WO2004052966A1 - A novel polymorph of clopidogrel hydrogen sulfate - Google Patents

Abstract

The invention provides a novel polymorph of clopidogrel hydrogen sulfate and processes for its preparation.

Description

A NOVEL POLYMORPH OF CLOPIDOGREL HYDROGEN SULFATE

FIELD OF THE INVENTION

The invention relates to a novel polymorph of methyl (+)- (S)- α-(2-chlorophenyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-5-acetate hydrogen sulfate also known as clopidogrel hydrogen sulfate, processes for its preparation and pharmaceutical composition containing it.

BACKGROUND

Clopidogrel hydrogen sulfate or methyl (+)- (S)- α-(2-chlorophenyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-5-acetate hydrogen sulfate is a platelet aggregation inhibitor which is described in Eur.Pat. No. 281459 (hereinafter referred to as "the '459 patent"). Various methods of synthesis of clopidogrel and its salts are disclosed in US 6,215,005, US 6,180,793, US 5,132,435, US 6,080,875 and WO 02/059128. Two forms of clopidogrel hydrogen chloride are so far known. U.S. Pat. No. 6,429,210 (hereinafter referred to as "the '210 patent") claims a polymorph of clopidogrel hydrogen sulfate, designated as Form II. '210 patent also indicated that the process described in '459 patent for the preparation of clopidogrel hydrogen sulfate leads to a polymorph which is called Form I. Form I and Form II have characteristic x-ray diffraction pattern, infrared absorption spectra. Significant reflections of x-ray powder diffraction pattern of Form I and Form II as represented by interplanar spacings are shown in Table I. Characteristic absorption bands of infrared spectra of Form I and Form II are shown in Table II .

According to the prior art, preparation of clopidogrel hydrogen sulfate Form I can be described as follows:

a) Methyl (+)- (S)- α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetate R-Camphor-10-suIfate (Clopidogrel camphor sulfonate ) in water is made alkaline with an aq. solution of sodium bicarbonate, aqueous layer is extracted with dichloromethane and the organic layer is dried to get a residue. b) The residue is dissolved in ice-cold acetone and then concentrated sulfuric acid is added. c) the precipitate obtained is filtered, washed and dried.

As described in patent '210, Form II of clopidogrel hydrogen sulfate is prepared by suspending methyl (+)- (S)- α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5- acetate R-camphor -10-sulfonate in dichloromethane, extracting camphorsulfonic acid into an aqueous potassium carbonate, concentrating the organic layer, dissolving the residue obtained in acetone, adding 96% sulfuric acid, seeding the resulting solution with clopidogrel hydrogen sulfate Form II to give Form II of clopidogrel hydrogen sulfate. A novel polymorph of clopidogrel hydrogen sulfate (hereinafter referred to as Form III) has been synthesized and characterized and it possesses distinct advantages over the previously known Forms. In accordance with the present invention, the new polymorph of clopidogrel hydrogen sulfate is found to be obtainable in highly pure form, that is free from Form I and Form II and contamination by solvates, is stable and does not convert automatically into other forms. So, Form III can be used in pharmaceutical formulation as a platelet aggregation inhibitor. Moreover, Preparation of Form III is very easy when compared with that of Form II.

The object of the present invention is to provide a substantially pure, stable and easily obtainable novel form of clopidogrel hydrogen sulfate (Form III), methods for preparing the novel form and pharmaceutical formulations containing the novel form.

SUMMARY OF THE INVENTION

The present invention relates to Form III clopidogrel hydrogen sulfate polymorph having a typical x-ray powder diffraction pattern of Fig. I. The significant reflections of Form III are shown in Table I wherein d represents the interplanar spacing and \I represents the relative intensities expressed as a percentage of most intense reflection.

The novel form is further characterized by its unique infrared (IR) spectrum of FIG. II. The characteristic absorption bands are shown in Table II.

This invention also relates to a method of preparing Form III of the clopidogrel hydrogen sulfate comprising the steps of:

a) suspending methyl (+)- (S)- α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridine-5-acetate R-Camphor-10-sulfate (Clopidogrel camphor sulfonate ) in an organic solvent b) extracting Camphor sulfonic acid with an aqueous solution of alkaline metal bicarbonate or alkaline metal carbonate c) concentrating organic phase and taking up the residue thus obtained in an alcohol or a mixer of alcohols d) adding sulfuric acid e) refluxing the contents for 1 to 1.5 hours f) Cooling to 25 to 35° C, optionally seeding with Form III clopidogrel hydrogen sulfate, stirring for 9 to 12 hours at this temperature, collecting the crystals formed and drying to give substantially pure Form III of clopidogrel hydrogen sulfate.

It has also been found that when clopidogrel camphorsulfonate containing less than 5% undesired related substances is used in the above process, Form III can be crystallized out of the reaction mixture in substantially pure form III, that is free from any other polymorph or solvates such as water or alcohols.

Another feature of the present invention is to provide an alternative process for preparing Form III clopidogrel hydrogen sulfate comprising the steps of:

a) dissolving Methyl (+)- (S)- α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-cJpyridine- 5-acetate R-Camphor-10-sulfate (Clopidogrel camphor sulfonate ) in an aqueous solution of alkaline metal bicarbonate or alkaline metal carbonate b) extracting Methyl (+)- (S)- α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 5-acetate into an organic solvent c) concentrating organic phase arid taking up the residue obtained in an alcohol or a mixer of alcohols d) adding sulfuric acid e) refluxing the contents for 1 to 1.5 hours f) cooling to 25 to 35° C, optionally seeding with Form III clopidogrel hydrogen sulfate, Stirring for 9 to 12 hours at this temperature, collecting the crystals formed and drying to give substantially pure Form III of clopidogrel hydrogen sulfate..

Still another feature of the present invention is to provide a process for preparing Form III clopidogrel hydrogen sulfate wherein Form I or Form II clopidogrel hydrogen sulfate is used as starting material instead of clopidogrel camphor sulfonate in the above processes.

Term "alcohol" includes any alcohol having 2-4 carbons. Preferred alcohols are ethanol and isopropyl alcohol. Alkaline metal includes sodium or potassium. Organic solvents include ethyl acetate, methylene dichloride and like.

As used herein, "substantially pure" refers to Form III associated with less than about 5% of any or both put together of Form I and Form II, preferably less than about 2% of any or both put together of Form I and Form II, and more preferably less than about 1% ^' of any or both put together of Form I and Form II. Further, "substantially pure" Form III contains less than about 1% related substances, wherein "related substances" refers to undesired chemical impurities or residual solvent or water.

Another object of the present invention is to provide pharmaceutical formulations comprising Form III Clopidogrel hydrogen sulfate as an active ingredient.

BREIF DESCRIPTION OF THE DRAWINGS

Embodiments of the invention are explained in greater detail by way of the accompanying figures: °

Fig. I : x-ray diffraction pattern obtained for Form III clopidogrel hydrogen sulfate

Fig. II : Infrared spectrum of Form III clopidogrel hydrogen sulfate.

DETAILED DISCRETION OF THE INVENTION

The present invention provides Form III clopidogrel hydrogen sulfate polymorph having a typical x-ray powder diffraction pattern of Fig. I The characteristic interplanar spacings of Form III are shown in Table I. Characteristic reflections shown in table I differentiate Form III from Form I and Form II.

This invention also relates to a method of preparing Form III of the clopidogrel hydrogen sulfate comprising the steps of:

a) suspending methyl (+)- (S)- α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridine-5-acetate R-Camphor-10-sulfate (Clopidogrel camphor sulfonate ) in an organic solvent b) extracting Camphor sulfonic acid with an aqueous solution of alkaline metal bicarbonate or alkaline metal carbonate c) concentrating organic phase and taking up the residue thus obtained in an alcohol or a mixer of alcohols d) adding sulfuric acid e) refluxing the contents for 1 to 1.5 hours f) Cooling to 25 to 35° C, optionally seeding with Form III clopidogrel hydrogen sulfate, stirring for 9 to 12 hours at this temperature, collecting the crystals formed and drying to give substantially pure Form III of clopidogrel hydrogen sulfate. It has also been found that when clopidogrel camphorsulfonate containing less than 5% undesired related substances is used in the above process, Form III can be crystallized out of the reaction mixture in substantially pure form III, that is free from any other polymorph or solvates such as water or alcohols.

Another feature of the present invention is to provide an alternative process for preparing Form III clopidogrel hydrogen sulfate comprising the steps of:

g) dissolving Methyl (+)- (S)- α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 5-acetate R-Camphor-10-sulfate (Clopidogrel camphor sulfonate ) in an aqueous solution of alkaline metal bicarbonate or alkaline metal carbonate h) extracting Methyl (+)- (S)- α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 5-acetate into an organic solvent i) concentrating organic phase and taking up the residue obtained in an alcohol or a mixer of alcohols j) adding sulfuric acid k) refluxing the contents for 1 to 1.5 hours

I) cooling to 25 to 35° C, optionally seeding with Form III clopidogrel hydrogen sulfate, Stirring for 9 to 12 hours at this temperature, collecting the crystals formed and drying to give substantially pure Form 111 of clopidogrel hydrogen sulfate..

It has also been found that when clopidogrel camphorsulfonate containing less than 5% undesired related substances is used in the above process, Form 111 can be crystallized out of the reaction mixture in substantially pure form III, that is free from any other polymorph or solvates such as water or alcohols. Terms used in this specification have the following meanings.

"Alcohol" includes any alcohol having 2-4 carbons. Preferred alcohols are ethanol and isopropyl alcohol. Alkaline metal includes sodium or potassium. Organic solvents include ethyl acetate, methylene dichloride and like.

"Substantially pure" refers to Form III associated with less than about 5% of any or both put together of Form I and Form II, preferably less than about 2% of any or both put together of Form I and Form II, and more preferably less than about 1% of any or both put together of Form I and Form II. Further, "substantially pure" Form III contains less than about 1% related substances, wherein "related substances" refers to undesired chemical impurities or residual solvent or water. Advantageously, the novel polymorph of the invention is free from solvents, for example, existing as an anhydrate.

The novel form is further characterized by its unique infrared (IR) spectrum of FIG. II. i The characteristic absorption bands are shown in Table II. Characteristic absorption bands shown in table II differentiate Form III from Form I and Form II.

Table I

Form III Form 1 Form II d (A⁰) l/l. d (A⁰) l/l. d (A⁰) l/l.

8.02 100.0 9.60 100.0 6.86 61.7

6.62 38.6 8.13 37.2 6.49 33.1

6.29 23.0 5.80 16.8 5.66 29.8

4.85 15.9 4.95 16.8 5.01 44.4

4.71 41.9 4.80 25.5 4.80 55.8

4.30 16.2 4.31 39.0 4.11 100.0

4.04 21.6 3.86 19.1 3.87 61.4

3.87 21.9 3.83 52.0 3.74 37.9

3.43 15.5 3.80 42.5 3.60 56.3

3.17 9.9 3.49 58.8

3.07 9.9

Table II

Form III Form I Form II

Wavelength Wavelength Wavelength

(cm^"1 ) (cm^'1 ) (cm^"1 )

1226 2987 2551

1450 1753 1753

1433 1222 1497

1753 1175 1189

764 841 1029

731

1192

Another object of the present invention is Pharmaceutical formulations comprising Form III Clopidogrel hydrogen sulfate as an active ingredient. Each unit dose contains 50 mg to 100 mg of active ingredient. Form III is formulated with one or more pharmaceutically acceptable carriers, excipients or diluents. Any conventional technique may be used for the preparation of pharmaceutical formulation according to the invention. Examples of suitable carriers include sugars, gum arabic, gelatin, syrup, talc, magnesium stearate, mineral oil and like. The active ingredient may be contained in a formulation that provides quick release, sustained release or delayed release after administration to the patient. Pharmaceutical compositions may be formulated for oral delivery. Formulations may be in the form of capsules, tablets or gels for oral delivery.

The following examples are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. Example 1

Methyl (+)- (S)- α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetate R- Camphor 10-sulfate (Clopidogrel camphor sulfonate ) (50 gm) is suspended in methylenedichloride(250 ml). Camphorsulfonic acid is extracted with Saturated aqueous solution of sodium bicarbonate(220 ml). Organic layer is isolated, washed with 5% aq. Sodium chloride solution and the solvent is distilled off under vacuum. The residue (Clopidogrel base) thus obtained is suspended in isopropyl alcohol (540 ml). 98% Sulfuric acid (4.5 ml) is added and heated the contents for 3 hours at 40 -45° C. The reaction mixture is then refluxed for one hour, Cooled to 30 - 35° C and then stirred for 10 hours. Separated crystals are filtered, washed with isopropyl alcohol and dried to obtain 18 gm of Form III clopidogrel hydrogen sulfate (purity(by HPLC) : 99.6%).

Example 2 Example 1 is repeated by seeding the contents during maintenance at 30 - 35° C with Form III clopidogrel hydrogen sulfate to give 19.8 gm of Form III clopidogrel hydrogen sulfate (purity(by HPLC) : 99.8%).

Example 3 Example 1 is repeated by using clopidogrel camphor sulfonate (50 gm, 3% related substances by HPCL) to give 15.2 gm of Form III clopidogrel hydrogen sulfate(purity(by HPLC) : 99.2%).

Example 4 Methyl (+)- (S)- α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetate R- Camphor-10-sulfate (Clopidogrel camphor sulfonate ) (20 gm) is dissolved in water and the pH of the solution is adjusted to 9 - 9.5 with saturated aqueous solution of sodium bicarbonate. The aqueous layer is extracted with ethyl acetate(100 ml). Organic layer is isolated, washed with 5% aq. Sodium chloride solution (60 ml) and the solvent is distilled off under vacuum. Residue thus obtained is taken up in isopropyl alcohol. 98% Sulfuric acid (1.8 ml) is added and heated the contents for 3 hours at 40 -45° C. The reaction mixture is then refluxed for one hour, cooled to 30 - 35° C and then stirred for 10 hours. Separated crystals are filtered, washed with isopropyl alcohol and dried to obtain 7.3 gm Form III clopidogrel hydrogen sulfate(purity(by HPLC) : 99.8%)..

Example 5 Example 4 is repeated by using Form I clopidogrel hydrogen sulfate instead of Clopidogrel camphor sulfonate to give Form III clopidogrel hydrogen sulfate Example 6

Form II Clopidogrel hydrogen sulfate (10 gm) is suspended in ethyl acetate(50 ml). The organic layer is washed with saturated aqueous potassium carbonate (40 ml). Organic layer is then washed with 5% aq. Sodium chloride solution and solvent is distilled off under vacuum. Residue thus obtained is suspended in isopropyl alcohol. 98% Sulfuric acid(1.2 ml) is added and heated the contents for 3 hours at 40 -45° C. The reaction mixture is then refluxed for one hour, Cooled to 30 - 35° C and then stirred for 10 hours. Separated crystals are filtered, washed with isopropyl alcohol and dried to obtain 3.6 gm Form III clopidogrel hydrogen sulfate(purity(by HPLC) : 99.8%).

Claims

We claim

1. A clopidogrel hydrogen sulfate polymorph (Form III) characterized by an x-ray powder diffraction pattern having characteristic interplanar spacings at about 8.02,

6.62, 6.29, 4.85, 4.71 , 4.30, 4.04, 3.87, 3.43, 3.17, 3.07 A⁰ 2. A clopidogrel hydrogen sulfate polymorph (Form III) characterized by an infrared absorption bands having character absorption bands at approximately 1226, 1450,

1433, 1753, 764, 731 and 1192 cm^"1 3. A clopidogrel hydrogen sulfate polymorph (Form III) as claimed in claim I which is substantially pure.

4. A clopidogrel hydrogen sulfate polymorph (Form III) as claimed in claim I which contains less than about 2% content of Form I as hereinbefore defined.

5. A clopidogrel hydrogen sulfate polymorph (Form III) as claimed in claim I which contains less than about 2% content of Form II as hereinbefore defined.

6. A clopidogrel hydrogen sulfate polymorph (Form III) characterized by an x-ray powder diffraction pattern of Fig. I

7. A method of preparing Form III of the clopidogrel hydrogen sulfate comprising the steps of:

a) suspending methyl (+)- (S)- α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridine-5-acetate R-Camphor-10- sulfonate (Clopidogrel camphor sulfonate ) in an organic solvent b) extracting Camphor sulfonic acid with an aqueous solution of alkaline metal bicarbonate or alkaline metal carbonate c) concentrating organic phase and taking up the residue thus obtained in an alcohol or a mixer of alcohols d) adding sulfuric acid e) refluxing the contents for 1 to 1.5 hours f) Cooling to 25 to 35° C, optionally seeding with Form III clopidogrel hydrogen sulfate, stirring for 9 to 12 hours at this temperature, collecting the crystals formed and drying to give substantially pure Form III of clopidogrel hydrogen sulfate wherein

"alcohol" is any alcohol having 2-4 carbons, preferred alcohols being ethanol and isopropyl alcohol, alkaline metal is sodium or potassium, organic solvents include ethyl acetate, methylene dichloride.

8. A method according to claim 7 wherein alcohol is isopropyl alcohol.

9. A method of preparing Form III of the clopidogrel hydrogen sulfate comprising the steps of:

a) suspending Form I or Form II Clopidogrel hydrogen sulfate in an organic solvent b) extracting Camphor sulfonic acid with an aqueous solution of alkaline metal bicarbonate or alkaline metal carbonate c) concentrating organic phase and taking up the residue thus obtained in an alcohol or a mixer of alcohols d) adding sulfuric acid e) refluxing the contents for 1 to 1.5 hours f) Cooling to 25 to 35° C, optionally seeding with Form III clopidogrel hydrogen sulfate, stirring for 9 to 12 hours at this temperature, collecting the crystals formed and drying to give substantially pure Form III of clopidogrel hydrogen sulfate. wherein "alcohol" is any alcohol having 2-4 carbons, preferred alcohols being ethanol and isopropyl alcohol, alkaline metal is sodium or potassium, organic solvents include ethyl acetate, methylene dichloride.

10. A method of preparing Form III clopidogrel hydrogen sulfate comprising the steps of:

a) dissolving Methyl (+)- (S)- α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 5-acetate R-Camphor-10-sulfate (Clopidogrel camphor sulfonate ) in an aqueous solution of alkaline metal bicarbonate or alkaline metal carbonate b) extracting Methyl (+)- (S)- α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 5-acetate into an organic solvent c) concentrating organic phase and taking up the residue obtained in an alcohol or a mixer of alcohols d) adding sulfuric acid e) refluxing the contents for 1 to 1.5 hours f) cooling to 25 to 35° C, optionally seeding with Form III clopidogrel hydrogen sulfate, Stirring for 9 to 12 hours at this temperature, collecting the crystals formed and drying to give substantially pure Form 111 of clopidogrel hydrogen sulfate. wherein

"alcohol" is any alcohol having 2-4 carbons, preferred alcohols being ethanol and isopropyl alcohol, alkaline metal is sodium or potassium, organic solvents include ethyl acetate, methylene dichloride.

11. A process according to claim 10 wherein alcohol is isopropyl alcohol.

12. A pharmaceutical formulation comprising Form III clopidogrel hydrogen sulfate as claimed by claim 1 associated with one or more pharmaceutically acceptable carriers, excipients, or diluents.