WO2008032995A1 - Clopidogrel(+)-camphorsulfonate salt, method of preparing the same and a pharmaceutical composition comprising the same - Google Patents
Clopidogrel(+)-camphorsulfonate salt, method of preparing the same and a pharmaceutical composition comprising the same Download PDFInfo
- Publication number
- WO2008032995A1 WO2008032995A1 PCT/KR2007/004441 KR2007004441W WO2008032995A1 WO 2008032995 A1 WO2008032995 A1 WO 2008032995A1 KR 2007004441 W KR2007004441 W KR 2007004441W WO 2008032995 A1 WO2008032995 A1 WO 2008032995A1
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- WO
- WIPO (PCT)
- Prior art keywords
- clopidogrel
- weight
- pharmaceutical composition
- composition
- camphorsulfonate salt
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention relates to a crystalline clopidogrel (+)-camphorsulfonate salt, a method of preparing the same, and a composition containing the same as effective ingredient for treating and preventing platelet related vascular disorder.
- Clopidogrel is known as effective drug for treating and preventing platelet related vascular disorder.
- the structural formula of clopidogrel is as shown in the following formula 2, and the chemical name is ( + )-(S)- ⁇ -(o-chlorophenyl)-6,7-dehydrothieno[3,2-a]pyridyl- 5(4H)-acetate.
- Clopidogrel is disclosed in EP 281,459 Bl and USP 4,847,265.
- a clopidogrel free base is oil having high viscosity, and so is difficult to purify. Also, it is unstable, and so is difficult to keep pharmaceutical purity and make a formulation. Thus, clopidogrel is needed to be converted to a crystalline state that is stable and can easily be purified for preparing a pharmaceutical composition for the treatment and prevention of the disorder.
- a general method to do so is using pharmaceutically acceptable inorganic acid or organic acid to make acid addition salts.
- EP 281,459 Bl and USP 4,847,265 disclose various clopodogrel acid addition salts using many inorganic acids and organic acids, but the salts are non-crystalline, highly hygroscopic, and difficult to purify.
- clopidogrel hydrogen sulfate salt sulfuric acid addition salt
- Plavix tablet is very crystalline and hygroscopic, compared with the above mentioned salts.
- sulfuric acid used to prepare the clopidogrel hydrogen sulfate is strong acid, sulfuric acid may react to the prepared product to decompose it, and the decomposed product affects the stability of the drug (H. Agrawal et al, Talanta, 61: 581-589, 2003).
- Plavix increased hydrolysate by about 8 times, levo-rotatory isomer by about 1.5 times, and total impurity by about 3 times, under generally accelerated stability test condition (40 ° C , 75 % relative humidity, and 3 months), compared with initial Plavix (Y. Gomez et al, J. Pharm. Biomed. Anal.34: 341-348, 2004). And, clopidogrel hydrogen sulfate having excipients containing metal may be unstable.
- clopidogrel salts should be easily purified, heat stable, not be converted to hydrolysate of formula 4, maintain clopidogrel form hydrolyzed by moisture, and be highly soluble in water.
- the present inventors have studied to solve the problem of clopidogrel acid addition salts, and discovered that crystalline clopidogrel (+), (-)-camphorsulfonate salts are optically pure, heat stable and non-hygroscopic. Also, the inventors found out that clopidogrel (+) camphorsulfonate salt has excellent water solubility, compared with clopidogrel (-) camphorsulfonate salt, and that clopidogrel (+) camphorsulfonate salt provides high purity in the preparation process.
- a pharmaceutical composition containing clopidogrel (+) camphorsulfonate salt is more effective for preventing and treating platelet related vascular disorder than a composition containing clopidogrel acid addition salts.
- the object of the present invention is to provide a crystalline clopidogrel (+)- camphorsulfonate salt which is optically pure, non-hygroscopic, and stable to moisture and heat, and has high optical purity and improved effect; a method of preparing the same; and a composition containing the same as effective ingredient for treating and preventing platelet related vascular disorder.
- the present invention provides a crystalline clopidogrel (+)-camphorsulfonate salt having the following formula 1 :
- the present invention provides a crystalline clopidogrel (+) -camphorsulfonate salt having X-ray powder diffraction pattern peak at 2 ⁇ (I/Io> 10%)angles of 8.2, 9.5, 11.1, 11.4, 11.9, 12.9, 13.2, 14.0, 14.9, 15.2, 17.0, 18.2, 18.7, 19.7, 2 0.3, 21.3, 22.3, 22.6, 23.3, 23.4, 23.9, 25.0, 25.9, 26.1, 27.1, 28.2, 29.0, 29.2, 30.6, 30.8, 31.2, and 38.3.
- the present invention provides a method of preparing the crystalline clopidogrel (+)-camphorsulfonate salt of formula 1 , comprising a step of reacting clopidogrel free base of formula 2 with (+)-camphorsulfonic acid of the following formula 3 in organic solvent;
- the organic solvent in the present invention is selected from the group consisting of methylacetate, ethylacetate, n-propylacetate, isopropylacetate, acetone, methylethylketon, methylisobutylketone, acetonitrile, tetrahydrofurane, 1,4-dioxane, and mixtures thereof.
- the organic solvent is selected from the group consisting of ethylacetate, acetone, and mixtures thereof.
- the mole ratio of (+)-camphorsulfonic acid to the clopidogrel free base may be 0.5- 2, preferably 0.9- 1.1.
- the reaction temperature is room temperature to a boiling point of used solvent, preferably room temperature for 1 to 24 hours, after adding the (+)-camphorsulfonic acid.
- Clopidogrel free base of formula 2 a starting material, can be prepared by the method disclosed in EP 281,495 Bl and USP 4,847,265.
- Camphorsulfonic acid organic acid used in the present invention, is almost non-toxic suitable for pharmaceutical use (for example, LDs 0 of (ls)-(+)-camphorsulfonic acid as free acid is 2502mg/kg when it is injected hypodermically to mice, and LD 50 of the acid is more than 316mg/kg when it is injected orally to common quails; PH ARAT 1,150,1946.,
- the clopidogrel (+)-camphorsulfonate salt of the present invention prepared by the above method is optically pure, stable to moisture and heat, and non-hygroscopic, it can be used as effective ingredient of a pharmaceutical composition for treating and preventing platelet related vascular disorder with pharmaceutically acceptable carrier.
- the present invention provides a use of the clopidogrel (+)-camphorsulfonate salt of the present invention for manufacturing a medicine for treating and preventing platelet related vascular disorder. Also, the present invention provides a method for treating and preventing platelet related vascular disorder comprising administering clopidogrel (+)- camphorsulfonate salt of the present invention to a mammal (a patient) in need thereof.
- the present invention provides a pharmaceutical composition containing the clopidogrel (+)-camphorsulfonate salt of the present invention as effective ingredient for medicine for treating and preventing platelet related vascular disorder.
- the amount of clopidogrel (+)-camphorsulfonate salt in the pharmaceutical composition of the present invention is 0.1 to 95% by weight based on the total weight of the composition, preferably 1 to 70% by weight, more preferably 1 to 50% by weight.
- the pharmaceutical composition containing the clopidogrel (+)-camphorsulfonate salt of the present invention can comprise an excipient of 30 to 50% by weight, a binder of 1 to 20% by weight, a disintegrating agent of 1 to 20% by weight, a surface active agent of 0.1 to 10% by weight, and a coating agent of 1 to 10% by weight.
- excipients in the present invention can be ones generally used in the art for preparing a pharmaceutical composition.
- the examples of excipients include lactose, low substituted hydroxypropylcellulose, corn starch, pre-gelatinized starch, mannitol, sorbitol, microcrystalline cellulose, and mixtures thereof.
- the disintegrating agents in the present invention can be ones generally used in the art for preparing a pharmaceutical composition.
- the examples of disintegrating agents include low substituted hydroxypropylcellulose, crospovidone, sodium croscarmellose, sodium carboxy methyl starch, sodium carboxymethylcellulose, chitosan, and mixture thereof.
- the binders in the present invention can be ones generally used in the art for preparing a pharmaceutical composition.
- the examples of binders include povidone, microcrystalline cellulose, hydroxymethylcellulose, hydroxyethylcelluose, copovidone, and mixtures thereof.
- the surface active agents in the present invention can be ones generally used in the art for preparing a pharmaceutical composition.
- the examples of surface active agents include polysorbate, polyethyleneglycol, glycerin, poloxamer, Sodium lauryl sulfate, cetanol, and mixture thereof.
- the lubricants in the present invention can be ones generally used in the art for preparing a pharmaceutical composition.
- the examples of lubricants include hydrogenated castor oil, glyceryl behenate, palmitic acid, polyethyleneglycol, and mixtures thereof.
- the present invention provides a pharmaceutical composition for preventing and treating platelet related disorder comprising the crystalline clopidogrel (+)-camphorsulfonate salt as an effective ingredient, and a solution adjuvant.
- the amount of clopidogrel (+)-camphorsulfonate salt contained in the pharmaceutical composition is 0.1 to 95% by weight based on the total weight of the composition, and the amount of solution adjuvant is 5 to 99.9% by weight based on the total weight of the composition.
- the clopidogrel (+)-camphorsulfonate salt is contained in 1 to 70% by weight based on the total weight of the composition, and the solution adjuvant is contained in 30 to 99% by weight based on the total weight of the composition.
- composition of the present invention can be prepared by combining the clopidogrel (+)-camphorsulfonate salt of the present invention with pharmaceutically acceptable carrier, diluent, excipient, solvent adjuvant, etc.
- pharmaceutically acceptable carrier diluent, excipient, solvent adjuvant, etc.
- carriers diluents, excipients, solvent adjuvants, etc.
- excipients such as starch, sugar and mannitol
- filler and extenders such as calcium phosphate and silicic acid derivatives
- binders such as cellulose derivatives (like carboxymethylcellulose, hydroxypropylcellulose, etc), gelatin, alginic acid salt, and polyvinyl pyrrolidone
- lubricants such as talc, calcium and magnesium stearate, hydrogenated castor oil, and solid polyethylene glycol
- disintegrating agents such as povidone, sodium croscarmellose, and crospovidone
- solvent adjuvants such as polysorbate, cetanol, glycerol monostearate, glyceride class [like lauroly macrogolglyceride (Gelucire 44/14) and stearoyl macrogolglyceride (Gelucire 50/13), propylene glycol caprylate (caproylPGMC) and propyleneglycol monocaprylate(Caproyl 90),
- Orally administrable formulations of the present pharmaceutical composition can be coated by coating agent containing a plasticizer.
- the coating agents of the present invention include: water soluble resins such as polyethyleneglycol, polyethyleneoxide, gelatin, carbohydrates (starch, dextran sulfate, sucrose, corn syrup, etc.), celluloses (carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, methylhydroxyethylcellulose, etc.), arabino galactan, polyvinylalcohol, polyacrylic acids (polyvinylpyrrolidon, etc), inorganic materials (calcium sulfate, silicate, clay etc.) and gums (arabic gum, agar, carrageenan, sodium alginate, etc.); non-water soluble resins such as ethylcellulose, polyethylene, polymetaacrylate, Eudragit, polyamide(nylon etc.), poly(ethylene-vinylacetate) copo
- the pharmaceutical composition containing the clopidogrel (+)-camphorsulfonate salt of the present invention as an effective ingredient can be administrated orally or parenterally, preferably orally.
- the means of administration can be oral solid medicines such as pulvis, granulum, capsule, tablet, pillet, chewable tablet, troche, etc.; oral solution medicines such as liquid drug, syrup drug, elixir, orally suspension, emulsion, etc.; and parenteral solid medicines such as pillet and insertion drug for hypodermic injection
- the present invention provides a use of the pharmaceutical composition containing the clopidogrel (+)-camphorsulfonate salt of the present invention for manufacturing a medicine for treating and preventing platelet related vascular disorder. Also, the present invention provides a method for treating and preventing platelet related vascular disorder comprising administering the pharmaceutical composition containing an effective dose of clopidogrel (+)-camphorsulfonate salt of formula 1 to a mammal(a patient) in need thereof.
- the clopidogrel (+)-camphorsulfonate salt of formula 1 in the present invention can be orally administrated to a mammal comprising human as the dosage of 1 to 1 ,000mg/kg(body weight)/day, preferably 25 to 250mg/kg(body weight)/day, all at once or more than once a day.
- the clopidogrel (+)-camphorsulfonate salt of the present invention can achieve conveniently optical purity that is pharmaceutically required in a preparing process, and can keep the high quality as effective ingredient of pharmaceutical composition for a long time due to excellent stability to moisture and heat.
- the salt has the same as or more pharmacological effect than the disclosed hydrogen sulfate salt, and so are useful for treating or preventing platelet related disease.
- the soft capsule and hard capsule containing the clopidogrel (+)- camphorsulfonate salt, galenical pharmacally prepared, has water solubility increased, compared with general tablet, and has the bioavailability increased.
- Fig. 1 is a schematic drawing illustrating the analytic results of differential scanning calorimeter of clopidogrel (+)-camphorsulfonate salt of Example 1 of the present invention.
- Fig. 2 is a schematic drawing illustrating the analytic results of X-ray diffraction spectroscopy of clopidogrel (+)-camphorsulfonate salt of Example 1 of the present invention.
- Fig. 3 is a schematic drawing illustrating the analytic results of differential scanning calorimeter of clopidogrel (+)-camphorsulfonate salt of Example 2 of the present invention.
- Fig. 4 is a schematic drawing illustrating the analytic results of X-ray diffraction spectroscopy of clopidogrel (+)-camphorsulfonate salt of Example 2 of the present invention.
- Fig. 5 represents flow outing phase of the tablet of Preparation Example 1 of the present invention in pH 2.0 USP buffer solution.
- Fig. 6 represents flow outing phase of the tablet of Preparation Example 2 of the present invention in pH 2.0 USP buffer solution.
- Fig. 7 represents flow outing phase of the tablet of Preparation Example 3 of the present invention in pH 2.0 USP buffer solution.
- Fig. 8 represents flow outing phase of the tablet of Preparation Example 4 of the present invention in pH 2.0 USP buffer solution.
- Fig. 9 represents flow outing phase of the soft capsule or hard capsule of Preparation Example 25 of the present invention in water.
- Fig. 10 represents flow outing phase of the tablet of Preparation Example 26 of the present invention in pH 2.0 USP buffer solution.
- Fig. 11 represents flow outing phase of the soft or hard capsule of Preparation Example
- Fig. 12 represents flow outing phase of the soft or hard capsule of Preparation Example
- Fig. 13 represents flow outing phase of the soft or hard capsule of Preparation Example
- Fig. 14 represents flow outing phase of the soft or hard capsule of Preparation Example
- Fig. 15 represents the content change of the tablet of Preparation Example 1 and Comparative Example 2 of the present invention in a stability test.
- Fig. 16 represents the result of a bleeding time test of Example 1 and Comparative Example 1 of the present invention.
- Fig. 17 represents the results of inhibition effect test to platelet aggregation of Example 1 and Comparative Example 1 of the present invention.
- HPLC high-performance liquid chromatography
- the method of preparing granules was a dry or wet granule pressure method disclosed in "Galenical pharmacy” (Issue Date: March 1995) issued from the Pharmacology Department of Korean Pharmacy College Council
- Clopidogrel hydrogen sulfate salt was prepared by the method disclosed in KP Nos. 0511238 and 0103094.
- Granules were prepared by a general method of preparing granules, and hydrogenated castor oil of 3.3mg was added to the granules. The mixture was tabletted by using a general tablet machine. The tablet of Clopidogrel hydrogen sulfate salt was prepared through a film coating process using Opadry 03B44038.
- Example 1 Preparation of clopidogrel (+)-camphorsulfonate salt (formula 1)
- the solution of Clopidogrel of 10.Og dissolved in the Ethyl acetate of 70 ml was added to (+)-camphorsulfonic acid of 7.23 g, and the solution was stirred at room temperature for 12 hours.
- Thus generated crystal was filtered, and washed with ethylacetate 20ml After the crystal was dried at 40 ° C , the title compound was obtained by 15.68g (yield 91%) as white crystal.
- X-ray diffraction spectrum data is shown in the following Table 1 , and the graph is shown in Fig 2.
- X-ray diffraction spectrum data is shown in the following Table 2, and the graph is shown in Fig. 4.
- the title compound was prepared by the method disclosed in the Example 1, except using ( ⁇ )-camphorsulfonic acid, instead of (+)-camphorsulfonic acid.
- Clopidogrel (+)-camphorsulfonate salt of 129.16mg, mannitol of 81.84mg, crospovidone of 30 mg, per tablet povidone of 15mg was added to purified water to prepare a binder solution.
- Granules were prepared by a general method of preparing granules, and hydrogenated castor oil of 4mg was added to the granules. And, the mixture was tabletted by using a general tablet machine.
- the tablet of Clopidogrel (+)-camphorsulfonate salt was prepared through a film coating process using Opadry 03B44038.
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using lactose, instead of mannitol.
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using corn starch, instead of mannitol.
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using pre-gelatinized starch, instead of mannitol.
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using microcrystalline cellulose, instead of mannitol.
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using Sodium Carboxy methyl Starch, instead of crospovidone.
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using Sodium Carboxy methylcellulose, instead of crospovidone.
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1 , except using chitosan, instead of crospovidone.
- Preparation Example 14 A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using microcrystallinecellulose, instead of povidone.
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using hydroxymethylcellulose, instead of povidone.
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using copovidone, instead of povidone.
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using cetanol, instead of polysorbate.
- Preparation Example 19 A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using cetanol, instead of polysorbate.
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 7, except using glycerin, instead of polysorbate.
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 7, except using sodium lauryl sulfate, instead of polysorbate.
- Preparation Example 22 A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using glyceryl behenate, instead of hydrogenated castor oil.
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using palmitic acid, instead of hydrogenated castor oil.
- a tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using polyethyleneglycol, instead of hydrogenated castor oil.
- Clopidogrel (+)-camphorsulfonate salt of 129.16 mg was added to the solution, and the mixture was homogenized. The homogenous liquid mixture was inserted to soft or hard capsules, and cooled at room temperature.
- Clopidogrel hydrogen sulfate salt of Comparative Example 1 Clopidogrel (+)- camphorsulfonate salt of Example 1
- Clopidogrel (-)-camphorsulfonate salt of Example 2 were tested for stability in an exposed state under 60 ⁇ 2 ° C and relative humidity of 75 ⁇ 5 % , against moisture and heat for 4 weeks. Particularly, while the samples were exposed under the above conditions for 4 weeks, the contents of active ingredients in the samples were measured at 1 st , 2 nd , 3 rd and 4 th week by HPLC, based on the initial (0 week) contents of active ingredients in the samples.
- Clopidogrel acid addition salts of Comparative Example 1, Example 1 and Example 2 were tested for hygroscopicity in an exposed state under 60 ⁇ 2 ° C and relative humidity 75 ⁇ 5 % for 7 days.
- the moisture contents of Clopidogrel acid addition salts were measured by Karl- Fisher moisture measurement. [Table 5]
- the Clopidogrel (+)-camphorsulfonate salt of the present invention is non-hygroscopic and stable against moisture and heat.
- the contents and optical purity of clopidogrel in Clopidogrel (+)-camphorsulfonate were almost not changed under the accelerated condition for a long time, and the Clopidogrel (+)-camphorsulfonate generated a less amount of hydrolysate, compared with Clopidogrel hydrogen sulfate.
- Clopidogrel free bases having optical purities of about 97%ee, 98.6 %ee and 99.3 %ee, optionally prepared, were converted to Clopidogrel hydrogen sulfate, Clopidogrel (+)- camphorsulfonate salt, and Clopidogrel (-)-camphorsulfonate salt, respectively, by the methods disclosed in Comparative Example 1, Example 1, and Example 2.
- the optical purities of the prepared Clopidogrel acid addition salts were measured under analysis condition B to confirm whether the optical purity of clopidogrel is increased through the preparation process of salts.
- Clopidogrel (+)-camphorsulfonate salt is excellent compared with that of Clopidogrel (-)-camphorsulfonate salt.
- the result proves that Clopidogrel (+)-camphorsulfonate salt of the present invention is suitable for a pharmaceutical composition, compared with the Clopidogrel salts known.
- the elution test method the apparatus 2 of the elution test method in the Korean Pharmacopoeia (Issue Date: 2003; 8 TH Ed.)
- Paddle rotational rate 50 rpm
- Test temperature 37.0 ⁇ 0.5 ° C
- the detection time 5, 10, 15, and 30 r ⁇ in
- the elution test method the apparatus 2 of the elution test method in the Korean
- the detection time 5, 10, 15, 30, and 45 min
- the results are based on the statistical analysis results by Dunnet test of A NOVA.
- G3 The group of administrating Clopidogrel (+)-camphorsulfonate salt of 10mg/kg (Experimental administration group)
- G5 The group of administrating Clopidogrel hydrogen sulfate salt of 3mg/kg (Control administration group)
- G6 The group of administrating Clopidogrel hydrogen sulfate salt of 10mg/kg (Control administration group)
- (+)-camphorsulfonate salt were statistically significantly increased.
- Clopidogrel hydrogen sulfate of Example 1 and the Clopidogrel (+)-camphorsulfonate salt of the present invention were tested for the effect of preventing aggregation of the platelets.
- the rats' blood was used.
- the blood was centrifuged at l,000rpm for lOmin to gain platelet-rich plasma (PRP, below).
- the number of platelet was counted by a blood test machine (CELL-DYN 3700, Abbot, USA), and the platelet plasma was diluted by injecting saline water to adjust the number of platelet to 3 ⁇ lO 8 cells/ml.
- the blood clotting was measured within 3 hours from the blood collection, and PRP was stored at room temperature.
- the aggregation of the platelets was monitored by an aggregometer (560-Ca Whole Blood Lumi-aggregometer, Chrono-log Co., Ltd., USA), and the sample was stabilized at 37 "C .
- Excipient Control group 5% gum Arabic solution distilled water, wherein gum Arabic was purchased from Daihan Pharm Co. Ltd.
- G2 The group of administrating Clopidogrel (+)-camphorsulfonate salt of 3mg/kg (Experimental administration group)
- G3 The group of administrating Clopidogrel (+)-camphorsulfonate salt of 10mg/kg (Experimental administration group)
- Clopidogrel (+)-camphorsulfonate salt effectively inhibited platelet aggregations induced by ADP, which proves that Clopidogrel (+)-camphorsulfonate salt is effective for the prevention and treatment of platelet related disorder.
- the clopidogrel (+)-camphorsulfonate salt of the present invention can easily achieve optically purity that is pharmaceutically required in a preparation process, and keep high quality as effective ingredient of a pharmaceutical composition for a long time due to excellent stability against moisture and heat. And, the salt has the same or more pharmacological effect than known hydrogen sulfate salt, and so is useful for treating or preventing platelet related disorder. And, the soft capsule and hard capsule containing the clopidogrel (+)- camphorsulfonate salt, galenically pharmacally prepared, has water solubility increased, compared with general tablet, and the bioavailability increased.
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Abstract
The present invention provides a crystalline clopidogrel (+)-camphorsulfonate salt, a method of preparing the same, and a composition containing the same as effective ingredient for treating and preventing platelet related vascular disorder. The clopidogrel (+)-camphorsulfonate salt of the present invention has excellent pharmaceutical effect, and is pharmaceutically stable due to their optical purity, thermostable, and non-hygroscopic.
Description
CLOPIDOGREL (+)-CAMPHORSULFONATE SALT, METHOD OF PREPARING THE SAME AND A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
TECHNICAL FIELD
The present invention relates to a crystalline clopidogrel (+)-camphorsulfonate salt, a method of preparing the same, and a composition containing the same as effective ingredient for treating and preventing platelet related vascular disorder.
BACKGROUND ART
Clopidogrel is known as effective drug for treating and preventing platelet related vascular disorder. The structural formula of clopidogrel is as shown in the following formula 2, and the chemical name is ( + )-(S)-α-(o-chlorophenyl)-6,7-dehydrothieno[3,2-a]pyridyl- 5(4H)-acetate. Clopidogrel is disclosed in EP 281,459 Bl and USP 4,847,265.
<Formula 2>
And, clopidogrel hydrogen sulfate salt, sulfuric acid addition salt, is presently marketed as Plavix tablet, and is very crystalline and hygroscopic, compared with the above mentioned
salts. But, since sulfuric acid used to prepare the clopidogrel hydrogen sulfate is strong acid, sulfuric acid may react to the prepared product to decompose it, and the decomposed product affects the stability of the drug (H. Agrawal et al, Talanta, 61: 581-589, 2003). Also, it is reported that Plavix increased hydrolysate by about 8 times, levo-rotatory isomer by about 1.5 times, and total impurity by about 3 times, under generally accelerated stability test condition (40 °C , 75 % relative humidity, and 3 months), compared with initial Plavix (Y. Gomez et al, J. Pharm. Biomed. Anal.34: 341-348, 2004). And, clopidogrel hydrogen sulfate having excipients containing metal may be unstable.
Thus, it is needed that clopidogrel salts should be easily purified, heat stable, not be converted to hydrolysate of formula 4, maintain clopidogrel form hydrolyzed by moisture, and be highly soluble in water.
<Formula 4>
Accordingly, the development of clopidogrel acid addition salts having non-hygroscopicity, moisture stability, heat stability and highly optical purity has been required.
The present inventors have studied to solve the problem of clopidogrel acid addition salts, and discovered that crystalline clopidogrel (+), (-)-camphorsulfonate salts are optically pure, heat stable and non-hygroscopic. Also, the inventors found out that clopidogrel (+) camphorsulfonate salt has excellent water solubility, compared with clopidogrel (-) camphorsulfonate salt, and that clopidogrel (+) camphorsulfonate salt provides high purity in the preparation process. That is, the present inventors confirmed that a pharmaceutical composition containing clopidogrel (+) camphorsulfonate salt is more effective for preventing and treating platelet related vascular disorder than a composition containing clopidogrel acid addition salts.
DISCLOSURE OF THE INVENTION
TECHNICAL PROBLEM
The object of the present invention is to provide a crystalline clopidogrel (+)- camphorsulfonate salt which is optically pure, non-hygroscopic, and stable to moisture and heat, and has high optical purity and improved effect; a method of preparing the same; and a composition containing the same as effective ingredient for treating and preventing platelet related vascular disorder.
TECHNICAL SOLUTION
The present invention provides a crystalline clopidogrel (+)-camphorsulfonate salt having the following formula 1 :
<Formula 1>
The present invention provides a crystalline clopidogrel (+) -camphorsulfonate salt having X-ray powder diffraction pattern peak at 2Θ(I/Io> 10%)angles of 8.2, 9.5, 11.1, 11.4, 11.9, 12.9, 13.2, 14.0, 14.9, 15.2, 17.0, 18.2, 18.7, 19.7, 2 0.3, 21.3, 22.3, 22.6, 23.3, 23.4, 23.9, 25.0, 25.9, 26.1, 27.1, 28.2, 29.0, 29.2, 30.6, 30.8, 31.2, and 38.3.
Also, the present invention provides a method of preparing the crystalline clopidogrel (+)-camphorsulfonate salt of formula 1 , comprising a step of reacting clopidogrel free base of formula 2 with (+)-camphorsulfonic acid of the following formula 3 in organic solvent;
<Formula 1>
<Formula 3>
The organic solvent in the present invention is selected from the group consisting of methylacetate, ethylacetate, n-propylacetate, isopropylacetate, acetone, methylethylketon, methylisobutylketone, acetonitrile, tetrahydrofurane, 1,4-dioxane, and mixtures thereof. Preferably, the organic solvent is selected from the group consisting of ethylacetate, acetone, and mixtures thereof.
In the present invention, the mole ratio of (+)-camphorsulfonic acid to the clopidogrel free base may be 0.5- 2, preferably 0.9- 1.1.
In the method of the present invention, the reaction temperature is room temperature to a boiling point of used solvent, preferably room temperature for 1 to 24 hours, after adding the (+)-camphorsulfonic acid.
Clopidogrel free base of formula 2, a starting material, can be prepared by the method disclosed in EP 281,495 Bl and USP 4,847,265.
Camphorsulfonic acid, organic acid used in the present invention, is almost non-toxic suitable for pharmaceutical use (for example, LDs0 of (ls)-(+)-camphorsulfonic acid as free acid is 2502mg/kg when it is injected hypodermically to mice, and LD50 of the acid is more than 316mg/kg when it is injected orally to common quails; PH ARAT 1,150,1946.,
EESADV6,149,1882).
Because the clopidogrel (+)-camphorsulfonate salt of the present invention prepared by the above method is optically pure, stable to moisture and heat, and non-hygroscopic, it can be used as effective ingredient of a pharmaceutical composition for treating and preventing platelet related vascular disorder with pharmaceutically acceptable carrier.
Thus, the present invention provides a use of the clopidogrel (+)-camphorsulfonate salt of the present invention for manufacturing a medicine for treating and preventing platelet related vascular disorder. Also, the present invention provides a method for treating and preventing platelet related vascular disorder comprising administering clopidogrel (+)- camphorsulfonate salt of the present invention to a mammal (a patient) in need thereof.
Moreover, the present invention provides a pharmaceutical composition containing the clopidogrel (+)-camphorsulfonate salt of the present invention as effective ingredient for medicine for treating and preventing platelet related vascular disorder.
The amount of clopidogrel (+)-camphorsulfonate salt in the pharmaceutical composition of the present invention is 0.1 to 95% by weight based on the total weight of the composition, preferably 1 to 70% by weight, more preferably 1 to 50% by weight.
The pharmaceutical composition containing the clopidogrel (+)-camphorsulfonate salt of the present invention can comprise an excipient of 30 to 50% by weight, a binder of 1 to 20% by weight, a disintegrating agent of 1 to 20% by weight, a surface active agent of 0.1 to 10% by weight, and a coating agent of 1 to 10% by weight.
The excipients in the present invention can be ones generally used in the art for preparing a pharmaceutical composition. The examples of excipients include lactose, low substituted hydroxypropylcellulose, corn starch, pre-gelatinized starch, mannitol, sorbitol, microcrystalline cellulose, and mixtures thereof.
The disintegrating agents in the present invention can be ones generally used in the art for preparing a pharmaceutical composition. The examples of disintegrating agents include
low substituted hydroxypropylcellulose, crospovidone, sodium croscarmellose, sodium carboxy methyl starch, sodium carboxymethylcellulose, chitosan, and mixture thereof.
The binders in the present invention can be ones generally used in the art for preparing a pharmaceutical composition. The examples of binders include povidone, microcrystalline cellulose, hydroxymethylcellulose, hydroxyethylcelluose, copovidone, and mixtures thereof.
The surface active agents in the present invention can be ones generally used in the art for preparing a pharmaceutical composition. The examples of surface active agents include polysorbate, polyethyleneglycol, glycerin, poloxamer, Sodium lauryl sulfate, cetanol, and mixture thereof.
The lubricants in the present invention can be ones generally used in the art for preparing a pharmaceutical composition. The examples of lubricants include hydrogenated castor oil, glyceryl behenate, palmitic acid, polyethyleneglycol, and mixtures thereof.
Also, the present invention provides a pharmaceutical composition for preventing and treating platelet related disorder comprising the crystalline clopidogrel (+)-camphorsulfonate salt as an effective ingredient, and a solution adjuvant.
The amount of clopidogrel (+)-camphorsulfonate salt contained in the pharmaceutical composition is 0.1 to 95% by weight based on the total weight of the composition, and the amount of solution adjuvant is 5 to 99.9% by weight based on the total weight of the composition. Preferably, the clopidogrel (+)-camphorsulfonate salt is contained in 1 to 70% by weight based on the total weight of the composition, and the solution adjuvant is contained in 30 to 99% by weight based on the total weight of the composition.
And, the composition of the present invention can be prepared by combining the clopidogrel (+)-camphorsulfonate salt of the present invention with pharmaceutically acceptable carrier, diluent, excipient, solvent adjuvant, etc.
The examples of carriers, diluents, excipients, solvent adjuvants, etc. that are suitable for the composition of the present invention include: excipients such as starch, sugar and mannitol; filler and extenders such as calcium phosphate and silicic acid derivatives; binders such as cellulose derivatives (like carboxymethylcellulose, hydroxypropylcellulose, etc), gelatin, alginic acid salt, and polyvinyl pyrrolidone; lubricants such as talc, calcium and magnesium stearate, hydrogenated castor oil, and solid polyethylene glycol; disintegrating agents such as povidone, sodium croscarmellose, and crospovidone; solvent adjuvants such as polysorbate, cetanol, glycerol monostearate, glyceride class [like lauroly macrogolglyceride (Gelucire 44/14) and stearoyl macrogolglyceride (Gelucire 50/13), propylene glycol caprylate (caproylPGMC) and propyleneglycol monocaprylate(Caproyl 90), oleoyl macrogolglyceride(Labrafil Ml 944 CS), linoleoyl macrogolglyceride(Labrafil M2125 CS), caprylocaproyl macrogol glycerides(Labrasol), propyleneglycol laurate (lauroglycol FCC) and propyleneglycol monolaurate (lauroglycol 90), glyceryl monolinorate(Mycin 35-1), glyceryl monooleate(Peceol) and polyglycerine oleate(Pluriol)], etc.
Orally administrable formulations of the present pharmaceutical composition can be coated by coating agent containing a plasticizer. The coating agents of the present invention include: water soluble resins such as polyethyleneglycol, polyethyleneoxide, gelatin, carbohydrates (starch, dextran sulfate, sucrose, corn syrup, etc.), celluloses (carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, methylhydroxyethylcellulose, etc.), arabino galactan, polyvinylalcohol, polyacrylic acids (polyvinylpyrrolidon, etc), inorganic materials (calcium sulfate, silicate, clay etc.) and gums (arabic gum, agar, carrageenan, sodium alginate, etc.); non-water soluble resins such as ethylcellulose, polyethylene, polymetaacrylate, Eudragit, polyamide(nylon etc.), poly(ethylene-vinylacetate) copolymer, cellulose nitrate, silicon and poly()actic acid-glycollic acid)copolymer etc.; enteric resins such as cellulose acatete phthalate, shellac, sein, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate and Eudragit L 100, SlOO, etc; wax; and lipids such as paraffin, carnauba, spermaceti, beeswax, stearic acid, stearyl alcohol, glyceryl stearate, tristearin, etc.
The pharmaceutical composition containing the clopidogrel (+)-camphorsulfonate salt of the present invention as an effective ingredient can be administrated orally or parenterally,
preferably orally. And, the means of administration can be oral solid medicines such as pulvis, granulum, capsule, tablet, pillet, chewable tablet, troche, etc.; oral solution medicines such as liquid drug, syrup drug, elixir, orally suspension, emulsion, etc.; and parenteral solid medicines such as pillet and insertion drug for hypodermic injection
The present invention provides a use of the pharmaceutical composition containing the clopidogrel (+)-camphorsulfonate salt of the present invention for manufacturing a medicine for treating and preventing platelet related vascular disorder. Also, the present invention provides a method for treating and preventing platelet related vascular disorder comprising administering the pharmaceutical composition containing an effective dose of clopidogrel (+)-camphorsulfonate salt of formula 1 to a mammal(a patient) in need thereof.
The clopidogrel (+)-camphorsulfonate salt of formula 1 in the present invention can be orally administrated to a mammal comprising human as the dosage of 1 to 1 ,000mg/kg(body weight)/day, preferably 25 to 250mg/kg(body weight)/day, all at once or more than once a day.
ADVANTAGEOUS EFFECTS The clopidogrel (+)-camphorsulfonate salt of the present invention can achieve conveniently optical purity that is pharmaceutically required in a preparing process, and can keep the high quality as effective ingredient of pharmaceutical composition for a long time due to excellent stability to moisture and heat. The salt has the same as or more pharmacological effect than the disclosed hydrogen sulfate salt, and so are useful for treating or preventing platelet related disease. The soft capsule and hard capsule containing the clopidogrel (+)- camphorsulfonate salt, galenical pharmacally prepared, has water solubility increased, compared with general tablet, and has the bioavailability increased.
DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic drawing illustrating the analytic results of differential scanning calorimeter of clopidogrel (+)-camphorsulfonate salt of Example 1 of the present invention.
Fig. 2 is a schematic drawing illustrating the analytic results of X-ray diffraction spectroscopy of clopidogrel (+)-camphorsulfonate salt of Example 1 of the present invention.
Fig. 3 is a schematic drawing illustrating the analytic results of differential scanning calorimeter of clopidogrel (+)-camphorsulfonate salt of Example 2 of the present invention.
Fig. 4 is a schematic drawing illustrating the analytic results of X-ray diffraction spectroscopy of clopidogrel (+)-camphorsulfonate salt of Example 2 of the present invention.
Fig. 5 represents flow outing phase of the tablet of Preparation Example 1 of the present invention in pH 2.0 USP buffer solution.
Fig. 6 represents flow outing phase of the tablet of Preparation Example 2 of the present invention in pH 2.0 USP buffer solution.
Fig. 7 represents flow outing phase of the tablet of Preparation Example 3 of the present invention in pH 2.0 USP buffer solution.
Fig. 8 represents flow outing phase of the tablet of Preparation Example 4 of the present invention in pH 2.0 USP buffer solution.
Fig. 9 represents flow outing phase of the soft capsule or hard capsule of Preparation Example 25 of the present invention in water.
Fig. 10 represents flow outing phase of the tablet of Preparation Example 26 of the present invention in pH 2.0 USP buffer solution.
Fig. 11 represents flow outing phase of the soft or hard capsule of Preparation Example
27 of the present invention in pH 2.0 USP buffer solution.
Fig. 12 represents flow outing phase of the soft or hard capsule of Preparation Example
28 of the present invention in pH 2.0 USP buffer solution.
Fig. 13 represents flow outing phase of the soft or hard capsule of Preparation Example
29 of the present invention in water.
Fig. 14 represents flow outing phase of the soft or hard capsule of Preparation Example
30 of the present invention in water.
Fig. 15 represents the content change of the tablet of Preparation Example 1 and Comparative Example 2 of the present invention in a stability test.
Fig. 16 represents the result of a bleeding time test of Example 1 and Comparative Example 1 of the present invention.
Fig. 17 represents the results of inhibition effect test to platelet aggregation of Example 1 and Comparative Example 1 of the present invention.
MODE FOR INVENTION
The following examples are intended to further illustrate the present invention, and the scope of the present invention is not intended to be limited thereby in any way.
The analysis condition of high-performance liquid chromatography (HPLC) used for the analysis of contents of Clopidogrel acid addition salts, impurity contents and optical purity in the following comparative examples and examples, and the method of preparing granules are the following. Below, the unit %ee means % enantiomeric excess.
[Condition A] Measurement of the contents of clopidogrel acid addition salts Column: Kromasil Clδ, 5μm (4.6mm x 250mm) Detection wavelength: 215 nm Flow rate: 1.0 M/min
Eluant: methanol: water (sodium 1 -Hexanesulphonate 0.9g, pH2.5 phosphoric acid) = 65:35(v/v):
[Condition B] Measurement of the optical purity of clopidogrel acid addition salts Column: ULTRON ES-OVM, 5μm (4.6 mm x 150mm) Detection wavelength: 220 nm Flow rate: 1.0 m#/min
Eluant: 0.0 IM Potassium dihydrogen phosphate solution: ACN=75:25(v/v)
[The method of preparing granules]
The method of preparing granules was a dry or wet granule pressure method disclosed in "Galenical pharmacy" (Issue Date: March 1995) issued from the Pharmacology Department of Korean Pharmacy College Council
Comparative Example 1: Preparation of Clopidogrel hydrogen sulfate salt
The Clopidogrel hydrogen sulfate salt was prepared by the method disclosed in KP Nos. 0511238 and 0103094.
Melting point: 176°C
The contents of moisture (Karl-Fisher measurement): below 0.1 % Contents of Clopidogrel hydrogen sulfate salt (HPLC, Condition A): 99.9% Optical purity (HPLC, Condition B): 99.3 % ee
Comparative Example 2: Preparation of the tablet of Clopidogrel hydrogen sulfate salt (preparation of the control drug for the stability test)
After combining Clopidogrel hydrogen sulfate salt of 97.87 mg, mannitol of 68.92 mg, low- hydrated microcrystalline cellulose of 31 mg, polyethyleneglycol of 34mg and low substituted hydroxypropylcellulose of 12.9 mg, per tablet, purified water was added to the mixture.
Granules were prepared by a general method of preparing granules, and hydrogenated castor oil of 3.3mg was added to the granules. The mixture was tabletted by using a general tablet machine. The tablet of Clopidogrel hydrogen sulfate salt was prepared through a film coating process using Opadry 03B44038.
Example 1; Preparation of clopidogrel (+)-camphorsulfonate salt (formula 1)
The solution of Clopidogrel of 10.Og dissolved in the Ethyl acetate of 70 ml was added to (+)-camphorsulfonic acid of 7.23 g, and the solution was stirred at room temperature for 12 hours. Thus generated crystal was filtered, and washed with ethylacetate 20ml After the crystal was dried at 40 °C , the title compound was obtained by 15.68g (yield 91%) as white crystal.
The contents of moisture (Karl-Fisher measurement): below 0.1 %
Contents of clopidogrel (+)-camphorsulfonate salt (HPLC, Condition A): 99.6%
Optical purity (HPLC, Condition B): 99.8 %ee
- Η-NMR(200 MHZ, DMSO-d6, ppm): δ 0.74(s, 3H), 1.05(s, 3H), 1.30(m, 2H), 1.70 - 1.95(m, 3H), 2.25(dd, IH), 2.40(d, IH), 2.70(dd, IH), 2.90(d, IH), 3.08(brs, 2H), 3.50(brs, 2H), 3.74(s, 3H), 4.25(brs, 2H), 5.68(s, IH), 6.88(d, IH), 7.44(d, IH), 7.50~7.75(m, 4H)
- IR(KBr, cm"1): 2965, 1734, 1451, 1300, 1241, 1147, 1028, 842, 752
- Differential Scanning Calorimeter (DSC, 10°C/min): starting point: 148.7 °C, the minimum point 152.9 °C (see Fig. 1)
X-ray diffraction spectrum data is shown in the following Table 1 , and the graph is shown in Fig 2.
[Table 1]
Example 2: Preparation of clopidogrel (-)-camphorsulfonate salt
The solution of Clopidogrel of 10. Og dissolved in the acetone of 100m# was added to (-)- camphorsulfonic acid of 7.23 g, and the solution was stirred at room temperature for 12 hours. Thus generated crystal was filtered, and washed with acetone of 20 ml After the crystal was dried at 40 °C, the title compound was obtained by 15.16g (yield 88%) as white crystal.
The contents of moisture (Karl-Fisher measurement): below 0.1 % Contents of clopidogrel (-)-camphorsulfonate salt (HPLC, Condition A): 99.7% Optical purity (HPLC, Condition B): 99.7%ee
- IR(KBr, cm"1): 2953, 1736, 1453, 1303, 1242, 1188, 1056, 845, 752
- Differential Scanning Calorimeter (DSC, 10°C/min): starting point: 165.2 °C, the minimum point 167.5 °C (see Fig. 3)
X-ray diffraction spectrum data is shown in the following Table 2, and the graph is shown in Fig. 4.
[Table 2]
Example 3: Preparation of clopidogrel (±)-eamphorsulfonate salt
The title compound was prepared by the method disclosed in the Example 1, except using (±)-camphorsulfonic acid, instead of (+)-camphorsulfonic acid.
Preparation Example 1
After combining Clopidogrel (+)-camphorsulfonate salt of 129.16mg, mannitol of 81.84mg, crospovidone of 30 mg, per tablet, povidone of 15mg was added to purified water to prepare a binder solution. Granules were prepared by a general method of preparing granules, and hydrogenated castor oil of 4mg was added to the granules. And, the mixture was tabletted by using a general tablet machine. The tablet of Clopidogrel (+)-camphorsulfonate salt was prepared through a film coating process using Opadry 03B44038.
Preparation Example 2
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using lactose, instead of mannitol.
Preparation Example 3
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using copovidone, instead of povidone.
Preparation Example 4 A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except adding polysorbate 80.
Preparation Example 5
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using corn starch, instead of mannitol.
Preparation Example 6
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using pre-gelatinized starch, instead of mannitol.
Preparation Example 7
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the
Preparation Example 1, except using sorbitol, instead of mannitol.
Preparation Example 8
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using microcrystalline cellulose, instead of mannitol.
Preparation Example 9 A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using low substituted hydroxypropylcellulose, instead of crospovidone.
Preparation Example 10 A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using croscarmellose sodium, instead of crospovidone.
Preparation Example 11
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using Sodium Carboxy methyl Starch, instead of crospovidone.
Preparation Example 12
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using Sodium Carboxy methylcellulose, instead of crospovidone.
Preparation Example 13
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1 , except using chitosan, instead of crospovidone.
Preparation Example 14 A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using microcrystallinecellulose, instead of povidone.
Preparation Example 15
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using hydroxymethylcellulose, instead of povidone.
Preparation Example 16
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using copovidone, instead of povidone.
Preparation Example 17
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the
Preparation Example 1, except using polyethyleneglycol, instead of polysorbate.
Preparation Example 18
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using cetanol, instead of polysorbate.
Preparation Example 19
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 7, except using glycerin, instead of polysorbate.
Preparation Example 20
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the
Preparation Example 7, except using poloxamer instead of polysorbate.
Preparation Example 21
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 7, except using sodium lauryl sulfate, instead of polysorbate.
Preparation Example 22 A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using glyceryl behenate, instead of hydrogenated castor oil.
Preparation Example 23
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using palmitic acid, instead of hydrogenated castor oil.
Preparation Example 24
A tablet of Clopidogrel (+)-camphorsulfonate salt was prepared by the method disclosed in the Preparation Example 1, except using polyethyleneglycol, instead of hydrogenated castor oil.
Preparation Example 25
After heating and dissolving Gelucire 44/14 of 260mg per capsule at below 60 °C , Clopidogrel (+)-camphorsulfonate salt of 129.16 mg was added to the solution, and the mixture was homogenized. The homogenous liquid mixture was inserted to soft or hard capsules, and cooled at room temperature.
Preparation Example 26
After heating and dissolving Gelucire 44/14 of 390mg per capsule at below 60 °C, Clopidogrel (+)-camphorsulfonate salt of 129.16 mg was added to the solution, and the mixture was homogenized. The homogenous liquid mixture was inserted to soft or hard capsules, and cooled at room temperature.
Preparation Example 27
After heating and dissolving v44/14 of 230mg per capsule at below 60 °C, Labrafil M1944CS of 30mg was added thereto and combined. And, Clopidogrel (+)-camphorsulfonate salt of 129.16 mg was added to the solution, and the mixture was homogenized. The homogenous liquid mixture was inserted to soft or hard capsules, and cooled at room temperature.
Preparation Example 28
After heating and dissolving Gelucire 44/14 of 210mg per capsule at below 60 °C, Labrasol of 70mg was added thereto, and combined. And, Clopidogrel (+)-camphorsulfonate salt of 129.16 mg was added to the solution, and the mixture was homogenized. The homogenous liquid mixture was inserted to soft or hard capsules, and cooled at room temperature.
Preparation Example 29
After heating and dissolving Gelucire 44/14 of 90mg per capsule at below 60 °C, Labrasol of 210mg was added thereto, and combined. And, Clopidogrel (+)-camphorsulfonate salt of 129.16 mg was added to the solution, and the mixture was homogenized. The homogenous liquid mixture was inserted to soft or hard capsules, and cooled at room temperature.
Preparation Example 30 After heating and dissolving Gelucire 44/14 of 300mg per capsule at below 60 "C , Clopidogrel (+)-camphorsulfonate salt of 129.16 mg was added to the solution, and the mixture was homogenized. The homogenous liquid mixture was inserted to soft or hard capsules, and cooled at room temperature.
Experimental Example 1: The stability test of Clopidogrel acid addition salt against moisture and heat
Clopidogrel hydrogen sulfate salt of Comparative Example 1, Clopidogrel (+)-
camphorsulfonate salt of Example 1, and Clopidogrel (-)-camphorsulfonate salt of Example 2 were tested for stability in an exposed state under 60±2 °C and relative humidity of 75±5 % , against moisture and heat for 4 weeks. Particularly, while the samples were exposed under the above conditions for 4 weeks, the contents of active ingredients in the samples were measured at 1st, 2nd, 3rd and 4th week by HPLC, based on the initial (0 week) contents of active ingredients in the samples.
The contents of clopidogrel acid addition salt were measured by analysis condition A of HPLC, and the generated impurity (hydrolysate) contents of clopidogrel acid addition salt were measured by analysis condition B of HPLC. The results were shown in the following Tables 3 and 4.
[Table 3]
[Table 4]
Experimental Example 2: The hygroscopicity test of Clopidogrel acid addition salt
Clopidogrel acid addition salts of Comparative Example 1, Example 1 and Example 2 were tested for hygroscopicity in an exposed state under 60±2 °C and relative humidity 75±5 % for 7 days. The moisture contents of Clopidogrel acid addition salts were measured by Karl- Fisher moisture measurement.
[Table 5]
As Tables 3, 4 and 5 show, the Clopidogrel (+)-camphorsulfonate salt of the present invention is non-hygroscopic and stable against moisture and heat. Thus, the contents and optical purity of clopidogrel in Clopidogrel (+)-camphorsulfonate were almost not changed under the accelerated condition for a long time, and the Clopidogrel (+)-camphorsulfonate generated a less amount of hydrolysate, compared with Clopidogrel hydrogen sulfate.
Experimental Example 3: The optical purity increase test of Clopidogrel acid addition salt
Clopidogrel free bases having optical purities of about 97%ee, 98.6 %ee and 99.3 %ee, optionally prepared, were converted to Clopidogrel hydrogen sulfate, Clopidogrel (+)- camphorsulfonate salt, and Clopidogrel (-)-camphorsulfonate salt, respectively, by the methods disclosed in Comparative Example 1, Example 1, and Example 2. The optical purities of the prepared Clopidogrel acid addition salts were measured under analysis condition B to confirm whether the optical purity of clopidogrel is increased through the preparation process of salts. As the following Table 6 shows, the optical purity of Clopidogrel hydrogen sulfate known was not increased at all through the preparation process of salts, but the optical purity of the Clopidogrel camphorsulfonate salt of the present invention was increased through the preparation process of salts.
[Table 6]
After the Clopidogrel camphorsulfonate salts prepared in Example 1 and Example 2 were saturated in water, the solubility of the salts was measured by the analysis condition A of HPLC. [Table 7]
As Table 7 shows, the solubility of Clopidogrel (+)-camphorsulfonate salt is excellent compared with that of Clopidogrel (-)-camphorsulfonate salt. The result proves that Clopidogrel (+)-camphorsulfonate salt of the present invention is suitable for a pharmaceutical composition, compared with the Clopidogrel salts known.
Experimental Example 5: The elution test of tablets containing clopidogrel (+)- camphorsulfonate salt
The elution properties of tablets of the Preparation Examples 1 to 4 and Plavix tablet of Sanofi Synthelabo company were tested.
- Elution condition -
Elution test solution: pH 2.0 USP buffer solution
The elution test method: the apparatus 2 of the elution test method in the Korean Pharmacopoeia (Issue Date: 2003; 8TH Ed.) Paddle rotational rate: 50 rpm Test temperature: 37.0±0.5 °C The detection time: 5, 10, 15, and 30 rήin
The results of elution test experimented by the condition are shown in Figs. 5 to 8. The results show that the all the tablets of Preparation Examples 1 to 4 have faster elution rate than Plavix tablet. Thus, Clopidogrel (+)-camphorsulfonate salt is expected to have faster pharmacological activity than Plavix tablet, control drug, when they are administrated in vivo.
Experimental Example 6: The elution test of soft or hard capsules containing
Clopidogrel (+)-camphorsulfonate salt
The elution properties of soft or hard capsules of the Preparation Examples 25 to 30 and Plavix tablet of Sanofi Synthelabo company were tested.
- Elution condition -
Elution test solution: pH 2.0 USP buffer solution
The elution test method: the apparatus 2 of the elution test method in the Korean
Pharmacopoeia (Issue Date: 2003; 8TH Ed.)
Paddle rotational rate: 50 rpm
Test temperature : 37. O±O .5 °C
The detection time: 5, 10, 15, 30, and 45 min
The results of elution test experimented by the condition show in Figs. 9 to 14. The results show that the all the capsules of Preparation Examples 25 to 30 have equal to or faster elution rate than Plavix tablet. Thus, Clopidogrel (+)-camphorsulfonate salt is expected to have faster pharmacological activity than Plavix tablet, control drug, when they are administrated in vivo.
Experimental Example 7: The stability test of tablets of Clopidogrel (+)- camphorsulfonate salt
The tablets of Preparation Example 1 and Comparative Example 2 were tested for stability under the accelerated condition (40°C±2, RH75%±5). To shorten the test time, naked tablets without a package were used to the test. The changes of physical properties and contents of Clopidogrel were measured per 4 weeks to 16 weeks from the beginning. The results are shown in Table 8 and Fig. 15.
[Table 8]
Experimental Example 8: The test for confirming extended bleeding time of Clopidogrel (+)-camphorsulfonate salt The effects of the bleeding times of the Clopidogrel hydrogen sulfate of Comparative 1 and Clopidogrel (+)-camphorsulfonate salt of Example 1 were measured by rats. As the bleeding time is regarded as a standard method for measuring the extent of homeostasis, the test was conducted as follows:
Specific Pathogen Free rats (male Sprague-Dawley, body weight 270±25g, 8 week old, n=8; Coretech. Co., Ltd.) were divided into control group and experiment group, and the Clopidogrel hydrogen sulfate salt of 3mg, lOmg, and 30mg/kg, and Clopidogrel (+)- camphorsulfonate salt of 3mg, lOmg, and 30mg/kg were orally administrated to the rats of each group 4 hours before measuring the bleeding time. And, the rats were anesthetized by abdominally administrating pentobarbital of 40mg/kg to the rats in 4 hours after administrating the sample. After confirming the anesthesia of rats, 4mm was cut from the end of the rats' tails. And, the rats' tails were dipped in saline water at 37 °C, and the time to stop bleeding was measured by the unit of second by using a timer. The results are shown in the following Table 9 and Fig. 16, wherein the maximum time measured was to 1,800 seconds, more time than 1,800 seconds was regarded as l,800seconds for the purpose of statistical analysis.
[Table 9]
The data are average values of the measured number 8 ± Standard deviation (n=8). The results are based on the statistical analysis results by Dunnet test of A NOVA.
* significantly different from Gl, PO.05
** significantly different from Gl, P<0. Ol Gl : Excipient Control group (5% gum Arabic solution distilled water, wherein gum Arabic was purchased from Daihan Pharm Co.Ltd)
G2: The group of administrating Clopidogrel (+)-camphorsulfonate salt of 3mg/kg
(Experimental administration group)
G3: The group of administrating Clopidogrel (+)-camphorsulfonate salt of 10mg/kg (Experimental administration group)
G4: The group of administrating Clopidogrel (+)-camphorsulfonate salt of 30mg/kg
(Experimental administration group)
G5: The group of administrating Clopidogrel hydrogen sulfate salt of 3mg/kg (Control administration group) G6: The group of administrating Clopidogrel hydrogen sulfate salt of 10mg/kg (Control administration group)
G7: The group of administrating Clopidogrel hydrogen sulfate salt of 30mg/kg (Control administration group) a) Increase rate (%) = [(B-A)]/A x 100 A = bleeding time of excipient control group
B = bleeding time of administration group
As Table 9 and Fig. 16 show, the bleeding times of the groups of administrating Clopidogrel
(+)-camphorsulfonate salt were statistically significantly increased.
Experimental Example 9: The test to platelets aggregation inhibition effect of Clopidogrel (H-)-camphorsulfonate salt
The Clopidogrel hydrogen sulfate of Example 1 and the Clopidogrel (+)-camphorsulfonate salt of the present invention were tested for the effect of preventing aggregation of the platelets. To measure the antithrombotic effect by using platelets aggregation inhibition activity as
indicator, the rats' blood was used.
Specific Pathogen Free rats (male Sprague-Dawley, body weight 270±25g, 8 week old, n=8; Coretech. Co., Ltd.) were divided into control group and experiment group, and the Clopidogrel hydrogen sulfate salt of 3mg and 10mg/kg, and Clopidogrel (+)-camphorsulfonate salt of 3mg and 10mg/kg were orally administrated to the rats of each group. The blood taken from the rats' posterior cerebral arteries after 4 hours was mixed with 3.8% of sodium citrate solution (blood : 3.8%; sodium citrate solution =1 :9, v/v) to prevent blood clotting. After taken, the blood was centrifuged at l,000rpm for lOmin to gain platelet-rich plasma (PRP, below). The number of platelet was counted by a blood test machine (CELL-DYN 3700, Abbot, USA), and the platelet plasma was diluted by injecting saline water to adjust the number of platelet to 3χlO8 cells/ml. The blood clotting was measured within 3 hours from the blood collection, and PRP was stored at room temperature. The aggregation of the platelets was monitored by an aggregometer (560-Ca Whole Blood Lumi-aggregometer, Chrono-log Co., Ltd., USA), and the sample was stabilized at 37 "C . After 450μl (P/N:312) of cuvette was stuck on a heating place, the cuvette was heated for 5 min. And, 480μl of PRP was injected into the cuvette and stirred. In 1.5 min after the stirring, 20μl of ADP (Adenosine 5'- Diphosphate) solution was injected into the cuvette, and the aggregation effect was measured. The results are shown in the following Table 10 and Fig.17. [Table 10]
* significantly different from Gl, P<0.05
** significantly different from Gl, PO.01
Gl: Excipient Control group (5% gum Arabic solution distilled water, wherein gum Arabic was purchased from Daihan Pharm Co. Ltd)
G2: The group of administrating Clopidogrel (+)-camphorsulfonate salt of 3mg/kg
(Experimental administration group)
G3: The group of administrating Clopidogrel (+)-camphorsulfonate salt of 10mg/kg (Experimental administration group)
G5: The group of administrating Clopidogrel hydrogen sulfate salt of 3mg/kg (Control dministration group)
G6: The group of administrating Clopidogrel hydrogen sulfate salt of 10mg/kg (Control administration group) b) Inhibition rate (%) = [(C-D)]/C x 100
C = bleeding-inhibited time of excipient control group D = bleeding time of administration group
As Table 10 and Fig.17 show, Clopidogrel (H-)-camphorsulfonate salt effectively inhibited platelet aggregations induced by ADP, which proves that Clopidogrel (+)-camphorsulfonate salt is effective for the prevention and treatment of platelet related disorder.
INDUSTRIAL APPLICABILITY
The clopidogrel (+)-camphorsulfonate salt of the present invention can easily achieve optically purity that is pharmaceutically required in a preparation process, and keep high quality as effective ingredient of a pharmaceutical composition for a long time due to excellent stability against moisture and heat. And, the salt has the same or more pharmacological effect than known hydrogen sulfate salt, and so is useful for treating or preventing platelet related disorder. And, the soft capsule and hard capsule containing the clopidogrel (+)- camphorsulfonate salt, galenically pharmacally prepared, has water solubility increased, compared with general tablet, and the bioavailability increased.
Claims
1. A crystalline clopidogrel (+)-camphorsulfonate salt having the following formula 1 :
2. The crystalline clopidogrel (+)-camphorsulfonate salt of claim 1 having X-ray powder diffraction pattern peak at 2Θ(I/Io> 10%)angles of 8.2, 9.5, 11.1, 11.4, 11.9, 12.9, 13.2, 14.0, 14.9, 15.2, 17.0, 18.2, 18.7, 19.7, 2 0.3, 21.3, 22.3, 22.6, 23.3, 23.4, 23.9, 25.0, 25.9, 26.1, 27.1, 28.2, 29.0, 29.2, 30.6, 30.8, 31.2, and 38.3.
3. A method of preparing the crystalline clopidogrel (+)-camphorsulfonate salt of formula 1 in claim 1 , comprising a step of reacting clopidogrel free base of the following formula 2 with (+)-camphorsulfonic acid of the following formula 3 in organic solvent;
<Formula 2>
<Formula 3>
4. The method of claim 3, wherein the organic solvent is selected from the group consisting of methylacetate, ethylacetate, n-propylacetate, isopropylacetate, acetone, methylethylketon, methylisobutylketone, acetonitrile, tetrahydrofurane, and mixtures thereof.
5. The method of claim 4, wherein the organic solvent is selected from the group consisting of ethylacetate, acetone, and mixtures thereof.
6. The method of claim 3, wherein the mole ratio of (+)-camphorsulfonic acid to the clopidogrel free base is 0.5- 2.
7. The method of claim 6, wherein the mole ratio of (+)-camphorsulfonic acid to the clopidogrel free base is 0.9- 1.1.
8. A pharmaceutical composition for preventing and treating platelet related disorder comprising the crystalline clopidogrel (+)-camphorsulfonate salt of claim 1 as an effective ingredient.
9. The pharmaceutical composition of claim 8, wherein the clopidogrel (+)-camphorsulfonate salt is contained in 0.1 to 95% by weight, based on the total weight of the composition.
10. The pharmaceutical composition of claim 9, wherein the clopidogrel (+)-camphorsulfonate salt is contained in 1 to 50% by weight based on the total weight of the composition.
11. The pharmaceutical composition of claim 8, wherein the composition comprises 30 to 50% by weight of excipient, 1 to 20% by weight of binder, 1 to 20% by weight of disintegrating agent, 0.1 to 10% by weight of surface active agent, and 1 to 10% by weight of coating agent.
12. A pharmaceutical composition for preventing and treating platelet related disorder comprising the crystalline clopidogrel (+)-camphorsulfonate salt of claim 1 as an effective ingredient, and a solution adjuvant.
13. The pharmaceutical composition of claim 12, wherein the clopidogrel (+)- camphorsulfonate salt is contained in 0.1 to 95% by weight based on the total weight of the composition, and the solution adjuvant is contained in 5 to 99.9%by weight based on the total weight of the composition.
14. The pharmaceutical composition of claim 13, wherein the clopidogrel (+)- camphorsulfonate salt is contained in 1 to 70% by weight based on the total weight of the composition, and the solution adjuvant is contained 30 to 99%by weight based on the total weight of the composition.
15. The pharmaceutical composition of claim 12, wherein the solution adjuvant is one or more selected from the group consisting of lauroly macrogolglyceride, stearoyl macrogolglyceride, propylene glycol caprylate and propyleneglycol monocaprylate, oleoyl macrogolglyceride, linoleoyl macrogolglyceride, Caprylocaproyl macrogol glycerides, propyleneglycol laurate and propyleneglycol monolaurate, glyceryl monolinorate, glyceryl monooleate, and polyglycerine oleate.
16. The pharmaceutical composition of claim 8 or claim 12, wherein the pharmaceutical composition is an oral administration agent.
17. A use of the pharmaceutical composition comprising the crystalline clopidogrel (+)- camphorsulfonate salt of claim 1 for manufacturing medicine of preventing and treating platelet related disorder.
18. The use of the pharmaceutical composition of claim 17, wherein the clopidogrel (+)- camphorsulfonate salt is contained in 0.1 to 95% by weight based on the total weight of the composition.
19. The use of the pharmaceutical composition of claim 18, wherein the clopidogrel (+)- camphorsulfonate salt is contained in 1 to 50% by weight based on the total weight of the composition.
20. The use of the pharmaceutical composition of claim 17, wherein the composition comprises 30 to 50% by weight of excipient, 1 to 20% by weight of binder, 1 to 20% by weight of disintegrating agent, 0.1 to 10% by weight of surface active agent, and 1 to 10% by weight of coating agent.
21. The use of the pharmaceutical composition of claim 17, wherein the pharmaceutical composition comprises a solution adjuvant.
22. The use of the pharmaceutical composition of claim 21, wherein the clopidogrel (+)- camphorsulfonate salt is contained in 0.1 to 95% by weight based on the total weight of the composition, and the solution adjuvant is contained in 5 to 99.9%by weight based on the total weight of the composition.
23. The use of the pharmaceutical composition of claim 22, wherein the clopidogrel (+)- camphorsulfonate salt is contained in 1 to 70% by weight based on the total weight of the composition, and the solution adjuvant is contained in 30 to 99%by weight based on the total weight of the composition.
24. The use of the pharmaceutical composition of claim 21, wherein the solution adjuvant is one or more selected from the group consisting of lauroly macrogolglyceride, stearoyl macrogolglyceride, propylene glycol caprylate and propyleneglycol monocaprylate, oleoyl macrogolglyceride, linoleoyl macrogolglyceride, Caprylocaproyl macrogol glycerides, propyleneglycol laurate and propyleneglycol monolaurate, glyceryl monolinorate, glyceryl monooleate, and polyglycerine oleate.
25. The use of the pharmaceutical composition of claim 17, wherein the pharmaceutical composition is an oral administration agent.
26. A method for preventing and treating platelet related disorder comprising administering a pharmaceutical composition comprising the crystalline clopidogrel (+)-camphorsulfonate salt of claim 1 to a mammal in need of the prevention or treatment.
27. The method of claim 26, wherein the clopidogrel (+)-camphorsulfonate salt is contained in
0.1 to 95% by weight based on the total weight of the composition.
28. The method of claim 27, wherein the clopidogrel (+)-camphorsulfonate salt is contained in 1 to 50% by weight based on the total weight of the composition.
29. The method of claim 26, wherein the composition comprises 30 to 50% by weight of excipient, 1 to 20% by weight of binder, 1 to 20% by weight of disintegrating agent, 0.1 to 10% by weight of surface active agent, and 1 to 10% by weight of coating agent.
30. The method of claim 26, wherein the pharmaceutical composition comprises a solution adjuvant.
31. The method of claim 30, wherein the clopidogrel (+)-camphorsulfonate salt is contained in 0.1 to 95% by weight based on the total weight of the composition, and the solution adjuvant is contained in 5 to 99.9%by weight based on the total weight of the composition.
32. The method of claim 31, wherein the clopidogrel (+)-camphorsulfonate salt is contained in 1 to 70% by weight based on the total weight of the composition, and the solution adjuvant is contained in 30 to 99%by weight based on the total weight of the composition.
33. The method of claim 30, wherein the solution adjuvant is one or more selected from the group consisting of lauroly macrogolglyceride, stearoyl macrogolglyceride, propylene glycol caprylate and propyleneglycol monocaprylate, oleoyl macrogolglyceride, linoleoyl macrogolglyceride, Caprylocaproyl macrogol glycerides, propyleneglycol laurate and propyleneglycol monolaurate, glyceryl monolinorate, glyceryl monooleate, and polyglycerine oleate.
34. The method of claim 26, wherein the pharmaceutical composition is an oral administration agent.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2006-0089694 | 2006-09-15 | ||
| KR20060089694 | 2006-09-15 | ||
| KR20070064519 | 2007-06-28 | ||
| KR10-2007-0064519 | 2007-06-28 |
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| Publication Number | Publication Date |
|---|---|
| WO2008032995A1 true WO2008032995A1 (en) | 2008-03-20 |
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ID=39183993
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2007/004441 WO2008032995A1 (en) | 2006-09-15 | 2007-09-14 | Clopidogrel(+)-camphorsulfonate salt, method of preparing the same and a pharmaceutical composition comprising the same |
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| Country | Link |
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| WO (1) | WO2008032995A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6800759B2 (en) * | 2002-08-02 | 2004-10-05 | Teva Pharmaceutical Industries Ltd. | Racemization and enantiomer separation of clopidogrel |
| WO2005100364A1 (en) * | 2004-04-19 | 2005-10-27 | Krka, Tovarna Zdravil, D.D. Novo Mesto | Processes for the preparation of clopidogrel hydrogen sulfate polymorphic form i |
| WO2006091847A2 (en) * | 2005-02-24 | 2006-08-31 | Teva Pharmaceutical Industries Ltd. | Clopidogrel base suitable for pharmaceutical formulation and preparation thereof |
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2007
- 2007-09-14 WO PCT/KR2007/004441 patent/WO2008032995A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6800759B2 (en) * | 2002-08-02 | 2004-10-05 | Teva Pharmaceutical Industries Ltd. | Racemization and enantiomer separation of clopidogrel |
| WO2005100364A1 (en) * | 2004-04-19 | 2005-10-27 | Krka, Tovarna Zdravil, D.D. Novo Mesto | Processes for the preparation of clopidogrel hydrogen sulfate polymorphic form i |
| WO2006091847A2 (en) * | 2005-02-24 | 2006-08-31 | Teva Pharmaceutical Industries Ltd. | Clopidogrel base suitable for pharmaceutical formulation and preparation thereof |
Non-Patent Citations (1)
| Title |
|---|
| ENJALBERT R. ET AL.: "Crystal and molecular structure of methyl a-6,7-dihydrothieno[3,2-c]pyrid-5-(4aH)-yl(o-chlorophenyl)acetate camphosulfonate. Absolute configuration", ZEITSCHRIFT FUER KRISTALLOGRAPHIC, vol. 188, no. 1-2, 1989, pages 85 - 93 * |
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