FIELD OF THE INVENTION [0001] The present invention relates to a novel, amorphous form of clopidogrel hydrochloride, to processes for the preparation thereof, to a pharmaceutical composition comprising the novel amorphous form, and to use of the amorphous form as a blood platelet aggregation inhibitor and an antithrombotic agent.

TECHNICAL BACKGROUND

[0002] Clopidogrel (administered as its hydrogensulfate salt) is a well known inhibitor of induced platelet aggregation. It acts by inhibiting the binding of adenosine phosphate to its receptor. The chemical name of clopidogrel is methyl (+)-(S)-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5(4H)-acetate. It may be represented by the formula (I) below:-

[0003] Clopidogrel was described in the patent EP 0099802 and in Example 1 was purified without any details by means of its hydrochloride, m.p. 130-140 0C. The patent is completely silent about the crystal form of the product and IR or XRPD data.

[0004] Clopidogrel hydrogensulfate and other salts (e.g., hydrochloride, hydrobromide) were described in patent EP 281,459. According to Example Id, the hydrochloride of methyl (2- chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridene-5(4H)-acetate (dextro-rotatory) is prepared by dissolving of clopidogrel free base in diethyl ether and precipitating with solution of IN HCl in diethyl ether. The white crystal product is characterized by its m.p. 1170C and optical rotation of [α]D20= + 62.23 (c = 1.82g/100ml, methanol). Characterizing data for the crystal form are not disclosed.

[0005] In United States patent number 5,204,469, a process for the preparation of an N- phenylacetic acid derivative of tetrahydrothieno/3,2-c/pyridine and its chemical intermediate is disclosed. According to Example 7, dextrorotatory methyl (2-chlorophenyl)-6,7-dihydrothieno[3/2- c]pyridene-5(4H)-acetate hydrochloride is prepared by the dissolution of clopidogrel free base in diethyl ether and precipitation with HCl-saturated diethyl ether. The product melts at about 130-140 0C. + 63 (c = 1, methanol). Characterizing data for the crystal form are not disclosed.

[0006] In WO98/51681, Example 12, methyl (2-chloroρhenyl)-6,7-dihydrothieno[3,2- c]pyridene-5(4H)-acetate hydrochloride hydrate is prepared by dissolving methyl (2-chlorophenyl)-6,7- dihydrothieno[3,2-c]ρyridene-5(4H)-acetate in acetone, and adding a solution of cone, hydrochloric acid at 5-100C. The product slowly crystallizes, m.p. 138-1400C. The product was identified by elementary analysis, IR, spectrum, 1H-NMR investigation. (No data given) According to said patent specification, Example 21, the methyl (+)-(S)-(2-chlorophenyl)-6,7-dihydrothieno[3/2-c]pyridene-5( 4H)- acetate hydrochloride is prepared by dissolving of dextrarotatory methyl (2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridene-5(4H)-acetate intermediate in diethyl ether and introducing anhydrous gaseous hydrogen chloride into the solution. The crystal product is characterized by melting point of 130-132 0C and optical rotation of [cφ22= + 60°. Optical purity: 99% (HPLC investigation).

[0007] In international patent application, publication no. WO 00/27840, Example 11, methyl (+)-(S)-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridene-5( 4H)-acetate hydrochloride is prepared in a similar way. The crystal product is characterized by melting point of 130-1320C and optical rotation of [cφ22= + 60°. Optical purity: 99% (HPLC investigation).

[0008] There is no teaching of the crystal form of the aforementioned products; characterizing data of the form are not disclosed.

[0009] New crystalline forms I and II of methyl (+)-(S)-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridene-5(4H)-acetate hydrochloride and hydrates thereof and processes for their preparation are described in WO 03/066637. According to said patent specification, the process for the preparation of form I comprises dissolving of (+)-(S)-(2-chlorophenyl)-6,7-dihydrothieno[3,2- c]pyridene-5(4H)-acetate in solvent (s) and admixing with a solution of hydrogen chloride. As solvents in the examples are introduced: e.g. acetone, tetrahydrofuran, ethyl acetate, and to the reaction mixture gaseous or dissolved hydrogen chloride is added. The mixture is stirred for 2 hrs at room temperature and thereafter allowed to stand in a refrigerator for 16 hrs. Crystalline product is filtered off and characterized by melting point 140-141 0C. The melting point of the new form I is significantly different from that of the data disclosed in prior art.

[0010] The process for the preparation of form II comprises dissolving of (+)-(S)-(2- chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridene-5(4H)-acetate in solvent(s) and admixing with a solution of hydrogen chloride. The process according to the claims comprises using acetone, acetonitrile, ethyl acetate. In the example, mixture is stirred 16 hrs at room temperature. Crystalline product, form II is filtered off and characterized by melting point 143-1440C.

[0011] The melting point of the new form II is significantly different from that of the data disclosed in prior art.

[0012] In the patent specification for WO 03/066637, forms I and II are characterized by the X-ray powder diffraction pattern, but the patent specification does not suggest or disclose the existence of an amorphous form of clopidogrel hydrochloride.

[0013] International patent application, publication number WO 03/051362 discloses clopidogrel hydrogensulfate in amorphous form.

[0014] International patent application, publication number WO 04/026879 generically discloses clopidogrel and its pharmaceutically acceptable salts in amorphous form. Clopidogrel hydrogensulfate in amorphous form is exemplified.

[0015] It is well known that one of the most important physical properties of pharmaceuticals (amorphous versus crystalline) is their solubility. (Konno T., Chem. Pharm. Bull., 1990, 38, 2003). In some therapeutic indications, the bioavailability is one of the key parameters determining the form of the substance to be used in pharmaceutical formulation. There can be many advantages mediated by using the amorphous form of a drug. The most important are enhanced solubility and bioavailability. It has been found that the crystalline form is less readily soluble than the amorphous one, therefore processes have been developed for the production of amorphous forms.

SUMMARY OF THE INVENTION

[0016] The present invention provides clopidogrel hydrochloride in amorphous form. - A -

[0017] The present invention also provides a process for preparing clopidogrel hydrochloride in amorphous form, comprising the step of preparing a solution of clopidogrel hydrochloride in a polar, a dipolar or a less polar aprotic solvent, or a mixture thereof, admixing the solution with an antisolvent to precipitate clopidogrel hydrochloride and separating the clopidogrel hydrochloride.

[0018] In another aspect, the present invention provides a process for the preparation of clopidogrel hydrochloride in amorphous form, comprising the step of preparing a solution of clopidogrel hydrochloride in a polar, a dipolar or a less polar aprotic solvent, or a mixture thereof, removing the solvent from the solution to obtain a residue, admixing the residue with an antisolvent to precipitate clopidogrel hydrochloride and separating the clopidogrel hydrochloride.

[0019] In another aspect, the present invention provides a process for the preparation of clopidogrel hydrochloride in amorphous form, comprising the step of preparing a solution of clopidogrel hydrochloride in a polar, a dipolar or a less polar aprotic solvent, admixing the solution with an antisolvent, removing the polar, dipolar or less polar aprotic solvent from the solution to precipitate clopidogrel hydrochloride and separating the clopidogrel hydrochloride.

[0020] In another aspect, the present invention provides a process for the preparation of clopidogrel hydrochloride in amorphous form, comprising the step of preparing a solution of clopidogrel hydrochloride in acetone, a C1-C4 alcohol, such as methanol or ethanol, or tetrahydrofuran, and removing the solvent from the solution.

[0021] In another aspect, the present invention provides a process for the preparation of the amorphous form of clopidogrel hydrochloride in a protic, a polar, a dipolar or a less polar aprotic solvent selected from Ci to Cs alcohols, tetrahydrofuran, acetonitrile, Q to CO ketones, dimethylf ormamide, water and mixture thereof. Preferred anti-solvents are C2 to O ethers, Ci to Q acetates, cyclohexane, toluene.

[0022] In yet another aspect, the present invention provides a process for the preparation of clopidogrel hydrochloride in amorphous form, which comprises adding hydrogen chloride to a solution of clopidogrel in a solvent selected from a Q-Cs dialkyl ether, a Cs-Cs linear, branched or cyclic hydrocarbon and mixtures thereof, to precipitate clopidogrel hydrochloride; and separating the precipitated clopidogrel hydrochloride from the solvent.

BRIEF DESCRIPTION OF THE FIGURES

[0023] FIG. 1 is a powder X-ray diffraction (XRPD) pattern of the amorphous form of clopidogrel hydrochloride. Equipment: powder diffractometer PHILIPS 1050, CuK α, radiation (λ = 0,15419 ran). Exciting voltage: 4OkV, anode current: 35mA, measure range: 3°- 60°, step size: 0,01°. Sample: surface plain, in nickel sample holder, measured and stored at room temperature.

[0024] FIG. 2 is is a FTIR spectrum of the amorphous form of clopidogrel hydrochloride. Equipment- Nicolet, Impact 410, KBr tablet

[0025] FIG. 3 is is a differential scanning calorimetric (DSC) thermogram of the amorphous form of clopidogrel hydrochloride. Equipment: Differential scanning calorimeter Perkin-Elmer DSC-7. The temperature scale was calibrated using the standards In, Sn and Zn. The enthalpic scale was calibrated to the enthalpy of In fusion. Samples of 3-4 mg were placed in standard aluminum pans, nitrogen was used as a purge gas. In the records, endothermic peaks are oriented upwards. The records were corrected for the baseline. DSC profile is characterized by broad endothermic peak about 65-800C and sharp endothermic peak about 125 0C, due to the decomposition.

DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention provides a novel amorphous form of clopidogrel hydrochloride. The new form is characterized by powder X-ray diffraction pattern (Fig.l). The pattern is without intense focused reflections and is featureless except for a halo with a maximum about 12.3, 24.1 degrees two-theta.

[0027] In accordance with the invention, the amorphous form is highly pure. More preferably, it is essentially free of crystalline clopidogrel hydrochloride. Most preferably the amorphous clopidogrel hydrochloride is free of crystalline clopidogrel hydrochloride, within the detection limit of a powder X-ray diffractometer comparable to the instrumentation described. The purity of clopidogrel hydrochloride can be assessed by a comparison of the XRPD pattern of an unknown sample with those of mixtures of authentic pure amorphous and pure crystalline clopidogrel hydrochloride.

[0028] The amorphous form produces a differential scanning calorimetric (DSC) thermogram (Fig.3.) without maximum exotherm.

[0029] The novel amorphous form of clopidogrel hydrochloride exhibits a FTIR spectrum (Fig.2.) with characteristic absorption band at about 596, 723, 760, 840, 1038, 1178, 1220, 1290, 1321, 1436, 1479, 1751, 2454, 2952, 3410 cm-1.

[0030] . The present invention further provides a process for the preparing a novel amorphous form of clopidogrel hydrochloride comprising the steps of preparing a solution of clopidogrel hydrochloride in a polar, dipolar or a less polar aprotic solvent, removing the solvent from the solution to obtain a residue, admixing the residue with an antisolvent to precipitate clopidogrel hydrochloride, and separating the clopidogrel hydrochloride. The solution of clopidogrel hydrochloride in a polar, dipolar or less polar aprotic solvent may be heated to increased the solubility of the clopidogrel hydrochloride. The polar, dipolar or less polar aprotic solvent may be selected from Ci to Q alcohols, tetrahydrofuran, acetonitrile, C3 to Ce ketones, dimethylformamide, water and mixtures thereof. After dissolution, the solution may be cooled, preferably to room temperature. The aforementioned polar, dipolar or less polar aprotic solvent may optionally be removed from the solution to obtain a foam or oily residue. Preferably, the removal of the solvent is carried out in the processes of the present invention by evaporation. Preferably, the solvent/solvents are removed be evaporation under ambient or reduced pressure. The antisolvent in such a case is then added to the foam or the oily residue. Alternatively, a solution of clopidogrel hydrochloride in a polar, dipolar or less polar aprotic solvent may be slowly added to the antisolvent in order to precipitate clopidogrel hydrochloride. Preferred as antisolvents are C2 to O dialkyl ethers, Ci to C4 acetates, toluene. In another preferred embodiment, the ether is diethyl or methyl t.-butyl ether or toluene. A precipitate forms in the antisolvent. The precipitate should be separated from reaction mixture at early stage, preferably within a few hours. The precipitate may be collected by techniques well-known in the art e.g. filtration, centrifugation. The precipitate may be dried under ambient or reduced pressure

[0031] The present invention also provides a process for the preparation of clopidogrel hydrochloride comprising the steps of preparing a solution of clopidogrel hydrochloride in a polar, dipolar or less polar aprotic solvent, admixing the solution with an antisolvent, removing the polar, dipolar or less polar aprotic solvent from the solution to precipitate clopidogrel hydrochloride and separating the clopidogrel hydrochloride. In a preferred embodiment, the antisolvent is toluene or cyclohexane. Preferably, the antisolvent is heated to a temperature of about room temperature to reflux so that the clopidogrel hydrochloride becomes more soluble in the antisolvent, with temperatures at or near reflux being preferred. After addition of the mixture to the solvent, the resulting mixture is preferably cooled to about room temperature, though one skilled in the art may appreciate than other temperatures may be achieve the same result. To obtain the amorphous form, the polar, dipolar or less polar aprotic solvent and antisolvent are removed, preferably by evaporation, to leave amorphous form. The present invention provides a process for preparation the amorphous form of clopidogrel hydrochloride comprising the steps of preparing a solution of clopidogrel hydrochloride in a solvent selected from Ci to Q alcohols, tetrahydrofuran, acetonitrile, C3 to Ce ketones, dimethylformamide, water and mixtures thereof and removing solvent to obtain the amorphous form. The mixture of clopidogrel hydrochloride and solvent is heated to form a solution. In a preferred embodiment a mixture is heated to reflux for a few hours. After heating, the solution is preferably cooled to about room temperature. The solution may be stirred for a few hours. After stirring, the solvent is removed to obtain a powder, which is the amorphous form of clopidogrel hydrochloride. The solvent may be evaporated and temperature may be increased. One skilled in the art would appreciate that the conditions and yield may vary when starting with clopidogrel base rather than clopidogrel hydrochloride prepared in reaction mixture.

[0032] The present invention also provides a process for the preparation of clopidogrel hydrochloride in amorphous form, which comprises adding hydrogen chloride to a solution of clopidogrel in a solvent selected from a C4-C8 dialkyl ether, a Cs-Cs linear, branched or cyclic hydrocarbon and mixtures thereof, to precipitate clopidogrel hydrochloride; and separating the precipitated clopidogrel hydrochloride from the solvent. In this process, the Q-Cs linear, branched or cyclic hydrocarbon may be, for example, a Cs-Cs linear, branched or cyclic alkane. The dialkyl ether may be selected, for example, from diethyl ether, diisopropyl ether, and tert-butyl methyl ether and the C5-C8 linear, branched or cyclic hydrocarbon may be selected, for example, from n-hexane and cyclohexane. The hydrogen chloride is conveniently added to the solution of clopidogrel at a temperature in the range of from -15 to 25 BC. The mixture of the solvent and precipitate of clopidogrel hydrochloride is conveniently maintained at a temperature of from -15 to 25 aC for from 20 to 120 minutes prior to separating the clopidogrel hydrochloride from the solvent. The hydrogen chloride may be added to the solution as a gas or as a solution of hydrogen chloride in a solvent selected from a Q-Cs dialkyl ether, a Cs-Cs linear, branched or cyclic hydrocarbon and mixtures thereof. In one embodiment, from 0.9 to 1.5 molar equivalents of hydrogen chloride are added to the solution of clopidogrel. The separated clopidogrel hydrochloride may conveniently be dried in a vacuum at a temperature below 30 SC.

[0033] Pharmaceutical compositions of the present invention contain clopidogrel hydrochloride amorphous form, optionally in mixture with other form(s) and active ingredients. Excipients are added to the composition for variety of purposes. Diluents (e.g. macrocrystalline cellulose, talc, calcium carbonate, magnesium oxide) increased the bulk of solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for patient and care give to handle. Binders for solid pharmaceutical compositions include, e.g., dextrin, gelatin, povidone, maltodextrin. Disintegrants include, e.g., colloidal silicon dioxide, crospovidone, starch. Glidants also can be added to improve the flowability of a non-compacted solid composition and improve the accuracy of dosing. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and references works in the field the art. Dosage forms include solid dosage forms like tablets, powders, capsules as well as liquid syrups, suspensions. The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.

EXAMPLES

Example 1 [0034] Clopidogrel base (0.37 g) was dissolved in ethanol (3 ml) and ethanol (0.37 ml) containing hydrogen chloride are added. The reaction mixture was stirred at room temperature for 2 hours and the solvent was evaporated to dryness under reduced pressure. Then, diethyl ether (12 ml) was added and stirred at room temperature for 2 hours. The solid was collected by filtration, washed with diethyl ether and dried at 35 0C in a vacuum oven for 12 hours to obtain 0.3 g of amorphous form of clopidogrel hydrochloride.

Example 2 [0035] Clopidogrel base (0.98 g) was dissolved in tetrahydrofuran (8 ml) and cone, hydrochloric acid (0.37 ml) was added. The reaction mixture was stirred at room temperature for 2 hours and the solvent was evaporated to dryness under reduced pressure. Then, diethyl ether (12 ml) was added and stirred at room temperature for 2 hours. The solid was collected by filtration, washed with diethyl ether and dried at 35 0C in a vacuum oven for 12 hours to obtain 0.9 g of amorphous form of clopidogrel hydrochloride.

Example 3 [0036] Clopidogrel base (0.37 g) was dissolved in acetone (3 ml) and ethanol (0.37 ml) containing hydrogen chloride was added. The reaction mixture was stirred at room temperature for 2 hours and poured with stirring onto toluene (25 ml) at a temperature of 105 0C. The mixture was cooled, the volume was reduced to 20 ml and the mixture was stirred at room temperature 2 hours. The solid was collected by filtration, washed with diethyl ether and dried at 35 0C in a vacuum oven for 12 hours to obtain 0.3 g of amorphous form of clopidogrel hydrochloride.

Example 4 [0037] Clopidogrel base (0.32 g) was dissolved in ethyl acetate (3 ml) and ethyl acetate (0.3 ml) containing hydrogen chloride was added. The reaction mixture was stirred at room temperature for 2 hours and the solvent was evaporated to dryness under reduced pressure. Then, tetrahydrofuran (3 ml) and water (0.3 ml) were added and the mixture was stirred under reflux for 24 hours. The mixture was cooled to a temperature of 0 - 5 0C with stirring. The solid was collected by filtration, dried at 35 0C in a vacuum oven for 12 hours to obtain 0.3 g of amorphous form of clopidogrel hydrochloride.

Example 5 [0038] Clopidogrel hydrochloride m.p .~ 1340C (0.3g) was dissolved in acetone (3 ml) at a temperature of 55 0C. The reaction mixture was poured with stirring onto toluene (17 ml) at a temperature of 105 0C. The mixture was cooled to a temperature of 25-30 0C and filtered. The filtrate was evaporated to dryness. The solid was collected, washed with diethyl ether and dried at 35 0C in a vacuum oven for 12 hours to obtain 0.2 g of amorphous form of clopidogrel hydrochloride.

Example 6 [0039] Clopidogrel hydrochloride m.p .- 1340C (0.3g) was dissolved in acetone (3 ml) at a temperature of 55-560C. The reaction mixture was stirred at reflux temperature for 6 hours. The solvent was evaporated to dryness under reduced pressure at a temperature of 55-56 0C. The solid was collected, washed with diethyl ether and dried at 350C in a vacuum oven for 12 hours to obtain 0.2 g of amorphous form of clopidogrel hydrochloride.

Example 7 [0040] Clopidogrel base (0.76g) was dissolved in cyclohexane (20ml) at a temperature of 78 0C, then filtered and cooled down to 00C. Hydrogen chloride gas (0.08g) was then added. The reaction mixture was then stirred at room temperature for 1 hour. The solid which had formed was then collected by filtration, washed with diethyl ether and dried at 250C in a vacuum oven for 12 hours to afford 0.3g of amorphous clopidogrel hydrochloride as a glassy form. Q- (argentometry) - 11.8 %.

Example 8 [00411 Qopidogrel base (0.84g) was dissolved in tert. butyl methyl ether (20ml) and hydrogen chloride gas (0.14gl) was added at -50C. The reaction mixture was stirred at -50C. After 2 hours, the solvent was evaporated to dryness under reduced pressure. Then, tert. butyl methyl ether (12 ml) was added and stirred at room temperature 2 hours. The solid which had formed was collected by filtration, washed with tert. butyl methyl ether and dried at 35 0C in a vacuum oven for 12 hours to obtain 0.9g of amorphous clopidogrel hydrochloride.

Example 9 [0042] In 0.5-liter 3-necked flat bottom flask equipped with a thermometer, magnetic stirrer and two inlet tubes, clopidogrel base (10.6g) was dissolved in tert. butyl methyl ether (200 ml). A vigorous stream of hydrogen chloride gas (1.5g) was introduced to the reaction mixture with rapid stirring. The reaction mixture was stirred at a temperature of 00C for 0.4 hours. The solid which has formed was collected by filtration, washed with tert. butyl methyl ether and dried at 350C in a vacuum oven for 12 hours to obtain 9.3g of the amorphous form of clopidogrel hydrochloride. M.p. 92-950C, Q- (argentometry) 10.3%.

Example 10 [0043] Qopidogrel base (0.32g) was dissolved in n-hexane (20ml) at a temperature of 450C. The mixture was then cooled to -5°C and diethyl ether (25ml) containing hydrogen chloride (0.4g) was added. The reaction mixture was stirred at a temperature of -15 0C for 2 hours. The solid which formed was then collected by filtration and dried at 35 0C in a vacuum oven for 12 hours to obtain 0.3g of the amorphous form of clopidogrel hydrochloride.