WO2006023676A1

WO2006023676A1 - Clopidogrel napsylate salt

Info

Publication number: WO2006023676A1
Application number: PCT/US2005/029449
Authority: WO
Inventors: Miroslav Veverka; Eva Veverkova; Alexandr Jegorov
Original assignee: Ivax Pharmaceuticals S.R.O.
Priority date: 2004-08-21
Filing date: 2005-08-17
Publication date: 2006-03-02
Also published as: GB0418580D0

Abstract

Crystalline and amorphous forms of clopidogrel napsylate are useful in the preparation of dosage forms of the antithrombotic agent, clopidogrel.

Description

CLOPIDOGREL NAPSYLATE SALT

INVENTORS: Miroslav VEVERKA, Eva VEVERKOVA, Alexandr JEGOROV (Attorney Docket No.: GAL0033-PCT)

FIELD OF THE INVENTION

[0001] The present invention relates to a novel salt of clopidogrel, to physical forms of the salt, to processes for preparing the salt, to pharmaceutical compositions comprising the salt, and to the use of the salt as a pharmaceutical, in particular as a blood platelet aggregation inhibitor.

TECHNICAL BACKGROUND

[0002] Clopidogrel is a well-known inhibitor of induced platelet aggregation and is used in the prophylaxis and treatment of atherosclerotic cardiovascular disorders, such as myocardial infarction and stroke. 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 formula I. It may be represented by the formula (I) below: -

The compound contains a basic nitrogen atom and may therefore form acid addition salts.

[0003] In the development of a dosage form for a compound capable of forming salts, it is well known in the art to look for different salt forms of the compound, and to seek a physical form of the salt that can readily be prepared and used in the large scale manufacture of a dosage form that achieves a safe and therapeutically effective response. [0004] Clopidogrel is presently available commercially in a dosage form containing clopidogrel hydrogensulfate in crystalline form.

[0005] Clopidogrel hydrogensulfate in crystalline form, and certain other acid addition salts, are disclosed in European patent application, publication number 281,459.

[0006] It has been recognised in the art that alternative, potentially better, dosage forms of clopidogrel may be found that contain a different physical form of clopidogrel hydrogensulfate or a physical form of a different salt. A substantial effort has been invested by several different groups in the search for new physical forms of clopidogrel salts, and this has led to the publication of several patent specifications. One such patent specification is WO 04/026879, which suggests using clopidogrel and its pharmaceutically acceptable salts in amorphous form. The specification provides a long list of "pharmaceutically acceptable salts" which are said to be commonly used in the pharmaceutical industry, but does not specifically disclose any salt of clopidogrel other than the hydrogensulfate in amorphous form.

[0007] It has now been found that clopidogrel forms a naphthalene-2-sulfonate

(napsylate) salt that may be obtained in crystalline and amorphous forms that have particularly advantageous properties.

SUMMARY OF THE INVENTION

[0008] The present invention provides clopidogrel napsylate salt.

[0009] In another aspect, the present invention provides clopidogrel napsylate salt in crystalline form.

[0010] In yet another aspect, the present invention provides clopidogrel napsylate salt in a crystalline form that affords an FTIR spectrum with characteristic absorption bands at about 1745, 1474, 1329, 1243, 1220, 1135 1089, and 1032 cm^'1.

[0011] In another aspect, the present invention provides clopidogrel napsylate salt in amorphous form. [0012] In yet another aspect, the present invention provides a pharmaceutical composition, which comprises clopidogrel napsylate salt as described hereinabove and a pharmaceutically acceptable carrier.

[0013] In another aspect, the present invention provides a process for the preparation of clopidogrel napsylate salt as described hereinabove, which comprises:

(a) reacting clopidogrel with naphthalene-2-sulfonic acid or

(b) reacting an acid addition salt of clopidogrel with a metal salt of naphthalene-2- sulfonic acid; and optionally

(c) washing the product of step (a) or (b) in a solvent.

[0014] In yet another aspect, the present invention provides a method of inhibiting platelet aggregation in a patient requiring treatment, which comprises administering to the patient an effective amount of clopidogrel napsylate salt as described hereinabove.

[0015] In a further aspect, the present invention provides clopidogrel napsylate salt as described hereinabove for use in therapy.

[0016] In another aspect, the present invention provides the use of clopidogrel napsylate salt as described hereinabove in the manufacture of a medicament for use as a platelet aggregation inhibitor.

BRIEF DESCRIPTION OF THE FIGURES

[0017] FIG. 1 is a powder X-ray diffraction (XRPD) pattern of clopidogrel napsylate in amorphous form.

[0018] FIG. 2 is a powder X-ray diffraction (XRPD) pattern of clopidogrel napsylate in crystalline form.

[0019] XRPD Equipment: powder diffractometer PHILIPS 1050, CuK α, radiation

(0,15419 nm). Exciting voltage: 40 kV, anode current: 35mA, measure range: 3°- 60°, step size: 0,01°. Sample: surface plain, in nickel sample holder, measured and stored at room temperature.

[0020] FIG. 3 is a FTIR spectrum of clopidogrel napsylate in amorphous form.

[0021] FIG. 4 is a FTIR spectrum of clopidogrel napsylate in crystalline form.

[0022] FTIR Equipment- Nicolet, Impact 410, KBr tablet.

[0023] FIG. 5 is a differential scanning calorimetric (DSC) thermogram of clopidogrel napsylate in crystalline and amorphous forms.

[0024] 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 Infusion. Samples of 3-4 mg were placed in standard aluminium pans and nitrogen was used as a purge gas. In the records, endothermal peaks are oriented upwards. The records were corrected for the baseline.

DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention provides clopidogrel napsylate salt.

[0026] It has been found that the salt can readily be prepared in crystalline and amorphous forms, each of which possesses particularly advantageous properties.

[0027] In another aspect, the present invention provides clopidogrel napsylate salt in crystalline form.

[0028] The crystalline clopidogrel napsylate salt that has been prepared has been found to afford the FTIR spectrum shown in Figure 4. The FTIR spectrum contains characteristic absorption bands at about 1745, 1474, 1329, 1243, 1220, 1135 1089, and 1032 cm^" . [0029] Accordingly, in another aspect, the present invention provides clopidogrel napsylate salt in a crystalline form that affords a FTIR spectrum with characteristic absorption bands at about 1745, 1474, 1329, 1243, 1220, 1135 1089, and 1032 cm^'1.

[0030] The crystalline clopidogrel napsylate salt that has been prepared has been found to afford the X-ray powder diffraction pattern shown in Figure 2.

[0031] A more detailed analysis of the diffraction pattern shown in Figure 2 is provided in Table 1 below.

[0032] Table 1. Position of diffraction lines and relative intensities.

d[A] Int(rel) d[A] Int(rel) d[A] Int(rel)

13.046 16 4.392 53 3.244 12

10.734 26 4.201 37 3.229 12

10.309 52 4.166 100 3.178 19

7.138 18 4.074 10 3.112 13

7.020 17 3.973 37 3.044 9

6.773 29 3.867 49 2.966 5

6.539 64 3.833 21 2.788 11

5.756 6 3.770 49 2.754 15

5.260 63 3.600 46 2.720 9

5.145 68 3.553 36 2.710 9

4.862 9 3.516 61 2.647 9

4.672 67 3.448 14 2.633 7

4.519 44 3.385 4 2.586 11

4.446 25 3.294 22

[0033] Clopidogrel napsylate salt in the crystalline form described hereinabove possesses particularly advantageous properties. In particular, it has advantageous storage stability (e.g. low hygroscopicity), solubility and dissolution properties. [0034] Advantageous storage properties were surprisingly observed when compared to clopidogrel hydrogensulphate, clopidogrel base, clopidogrel base on carrier and clopidogrel HCl. Advantageous properties were also observed in the commonly used stress tests using high temperature, oxidation, acid hydrolysis and alkaline hydrolysis and in accelerated stability tests at 4O⁰C and 75% RH when compared to clopidogrel hydrogensulphate, clopidogrel base, clopidogrel base on carrier and clopidogrel HCl .

[0035] In another aspect, the present invention provides clopidogrel napsylate salt in amorphous form.

[0036] Clopidogrel napsylate salt in amorphous form also possesses particularly advantageous properties.

[0037] The clopidogrel napsylate salt in amorphous form is preferably substantially free of crystalline material.

[0038] The amorphous clopidogrel napsylate salt that has been prepared has been found to afford the FTIR spectrum shown in Figure 3. The FTIR spectrum contains characteristic absorption bands at about 1749,1503,1436,1224, 1161, and 1090 cm^"1.

[0039] The amorphous clopidogrel napsylate salt that has been prepared has also been found to afford the X-ray powder diffraction pattern shown in Figure 1.

[0040] The amorphous form produces a differential scanning calorimetric (DSC) thermogram without maximum exotherm with Tg about 75 ⁰C. For the crystalline form of clopidogrel napsylate, onset about 123 ⁰C was observed.

[0041] The salt may be prepared by a process, which comprises:

(a) reacting clopidogrel with naphthalene-2-sulfonic acid;or

(b) reacting an acid addition salt of clopidogrel with a metal salt of naphthalene-2-sulfonic acid; and optionally

(c) washing the product of step (a) or (b) in a solvent. [0042] Process (a) is conveniently performed in the presence of a solvent, for example a (1-5C) alkanol, such as methanol, ethanol or isopropanol; a cyclic ether, such as dioxan or tetrahydrofuran; a nitrile, such as acetonitrile; a (3-6C) dialkyl ketone, such as acetone or methyl isobutyl ketone; an amide, such as dimethylformamide or dimethylacetamide; an ester, such as ethyl acetate; an aromatic hydrocarbon, such as toluene; water, or a mixture thereof. The clopidogrel is conveniently dissolved in a solvent, then the naphthalene-2-sulfonic acid is added. The temperature at which the process is performed is conveniently in the range of from 0 to 120 °C, such as from ambient temperature (about 25 °C) up to reflux. Preferably at least one molar equivalent of naphthalene-2-sulfonic acid is used, more preferably 1-1.25 molar equivalent of naphthalene-2-sulfonic acid is used.

[0043] In process (b), the acid addition salt of clopidogrel may be, for example, the hydrogensulfate, hydrochloride or camphorsulfonic acid salt. The metal salt of naphthalene- 2-sulfonic acid may be, for example, an alkali or alkaline earth metal salt of naphthalene-2- sulfonic acid, such as the sodium, potassium or calcium salt, preferably the metal is sodium. The process is conveniently performed in the presence of a solvent, for example a (1-5C) alkanol, such as methanol, ethanol or isopropanol; a cyclic ether, such as dioxan or tetrahydrofuran; a nitrile, such as acetonitrile; a (3-6C) dialkyl ketone, such as acetone or methyl isobutyl ketone; an amide, such as dimethylformamide or dimethylacetamide; an ester, such as ethyl acetate; an aromatic hydrocarbon, such as toluene; water, or a mixture thereof. The temperature at which the process is performed is conveniently in the range of from 0 to 120 °C, such as from ambient temperature (about 25 °C) up to reflux. Preferably at least one molar equivalent of the metal salt of naphthalene-2-sulfonic acid is used. The components of the reaction mixture may conveniently be heated under reflux for several hours, preferably the reflux time is 2 to 5 hours, then cooled and filtered. The solvent may then be removed to afford a solid. The solid may then be treated with a solvent in which clopidogrel napsylate is soluble, such as isopropanol, any residual inorganic salt removed by filtration, and the clopidogrel napsylate allowed to crystallize out.

[0044] Process (c) may be used if the molar equivalent of naphthalene-2-sulfonic acid is over 1.5. Washing is conveniently performed in the presence of a solvent, for example a (1- 5C) alkanol, such as methanol, ethanol or isopropanol; a cyclic ether, such as dioxan or tetrahydrofuran; a nitrile, such as acetonitrile; a (3-6C) dialkyl ketone, such as acetone or methyl isobutyl ketone; an amide, such as dimethylformamide or dimethylacetamide; an ester, such as ethyl acetate; an aromatic hydrocarbon, such as toluene; water, or a mixture thereof and the clopidogrel napsylate allowed to crystallise out as previously described.

[0045] Clopidogrel napsylate salt in crystalline or amorphous form may be obtained depending upon how the salt is formed in solution, and then recovered. For example, it may be prepared by removing solvent from the solution, by cooling the solution, or by adding an anti-solvent, for example a (2-6C) dialkyl ether, such as methyl t-butyl ether, a (1-4C) alkylacetate, such as ethyl acetate, cyclohexane or toluene.

[0046] It has been observed that form of solid phase is temperature dependent. If working at ambient temperature, e.g. 20-30⁰C, clopidogrel napsylate crystallised out. However, the formation of amorphous form of clopidogrel napsylate may be observed at elevated temperature. Further aspect of solid form formation relates to the solvent used. It has been observed that clopidogrel napsylate is crystallised or precipitated from a solution in a solvent dependent mode. For instance, the addition of naphthalene 2-sulphonic acid in water to clopidogrel base in isopropanol in the range of 60-100 ⁰C, more preferably 70-90 ⁰C, or more preferably at 80 ⁰C may produce the amorphous form of clopidogrel napsylate.

[0047] The present invention also provides a process for preparing clopidogrel napsylate in amorphous form, comprising the step of preparing a solution of clopidogrel napsylate in a polar, a dipolar or a less polar aprotic solvent, or a mixture thereof, admixing the solution with an antisolvent to precipitate clopidogrel napsylate and separating the clopidogrel napsylate.

[0048] In another aspect, the present invention provides a process for the preparation of clopidogrel napsylate in amorphous form, comprising the step of preparing a solution of clopidogrel napsylate 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 napsylate and separating the clopidogrel napsylate.

[0049] In another aspect, the present invention provides a process for the preparation of clopidogrel napsylate in amorphous form, comprising the step of preparing a solution of clopidogrel napsylate in acetone, a C₁-C₄ alcohol, such as methanol or ethanol, or tetrahydrofuran, and removing the solvent from the solution.

[0050] In another aspect, the present invention provides a process for the preparation of clopidogrel napsylate in crystalline form, comprising the step of preparing a solution of clopidogrel napsylate in acetone, a C₁-C₄ alcohol, such as methanol or ethanol, or tetrahydrofuran, and forming a crystalline form from a solution and separating the precipitate. A crystalline material is formed after cooling of the solution or to the solution the antisolvent is added. Also the crystalline form may be obtained crystallization of amorphous form by techniques well-known in the art.

[0051] The clopidogrel napsylate salt will generally be administered to patients in a pharmaceutical composition.

[0052] According to another aspect, therefore, the present invention provides a pharmaceutical composition, which comprises clopidogrel napsylate salt and pharmaceutically acceptable carrier.

[0053] In the compositions of this invention, any conventional pharmaceutically acceptable carriers can be utilised. For oral administration, the pharmaceutical composition may be any of the conventional oral unit dosage forms, for example tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional excipients. Therefore, oral administration of the compositions may take the form of tablets or capsules, lozenges, etc. formulated in the conventional manner. The preferred unit oral dosage form for use in this invention is a tablet. Any conventional method of preparing pharmaceutical oral unit dosage forms can be utilised in preparing the unit dosage forms of this invention. The pharmaceutical oral unit dosage forms, such as the tablets, contain one or more of the conventional additional formulation ingredients. These ingredients are selected from a wide variety of excipients known in the pharmaceutical formulation art. According to the desired properties of the oral dosage form, any number of ingredients may be selected alone or in combination for their known use in preparing such dosage forms as tablets. The term "tablet" as used herein is intended to encompass compressed pharmaceutical dosages formulations of all sizes and shapes whether coated or uncoated. Excipients are added to the composition for variety of purposes. Diluents (e.g. microcrystalline 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, and 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 sirups, suspensions. The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.

[0054] In one embodiment of the invention, the pharmaceutical composition further comprises asprin.

[0055] In yet another aspect, the present invention provides a method of inhibiting platelet aggregation in a patient requiring treatment, which comprises administering to the patient an effective amount of clopidogrel napsylate salt.

[0056] The patient may be a human or non-human mammal, for example a companion animal such as a dog, cat or horse.

[0057] The term "effective amount" as used herein refers to an amount that is effective to inhibit platelet aggregation in the patient.

[0058] Situations in which inhibition of platelet aggregation is desirable include the prophylaxis and treatment of atherosclerotic cardiovascular disorders, such as myocardial infarction, stroke, transient ischaemic attacks, peripheral arterial disease, bypass surgery, arthritis and angioplasty.

[0059] The invention further provides clopidogrel napsylate salt for use in therapy. [0060] In another aspect, the present invention provides the use of clopidogrel napsylate salt in the manufacture of a medicament for use as a platelet aggregation inhibitor.

EXAMPLES

[0061] The following Examples illustrate the invention.

Example 1

[0062] Clopidogrel base (1.05 g) was dissolved in isobutyl methyl ketone (20 ml) and naphthalene 2-sulphonic acid (0.83 g) was added. The reaction mixture was stirred at room temperature for 24 hours and then the solvent was evaporated to dryness under reduced pressure. Diethyl ether (12 ml) was then added and stirred at room temperature for 2 hours. The solid was collected by filtration, washed with diethyl ether (3x7 ml) and dried at 35 ⁰C in a vacuum oven for 12 hours to obtain 0.3 g of amorphous clopidogrel napsylate. The product was characterised by X-ray powder diffraction (XRPD).

Example 2

[0063] Clopidogrel base (1.8 g) was dissolved in toluene (10 ml) and naphthalene 2- sulphonic acid (0.7 g) was added. The reaction mixture was heated under reflux for 2 hours and then the solvent was evaporated to dryness under reduced pressure. Diethyl ether (12 ml) was then added and the mixture was stirred at room temperature for 2 hours. The solid was then collected by filtration, washed with diethyl ether (2x 5 ml) and dried at 35 ⁰C in a vacuum oven for 12 hours to obtain 0.5 g of amorphous clopidogrel napsylate. The product was characterised by XRPD.

Example 3

[0064] The product of Example 2 was dissolved in toluene (13 ml) at reflux and t- butyl methyl ether (2 ml) was added. The reaction mixture was stirred at room temperature for 2 hours and then poured with stirring onto toluene (25 ml) at a temperature of 105 ⁰C. The mixture was then cooled, the volume of the solution was reduced to 8 ml and the mixture was intensively 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 crystalline form of clopidogrel napsylate. The product was characterised by XRPD and differential scanning calorimetry (DSC). Example 4

[0065] Clopidogrel base (0.68g) was dissolved in ethanol (13 ml) and naphthalene 2- sulphonic acid (0.78 g) in water (3 ml) was added. The reaction mixture was vigorously stirred at reflux for 2 hours, then the solvent was evaporated to 1/3 volume. Tert-butyl methyl ether (15 ml) was then added and the mixture was stirred for 24 hours. The solid was collected by filtration, dried at 35 ⁰C in a vacuum oven for 12 hours to obtain 0.3 g of clopidogrel napsylate in crystalline form. The product was characterised by XRPD and Fourier transform infrared spectroscopy (FTIR).

Example 5

[0066] Clopidogrel hydrogensulfate, m.p. ~ 184 ⁰C (1.78 g) was dissolved in methanol (25 ml) at a temperature of 55 ⁰C and naphthalene 2-sulphonic acid sodium salt (1.15 g) was added. The reaction mixture was vigorously stirred at reflux for 12 hours, and then cooled in a refrigerator for 8 hrs. The reaction mixture was filtered, evaporated to dryness and crystallised from isopropanol. From the cloudy solution the inorganic salt was filtered off and the filtrate was allowed to cool to 0 ⁰C. The solid was collected, washed with diethyl ether and dried at 35 ⁰C in a vacuum oven for 12 hours to obtain 1.9 g of clopidogrel napsylate.

Example 6

[0067] Clopidogrel napsylate m.p. ~ 134 ⁰C (0.3 g) was dissolved in acetone (5 ml) at a temperature of 55-56 ⁰C. The reaction mixture was stirred at reflux temperature for 2 hours. The solvent was then evaporated to dryness under reduced pressure at temperature 40- 45 ⁰C. 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 clopidogrel napsylate. The product was characterised by FTIR.

Example 7

[0068] Clopidogrel base (0.93 g) was dissolved in tetrahydrofuran (10 ml) and naphthalene 2-sulphonic acid (0.72 g) in tetrahydrofuran (7 ml) was added. The reaction mixture was stirred at room temperature for 24 hours and then the solvent was evaporated to dryness under reduced pressure. Tert.-butyl methyl ether (12 ml) was then added and stirred at room temperature for 2 hours. The solid was collected by filtration, washed with diethyl ether (2 x 7 ml) and dried at 35 ⁰C in a vacuum oven for 12 hours to obtain 0.3 g of clopidogrel napsylate.

Claims

What we claim is:

1. Clopidogrel napsylate salt.

2. Clopidogrel napsylate salt in crystalline form.

3. Clopidogrel napsylate salt in crystalline form having a FTIR spectrum with characteristic absorption bands at about 1745, 1474, 1329, 1243, 1220, 1135 1089, and 1032 cm^"1.

4. Clopidogrel napsylate salt in amorphous form.

5. A process for the preparation of clopidogrel napsylate salt as defined in any one of Claims 1 to 4, which comprises:

(a) reacting clopidogrel with naphthalene-2-sulfonic acid or

(b) reacting an acid addition salt of clopidogrel with a metal salt of naphthalene-2- sulfonic acid.

6. A process according to claim 5 additionally comprising: (c) washing the product of step (a) or (b) in a solvent.

7. A pharmaceutical composition, which comprises clopidogrel napsylate salt as claimed in any one of Claims 1 to 4 and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition as claimed in Claim 7, which further comprises asprin.

9. A method of inhibiting platelet aggregation in a patient requiring treatment, which comprises administering to the patient an effective amount of clopidogrel napsylate salt.

10. A method of inhibiting platelet aggregation in a patient requiring treatment, which comprises administering to the patient an effective amount of clopidogrel napsylate salt in crystalline form.

11. A method of inhibiting platelet aggregation in a patient requiring treatment, which comprises administering to the patient an effective amount of clopidogrel napsylate salt in crystalline form in crystalline form having a FTIR spectrum with characteristic absorption bands at about 1745, 1474, 1329, 1243, 1220, 1135 1089, and 1032 cm^"1.

12. A method of inhibiting platelet aggregation in a patient requiring treatment, which comprises administering to the patient an effective amount of clopidogrel napsylate salt in amorphous form.

13. Clopidogrel napsylate salt as defined in any one of Claims 1 to 4 for use in therapy.

14. Use of clopidogrel napsylate salt as defined in any one of Claims 1 to 4 in the manufacture of a medicament for use as a platelet aggregation inhibitor.