WO2006044548A2

WO2006044548A2 - Clopidogrel compositions

Info

Publication number: WO2006044548A2
Application number: PCT/US2005/036835
Authority: WO
Inventors: Mamta Mishra; Arunava Ghosh; Gurvinder Singh; Billa Praveen Reddy; Mailatur Sivaraman Mohan; Indu Bhushan; Prasada Raju Venkata Naga Kali Vara Vetukuri; Sreenadhacharyulu Kandala
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2004-10-14
Filing date: 2005-10-14
Publication date: 2006-04-27
Also published as: WO2006044548A3; EP1802280A2; EP1802280A4

Abstract

The invention provides clopidogrel base premixes with pharmaceutical excipients, pharmaceutical formulations containing the premixes, and their use in treatment of thrombotic disorders.

Description

CLOPIDOGREL COMPOSITIONS

INTRODUCTION TO THE INVENTION

The present invention relates to premix compositions comprising clopidogrel and a pharmaceutically acceptable excipient, and processes for the preparation of the premix compositions. The invention further relates to pharmaceutical dosage forms, medicaments and products containing the premix and processes for preparing the same. The invention also discloses therapeutic uses and methods of treatment employing the premix composition comprising clopidogrel or such pharmaceutical dosage forms, medicaments or products.

Atherosclerosis is the buildup of plaque in the wall of the arteries leading to thickening and reduction in the elasticity of the arteries. Atherosclerosis results from injury to the inside layer of the artery. The injury is caused by common activities and diseases such as high cholesterol, high blood pressure, smoking, and infections.

Plaques form on the inner walls of the arteries at the sites of injury to the blood vessels. The plaques are mainly composed of fatty tissue and smooth muscle cells. The formation of plaque often leads to blood clotting due to platelet aggregation at the site of injury. This clotting may result in a reduction or elimination of blood flow to vital organs causing heart attacks or other serious conditions. The plaque may also rupture and send a blood clot through the artery, referred to as an embolus, which if deposited in a smaller blood vessel may completely block blood flow to the organ which it supplies blood. Antiplatelet activity is desirable in inhibiting the often-fatal results of atherosclerosis.

Clopidogrel is an inhibitor of induced platelet aggregation and acts by inhibiting the binding of adenosine diphosphate to its receptor. Clopidogrel is metabolized by the liver into the active form. It shows antiplatelet activity for a duration of about ten days after medication has been stopped. Clopidogrel has the chemical name S-(+)-methyl- (2-chlorophenyl)-(6,7- dihydro-4H-thieno [3,2-C] pyrid-5-yl) acetate, or (+)-(S)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate, and has structural Formula I.

Formula I

Clopidogrel is a well known antithrombotic agent commercially available as PLAVIX™ tablets which contain about 98 mg of clopidogrel hydrogen sulfate (the molar equivalent of 75 mg of clopidogrel base).

Clopidogrel is disclosed in U.S. Patent Nos. 4,529,596 (EP 0099802, JP 59027895) and 6,258,961. U.S. Patent No. 4,529,596 discloses a racemic mixture of clopidogrel and processes for preparing such mixture. U.S. Patent No. 5,036,156 (EP 0420706, JP 3120286), U.S. Patent Nos.

6,080,875 (EP 0971915, JP 2001513806), and 6,180,793 (EP 0981529, IP 2001525829), and French Patent 2769313 are all incorporated herein by reference for their disclosure and preparation of clopidogrel.

U.S. Patent No. 5,036,156 discloses a method for preparing an intermediate in the synthesis of clopidogrel, 2-chloro-a-bromophenylacetic acid, and a process for condensing its methyl ester with tetrahydrothienopyridine.

French Patent No. 2769313 discloses an intermediate in the synthesis of clopidogrel, (R)-2-benzenesulfonyloxy-2-(2-chlorophenyl)acetic acid methyl ester, and processes for its preparation. This document further discloses converting the ester to clopidogrel by nucleophilic substitution with tetrahydrothienopyridine.

U.S. Patent No. 5,036,156 discloses preparation of pyridine derivatives by reacting a benzaldehyde with tribromomethane and potassium hydroxide in water and in the presence of an inert solvent.

European Patent 0 281 459 B describes crystalline Form 1 of (+)- clopidogrel bisulfate and European Patent Application 1 087 976 A describes its crystalline Form 2.

PCT application WO 2004/026879 describes amorphous clopidogrel and its salts, pharmaceutically acceptable preparations containing amorphous clopidogrel with a homo- or co-polymer of N-vinyl pyrrolidone and methods to prepare and use them. Amorphous clopidogrel, specially in the form of a complex with a homo- or co-polymer of N-vinyl pyrrolidone, is said to have several advantages over the crystalline clopidogrel salts, such as improved stability, higher solubility, non- hygroscopicity and improved processability. The application describes the preparation of the complexes through the co-dissolution of the clopidogrel base (either directly as a base or generated in situ through the addition of an acid to a solution of clopidogrel bisulfate) and the N-vinyl pyrrolidone polymer followed by evaporation of solvent to form a dry residue. Example 6 of PCT application WO 2004/026879 describes the conversion of clopidogrel base into a complex with polyvinylpyrrolidone. There is a need for a composition containing clopidogrel base which is free- flowing and which is amenable for use in the preparation of pharmaceutical compositions. The provision of such a free-flowing solid formulation of clopidogrel base would provide a much needed alternative to the use of the presently available crystalline salt forms of the drug.

SUMMARY OF THE INVENTION

The present invention relates to a premix composition comprising clopidogrel base and a pharmaceutically acceptable excipient and processes for the preparation of the premix composition.

The invention further relates to pharmaceutical dosage forms, medicaments and products containing the clopidogrel base premix and processes for preparing the same.

The invention also relates to clopidogrel base premixes and pharmaceutical compositions thereof comprising clopidogrel base having polymorphic stability.

Clopidogrel base in accordance with an aspect of the present invention is substantially free from crystalline clopidogrel.

In one embodiment, a premix composition containing clopidogrel is prepared by adsorbing a solution comprising clopidogrel base onto a pharmaceutical excipient or a mixture of pharmaceutical excipients and then removing solvent. The premix can be used directly, or used in combination with additional excipients to prepare desired pharmaceutical dosage forms. -A-

The invention further includes use of the clopidogrel base premix and the pharmaceutical compositions containing the premix in the treatment of disease conditions.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an X-ray diffraction pattern of a clopidogrel base premix. Fig. 2 is an X-ray diffraction pattern of tablets containing a clopidogrel base premix. Fig. 3 is an X-ray diffraction pattern of placebo tablets.

DETAILED DESCRIPTION

All the reports in the literature to date about clopidogrel are centered on the development of either novel polymorphs of clopidogrel bisulphate or the development of amorphous clopidogrel bisulphate. The use of clopidogrel base as an active pharmaceutical ingredient for developing a pharmaceutical dosage form has not been explored due to the inherent problems associated with the physical state in which clopidogrel base occurs. Clopidogrel base occurs as an amorphous semisolid paste-like mass. Hence the utilization of clopidogrel base as an active pharmaceutical ingredient in pharmaceutical dosage forms requires that the clopidogrel base be processed so as to render it suitable for further processing to develop a dosage form.

Conversion of clopidogrel base into a free-flowing powder with predefined characteristics suitable for its direct use as a medicament or which would allow its use in processing into pharmaceutical compositions, and this has been a major challenge faced by the pharmaceutical scientist.

The present inventors have surprisingly found that clopidogrel base when processed together with certain pharmaceutically acceptable excipient(s) in the presence of solvent(s) allows the formation of a premix product containing clopidogrel base, with enhanced stability. This premix, is easily isolated in the form of stable, free-flowing granules, which exhibit good processing characteristics and can be easily and conveniently processed into pharmaceutical compositions (such as, for example, tablets, capsules, and the like). "Premix" as in the invention refers to a solid composition, generally powders or granules, of clopidogrel base adsorbed onto at least one pharmaceutically acceptable excipient that is compatible with clopidogrel base. The flowability, processability and other characteristics of the clopidogrel base premix of the invention can be readily controlled through the choice of appropriate pharmaceutically acceptable excipients onto which the clopidogrel base is adsorbed. Thus, for example, the particle size and distribution of the clopidogrel base premix of the invention can be readily controlled by the proper choice of the pharmaceutically acceptable excipient(s) with a defined particle size and distribution. Subsequent processing, during which the clopidogrel base is adsorbed onto these excipients is generally does not result in a significant change in the particle size and distribution of the final premix. Thus, if a larger particle size premix is required, an excipient having the required large particles should be appropriately chosen and vice versa if a smaller particle size premix is desired. Mixing of more than one particle size excipient species is within the scope of the invention. Also, included are mixtures of premixes of clopidogrel base wherein the excipients onto which the clopidogrel base has been adsorbed, are different.

The clopidogrel base premix typically has a weight ratio of clopidogrel base to the pharmaceutically acceptable excipient from about 1 :1 to about 1 :10. The pharmaceutically acceptable excipient can be a mixture of more than one excipients.

In one embodiment of the present invention, the solid-state physical properties of clopidogrel base such as for example, the flowability and handling of the semisolid mass, are significantly modified. Clopidogrel base occurs as a semisolid mass which is difficult to handle and to process into a pharmaceutical formulation. The flowability of the clopidogrel base is significantly enhanced by its conversion into the premix according to this invention.

Flowability of materials is measured and represented using the Carr Index. The Carr Index is the percent ratio of the difference between tapped density and bulk density to tapped density described as:

Carr Index = [(Tapped density - Bulk density) ÷ Tapped density] x 100% The densities can be determined using the standard test method 616 (Bulk Density and Tapped Density) of United States Pharmacopeia 24, United States Pharmacopeial Convention, Inc., Rockville, Maryland, U.S.A., 1999.

Carr Index values below about 15% represent materials with very good flow properties and values above about 40% represent materials with very poor flow properties. The clopidogrel base premix of the present invention has a Carr Index which is substantially lower than the 40% described for products with poor flow properties. Values for Carr Index for the clopidogrel premix of the invention are generally less than about 35%, or less than about 30%, or less than about 25%, or less than about 20%, or less than about 15%. This indicates significantly improved flowability for the clopidogrel base through its conversion into a premix when compared with the clopidogrel base alone, which is a sticky semisolid material that does not flow when poured from a vial. Such a significant improvement in the flow properties of a material indicates superior handling capabilities during processing into pharmaceutical dosage forms.

Another important solid-state property of a pharmaceutical compound is its rate of dissolution in an aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach or in intestinal fluids can have therapeutic consequences because it affects the rate at which an orally-administered active ingredient reaches the bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid-state form of a compound may also affect its behavior on compaction and its storage stability.

The clopidogrel base in the form of the premix of the invention can be used to prepare pharmaceutical products having rapid release of the clopidogrel base into the digestive system of a patient.

In one of the embodiments of the invention, a process for the manufacture of a clopidogrel base premix is provided, which comprises:

1. dissolving clopidogrel base in a suitable solvent or solvent mixture, optionally in the presence of other additives, to provide a solution; 2. adsorbing the solution onto a solid excipient or a mixture of excipients to form a wet mass; and

3. drying the wet mass to form a dry premix.

The organic solvents suitable for the preparation of the clopidogrel base solution include but are not limited to alcohols, such as, for example, ethanol and isopropanol, water, acetic acid, acetone, anisole, ethyl acetate, isopropyl acetate, and the like, including mixtures thereof.

Any organic solvent is acceptable as long as the solvent is volatile (allowing substantially complete removal from the clopidogrel base premix), is a good solvent for the clopidogrel base and is compatible with the clopidogrel at the temperatures of processing. The temperature of the solvent can be raised to achieve complete solubilization of the clopidogrel base in the solvent(s), and/or to achieve a higher solute concentration. Frequently, it will be desired to use a solvent that will not extensively dissolve a solid excipient that is used for adsorbing the solution, or at least one member of a mixture of such excipients.

The concentration of clopidogrel base in the solution can be any concentration desired by the process operator, but is generally in the range of about 100 to 300 mg/ml, or about 145 to 300 mg/ml, or about 290 to 300 mg/ml. Of course, higher concentrations of the clopidogrel base in the solution will result from lower amounts of solvent(s) that are utilized, and this is usually desired to maximize clopidogrel concentration in the final premix. The concentration of the clopidogrel base in the solvent(s) will be determined by the solubility in the solvent(s), temperature of dissolution, compatibility, ease of solvent removal and other parameters that are readily apparent to a person skilled in the art. The clopidogrel base solution can optionally also contain other pharmaceutically acceptable additives such as, without limitation thereto, an antioxidant such as butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, and the like; an oil; a povidone; and mixtures of two or more additives. Useful excipients for adsorbing the clopidogrel solution to prepare the premix include, but are not limited to: diluents like starch, pregelatinized starch, lactose, mannitol, sorbitol, xylitol, sucrose, dextrates, dextrin, dextrose, microcrystalline cellulose, powdered cellulose, calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, and mixtures thereof; disintegrants like starch, pregelatinized starch, alginic acid, sodium alginate, crospovidone, sodium starch glycolate, croscarmellose and mixtures thereof; binders such as starches, microcrystalline cellulose, methylcellulose, cellulose ethers, sodium carboxymethylcellulose, ethylcellulose, dextrose, lactose, sucrose, sorbitol, mannitol, polyethylene glycol, polyvinylpyrrolidone, pectins, gelatin, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, and mixtures thereof; this list is not intended to be comprehensive, as many other excipient substances are useful in the invention. In many instances, a permix will contain at least one member of two or more different excipient classes.

The solution of clopidogrel base in the organic solvent is adsorbed onto an excipient or a mixture of excipients, typically using equipment such as a rapid mixer granulator, planetary mixer, mass mixer, ribbon mixer, fluid bed processor, and the like to achieve uniformity. The clopidogrel base solution can be added to the mixture of excipients rapidly or gradually, as desired. The mode of addition could be, for example, simple pouring or more refined techniques such as pumping using a positive displacement pump or sprinkling or spraying onto the surface of the mixture of excipients. Other techniques known to those skilled in the art for mixing solutions with solid substances are all included herein without limitation. The solution containing clopidogrel base in the solvent can be added to the excipient or mixture of excipients either at the temperature of solubilization or at another temperature, as desired.

The wet mass thus produced is dried to provide the clopidogrel base premix of the invention. The drying conditions are adjusted such as to obtain a desired solvent content, such as about 0.5-3 percent by weight, using any drying method such as, for example, tray drying, fluid bed drying, rotary cone vacuum drying, agitated thin film drying, lyophilization, and the like. Other methods of drying are all included herein without limitation. The drying temperature can frequently be made lower by applying a reduced pressure.

Clopidogrel base used in the present invention can be obtained by techniques and processes known to a person skilled in the art. Such processes include, for example, dissolution of any clopidogrel salt in a suitable organic solvent or mixture of solvents followed by neutralization of acidic components to provide the free base required for the invention. Other processes to convert a salt form of clopidogrel into its free base could also be used.

The salts of clopidogrel which find use in the conversion to the base required for the invention include, without limitation, any pharmaceutically acceptable salt of clopidogrel and include, for example, salts with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, or phosphoric acids and the like; salts with organic acids such as, for example, aliphatic mono- and di- carboxylic acids, phenyl-substituted acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids; and the like. Such salts with organic acids include for example acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methyl benzoate, o-acetoxybenzoate, naphthalene-2-benzoate, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, oxalate, phthalate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propionate, phenyl propionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1- sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like. Other salts of clopidogrel are also within the scope of the invention without limitation.

The clopidogrel base premix of the invention can be further processed into various pharmaceutical dosage forms as is, or by combining with pharmaceutically acceptable excipients. The different pharmaceutical dosage forms where the clopidogrel premix of the invention finds utility include, for example, tablets, capsules (hard and soft gelatin), granules, lozenges, sachets, pills, oral solutions, suspensions, and the like. Other pharmaceutically acceptable additives may be utilized as required for conversion of the premix into the final pharmaceutical dosage form and include, for example, diluents, lubricants, glidants, disintegrating agents, wetting agents, and the like. Useful pharmaceutically acceptable excipients include all of those excipients which are compatible with clopidogrel base, a number of which have been previously mentioned, for example as clopidogrel adsorbents. The various excipients include diluents or fillers such as sugar alcohols having 1-6 carbon atoms, saccharides, including monosaccharides and disaccharides, or cellulose and cellulose derivatives, disintegrants such as cellulose derivatives, both cross- linked or non cross-linked, disintegrants, and lubricants such as oils, waxes, stearates, metal oxides, and the like.

Useful sugar alcohols include mannitol, erythritol, sorbitol, xylitol, lactitol, maltitol etc. Useful disaccharides include lactose, sucrose, maltose, etc. Useful monosaccharides include dextrose. Useful disintegrants include micro-crystalline cellulose, powdered cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, and low substituted hydroxypropyl cellulose. Useful lubricants include stearic acid, magnesium stearate, zinc stearate, colloidal silicon dioxide, talc and the like.

The foregoing descriptions of excipients is not intended to be exhaustive. Those skilled in the art will be aware of many other substances that are useful in the practice of the invention, and the use of such substances is specifically included in this invention. Clopidogrel premix is useful to prepare pharmaceutical compositions that can be administered for the treatment, alleviation or amelioration of the symptoms or complications associated with thrombotic disorders. Thrombotic disorders are due to the formation or presence of a blood clot within a blood vessel due to prior and acute myocardial infarction, unstable and stable angina, acute reocclusion after percutaneous transluminal coronary angioplasty (PTCA), restenosis, thrombotic stroke, prior transient ischemic attack (TIA) and reversible ischemic neurological deficit (RIND). Clopidogrel premix according to the present invention prevents the onset of the symptoms or complications associated with thrombotic disorders. It also prevents the recurrence of secondary ischemic events following a primary ischemic event.

Pharmaceutical compositions containing clopidogrel premix can optionally be administered with one, or more than one, other therapeutic agents in the treatment of thrombotic disorders including, but not limited to, salicylates such as aspirin, angiotensin Il receptor antagonists such as candesartan, valsartan, eprosartan, losartan, irbesartan, saprisartan, zolasartan, saralasin, telmisartan, tasosartan, isoteoline, HMG CoA reductase inhibitors such as atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, pitvastatin, fluindostatin, mevastatin, velostatin and dalvastatin and their pharmaceutically acceptable salts, solvates, hydrates, enantiomers thereof. The different antithrombotic agents are well known to those skilled in the art, and the use of any of them falls within the scope of the invention.

The clopidogrel base premix renders clopidogrel base amenable for processing into a pharmaceutical composition. The clopidogrel premix offers numerous advantages to the formulator. The base premix occurs as free flowing particles and thereby offers the advantage to the formulator to directly compress the particles thereby minimizing various unit operations as granulation, drying, milling, sieving and the like. The clopidogrel base premix has bulk density not less than about 0.3 g/ml, a tapped density (determined after about 300-1250 taps) not less than about 0.4 g/ml and a Carr index not more than about 40%. The enhanced flow property and density enables compression of clopidogrel base premix into tablets, with or without granulation, and filling into capsules or sachets.

To make certain solid dosage forms, the components are required to be in a finely divided form. The clopidogrel premix of the present invention can be subject to operations such as size reduction, particle size classification such as by sieving, blending with other components, and the like, without substantial alteration of the flow properties and other important features of the premix.

Clopidogrel base, present in the premix compositions, will generally be substantially free of crystalline forms of clopidogrel. Typically, crystalline clopidogrel will be present at less that about 5 percent by weight, or less than about 2 percent by weight, or less than about 1 percent by weight, in the premix. The clopidogrel base premix prepared according to the present invention and further processed into a pharmaceutical composition exhibits polymorphic stability. X-ray powder diffraction ("XRD") of the premix of Example 1 and a tablet prepared according to Example 2 and containing the premix, as shown in Figs. 1 and 2, respectively, exemplifies this. The XRD studies show that there were no extra peaks other than the tablet placebo peaks in clopidogrel premix and the clopidogrel tablets (XRD of clopidogrel tablet placebo, prepared according to Example 3 and not including any clopidogrel, is shown as Fig. 3). Thus, it can be seen that there is no significant change in the polymorphic form of clopidogrel in the premix after processing into the pharmaceutical composition.

In the figures, all of the XRD patterns were obtained using Cu Ka radiation (1.541 A wavelength).

Certain aspects of the preparation of the clopidogrel base premix and the various dosage forms that can be formulated with clopidogrel base premix are further illustrated by the following examples, which are not to be construed as limiting the invention. EXAMPLE 1

A clopidogrel base premix was prepared, using the following:

Manufacturing process:

1. Dissolved clopidogrel base and BHA in 725 grams of isopropanol, with stirring.

2. Sifted mannitol, lactose, microcrystalline cellulose and fumed silica through a 40 ASTM mesh sieve .

3. Mixed Step 1 solution with Step 2 material thoroughly.

4. Dried the wet material at 40-45⁰C until a loss on drying at 105⁰C of 1-2 percent by weight was achieved.

5. Sifted dried granules through a 24 ASTM mesh sieve.

EXAMPLE 2

Tablets containing 75 mg of clopidogrel were prepared from the following:

Manufacturing process:

1. Blended the lactose, microcrystalline cellulose, and fumed silica.

2. Added the clopidogrel premix and blended.

3. Added the magnesium stearate and blended, then compressed the mixture into tablets.

EXAMPLE 3

Placebo tablets were prepared from the following:

Manufacturing process:

1. Blended the lactose, microcrystalline cellulose, and fumed silica.

2. Blended with magnesium stearate for 5 minutes and compressed the mixture into tablets.

EXAMPLE 4

Tablets containing 75 mg of clopidogrel were prepared from the following:

Manufacturing process:

1. Blended the lactose, croscarmellose sodium, microcrystalline cellulose, and fumed silica.

2. Added the clopidogrel premix and blended.

3. Added the magnesium stearate and blended.

4. Compressed the blend into tablets.

EXAMPLE 5

Capsules containing 75 mg of clopidogrel were prepared from the following:

Manufacturing process:

1. Blended the croscarmellose sodium, fumed silica, and microcrystalline cellulose.

2. Added the clopidogrel premix and blended.

3. Added the magnesium stearate, blended, and filled the blend into capsules.

EXAMPLE 6

A large scale production of clopidogrel premix was undertaken, using the following:

Manufacturing process:

1. Clopidogrel base and BHA were charged to a reactor at 27.5°C ± 7.5⁰C along with isopropanol and mixed for 15 to 20 minutes until a clear solution was obtained.

2. The clear solution was transferred to bottles purged with nitrogen.

3. Mannitol, lactose, microcrystalline cellulose, and fumed silica were charged to a rapid mixer granulator and mixed for 10 to 15 minutes at slow impeller and chopper speed. 4. The solution from step 2 was slowly poured onto the dry blend of step 3 under a slow speed of the impeller and chopper, over 10 to 15 minutes.

5. The speed of the impeller and chopper was changed to a high speed for 10 to 15 minutes.

6. The wet mass was dried in a rotary vacuum drier at 40-45⁰C under 600 mm Hg vacuum for 2 to 3 hours, until loss on drying at 105⁰C was 0.71 %.

7. Dried material was packed in a triple laminated foil bag, and the bag was placed in a metallic container.

8. Material obtained from the above process had the following characteristics: off-white powder with an assay of 21.9% clopidogrel w/w; bulk density untapped 0.53 g/ml, and tapped 0.59 g/ml; Carr Index 10.5%; and a particle size distribution as follows:

EXAMPLE 7

Tablets containing 75 mg of clopidogrel were prepared using the following:

Manufacturing process:

1. Blended the lactose, microcrystalline cellulose, and fumed silica.

2. Added the clopidogrel premix and blended.

3. Added magnesium stearate and compressed the mixture into tablets.

EXAMPLE 8

Dissolution of tablets containing the clopidogrel premix prepared in

Example 2 and commercial PLAVIX tablets was compared, using the standard test method 711 (Dissolution) from United States Pharmacopeia 24, United States Pharmacopeial Convention, Inc., Rockville, Maryland U.S.A. (1999). Apparatus Il of the test was used, and the dissolution medium was 1000 ml of a pH 2 buffer, with stirring at 75 rpm and a temperature of 37⁰C. The results were as follows:

Tablets containing the clopidogrel base premix thus provide a rapid release of clopidogrel, comparable to that of the commercially available product.

EXAMPLE 9

A clopidogrel base premix was prepared, using the following:

Manufacturing process:

1. Dissolved clopidogrel base in 1350 grams of isopropyl alcohol with stirring.

2. Sifted microcrystalline cellulose and silicon dioxide through a 40 ASTM mesh sieve .

3. Adsorbed Step 1 solution by pouring onto the Step 2 mmixture.

4. Dried the wet material at 40-45⁰C until a loss on drying at 105⁰C of 1 -2% w/w was achieved.

5. Sifted dried granules through a 24 ASTM mesh sieve. EXAMPLE 10

A clopidogrel base premix was prepared, using the following:

Manufacturing process:

1. Dissolved clopidogrel base, BHA and soya oil in 150 grams of isopropyl alcohol with stirring.

3. Adsorbed the Step 1 solution by pouring onto the Step 2 mixture.

4. Dried the wet material at 40-45⁰C until a loss on drying at 105⁰C of 1-2% w/w was achieved.

5. Sifted dried granules through a 24 ASTM mesh sieve.

EXAMPLE 11

A clopidogrel base premix was prepared, using the following:

Manufacturing process:

1. Dissolved clopidogrel base and povidone in 75 grams of isopropyl alcohol with stirring.

3. Adsorbed Step 1 solution by pouring onto the Step 2 mixture.

5. Sifted dried granules through a 24 ASTM mesh sieve.

EXAMPLE 12

A clopidogrel base premix was prepared, using the following:

Manufacturing process:

1. Dissolved clopidogrel base and povidone in 112.5 grams of isopropyl alcohol with stirring.

2. Sifted microcrystalline cellulose , lactose and croscarmellose sodium through a 40 ASTM mesh sieve .

3. Adsorbed Step 1 solution by pouring onto the Step 2 mixture.

5. Sifted dried granules through a 24 ASTM mesh sieve. EXAMPLE 13 A clopidogrel base premix was prepared, using the following:

Manufacturing process:

1. Dissolved clopidogrel base and BHA in 120 grams of isopropyl alcohol with stirring.

3. Adsorbed Step 1 solution by pouring onto the Step 2 mixture.

5. Sifted dried granules through a 24 ASTM mesh sieve.

EXAMPLE 14

A clopidogrel base premix is prepared, using the following:

Manufacturing process:

1. Dissolve clopidogrel base in 75 grams of isopropyl alcohol with stirring.

2. Sift microcrystalline cellulose through a 40 ASTM mesh sieve.

3. Adsorb the Step 1 solution by pouring onto the Step 2 material. 4. Dry the wet material at 40-45⁰C until a loss on drying at 105⁰C of 1 - 2% w/w is achieved.

5. Sift dried granules through a 24 ASTM mesh sieve.

EXAMPLE 15

A clopidogrel base premix is prepared, using the following:

Manufacturing process:

1. Dissolve clopidogrel base in 100 grams of isopropyl alcohol with stirring.

2. Sift lactose through a 40 ASTM mesh sieve.

3. Adsorb the Step 1 solution by pouring onto the Step 2 mixture. 4. Dry the wet material at 40-45⁰C until a loss on drying at 105⁰C of 1 ^■

2% w/w is achieved.

5. Sift dried granules through a 24 ASTM mesh sieve.

Claims

CLAIMS:

1. A solid premix comprising clopidogrel base, adsorbed onto at least one pharmaceutically acceptable excipient.

2. The solid premix of claim 1 , wherein clopidogrel base is substantially free from crystalline forms of clopidogrel.

3. The solid premix of claim 1 , wherein a pharmaceutical excipient comprises a sugar alcohol, disaccharide, or cellulose derivative.

4. The solid premix of claim 1 , having a weight ratio of clopidogrel to pharmaceutical excipient about 1 :1 to about 1 :10.

5. The solid premix of claim 1 , having a Carr Index less than about 40%.

6. The solid premix of claim 1 , having a Carr Index less than about 25%.

7. The solid premix of claim 1 , having a Carr Index less than about 15%.

8. A pharmaceutical composition, comprising the solid premix of claim 1 and at least one pharmaceutically acceptable excipient.

9. The pharmaceutical composition of claim 8, in the form of a tablet, powder, lozenge, sachet, or cachet.

10. The pharmaceutical composition of claim 8, which is contained within a capsule.

11. A process for preparing a solid premix comprising: a) adsorbing a solution comprising clopidogrel base onto a solid pharmaceutically acceptable excipient, or mixture of excipients; and b) removing solvent.

12. The process of claim 11 , wherein a pharmaceutically acceptable excipient comprises a diluent.

13. The process of claim 11 , wherein a pharmaceutically acceptable excipient comprises cellulose or a cellulose derivative.

14. The process of claim 11 , wherein a pharmaceutically acceptable excipient comprises a sugar alcohol.

15. The process of claim 11 , wherein a pharmaceutically acceptable excipient comprises a saccharide.

16. The process of claim 11 , wherein a pharmaceutically acceptable excipient comprises a disaccharide.

17. The process of claim 11 , wherein the solution further comprises an antioxidant.

18. The process of claim 11 , wherein the solution further comprises an oil.

19. The process of claim 11 , wherein the solution further comprises povidone.

20. A method for treatment of the human or animal body comprising administering a pharmaceutical composition incorporating the solid premix of claim 1.

21. The method of claim 20, further comprising administering a second therapeutic agent for the treatment of thrombotic disorders.