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 7 hour. The reaction 11 mass temperature was further raised to 28 to 30°C and maintained for 8.0 hour. The solid obtained was filtered under suction and washed with methyl propyl ketone, and dried in oven at 48° C for 3 hour. The solid after drying weighed 6.82 kg (90%) was Form I clopidogrel hydrogen sulphate (PXRD pattern incorporated: figure 1) 2) Clopidogrel base (5.79 kg) was dissolved in methyl isopropyl ketone (37 liter) at room temperature. This mixture was cooled to -10° C and concentrated sulphuric acid (96%, density = 1.83) was added (1.02 liter) 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 minutes. The formed crystals were stirred for 7 hour. The reaction mass temperature was further raised to 28 to 30°C and maintained for 8.0 hour. The solid obtained was filtered under suction and washed with methyl isopropyl ketone, and dried in oven at 48° C for 3 hour. The solid after drying weighed 6.82 kg (90%) was Form I clopidogrel hydrogen sulphate (PXRD pattern is identical with figure 1). 3) Clopidogrel base (5.79 kg) was dissolved in ethyl acetate (30 liter) at room temperature. This mixture was cooled to 18° C and concentrated sulphuric acid (96%, density = 1.83) was added (1.02 liter) maintaining temperature 18° to 20° C while addition. The reaction mass was stirred for 30 minutes and warmed slowly to 28° to 30° C in 30 to 40 minute. The formed crystals were stirred for 8 hour. The solid obtained was filtered under suction and washed with ethyl acetate, and dried in oven at 40° C for 3 hour. The solid after drying weighed 6.7 kg (88%) was Form I clopidogrel hydrogen sulphate (PXRD pattern is identical with figure 1). 4) Clopidogrel base (5.79 kg) was dissolved in ethyl acetate (30 liter) at room temperature. This mixture was heated to 45° C and concentrated sulphuric acid (96%, density = 1.83) was added (1.02 liter). The reaction mass was stirred for 30 minutes at 45° to 50° C. The formed crystals were cooled to 30° C in one hour and stirred for 4 hour. The solid obtained was filtered under suction and washed with ethyl acetate, and dried in oven at 48° C for 3 hour. The solid after drying weighed 6.5 kg (86%) 12 and identified as pure clopidogrel hydrogen sulphate Form II ( PXRD pattern incorporated : figure 2) 5) Clopidogrel base (5.79 kg) was dissolved in ethyl acetate (30 liter) at room temperature. This mixture was cooled to 20° C and concentrated sulphuric acid (98%, density = 1.84) was added (1.02 liter). The temperature rose to 28° C while addition and the reaction mass was stirred for 10 hour at 28° to 30° C. The solid obtained was filtered under suction and washed with ethyl acetate, and dried in oven at 40° C for 3 hour. The solid after drying weighed 6.8 kg (89.6%) and identified as pure clopidogrel hydrogen sulphate Form I (PXRD pattern is identical with figure 1). 6) Clopidogrel base (7.25 kg) was dissolved in isopropyl alcohol (62.5 liter) at room temperature. This mixture was maintained at 28° to 30°C and concentrated sulphuric acid solution in isopropyl alcohol (prepared by mixing 1.14 liter concentrated sulphuric acid and 43.5 liter isopropyl alcohol) was added. The reaction mass was stirred for 12 hour at 28° to 30° C. The solid obtained was filtered under suction and washed with ethyl acetate, and dried in oven at 48° C for 3 hours. The solid after drying weighed 7.6 kg (80%) and identified as pure clopidogrel hydrogen sulphate Form II (PXRD pattern as in example 4). 7) Clopidogrel base (5.79 kg) was dissolved in tetrahydrofuran (30 liter) at room temperature. This mixture was cooled to 10° to 15° C and concentrated sulphuric acid (80 %) solution 1.4 liter was added while maintaining the temperature under cooling. The reaction mass was stirred for 8 hour at 13° to 15° C. The solid obtained was filtered under suction and washed with tetrahydrofuran, and dried in oven at 48°C for 3 hour. The solid after drying weighed 5.9 kg (78%) and identified as pure clopidogrel hydrogen sulphate Form II (PXRD pattern as in example 4). 8) Clopidogrel base (5.79 kg) was dissolved in ethyl acetate (30 liter) at room temperature. This mixture was cooled to 5°C and concentrated sulphuric acid (98%), density = 1.84) was added (1.02 liter) while maintaining the temperature at 5° to 10° 13 C and the reaction mass was stirred for 3 hour at 10° to 15° C and maintained for 10 to 12 hour at 24° C . The solid obtained was filtered under suction and washed with ethyl acetate, and dried in oven at 48° C for 3 hour. The solid after drying weighed 6.9 kg (90%) and identified as pure clopidogrel hydrogen sulphate Form II ( PXRD pattern was identical as in example 4) 9) Clopidogrel base (5.79 kg) was dissolved in ethyl acetate (30 liter) at room temperature. This mixture was cooled to 10°C and concentrated sulphuric acid ( 98%, density = 1.84) was added (1.02 liter) while maintaining the temperature at 10° to 15° C and the reaction mass was stirred for 10 hour at 15° C. The solid obtained was filtered under suction and washed with ethyl acetate, and dried in oven at 48° C for 3 hours. The solid after drying weighed 6.7 kg (89.6%) and identified as pure clopidogrel hydrogen sulphate Form II (PXRD pattern was identical as in example 4). 14 We claim, 1. An industrial process for the manufacture of Form I crystals of (+)-(S)-clopidogrel hydrogen sulphate of Formula I comprising: COOMe H2S04 Formula I dissolving methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-5-acetate [(+)-(S)-clopidogrel base] in methyl propyl ketone, methyl isopropyl ketone, diethyl ketone or their mixture thereof, mixture of ethyl acetate and methyl propyl ketone, mixture of ethyl acetate and methyl isopropyl ketone, mixture of ethyl acetate and diethyl ketone at a temperature of about 20 to 30 ° C; cooling said clopidogrel base solution to a temperature of about -10 to 20 ° C; adding concentrated sulphuric acid to said cooled solution; maintaining said salt mixture at a temperature in the range of about 10 ° to 30 ° C to effect precipitation of (+)-(S)-clopidogrel hydrogen sulphate in Form I and filtering said crystals of Form I. 2. A process for the manufacture of Form I crystals of (+)-(S)-clopidogrel hydrogen sulphate of Formula I, wherein the said process comprising: dissolving methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-5-acetate [(+)-(S)-clopidogrel base] in ethyl acetate; cooling to a temperature of 18° to 20° C; mixing with concentrated sulphuric acid with or without allowing the temperature to raise to 28° to 30°C; maintaining the salt mixture at 28° to 30° C for 7 to 10 hours to effect precipitation of (+)-(S)-clopidogrel hydrogen sulphate in Form I and filtering said crystals of Form I. 3. The process as claimed in claims 1 , wherein said mixture of ketone solvents comprises mixture of methyl propyl ketone and methyl isopropyl ketone, mixture of methyl propyl ketone and diethyl ketone, mixture of methyl isopropyl ketone and diethyl ketone, in all proportion. 15 4. The process as claimed in claim 1, wherein the addition of said concentrated sulphuric acid is carried out while maintaining the temperature at -10 to 10° C. 5. The process as claimed in claim 2, wherein the addition of said concentrated sulphuric acid is carried out while maintaining the temperature at 18 to 24° C. 6. The process as claimed in any one of the preceding claim, wherein the strength of said sulphuric acid is about 95 to 98 % concentrated sulphuric acid. 7. The process as claimed in any one of the preceding claim, wherein the strength of said concentrated sulphuric acid is 96%. 8. The process as claimed in any one of the preceding claim, wherein the molar ratio of sulphuric acid used is 1.02 to 1.1 relative to (+)-(S)-clopidogrel base. 9. An industrial process for the preparation of Form II of (+)-(S)-clopidogrel hydrogen sulphate from solvents selected from ethyl acetate, isopropyl alcohol and tetrahydrofuran under conditions effective to form Form II. 10. The process as claimed in claim 9, wherein Form II of (+)-(S)-clopidogrel hydrogen sulphate is prepared from ethyl acetate comprising the steps of, dissolving (+)-(S)-clopidogrel base of Formula I in ethyl acetate; cooling the mixture to 5° to 10° C; mixing concentrated sulphuric acid while maintaining the said temperature; and maintaining the mixture under stirring at a temperature of 10° to 15° C for a period of 8 to 12 hours. 11. The process as claimed in claim 10, wherein said concentrated sulphuric acid is preferably 95 to 98% strength and used in a molar ratio of 1.02 to 1.1 moles relative to (+)-(S)-clopidogrel base. 12. The process as claimed in claim 9, wherein Form II of (+)-(S)-clopidogrel hydrogen sulphate is prepared from ethyl acetate comprising the steps of,c dissolving (+)-(S)-clopidogrel base of Formula I in ethyl acetate at a temperature of 45° to 50°C; mixing concentrated sulphuric acid while maintaining the said temperature; maintaining the mixture under stirring for a period of 1 to 3 hours at 45° to 50° C; cooling to a temperature of 30° to 32°C in 1 hour and maintaining for a period of 3 to 4 hours to yield (+)-(S)-clopidogrel hydrogen sulphate Form II. 16 13. The process as claimed in claim 9, wherein Form II of (+)(S)clopidogrel hydrogen sulphate is prepared from tetrahydrofuran comprising the steps of, dissolving (+)-(S)-clopidogrel base of Formula I in tetrahydrofuran at a temperature of 25° to 30°C; cooling to a temperature of 10° to 15° C; mixing concentrated sulphuric acid while maintaining the said temperature; and maintaining for a period of 6 to 8 hours to yield (+)-(S)-clopidogrel hydrogen sulphate Form II. 14. The process as claimed in claim 13, wherein the concentration of sulphuric acid is 80% and the molar ratio is 1.02 to 1.1 relative to (+)-(S)-clopidogrel base. 15. The process as claimed in claim 9, wherein Form II of (+)-(S)-clopidogrel hydrogen sulphate is prepared from isopropyl alcohol comprising the steps of, dissolving (+)-(S)-clopidogrel base of Formula I in isopropyl alcohol at a temperature of 28° to 30°C; mixing with concentrated sulphuric acid while maintaining the said temperature; and maintaining the mixture for a period of 6 to 8 hours at 28 ° to 30° C to yield (+)-(S)-clopidogrel hydrogen sulphate Form II. 16. The process as claimed in claim 15, wherein the concentration of sulphuric acid is preferably 95 to 98% and the molar ratio is 1.02 to 1.1 relative to (+)-(S)-clopidogrel base. 17. The process for preparing (+)-(S)-clopidogrel hydrogen sulphate polymorphs namely Form I and Form II as substantially described herein with reference to the foregoing examples 1 to 9. 17 Abstract: An improved process for manufacturing hydrogen sulfate salt of (+)-(S)-alpha-2-(chlorphenyl)-6,7-dihydrothieno [3,2-C] pyridine-5 (4-H)-acetic acid methyl ester, commonly known as Clopidogrel hydrogen sulphate, in two crystalline forms viz: Form-I and Form-II is disclosed herein. 1 3 DEC 2004

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10; Rule 13]
"An improved process for manufacture of crystalline Forms of methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno [3,2-C] pyridine-5-
acetate hydrogen sulphate salt"
(a) IPCA LABORATORIES LIMITED
(b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956
The following specification describes the nature of this invention and the manner in which it is to be performed:

Technical Field:
The invention relates to an improved process for manufacturing hydrogen sulfate salt of (+)-(S)-alpha-2-(chlorphenyl)-6,7-dihydrothieno [3,2-C] pyridine-5 (4-H)-acetic acid methyl ester of Formula I, commonly known as Clopidogrel hydrogen sulphate, in two crystalline forms viz: Form-I and Form-II.
Background and Prior Art:
Clopidogrel hydrogen sulfate [Formula-I, which is known as hydrogen sulfate of methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno [3,2-C] pyridine-5-acetate)] is an antithrombotic agent that was disclosed in Patent EP 281459 (herein after referred as '459 patent.) in its pure enantiomeric form for the first time.

Formula -1
The '459 patent teaches the isolation of the dextro rotatory isomer of Clopidogrel by diasteriomeric salt formation of racemic base of Clopidogrel using an optically active acid such as 10-L-camphor sulfonic acid in solvents like acetone, followed by successive recrystallization of the salt until a product with constant rotatory power was obtained. The pure dextrorotatory isomer of clopidogrel was released from the respective diasteriomeric salt by reaction with a base.
Clopidogrel freebase 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
2

184°C and optical rotation was +55.1° (c = 1.891 / CH30H). But '459 patent did not suggest any name to this polymorph of Clopidogrel hydrogen sulfate.
Subsequently International patent publication, WO 99/65915 (herein after referred as '915 patent), disclosed two polymorph forms of Clopidogrel hydrogen sulfate referred to as Form-I and Form-II. The '915 patent identified that the precipitation method 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 MDC and transformation of salt into the base with potassium carbonate solution. Clopidogrel base is extracted in MDC and 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 suitable for the production of the 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 the patent application WO 2004020443 (herein after referred as '443 patent).
According to the '443 patent application, a process was claimed to produce Form I consistently by forming hydrogen sulphate salt of clopidogrel from a solvent selected from the series of C1-C5 alcohols or their esters with C1-C4 acids, optionally of mixture of
3

alcohols and esters. The process involves dissolving clopidogrel base in solvents like isopropyl alcohol and/or butyl acetate, cooling the mixture, adding sulfuric acid and inoculating the mixture with Form-I of Clopidogrel hydrogen sulfate. Stirring the crystallized mixture precisely at a temperature between -5 and +15°C to get crystals of clopidogrel in Form-I. In another process variant, the subject of '443 patent, the clopidogrel hydrogen sulphate was directly dissolved at reflux in the above mentioned solvents and crystallized under cooling.
Although the process mentioned in the '443 patent application works in butyl acetate, which is a hazardous solvent (affects central nervous system and exposure limit is 150 ppm), but fails to give pure Form I in other industrially friendly solvents like ethyl acetate under the specified conditions. As the Form I is thermodynamically unstable, the process variant of dissolving clopidogrel hydrogen sulphate salt in solvents at higher temperature and cooling to precipitate Form I resulted in Form II or Form IV or their mixture with Form I.
This finding is in agreement with the prior art disclosed in United States patent application 2003/0225129 A2 (herein after referred as '129 patent), where isopropanol was used to produce Form-IV crystals ( Form IV of clopidogrel hydrogen sulphate is known to be its isopropyl alcohol solvate) by a process comprising the steps of preparing solution of Clopidogrel hydrogen sulfate either by using Clopidogrel base or its hydrogen sulfate salt in isopropyl alcohol at reflux and cooling to precipitate Clopidogrel hydrogen sulfate and separating the mentioned polymorph, i.e. Form IV.
The '129 patent also 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.
4

Moreover, in our hands under the specified conditions at lower temperature of-5° to 15 ° C, as claimed in the '443 patent, we found the crystals formed in ethyl acetate is Form II of clopidogrel hydrogen sulphate.
It is clear from above embodiments that same solvent gives two different crystalline forms under different experimental conditions.
So, it is evident from the prior art that methods to produce Form-I of clopidogrel hydrogen sulphate from different solvents are poorly reproducible, necessitating the optimization of experimental conditions other than of the selection of 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. 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, only 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.
Apart from the inconsistency of the process in solvents like ethyl acetate, the process given in the '443 patent application also suffers from operational problems from an industrial scale-up point of view as follows;
1. During the salt formation in solvents like ethyl acetate at lower temperature, the product forms a sticky & lumpy mass that sticks to the stirrer and difficult to disperse due to the lowered solubility at this condition,
2. The workability of the process found limit to single solvent mainly butyl acetate which is a hazardous and industrial unfriendly solvent,
3. The crystallization from comparatively high boiling solvent like butyl acetate (124° to 128 ° C) suffers from the problem of removal of solvent from the precipitate during drying, which is difficult on large scale as Form I crystals may convert to the undesirable Form II because that is the thermodynamically stable form, and
4. The crystal form obtained by performing the salt formation between 5° to 15° C in ethyl acetate is Form II of clopidogrel hydrogen sulphate. This may be due to the non-
5

dispersability of the sticky mass obtained under these conditions and the fast/prolonged stirring performed for dispersion, allows the crystals to grow and rearranges to the most stable form.
Thus there is a need to get industrially reliable process for the preparation of Form-I and Form-II without contamination of one into other Form. So it was of interest to find a suitable solvent where the crystallization can be performed at a temperature near to ambient temperature, for solving the inconsistency/operational problems in the prior art, yielding clopidogrel Form I in its pure state. Also of interest was to see its workability at higher temperature to affect a fast and easily dispersible crystallization conditions, an important factor for operations.
Another objective of the present invention was to find solvent systems where the Form I crystals of clopidogrel hydrogen sulphate can be efficiently and reproducibly formed on inductrial scale. Yet another area of interest was to find the conditions, where the transformation of Form I to Form II is taking place in the same solvent. These objectives become the subject of the present invention.
Summary of the invention:
The present invention provides an improved process for preparing and crystallizing out compound of formula (I) in solvents such as methyl propyl ketone, methyl isopropyl ketone, diethyl ketone or their mixture thereof, ethyl acetate, mixture of ethyl acetate and methyl propyl ketone, mixture of ethyl acetate and methyl isopropyl ketone, mixture of ethyl acetate and diethyl ketone, in its crystalline Form I in a reproducible manner without detectable contamination of form II.
In one aspect of the present invention the process comprises dissolving the clopidogrel base in solvent such as methyl propyl ketone or methyl isopropyl ketone or diethyl ketone or mixture of ethyl acetate and methyl propyl ketone or mixture of ethyl acetate and methyl isopropyl ketone, mixture of ethyl acetate and diethyl ketone at room temperature
6

(20 to 30° C), then cooling the obtained clopidogrel base solution to a temperature of-10 to 10° C, adding concentrated sulphuric acid (98%, d= 1.84) while maintaining the temperature in the range -10 to 20° C, further maintaining the temperature at about 10 to 30 ° C for about 12 to 17 hours and filtering the crystals of Form I obtained.
In another aspect of the present invention there is provided an improved manufacturing process for preparing compound of Formula (I) in ethyl acetate, in its crystalline Form-I in a reproducible manner without detectable contamination of Form-II at a temperature ranging from 18° to 30°C in optimum duration of 8 to 10 hours. The present invention also provides process for the formation of clopidogrel Form II from ethyl acetate at a temperature of 45°C to 50°C without detectable contamination of Form I.
The present invention also provides process for preparation of both Form-I and Form-II from the same solvent, i.e. ethyl acetate, at different experimental condition, which gives operation-wise flexibility and excellent reproducibility, making the process practical and plant friendly.
In another aspect, the present invention provides process for the preparation of Form II clopidogrel hydrogen sulphate from a commonly used solvent like isopropanol and tetrahydrofuran. The present invention also proves that not only the solvent but also the operational conditions are important to get different polymorphs of Clopidogrel hydrogen sulphate.
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 Powder X-Ray diffraction pattern (PXRD) of clopidogrel hydrogen
sulphate Form II prepared according to example 4 of the present invention.
Figure 3 represents Differential Scanning Calorimetry record of Form I of clopidogrel
hydrogen sulphate prepared according to example 1 of the present invention.
7

Figure 4 represents Differential Scanning Calorimetry record of Form II of clopidogrel
hydrogen sulphate prepared according to example 4 of the present invention.
Figure 5 represents Powder X-Ray diffraction pattern (PXRD) of clopidogrel hydrogen
sulphate Form I standard as given in '915 patent.
Figure 6 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 7 represents spectrogram obtained by Fourier Transform Infra Red spectrometry
(FTIR) of clopidogrel hydrogen sulphate Form II prepared according to example 4 of the
present invention.
Fig 8 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
This invention relates to the improved process for the preparation of Form I and II of Clopidogrel hydrogen sulphate on large scale.
Large scale production of these two crystalline Forms according to the process described in the '915 patent resulted in Form II or a mixture or contaminated with either forms at a higher percentage. Also the improved process of '443 patent application resulted in scale-up problems on large scale due to lump formation and semi-solid/sticky nature of the product at lower temperature. Also encountered problems in maintaining precise control of temperature at different set points as stated in the '443 patent on large scale production.
This lead us to find a flexible temperature range where these problems are minimized and ensure reproducibility of Form I and II, particularly Form I. This research has led to a process where Form I and Form II can be produced reliably from a single solvent.
8

In one aspect, the present invention provides a process for preparing polymorph Form I of clopidogrel hydrogen sulphate comprising dissolving the clopidogrel base in solvents like methyl propyl ketone, methyl isopropyl ketone, diethyl ketone or mixture thereof, or mixture of ethyl acetate and methyl propyl ketone or mixture of ethyl acetate and methyl isopropyl ketone, or mixture of ethyl acetate and diethyl ketone; cooling to a temperature of-10° C to 10° C; adding concentrated sulphuric acid (98%, d= 1.84) by maintaining the temperature at in the range of-10 to 20°C; raising to a temperature of 10° C to 15° C and maintaining for 5 to 7 hours; further raising to a temperature of 28° to 30° C and maintaining for a period of 7 to 10 hours and filtering the crystals obtained.
The mixture of ketone solvents include mixture of methyl propyl ketone and methyl isopropyl ketone, mixture of methyl propyl ketone and diethyl ketone, mixture of methyl isopropyl ketone and diethyl ketone, in all proportions.
In another aspect, the present invention provides a process for preparing polymorph Form I of clopidogrel hydrogen sulphate comprising steps of dissolving the clopidogrel base in ethyl acetate, cooling to a temperature of 18°C, adding concentrated sulphuric acid with or without maintaining temperature at 18°, raising to a temperature of 28° to 30° C and maintaining for a period of 7 to 10 hours and filtering the crystals obtained.
In the process, the temperature range of 18° to 30°C gave Form I reproducibly on a large scale. Within this temperature range an easily dispersible solid is obtained and slight imbalance of temperature is well tolerated to give Form I consistently.
In both the cases, in the process, the preferred concentration of sulphuric acid was in the range of 90% to 98% and the molar ratios were 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 was 96%.
In a preferred embodiment the exotherm of sulphuric acid addition is controlled by cooling and maintaining the temperature in between 18° to 24°C in case of solvent ethyl
9

acetate; and cooling and maintaining the temperature in between -10 to 10°C in case of solvents methyl propyl ketone, methyl isopropyl ketone, diethyl ketone or their mixture thereof, or mixture of ethyl acetate and methyl propyl ketone or mixture of ethyl acetate and methyl isopropyl ketone, or mixture of ethyl acetate and diethyl ketone.
The Form I so obtained was confirmed by PXRD, DSC and FTIR without any detectable quantity of Form II or other polymorphic Forms with respect to the standard Form I PXRD pattern as described in '915 patent.
In another aspect, Form II crystals of clopidogrel hydrogen sulphate is prepared from the same solvent ethyl acetate comprising steps of dissolving clopidogrel base in the solvent, heating to a temperature of 45° C, adding concentrated sulphuric acid, stirring the reaction mixture at 45° C to 50° C for a period of 1 hour, cooling to 30° C and continue stirring for a period of 4 to 7 hours to effect the complete crystallization.
In the process, the preferred concentration of sulphuric acid was in the range of 90 % to 98% and the molar ratios were in the range of 1.0 to 1.1 with respect to clopidogrel base. The most preferred concentration of sulphuric acid used in the salt formation was 96%.
The Form II obtained by the process of the invention was confirmed by PXRD, DSC and FTIR and found to be identical with it disclosed in the '915 patent without any detectable contamination of Form I.
In yet another aspect, Form II of clopidogrel is prepared from ethyl acetate at a lower temperature of 5° to 15° C comprising the steps of dissolving clopidogrel base in ethyl acetate at 25° to 30° C, cool to 5° to 15° C and mixing with cone, sulphuric acid at the said temperature, maintaining the mass under stirring for a period of 8 to 10 hours at 5 to 15 ° C to yield crystals of clopidogrel Form II. The crystals obtained are filtered and dried and is identified as Form II by PXRD, FTIR and DSC without detectable contamination of Form I.
10

To our surprise the crystal form obtained at temperature below 15° C and above 40° C process conditions are the stable Form II crystals, while the temperature range of 18° to 30° C processing conditions invariably yielded crystal Form I of clopidogrel hydrogen sulphate.
In another embodiment, the present invention provides a process for the preparation of Form II crystals of clopidogrel hydrogen sulphate from isopropyl alcohol comprising steps of dissolving clopidogrel base in solvent, adding concentrated sulphuric acid at a temperature of 28° to 30° C, stirring to effect complete crystallization for a period of 12 to 15 hours, filter and dry the crystals. The crystal form is identified equivalent to Form II. This solvent system (isopropyl alcohol) is, however, known to give Form IV.
In a preferred embodiment of the process the concentrated sulphuric acid is added as a solution in isopropyl alcohol.
The present invention also provides a process for the preparation of Form II of clopidogrel hydrogen sulphate from tetrahydrofuran comprising steps of dissolving clopidogrel base in solvent, cooling the reaction mass to a temperature of 10° to 15° C; adding concentrated sulphuric acid at a temperature of 10° to 15° C, stirring to effect complete crystallization for a period of 6 to 8 hours, filter and dry the crystals. The crystal form is identified equivalent to Form II.
The following actual examples further illustrate the present invention without limiting the scope of the invention substantially described.
Examples:
1) Clopidogrel base (5.79 kg) was dissolved in methyl propyl ketone (37 liter) at room temperature. This mixture was cooled to -10° C and concentrated sulphuric acid ( 96%, density =1.83 ) was added (1.02 liter) 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 7 hour. The reaction
11

mass temperature was further raised to 28 to 30°C and maintained for 8.0 hour. The solid obtained was filtered under suction and washed with methyl propyl ketone, and dried in oven at 48° C for 3 hour. The solid after drying weighed 6.82 kg (90%) was Form I clopidogrel hydrogen sulphate (PXRD pattern incorporated: figure 1)
2) Clopidogrel base (5.79 kg) was dissolved in methyl isopropyl ketone (37 liter) at room temperature. This mixture was cooled to -10° C and concentrated sulphuric acid (96%, density = 1.83) was added (1.02 liter) 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 minutes. The formed crystals were stirred for 7 hour. The reaction mass temperature was further raised to 28 to 30°C and maintained for 8.0 hour. The solid obtained was filtered under suction and washed with methyl isopropyl ketone, and dried in oven at 48° C for 3 hour. The solid after drying weighed 6.82 kg (90%) was Form I clopidogrel hydrogen sulphate (PXRD pattern is identical with figure 1).
3) Clopidogrel base (5.79 kg) was dissolved in ethyl acetate (30 liter) at room temperature. This mixture was cooled to 18° C and concentrated sulphuric acid (96%, density = 1.83) was added (1.02 liter) maintaining temperature 18° to 20° C while addition. The reaction mass was stirred for 30 minutes and warmed slowly to 28° to 30° C in 30 to 40 minute. The formed crystals were stirred for 8 hour. The solid obtained was filtered under suction and washed with ethyl acetate, and dried in oven at 40° C for 3 hour. The solid after drying weighed 6.7 kg (88%) was Form I clopidogrel hydrogen sulphate (PXRD pattern is identical with figure 1).
4) Clopidogrel base (5.79 kg) was dissolved in ethyl acetate (30 liter) at room
temperature. This mixture was heated to 45° C and concentrated sulphuric acid (96%,
density = 1.83) was added (1.02 liter). The reaction mass was stirred for 30 minutes at
45° to 50° C. The formed crystals were cooled to 30° C in one hour and stirred for 4
hour. The solid obtained was filtered under suction and washed with ethyl acetate,
and dried in oven at 48° C for 3 hour. The solid after drying weighed 6.5 kg (86%)
12

and identified as pure clopidogrel hydrogen sulphate Form II ( PXRD pattern incorporated : figure 2)
5) Clopidogrel base (5.79 kg) was dissolved in ethyl acetate (30 liter) at room temperature. This mixture was cooled to 20° C and concentrated sulphuric acid (98%, density = 1.84) was added (1.02 liter). The temperature rose to 28° C while addition and the reaction mass was stirred for 10 hour at 28° to 30° C. The solid obtained was filtered under suction and washed with ethyl acetate, and dried in oven at 40° C for 3 hour. The solid after drying weighed 6.8 kg (89.6%) and identified as pure clopidogrel hydrogen sulphate Form I (PXRD pattern is identical with figure 1).
6) Clopidogrel base (7.25 kg) was dissolved in isopropyl alcohol (62.5 liter) at room temperature. This mixture was maintained at 28° to 30°C and concentrated sulphuric acid solution in isopropyl alcohol (prepared by mixing 1.14 liter concentrated sulphuric acid and 43.5 liter isopropyl alcohol) was added. The reaction mass was stirred for 12 hour at 28° to 30° C. The solid obtained was filtered under suction and washed with ethyl acetate, and dried in oven at 48° C for 3 hours. The solid after drying weighed 7.6 kg (80%) and identified as pure clopidogrel hydrogen sulphate Form II (PXRD pattern as in example 4).
7) Clopidogrel base (5.79 kg) was dissolved in tetrahydrofuran (30 liter) at room temperature. This mixture was cooled to 10° to 15° C and concentrated sulphuric acid (80 %) solution 1.4 liter was added while maintaining the temperature under cooling. The reaction mass was stirred for 8 hour at 13° to 15° C. The solid obtained was filtered under suction and washed with tetrahydrofuran, and dried in oven at 48°C for 3 hour. The solid after drying weighed 5.9 kg (78%) and identified as pure clopidogrel hydrogen sulphate Form II (PXRD pattern as in example 4).
8) Clopidogrel base (5.79 kg) was dissolved in ethyl acetate (30 liter) at room temperature. This mixture was cooled to 5°C and concentrated sulphuric acid (98%), density = 1.84) was added (1.02 liter) while maintaining the temperature at 5° to 10°
13

C and the reaction mass was stirred for 3 hour at 10° to 15° C and maintained for 10 to 12 hour at 24° C . The solid obtained was filtered under suction and washed with ethyl acetate, and dried in oven at 48° C for 3 hour. The solid after drying weighed 6.9 kg (90%) and identified as pure clopidogrel hydrogen sulphate Form II ( PXRD pattern was identical as in example 4)
9) Clopidogrel base (5.79 kg) was dissolved in ethyl acetate (30 liter) at room temperature. This mixture was cooled to 10°C and concentrated sulphuric acid ( 98%, density = 1.84) was added (1.02 liter) while maintaining the temperature at 10° to 15° C and the reaction mass was stirred for 10 hour at 15° C. The solid obtained was filtered under suction and washed with ethyl acetate, and dried in oven at 48° C for 3 hours. The solid after drying weighed 6.7 kg (89.6%) and identified as pure clopidogrel hydrogen sulphate Form II (PXRD pattern was identical as in example 4).
14

We claim,

1. An industrial process for the manufacture of Form I crystals of (+)-(S)-clopidogrel
hydrogen sulphate of Formula I comprising:
COOMe
H2S04
Formula I

dissolving methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-5-acetate [(+)-(S)-clopidogrel base] in methyl propyl ketone, methyl isopropyl ketone, diethyl ketone or their mixture thereof, mixture of ethyl acetate and methyl propyl ketone, mixture of ethyl acetate and methyl isopropyl ketone, mixture of ethyl acetate and diethyl ketone at a temperature of about 20 to 30 ° C; cooling said clopidogrel base solution to a temperature of about -10 to 20 ° C; adding concentrated sulphuric acid to said cooled solution; maintaining said salt mixture at a temperature in the range of about 10 ° to 30 ° C to effect precipitation of (+)-(S)-clopidogrel hydrogen sulphate in Form I and filtering said crystals of Form I.
2. A process for the manufacture of Form I crystals of (+)-(S)-clopidogrel hydrogen
sulphate of Formula I, wherein the said process comprising:
dissolving methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-5-acetate [(+)-(S)-clopidogrel base] in ethyl acetate; cooling to a temperature of 18° to 20° C; mixing with concentrated sulphuric acid with or without allowing the temperature to raise to 28° to 30°C; maintaining the salt mixture at 28° to 30° C for 7 to 10 hours to effect precipitation of (+)-(S)-clopidogrel hydrogen sulphate in Form I and filtering said crystals of Form I.
3. The process as claimed in claims 1 , wherein said mixture of ketone solvents
comprises mixture of methyl propyl ketone and methyl isopropyl ketone, mixture of methyl propyl ketone and diethyl ketone, mixture of methyl isopropyl ketone
and diethyl ketone, in all proportion.
15

4. The process as claimed in claim 1, wherein the addition of said concentrated sulphuric acid is carried out while maintaining the temperature at -10 to 10° C.
5. The process as claimed in claim 2, wherein the addition of said concentrated sulphuric acid is carried out while maintaining the temperature at 18 to 24° C.
6. The process as claimed in any one of the preceding claim, wherein the strength of said sulphuric acid is about 95 to 98 % concentrated sulphuric acid.
7. The process as claimed in any one of the preceding claim, wherein the strength of said concentrated sulphuric acid is 96%.
8. The process as claimed in any one of the preceding claim, wherein the molar ratio of sulphuric acid used is 1.02 to 1.1 relative to (+)-(S)-clopidogrel base.
9. An industrial process for the preparation of Form II of (+)-(S)-clopidogrel hydrogen sulphate from solvents selected from ethyl acetate, isopropyl alcohol and tetrahydrofuran under conditions effective to form Form II.
10. The process as claimed in claim 9, wherein Form II of (+)-(S)-clopidogrel hydrogen sulphate is prepared from ethyl acetate comprising the steps of, dissolving (+)-(S)-clopidogrel base of Formula I in ethyl acetate; cooling the mixture to 5° to 10° C; mixing concentrated sulphuric acid while maintaining the said temperature; and maintaining the mixture under stirring at a temperature of 10° to 15° C for a period of 8 to 12 hours.
11. The process as claimed in claim 10, wherein said concentrated sulphuric acid is preferably 95 to 98% strength and used in a molar ratio of 1.02 to 1.1 moles relative to (+)-(S)-clopidogrel base.
12. The process as claimed in claim 9, wherein Form II of (+)-(S)-clopidogrel hydrogen sulphate is prepared from ethyl acetate comprising the steps of,c dissolving (+)-(S)-clopidogrel base of Formula I in ethyl acetate at a temperature of 45° to 50°C; mixing concentrated sulphuric acid while maintaining the said temperature; maintaining the mixture under stirring for a period of 1 to 3 hours at 45° to 50° C; cooling to a temperature of 30° to 32°C in 1 hour and maintaining for a period of 3 to 4 hours to yield (+)-(S)-clopidogrel hydrogen sulphate Form II.
16

13. The process as claimed in claim 9, wherein Form II of (+)(S)clopidogrel hydrogen sulphate is prepared from tetrahydrofuran comprising the steps of, dissolving (+)-(S)-clopidogrel base of Formula I in tetrahydrofuran at a temperature of 25° to 30°C; cooling to a temperature of 10° to 15° C; mixing concentrated sulphuric acid while maintaining the said temperature; and maintaining for a period of 6 to 8 hours to yield (+)-(S)-clopidogrel hydrogen sulphate Form II.
14. The process as claimed in claim 13, wherein the concentration of sulphuric acid is 80% and the molar ratio is 1.02 to 1.1 relative to (+)-(S)-clopidogrel base.
15. The process as claimed in claim 9, wherein Form II of (+)-(S)-clopidogrel hydrogen sulphate is prepared from isopropyl alcohol comprising the steps of, dissolving (+)-(S)-clopidogrel base of Formula I in isopropyl alcohol at a temperature of 28° to 30°C; mixing with concentrated sulphuric acid while maintaining the said temperature; and maintaining the mixture for a period of 6 to 8 hours at 28 ° to 30° C to yield (+)-(S)-clopidogrel hydrogen sulphate Form II.
16. The process as claimed in claim 15, wherein the concentration of sulphuric acid is preferably 95 to 98% and the molar ratio is 1.02 to 1.1 relative to (+)-(S)-clopidogrel base.
17. The process for preparing (+)-(S)-clopidogrel hydrogen sulphate polymorphs namely Form I and Form II as substantially described herein with reference to the foregoing examples 1 to 9.

17

Abstract:
An improved process for manufacturing hydrogen sulfate salt of (+)-(S)-alpha-2-(chlorphenyl)-6,7-dihydrothieno [3,2-C] pyridine-5 (4-H)-acetic acid methyl ester, commonly known as Clopidogrel hydrogen sulphate, in two crystalline forms viz: Form-I and Form-II is disclosed herein.
1 3 DEC 2004

AN IMPROVED PROCESS FOR MANUFACTURE OF CRYSTALLINE FORMS OF METHYL (+)-(S)-α-(2-CHLOROPHENYL)-4,5,6,7-TETRAHYDROTHIENO[3,2-C] PYRIDINE-5-ACETATE HYDROGEN SULPHATE SALT

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