MXPA06011131A

MXPA06011131A - Crystalline clopidogrel naphthalenesulfonate or hydrate thereof, method for preparing same and pharmaceutical composition containing same

Info

Publication number: MXPA06011131A
Application number: MXPA/A/2006/011131A
Authority: MX
Inventors: Sun Lee Gwan; Yun Sangmin; Sook Kim Eun; Seock Kim Hee; Suh Kweehyun; Sung Kwon Bo; Kyung Kim Cheol; Kyong Kim Han
Original assignee: Hanmi Pharm Co Ltd
Priority date: 2004-04-09
Filing date: 2006-09-28
Publication date: 2007-04-20

Abstract

A crystalline clopidogrel naphthalenesulfonate or a hydrate thereof, a method for preparing same, and a pharmaceutical composition containing same are provided.

Description

CRYSTALLINE CLOPIDOGREL OR HYDRATE NAPHTHALINSULPHONATE, METHOD FOR PREPARING THE SAME AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME FIELD OF THE INVENTION. The present invention relates to crystalline clopidogrel naphthatalensulfonate or hydrate thereof, a method for preparing the same, and a pharmaceutical composition containing the same. BACKGROUND OF THE INVENTION Clopidogrel ((+) - (S) -a- (o-chlorophenyl) -6,7-dihydrothieno [3,2- a] pyridin-5 (4H) -methyl acetate), the compound of Formula II is known as a medicament useful for the treatment and prevention of various vascular diseases associated with platelets such as stroke, cerebral arteriosclerosis, myocardial infarction, angina pectoris, arrhythmia, peripheral artery disease, and Burger's disease (see European Patent No. 281,459 Bl and U.S. Patent No. 4,847,265).

However, the clopidogrel itself as a free base form is an oil that is difficult to purify, and the ester group thereof is likely to hydrolyse to produce the acid of the formula (III) that has no biological activity. Also, under humid and heat conditions, it can be transformed into the levogyrator isomer of formula (IV) which has much less pharmacological activity. Accordingly, there has been a need to convert the clopidrogel to a crystalline form which is very stable and easily purifiable, and for the purpose, it is common to make an acid addition salt using the pharmaceutically acceptable inorganic or organic acid. 8ÜH (W) European Patent No. 281,459 Bl and the Patent of E.U.A. No. 4,847,265 disclose a number of acid addition salts of clopidogrel prepared using various inorganic or organic acids. However, it is described that most of these salts are amorphous, hygroscopic and / or low melt, which are unsuitable for use in pharmaceutical composition. Even the claimed crystalline salts such as hydrochloride, hydrobromide, hydrogen sulfate and taurocholate have some problems. The taurocholate is unsuitable for use as a pharmaceutically acidic addition salt of the clopidrogel because the taurocholic acid itself has another pharmacological activity, i.e., bile secretion. It was also confirmed by the inventors that the hydrochloride and hydrobromide salts are highly hygroscopic under a temperature condition of 60 ° C and 75% relative humidity, resulting in rubbery or liquefied form. In addition, it is known that clopidrogel hydrogen sulfate used in PLAVIX® (Sanofi-Synthelabo Inc.), a commercial tablet composition (see European Patent No. 281,459 Bl and Patent No. E. 6,429,210). it is also not stable enough (see H. Agrawal et al., Talanta, 61: 581-589, 2003). For example, it was reported PLAVIXR is unstable under an accelerated test condition (401C, 75% relative humidity, for 3 months), producing significant amounts of impurities (see Y.

Gómez et al-, J. Pharm. Biomed. Anal. 34: 341-348, 2004). In addition, clopidrogel hydrogen sulfate has two polymorphic forms that differ from each other in terms of physicochemical properties, and one of the two forms can be contaminated towards the other during its manufacture by varying from batch to batch. This makes it difficult to maintain a pharmacologically required homogeneous polymorphic state.

Consequently, there has been a need for better clopidrogel salt. The inventors unexpectedly found that crystalline clopidrogel naphthalenesulfonate is optically pure, less hygroscopic, and more stable towards moisture and heat than conventional acid addition salts. In this way, a pharmaceutical composition comprising the same is effective for the prevention or treatment of vascular diseases associated with platelet. SUMMARY OF THE INVENTION It is an object of the present invention to provide a crystalline clopidrogrel naphthalenesulfonate or a hydrate thereof, and a method to prepare it. Another object of the present invention is to provide a pharmaceutical composition containing the crystalline clopidrogrel naphthalenesulfonate or the hydrate thereof, for the prevention or treatment of vascular disease associated with platelet. BRIEF DESCRIPTION OF THE DRAWINGS The foregoing and other objects and features of the present invention will become apparent from the following description of the invention, when taken in conjunction with the accompanying drawings, which show respectively: Figure 1: a powder X-ray diffraction spectrum of the inventive clopidrogrel 2-naphthalenesulfonate; Figure 2: a differential scanning calorimeter of the inventive clopidrogrel 2-naphthalenesulfonate. Figure 3: a powder X-ray diffraction spectrum of the inventive clopidrogrel 1,5-naphthalenedisulfonate monohydrate; Figure 4: a differential scanning calorimeter of inventive clopidogrel 1,5-naphthalenedisulfonate monohydrate; Figure 5: the time-dependent changes (%) in the water content of the inventive acid addition salt of clopidogrel compared to clopidogrel hydrogen sulfate; Figure 6: the time-dependent changes (%) in the amount of clopidogrel of the acid addition salt of the invention compared to clopidogrel hydrogen sulfate; Figure 7: the time-dependent changes (%) in the amount of hydrolysed impurities of the inventive acid addition salt of clopidogrel compared to clopidogrel hydrogen sulfate; and Figure 8: the time-dependent changes (%) in the amount of levogyrate isomers of the inventive acid addition salt of clopidogrel compared to clopidrogrel hydrogen sulfate. DETAILED DESCRIPTION OF THE INVENTION In accordance with one aspect of the present invention, a crystalline clopidogrel naphthalenesulfonate of the formula (I) or a hydrate thereof is provided: (Wherein X is naphthalene monosulfonate when n is 1 or naphthalenedisulfonate wherein n is 2. In addition, there is provided a method for preparing a crystalline clopidogrel naphthalenesulfonate of the formula (I) or a hydrate thereof, comprising: reacting a Clopidogre free base of the formula (II) di) with a naphthalenesulfonic acid of the formula (V) or a hydrate thereof (H +) nXn- (V) in an organic solvent, wherein X is naphthalene monosulfonate when n is 1 or naphthalenedisulfonate when n is 2. According to another aspect of the present invention, there is provided a pharmaceutical composition containing the crystalline clopidogrel naphthalenesulfonate or the hydrate thereof, for the prevention or treatment of platelet-associated vascular disease. The crystalline clopidogrel naphthalenesulfonate of the formula (I) according to the present invention is a novel salt of clopidogrel, which is less hygroscopic, thermostable, and can be prepared in a much more optically pure form than any of the conventional salts. preferred embodiment of the present invention, the naphthalenesulfonate group (X) of the crystalline clopidogrel naphthalenesulfonate of the formula (I) or the hydrate thereof is derived from 2-naphthalenesulfonic acid, 3-naphthalenesulfonic acid, 1,2-naphthalenedisulfonic acid, 1,3-naphthalenedisulfonic, 1,4-naphthalenedisulfonic acid, acid 1,5-naphthalenedisulfonic acid, 1,6-naphthalenedisulfonic acid, 1,7-naphthalenedisulfonic acid, 1,8-naphthalenedisulfonic acid, 2,3-naphthalenedisulfonic acid, 2,6-naphthalenedisulfonic acid or 2,7-naphthalenedisulfonic acid; and clopidogrel 2-naphthalenesulfonate of the formula (Ia) (napsylate in accordance with INN), 1,5-naphthalenedisulfonate of the clopidogrel of the formula (Ib) (napadisylate in accordance with INN) being more preferred. (ib) In the present invention, the clopidogrel naphthalenesulfonate of the formula (I) forms a crystalline structure as an anhydrous or hydrous form thereof. For example, the clopidogrel naphthalenesulfonate of the formula (la) can be crystallized in the anhydrous form whose X-ray powder diffraction (XRD) scan shows larger crests having I / I0 values greater than 10% (100xI / I0 >) 10) to 2theta (20) of 6.7, 8.2, 8.5, 12.4, 13.0 13.5, 16.8, 17.2, 18.9, 19.6, 20.2, 21.2, 22.3, 22.9, 23. 2, 23.6, 24.7, 25.0, 25.3, 25.8, 27.0, 27.5, 28.0, 28.6, 32.1, 32.5, and 34.7 (Figure 1). The differential scanning calorimeter (DSC) curve of clopidogrel 2-naphthalenesulfonate at 10 ° C / min shows an absorption peak of approximately 55.3 J / g whose thermal absorption starts at around 146.7 ° C and is maximized around 150.9 ° C (Figure 2). The actually observed melting point of clopidogrel 2-naphthalenesulfonate is 150 to 151 ° C. The clopidogrel 1,5-naphthalenedisulfonate of the formula (Ib) is crystallized as a monohydrate whose XRD scan of powder shows larger ridges having I / I0 values greater than 10% (100xI / I0 >); 10) to 2Q of 7.6, 9.7, 10.7, 11.0, 12.1, 13.6, 14.2, 15.3, 16.6, 17.0, 18.1, 18.5, 19.8, 21.5, 22.2, 23.0, 23.5, 24.3, 24.8, 25.7, 26.4, 26.9, 27. 3, 28.4, and 29.0 (Figure 3). The DSC curve of said 1, 5-naphthalenedisulfonate of clopidogrel at 5 ° C / min shows an absorption peak at approximately 158.3 J / g whose heat absorption starts at around 219.3 ° C and maximizes around 226.4 ° C (Figure 4). The actually observed melting point of clopidogrel 1,5-naphthalenedisulfonate is 223 at 225 ° C. According to the present invention, the clopidogrel naphthalenesulfonate of the formula (I) can be prepared by reacting free base of clopidogrel with naphthalene mono-sulfonic acid, naphthalenedisulfonic acid or a hydrate thereof in an organic solvent. Specifically, the clopidogrel naphthalenesulfonate of the formula (I) is prepared by reacting the free base of clopidogrel of the formula (II) with naphthalenesulfonic acid of the formula (V) or a hydrate thereof in an organic solvent having no adverse effect on the the formation of salt, to obtain a crystalline product, followed by isolation of the crystalline product. The organic solvent that can be used in the present invention includes at least one solvent selected from the group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isoproyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acrylonitrile, methanol. , tetrahydrofuran, 1,4-dioxane and a mixture thereof; ethyl acetate, acetone and methanol being more preferred. In a preferred embodiment of the present invention, the organic solvent may contain up to 10% v / v. In the present invention, the organic solvent may be employed in an amount ranging from 1 to 20 per ml volume, preferably 3 to 10 per ml volume, based on the weight of the free base of clopidogrel Ig. In addition, the naphthalenesulfonic acid or a hydrate thereof can be employed in an amount ranging from 1.0 to 1.2 moles based on 1.0 mole of the free base of clopidogrel. In the present invention, the reaction can be carried out at a temperature ranging from -10 ° C to the boiling point of the solvent. However, the preferred reaction is carried out at a temperature ranging from 15 to 45 ° C for a period ranging from 1 to 24 hours after the addition of naphthalenesulfonic acid or a hydrate thereof to the mixture, followed by cooling and stirring the mixture at a temperature ranging from -10 to 10 ° C for a period ranging from 1 to 24 hours after the formation of precipitation. The precipitates formed in this way can be filtered under reduced pressure, and washed with an appropriate solvent. The precipitates are dried using an inert gas such as air and nitrogen under atmospheric pressure or under reduced pressure at a temperature ranging from 40 to 70 ° C. The free base of clopidogrel of the formula (II) used as a starting material in the present invention can be prepared according to the known method described in International Patent Publication No. WO. 02/59128. As naphthalenesulfonic acid is non-toxic (for example, LD5o of 2-naphthalenesulfonic acid is 4.440 mg / kg and the sodium salt thereof is 13,900 mg / kg, and that 1,5-naphthalenedisulfonic acid is 2.420 mg / kg, when administered orally to rat; see GISAAA, 39 (1), 101, 1974), can be used safely in the preparation of acid addition salts for a drug (see SM Berge et al., J. Pharm. Sci. 66: 1, 1977 ). The crystalline clopidogrel naphthalenesulfonate of the formula (I) prepared by the above method is non-hygroscopic, stable against moisture and heat, and optically pure. Thus, it may be useful for the prevention or treatment of vascular disease associated with platelet selected from the group consisting of stroke, cerebral arteriosclerosis, myocardial infarction, angina pectoris, arrhythmia, peripheral artery disease, and Burger's disease. In a preferred embodiment,. A pharmaceutical composition comprising the inventive clopidogrel naphthalenesulfonate as an active ingredient can be administered through the oral route and, in this way, the pharmaceutical composition of the present invention can be in the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. The pharmaceutical composition according to the present invention can be formulated together with pharmaceutically acceptable carriers, diluents or excipients, if necessary. Examples of suitable carriers, diluents, or excipients are excipients such as starch, sugar and mannitol; fillers or augmentation agents such as calcium phosphate and silica derivatives; binding agents such as carboxymethylcellulose or hydroxypropylcellulose cellulose derivatives, gelatin, arginic acid salt and polyvinylpyrrolidone; lubricating agents such as talc, magnesium or calcium stearate, hydrogenated castor oil and solid polyethylene glycol; disintegrants such as povidone, croscarmellose sodium and crospovidone; and surfactants such as polysorbate, cetyl alcohol and glycerol monostearate. In addition, various pharmaceutical compositions comprising a specific amount of active ingredient, together with or without additives such as said excipients, diluents or additives, can be prepared in accordance with any of the conventional procedures (see Remington's Pharmaceutical Science, Mack Publishing Company, Easton , PA, 19th Edition, 1995). In a preferred embodiment, the pharmaceutical composition according to the present invention may contain the clopidogrel naphthalenesulfonate or the hydrate thereof in an amount ranging from 0.1 to 95% by weight, preferably 1 to 70% by weight, based on the weight of the total composition. The clopidogrel naphthalenesulfonate of the formula '(I) according to the present invention can be administered orally to a subject in a dose ranging from 1 to 1000 mg / 60 kg of weight, preferably 25 to 250 mg / 60 kg of weight a day. The present invention will be described in more detail with reference to the Examples. However, it should be understood that the present invention is not restricted by the specific Examples. The HPLC analysis conditions employed in the Examples are listed below. Condition A: For the measurement of an acid addition salt assay of clopidogrel - Column: Kromasil C18, 5 μm (250 mm x 4.6 mm) - Detector: 220 nm - Flow rate: 1.5 ml / minute - Mobile phase : Na2HPO4-NaH2P04 of buffer solution: THF: CH3CN = 5: 2: 3 (v / v). Condition B: For the measurement of a quantity of hydrolysed impurities of an acid addition salt of clopidogrel - Column: Capcellpak C18MG, 5 um (250 mm x 4.6 mm) - Detector: 210 nm - Flow rate: 1.0 ml / min . - Mobile phase: buffer solution of KH2P04 / CH3CN (70/30): buffer solution of KH2P04 / CH3CH (30/70) = 0: 100 100: 0 (v / v, gradient elution) Condition C: For the measurement of an optical purity of an acid addition salt of clopidogrel - Column: Chiralpak AD, 5 um (250 mm x 4.6 mm) - Detector: 210 nm - Flow rate: 1.0 ml / min. - Mobile phase: n-hexane: isopropanol = 90:10 (v / v) Comparative Example 1: Preparation of clopidogrel hydrogen sulfate Clopidogrel hydrogen sulfate as a crystalline form 2 was prepared according to the method described in the patent from the USA No. 6,429,210 of clopidogrel free base having an optical purity of 99.3% ee that. it had been prepared by the method described in International Patent Publication No. WO 02/59128. p.f .: 176-177 ° C; water (Karl-Fisher titrator): less than 0.1%; assay (HPLC, condition A): 99.94%; and optical purity (HPLC, condition C): 99.3% ee. Example 1: Preparation of clopidogrel 2-naphthalenesulfonate (clopidogrel napsylate: formula (la)) 50 g of clopidogrel free base having an optical purity of 99.3% ee which was prepared by the method similar to that described in Patent Publication International No. WO 02/59128 were dissolved in 100 ml of ethyl acetate, and a solution containing 34.8 g of 2-naphthalenesulfonic acid monohydrate dissolved in a mixture of 150 ml of ethyl acetate and 5 ml of water was added to the same drops over a period of 30 minutes. Then, the mixture was stirred at room temperature for 12 hours, and then, at a temperature ranging from 0 to 5 for 4 hours. The formed precipitates were filtered, washed with 30 ml of ethyl acetate and dried at 50 ° C, to obtain 71.6 g of the title compound (yield: 87%) as a white crystal. p.f .: 151 ° C; water (Karl-Fisher titrator): less than 0.1%; assay (HPLC, condition A): 99.95%; optical purity (HPLC, condition C): 99.8% ee; and elementary analysis for C? 6H16ClN02S C? 0H8O3S (%): Calculated, C 89.91, H 4.56, N 2.64, S 12.10; Found, C 58.77, H 4.61, N 260, S 12.27. SH-NMR (300 Mhz, DMSO-d6, ppm); d 3.08 (brs, 2H), 350 (brs, 2H), 3.74 (s, 3H), 4.25 (brs, wH), 5.68 (s, 1H), 6.88 (d, 1H, J = 4.9 Hz), 7.44 (d, 1H, J = 4.9 Hz ), 7.53-7.60 (m, 4H), 7.62-7.77 (m, 3H), 7.80-7.98 (m, 3H), 8.15 (s, 1H), 10.85 (brs, 1H) IR (KBr, cm-1) : 3475, 2967, 1749, 1475, 1438, 1326, 1220, 1165, 1090, 1031 DSC. (10 ° C / minute): starting point: 146.67 ° C, lowest point 150.94 ° C (heat absorption 55.33 J / g). The result of powder X-ray diffraction analysis for the crystalline state of clopidogrel 2-naphthalenesulfonate showed that clopidogrel 2-naphthalenesulfonate was crystal having the characteristic diffraction pattern as shown in Figure 1. The main diffraction crests which have an I / lo value greater than 10%, are listed in Table 1. < Table 1 > 2T (± 2) d I / Io (%) 26 > (± 2) d I / Io (%) 6. 7 13.2 13.5 23.2 3.8 40.8 8. 2 10.8 38.1 23.6 3.8 99.8 8. 5 10.4 55.7 24.7 3.6 38.3 12. 4 7.2 17.6 25.0 3.6 32.7 13. 0 6.8 32.8 25.3 3.5 42.2 13. 5 6.6 65.2 25.8 3.5 24.3 16. 8 5.3 63.7 27.0 3.3 30.3 17. 2 5.2 60.2 27.5 3.2 15.1 18. 9 4.7 100.0 28.0 3.2 27.3 19. 6 4.5 66.0 28.6 3.1 11.4 . 2 4.4 75.7 32.1 2.8 14.9 21. 2 4.2 73.3 32.5 2.8 16.4 22. 3 4.0 25.1 34.7 2.6 14.4 22. 9 3.9 46.4 2 ?: diffraction angle, d: distance inside each crystal face, I / I0 (%): relative intensity of the peak. Example 2: Preparation of clopidogrel 1,5-naphthalenedisulfonate monohydrate (clopidogrel napadisilate, formula (Ib)) 50 g of clopidogrel free base having an optical purity of 99.3% ee prepared by the method similar to that described in International Patent Publication No. WO 02/59128 were dissolved in 300 ml of acetone, and a solution containing 28.9 g of 1,5-naphthalenedisulfonic acid tetrahydrate in a mixture of 290 ml of acetone and 10 ml of water was added to the same one drops during a period of 30 minutes. Then, the mixture was stirred at room temperature for 12 hours, and then, at a temperature ranging from 0 to 5 ° C for 4 hours. The precipitates formed in this manner were filtered, washed with 100 ml of cold acetone and dried at 50 ° C, to obtain 66.7 g of the title compound (yield: 90%) as a white crystal. p.f .: 223-225 ° C; water (Karl-Fisher detector): 1.95% (theoretical value of monohydrate: 1.90%, assay (HPLC, condition A): 99.96%, optical purity (HPLC, condition C): 99.8% ee, and elemental analysis for (C? 6H? 6ClN02S2 C10H8OsS2 H20 (%): Calculated: C 53.10, H 4.46, N 2.95, S 13.50, Found, 53.04, H 4.52, N 2.91, S 13.49, aH-NMR (300 Mhz, DMSO-d6, ppm): d 3.08 (brs, 2H), 3.47 (brs, 2H), 3.76 (s, 3H), 4.23 (brs, 2H), 5.66 (s, 1H), 6.89 (d, 1H, J = 5.0 Hz), 7.33- 7.74 (m, 6H), 7.93 (d, 1H, J = 7.0 Hz), 8.88 (d, 1H, J = 8.5Hz) IR. (KBr, cm'1): 3648, 3462, 2956, 1745, 1436, 1338, 1243, 1225, 1155, 1026 DSC (5 ° C / minute): starting point 219.3 ° C, lowest point 226. ° C (heat absorption 158.3 J / g) The result of light diffraction analysis X powder for the crystalline state, of the clopidogrel 1,5-naphthalenedisulfonate monohydrate showed that the clopidogrel 1,5-naphthalenedisulfonate monohydrate was crystal having the characteristic diffraction ridges as shown in F Figure 3. Diffraction ridges having I / I0 value greater than 10% are listed in Table 2. < Table 2 > 20 (± 2) d I / Io (%) 2T (+2) d I / Io (%) 7. 6 11.6 35.9 21.5 4.1 19.7 9. 7 9.1 17.2 22.2 4.0 72.0 . 7 8.3 30.4 23.0 3.9 37.9 11. 0 8.0 68.7 23.5 3.8 17.6 12. 1 7.3. 41.6 24.3 3.7 40.5 13. 6 6.5 14.3 24.8 3.6 45.8 14. 2 6.2 22.4 25.7 3.5 37.4 . 3 5.8 26.9 26.4 3.4 42.7 16. 6 5.3 32.0 26.9 3.3 12.5 17. 0 5.2 19.3 27.3 3.3 10.9 18. 1 4.9 100.0 28.4 3.1 24.9 18.5 4.8 22.0 29.0 3.1 13.2 19.8 4.5 76.7 20: diffraction angle, d: distance inside each glass face, I / I0 (%): peak relative intensity Example 3: Stability test of acid addition salts of clopidogrel under humid and heated condition. Clopidogrel hydrogen sulfate obtained in Comparative Example 1, and clopidogrel 2-naphthalenesulfonate and clopidogrel 1,5-naphthalenedisulfonate monohydrate obtained in Examples 1 and 2, respectively, were subjected to a condition of 60 + 2 ° C and 75 + 5% relative humidity over a period of more than 30 days to test their stabilities. Specifically, the ratios of the remaining amounts of the active compound on day 7, 14, 21, 28 and 35 relative to those of the initial day (0) were measured using HPLC. The acid addition salt assay of clopidogrel was measured using HPLC condition A, the amount of hydrolysed impurities of the acid addition salt of clopidogrel was measured using HPLC condition B, the optical purity of the acid addition salt of clopidogrel (ie, the amount of levogyrator isomers) was measured using the HPLC condition C, and the water content of the acid addition salt of clopidogrel was measured with a Karl-Fisher titrant. The results are shown in Tables 3 to 6 and Figures 5 to 8, respectively. <of.

; Table 3 > Comparison of hygroscopicity of an acid addition salt of clopidogrel Adding salt Water content (5) of acid of 0 day 7 days 14 days 21 days 28 days 35 clopidogrel days Hydrogen sulfate 0.1 0.1 0.1 0.4 2.0 4.8 2-Naphthalenesulphonate 0.1 0.1 0.1 0.1 0.1 0.1 1,5-naphthalene disulfonate monohydrate 1.8 1.8 1.9 1.9 1.8 1.9 < Table 4 > Comparison of quantity of an acid addition salt of clopidogrel Adding salt Relative amount compared to the amount of acid of initial clopidogrel 0 day 7 days 14 days 21 days 28 days 35 days Hydrogen sulfate 100 99.6 98.7 97.7 94.4 87.0 2-naphthalensul - fonate 100 99.1 99.3 99.1 99.0 99.0 1, 5-naphthalene disulfonate monohydrate 100 100 100 100 99.9 99.9 < Table 5 > Comparison of hydrolysed impurities (formula (III)) of an acid addition salt of clopidogrel Adding salt Amount of hydrolyzed acid impurities of an acid addition salt of clopidogrel clodiprogel (%) 0 days 14 days 28 days 35 days Hydrogen sulphate 0.0 0.63 2.0 4.8 2-naphthalensulphonate 0.0 0.12 0.16 0.18 1,5-naphthalene-disulfonate monohydrate 0.0 0.02 0. 04 0.05 < Table 6 > Comparison of levorotatory isomers (formula (IV)) of an acid addition salt of clopidogrel Adding salt number of levogyrating isomers of one acid addition acid salt of clopidogrel (%) clopidogrel 0 day 7 days 14 days 21 days 28 days 35 days Hydrogen sulphate 0.35 0.35 0.40 0.49 0.67 1.08 2-naphthalensulphonate 0.10 0.10 0.10 0.10 0.11 0.13 1, 5-naphthalene disulfonate monohydrate 0.10 0.10 0.10 0.09 0.11 0.10 As shown in Tables 3 to 6, the Inventive clopidogrel naphthalenesulfonate is less hygroscopic, and more stable against moisture and heat. Thus, there was no significant decline in the amount of optically pure clopidogrel after storage under a severe condition for a prolonged period, and the hydrolyzed impurities of clopidogrel naphthalenesulfonate were much less in amount than that observed for hydrogen sulfate. These results confirm that the pharmaceutical composition comprising the inventive clopidogrel naphthalenesulfonate according to the present invention is more effective than the conventional acid addition salts in the prevention or treatment for platelet-associated bascular disease. Example 4: Increasing optical purity effect during the formation of clopidogrel salt. Free bases of clopidogrel having optical purities of about 90% ee, 95% ee and 98% ee, respectively, were prepared and, clopidogrel hydrogen sulfates, and clopidogrel 2-naphthalenesulfonates and 1,5-naphthalenedisulfonate monohydrates of clopidogrel thereof were prepared using the procedures described in Comparative Example 1, and Examples 1 and 2, respectively. The optical purities of the acid addition salts obtained were then measured under HPLC condition C, and the degrees of improvement of optical purity are shown in Table 7. < Table 7 > Addition salt material obtained from split clopidogrel Sulphate-free base of 2-Naphthalenesul- monohydrate clopidrogrel 1,5-naphthalenedisulphonate hydrogen fonate 90.0 89.4 98.3 97.4 94.9 94.7 98.8 98.7 97.7 97.7 99.5 99.4 Unit:% ee (the amount of excess enantiomers) As shown in Table 7, the optical purity of clopidogrel naphthalenesulfonate according to the present invention was markedly improved during the process of preparing the same, while hydrogen sulfate of clopidogrel was not improved. Clopidogrel is subject to being partially racemized to its levogyrative isomer, and thus, a plurality of purification steps are required to achieve a pharmaceutically acceptable optical purity. However, the inventive method of preparing the naphthalenesulfonate provides a product that fills the pharmaceutical optical purity requirements, so that separate optical purification steps can be omitted. Test Example 1: Inhibitory effect of clopidogrel naphthalenesulfonate against platelet aggregation. The pharmacological activities to prevent the platelet aggregation of clopidogrel hydrogen sulfate obtained in Comparative Example 1, and the inventive clopidogrel 2-naphthalenesulfonate and the clopidogrel 1,5-naphthalenedisulfonate monohydrate obtained in Examples 1 and 2, respectively , were tested using rat blood in accordance with the conventional method (see Born G.VG.R & amp;; Cross, J. Physiol. 168: 178-195, 1963; O. Takahashi, Food & Chemical Toxicology 38: 203-218, 2000). The inhibition test of platelet aggregation was performed ex vivo, and the inhibitory activities of the acid addition salts of platelet counteraggregation acid induced by adenosine diphosphate (ADP), collagen and thrombin, respectively, were measured Twenty Sprague rats. Dawley females 11 to 12 weeks of age (average weight 270 + 25g) were divided into four groups each consisting of five rats, and each group of rats was administered orally with 20.0 mg / kg clopidogrel hydrogen sulfate (15.3 mg / kg as clopidogrel), 25.2 mg / kg of clopidogrel 2-naphthalenesulfonate, and 22.6 mg / kg of clopidogrel 1,5-naphthalenedisulfonate monohydrate dissolved in 1% DMSO based on a volume of 10 ml / kg body weight. For the group of control rats, only 1% DMSO solution was administered. Blood samples were taken using a syringe previously loaded with 3.8% citric acid solution from the abdominal artery of the animals under anesthesia, and the blood samples were subjected to centrifugation at 4 ° C and 1,000 rpm for 10 minutes to separate the samples. Rather platelet rich plasma (PRP). The separated plasma was further centrifuged four times at 4 ° C and 1,000 rpm to obtain PRP for testing. A portion of the PRP was subjected to further centrifugation at 4 ° C and 3,000 rpm for 10 minutes to prepare precipitated platelet, and the precipitated platelet was washed with a buffer (138 mM NaCl, 2.7 rnM KCl, 23 mM NaHCO3, 0.36 mM NaH2P05, 0.49 mM MgCl2, 0.25% gelatin, 5.5 nM glucose: pH 7.4) so that the optical density (OD) value at 260 nm corresponded to a platelet number that is about 1 x 108. To induce platelet aggregation, conventional ADP solution was added to the PRP above to determine the concentration until the final concentration of ADP became 5 uM. In addition, a conventional collagen solution (final concentration of 5 ug / ml) and conventional thrombin solution (final concentration 01. U / ml) was added to the previous wash plate solution to induce platelet aggregation. Each of the samples was shaken at 37 ° C and 900 rpm to measure the amount of platelet aggregation using an aggregate meter (Crono-Log Platelet Aggregometer). The degrees of platelet aggregation and inhibition were calculated using formulas 1 and 2, and the results are shown in Table 8. < Formula 1 > Degree of aggregation (%) = [(measured aggregation height) / (aggregation height when 100% was added)] x 100 < Formula 2 > Degree of inhibition (%) = [(control group aggregation height) - (aggregation height of drug administration group)] / (control group aggregation height) x 100. < Table 8 > The inhibitory effect of acid addition salts of clopidogrel Drug Admi- Material that induces the aggregation and nistrada concentration ADP (5uM) Collagen (5ug / ml) Thrombin (Dl U / MI: Reía- Reía- Relation Relation Relation Ratio of Agre - Inhi- of Aggregation of de gación bición gación Inhibi- Agre- Inhi- (%) * (%) (%) * tion gación bición (%) (%) Control 35.88+ - 80.31 + 82. 78+ 2.43 2.80 11 Sulfate 5.00+ 86.1 12.19 + 84.8 27 .22+ 67.1 Hydrogen 0.60 1.70 1.52 2-naphthalene 2.94+ • 91.8 1.88+ 97.9 15.00 + 81.9 sulfonate 0.21 0.25 1. 71 Monohydrate- 4.12+ 88.5 3.75+ 95.3 23. 61 + 71.5 to 1.5- 0.14 0.40! • 43 naphthalenesulfonate * p <0.001 ** amounts of 2-naphthalenesulfonate and 1,5-naphthalenedisulfonate monohydrate corresponding to the quantity of 20 mg of hydrogen sulfate are 25.2 mg and 22.6 mg, respectively, corresponding to 15.3 mg of clopidogrel Test Example 2: Effect of clopidogrel naphthalenesulfonate on tie mp of bleeding The effects on the bleeding time of conventional clopidogrel hydrogen sulfate obtained in Comparative Example 1 and the inventive clopidogrel 2-naphthalenesulfonate and clopidogrel 1,5-naphthalenedisulfonate monohydrate obtained in Examples 1 and 2, respectively , were tested using rat in accordance with the conventional method (see Dejana E & amp; amp;; Villa S, Thromb, Haemostas, 4-8: 108-111, 1982). The bleeding time is an index that represents the extension of thrombi formed by platelet aggregation and tests were performed using male and female rats. Forty male and female Sprague-Dawley rats from 11 to 12 weeks of age (average weight: 270 + 25g) were divided into four groups, each consisting of five male rats and five female rats, and the male rats of the first group were administered each orally with 5.0 mg / kg of clopidogrel hydrogen sulfate (3.83 mg / kg as clopidogrel) and the female rats of the first group were each administered orally with 2.5 mg / kg (1.92 mg / kg as clopidogrel). For the second group, the male and female rats were each administered orally with 6.30 mg / kg and 3.15 mg / kg of 2-naphthalenesulfonate of clppidogrel, respectively, and for the third group, the male and female rats were each administered orally. with 5.65 mg / kg and 2.83 mg / kg of clopidogrel 1,5-naphthalenedisulfonate monohydrate, respectively. The drug was administered orally in the form of a 1% DMSO solution in a volume amount of 10 ml / kg body weight. As a comparison, only 1% DMSO solution was administered to the last group of rats. After fixing a non-anesthetized rat with an experimental fastener, the tail of the rat was drilled in a 1.5 cm position from the end of the tail using a 26Gxl / 2, 0.45x13 mm needle at a depth of 1 mm. The time the bleeding stopped was measured by absorbing the blood by bleeding on a filter paper every 10 seconds. The result is shown in Table 9. < Table 9 > Effect on bleeding time of an acid addition salt of clopidogrel Drug admi- Male Female Nistracted Amount of Time Amount of Time of drug admi- ngred drug administered nistrated (sec) * nistrada (sec.) * (Mg / kg) (kg / kg) Comparison 85 + 7.1 - 105 + 5.0 Sulphate of 2.50 ** 127.5+ 5.00 *** 135 + 8.7 hydrogen 10.6 2-Naphthalen- 3.15 ** 157 + 10.6 6.30 *** 190 + 5.0 Sulphonate Monohydrate 2.83 ** 152.5 + 3.5 5.65 *** 163 + 5.8 of 1,5-naphthalenedisulfonate * p < 0.001 ** 2.50 mg of hydrogen sulfate, 3.15 mg of 2-naphthalenesulfonate and 2.83 mg of 1,5-naphthalenedisulfonate monohydrate correspond to 1.92 mg of clopidogrel *** 5.00 mg of hydrogen sulfate, 6.30 mg of 2-naphthalenesulfonate and 5.65 mg of 1,5-naphthalenedisulfonate monohydrate correspond to 3.83 mg of clopidogrel. As can be seen from Tables 8 and 9, the inventive clopidogrel naphthalenesulfonate inhibits platelet aggregation induced by ADP, collagen or thrombin, and significantly prolongs the bleeding time compared to conventional acid addition salts, v.gr ., hydrogen sulfate. Therefore, clopidogrel naphthalenesulfonate according to the present invention is more effective than any of the conventional acid addition salts in the prevention or treatment of vascular diseases associated with platelet. The clopidogrel naphthalenesulfonate of the present invention can be formulated alone or in a combination with pharmaceutically acceptable additives, in accordance with any of the conventional methods used to prepare soft or hard capsules or tablets. The following Preparation Examples are intended to further illustrate the present invention without limiting its scope. Preparation Example 1: Soft or hard capsule 1 A gelatin capsule was prepared using the following ingredients: Amount (mg / capsule) Clopidogrel-2 naphthalenesulfonate 120 Lactose 100 Corn starch 25 Silicon dioxide colloidal 3 Magnesium stearate 2 Total Preparation Example 2: Soft or hard capsule 2 A gelatin capsule was prepared using the following ingredients: Amount (mg / capsule) Clopidogrel 1,5-naphthalenedisulfonate monohydrate 110 Lactose 110 Corn starch 25 Silicon dioxide colloid 3 Magnesium Stearate 2 Total 250 Preparation Example 3: Tablet 1 A tablet was prepared using the following ingredients: Amount (mg / tablet) Clopidogrel 2-naphthalenesulfonate 120 Anhydrous lactose 90 Microcrystalline cellulose 30 Hydroxypropylcellulose 5 Polysorbate 2 'Hydrogenated castor oil 1 Magnesium stearate 1 Solid polyethylene glycol 1 Total 250 Preparation example 4: Tablet 2 A tablet was prepared using the following ingredients: Amount (mg / tablet) Clopidogrel 1,5-naphthalenedisulfonate monohydrate 110 Lactose anhydrous 100 Microcrystalline cellulose 30 Hydroxypropylcellulose 5 Polysorbate 2 Hydrogenated castor oil 1 Magnesium stearate 1 Solid polyethylene glycol 1 Total 250 As discussed above, the clopidogrel naphthalenesulfonate in accordance with present invention easily fills the optical purity required by the pharmaceutical formulation by simply carrying out the inventive process. Clopidogrel naphthalenesulfonate is very stable against moisture and heat, so that a high purity of active ingredient can be maintained for a long time. In addition, clopidogrel naphthalenesulfonate is better than conventional salts in terms of pharmaceutical effects in animal experiments using rats. Accordingly, clopidogrel naphthalenesulfonate according to the present invention is more useful than any of the conventional acid addition salts in the prevention or treatment for platelet-associated vascular disease. While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes can be made to the invention by those skilled in the art that also fall within the scope of the invention as defined by the claims. annexes.

Claims

CLAIMS 1.- A crystalline clopidogrel naphthalenesulfonate of the formula (I) or a hydrate thereof: 0) wherein X is naphthalene monosulfonate when n is 1 or naphthalenedisulfonate when n is 2. 2. The crystalline clopidogrel naphthalenesulfonate or the hydrate thereof according to claim 1, which is represented by the formula (Ia): 3. A crystalline clopidogrel naphthalenesulfonate of the formula (la), whose powder X-ray diffraction scan shows larger ridges having I / I0 values greater than 10% at 20 = 6.7, 8.2, 8.5, 12.4, 13.0, 13.5, 16.8, 17.2, 18.9, 19.6, 20.2, 21.2, 22.3, 22.9, 23.2, 23.6, 24.7, 25.0, 25.3, 25.8, 27.0, 27.5, 28.0, 28.6, 32.1, 32.5, 34.7. 4. - The crystalline clopidogrel naphthalenesulfonate or the hydrate thereof according to claim 1, which is represented by the formula (Ib). 5. - A monohydrate of a crystalline clopidogrel naphthalenesulfonate of the formula (Ib) whose powder X-ray diffraction scan shows larger ridges having I / lo values greater than 10% at 20 = 7.6, 9.7, 10.7, 11.0, 123.1, 13.6, 14.2, 15.3, 16.6, 17.0, 18.1, 18.5, 19.8, 21.5, 22.2, 23.0, 23.5, 24.3, 24.8, 25.7, 26.4, 26.9, 27.3, 28.4, 29.0. (Ib) 6. - A method for preparing a crystalline clopidogrel naphthalenesulfonate of the formula (I) or a hydrate thereof, comprising: (1) reacting a clopidogrel-free base of the formula (II) with a naphthalenesulfonic acid of the formula (V) or a hydrate thereof (H +) mXn- (V) in an organic solvent, wherein X is naphthalene monosulfonate when n is 1 or naphthalenedisulfonate when n is 2. 1. - The method of according to claim 6, wherein the organic solvent is selected from the group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, methanol, tetrahydrofuran, and the like. , 4-dioxane and a mixture thereof. 8. - The method according to claim 6, wherein the naphthalenesulfonic acid or the hydrate thereof is used in an amount that varies from

1. 0 to 1.2 moles based on 1.0 mole of the free base of clopidrogel. 9. A pharmaceutical composition for the prevention or treatment of a platelet-associated vascular disease, comprising the crystalline clopidogrel naphthalenesulfonate or the hydrate thereof according to claim 1 as an active ingredient in the absence of or in the presence of a carrier, pharmaceutically acceptable diluent or excipient. 10. The pharmaceutical composition according to claim 9, which is administered orally. 11. The pharmaceutical composition according to claim 9, wherein the crystalline clopidogrel naphthalenesulfonate or the hydrate thereof is present in the amount ranging from 0.1 to 95% by weight based on the total weight of the composition. 1

2. The pharmaceutical composition according to claim 9, wherein the crystalline clopidogrel naphthalenesulfonate or the hydrate thereof is present in the amount ranging from 1 to 70% by weight based on the total weight of the composition. 1

3. The pharmaceutical composition according to claim 9, wherein the vascular disease associated with plaque is attack, cerebral arteriosclerosis, myocardial infarction, angina pectoris, arrhythmia, peripheral artery disease, or Burger's disease.