GB2393181A

GB2393181A - Amorphous clopidogrel

Info

Publication number: GB2393181A
Application number: GB0221788A
Authority: GB
Inventors: Dharmaraj Ramachandra Rao; Rajendra Narayanrao Kankan
Original assignee: Cipla Ltd
Current assignee: Cipla Ltd
Priority date: 2002-09-19
Filing date: 2002-09-19
Publication date: 2004-03-24
Also published as: GB2407814A; AU2003269140A1; WO2004026879A1; GB0221788D0; KR20050071495A; GB0504151D0; DE10393290T5; RU2005110917A

Abstract

Clopidogrel, or a pharmaceutically acceptable salt thereof, eg. the bisulfate, in an amorphous form shows good stability characteristics in pharmaceutical formulations for treating thrombotic disorders.

Description

1 2393181

CLOPIDOGREL

The present invention relates to amorphous clopidogrel, pharmaceutical compositions, medicaments and products containing the same, processes for preparing amorphous clopidogrel and to therapeutic uses and therapeutic methods of treatment employing amorphous clopidogrel or such pharmaceutical compositions, medicaments or products.

Clopidogrel is the international non-proprietary name of methyl (S)-a-(2chlorophenyl)-6,7-

dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester. Clopidogrel is a well known antithrombotic agent and the preparation thereof is described in European patent 0099802B.

European patent 0281459B describes enantiomers of clopidogrel, in particular the preparation of the bisulfate salt of the (+), or dextro rotatory, form of clopidogrel, also known as clopidogrel bisulfate Form 1.

European patent application 1087976A describes a further polymorph of the bisulfate salt of the (+) form of clopidogrel, known as clopidogrel bisulfate Form 2.

Hitherto known crystalline salts of clopidogrel have exhibited certain disadvantages, in particular in terms of their low solubility and in connection with the pharmaceutical formulation thereof. Improvement in the physical characteristics associated with known clopidogrel salts would potentially offer a more beneficial therapy utilising clopidogrel and enhanced manufacturing capabilities therefor.

We have found that the problems associated with the known crystalline forms of clopidogrel can be reduced, or overcome, by using amorphous clopidogrel.

In one aspect, the invention provides amorphous clopidogrel and pharmaceutically acceptable salts thereof.

The term "pharmaceutically acceptable salt" as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Typical inorganic acids

used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzo ate, methylb enzo ate, o-acetoxyb enzo ate, naphthal ene-2 -

benzoate, bromide, isobutyrate, phenylbutyrate, beta -hydroxybutyrate, chloride, cinnamate, citrate, form ate, fumarate, glycol ate, heptanoate, lactate, mal eate, hydroxymal eate, mal onate, mesyl ate, nitrate, oxalate, phthal ate, phosphate, monohydro genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propi on ate, phenylpropionate, 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. A preferred salt is the bisulfate salt.

In one particularly preferred embodiment, the invention provides the bisulfate salt of the (+) form of clopidogrel, in an amorphous form.

The present invention also provides amorphous clopidogrel bisulfate having an X-ray diffraction pattern as shown in Figure 1.

The term "amorphous" as used herein denotes a physical state which is not crystalline and may be verified by X-ray diffraction and other means including but not limited to observation with a polarized light microscope and differential scanning calorimetry. More particularly, amorphous clopidogrel in accordance with the present invention is preferably essentially free from any crystalline form of clopidogrel.

Amorphous clopidogrel according to the present invention exhibits a number of advantages compared to crystalline forms of clopidogrel.

For example, our studies have indicated that amorphous clopidogrel according to the present invention is stable. It may be preferred, however, that conversion of amorphous clopidogrel according to the present invention to a crystalline form may be further obviated by the addition of any number of stabiliser materials known in the art, such as, for example, a PVP polymer, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyethylene glycol (PEG), cyclodextrin, and the like. Furthermore, in terms of stability, we have also demonstrated that amorphous clopidogrel according to the present invention is substantially non-hygroscopic.

In particular the present invention further provides amorphous clopidogrel substantially as hereinbefore described together with a PVP polymer and more particularly there is further provided by the present invention a pharmaceutically acceptable preparation comprising an effective amount of amorphous clopidogrel substantially as hereinbefore described, together with an excipient matrix comprising at least a homopolymer or copolymer of N-vinyl pyrrolidone, wherein said homopolymer or copolymer of N-vinyl pyrrolidone is complexed with said amorphous clopidogrel.

A homopolymer of N-vinyl pyrrolidone suitable for use according to the present invention can comprise water soluble polyvinylpyrrolidones, such as PVP K-12, PVP K-15, PVP K-17, PVP K-25, PVP K-30, PVP K-60, PVP K-90 and PVP K-120. Preferably PVP K-30, PVP K-

60 or PVP K-90 is employed according to the present invention, in particular PVP K-30.

Alternatively, a homopolymer of N-vinyl pyrrolidone suitable for use according to the present invention might comprise a water insoluble cross linked polyvinylpyrrolidone. A water insoluble cross linked polyvinylpyrrolidone that might be employed according to the present invention can include crospovidone.

Suitably, such complexes present in preparations according to the present invention are easily isolated in the form of stable powders which exhibit excellent handling properties.

Pharmaceutical preparations according to the present invention can, for example, be easily and conveniently processed into final dosage forms (such as tablets, capsules and the like) substantially as hereinafter described in greater detail without the need for substantial stabilising precautions during processing.

Amorphous clopidogrel according to the present invention can be further characterized as having a solubility in the range of about 0.2 to 0.3 g/ml in methanol, typically about 0.25 g/ml, which is approximately 1.5 times greater than the solubility of a crystalline form of clopidogrel. Advantages of increased solubility include, but are not limited to, improved bioavailability, ease in processing the amorphous material, ease in formulation and delivery of the material, and the like.

Amorphous clopidogrel according to the present invention also exhibits a low bulk density in the range of about 0.2 to 0.5 g/ml compared to crystalline forms exhibiting a density in the range of about 0.6 to 0. 9g/ml. This low density can offer further advantages in terms of formulation of dosage forms, for example milling operations might be avoided which in turn might lead to avoidance of racemisation due to heat sensitivity and / or abrasion.

Amorphous clopidogrel according to the present invention can also be further characterized as having a melting point in the range of 85 to 95 C, more typically in the range of 88 to 92 C and even more typically a melting point of about 90 C. Crystalline clopidogrel exhibits a melting point in the range of about 174 to 186 C.

As hereinbefore described, clopidogrel is an antithrombotic agent. More particularly, clopidogrel inhibits platelet aggregation.

Amorphous clopidogrel according to the present invention is therapeutically useful in the treatment of symptoms of, and / or occurrence of, thrombotic disorders in animal patients.

The term "treatment" as used herein denotes the management and care of an animal patient for the purpose of combating thrombotic disorders and includes the administration of amorphous clopidogrel of the present invention to prevent the onset of the symptoms or complications associated with thrombotic disorders, alleviating or ameliorating the symptoms or complications associated with thrombotic disorders, or substantially eliminating thrombotic disorders. The term "thrombotic disorders" as used herein denotes a disorder relating to, or affected with, the formation or presence of a blood clot within a blood vessel.

Thrombotic disorders include, but are not limited 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). Amorphous clopidogrel according to the present invention can be particularly suitable for use in the prevention of recurrence of secondary ischemic events following a primary ischemic event.

The present invention further provides for pharmaceutically acceptable compositions for administering to an animal patient, including humans, in need of treatment for thrombotic disorders, which comprises an effective amount of amorphous clopidogrel as described herein (optionally provided by a pharmaceutically acceptable preparation substantially as hereinbefore described), together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

As used herein, the term "effective amount" means an amount of amorphous clopidogrel which is capable of treating (for example inhibiting, alleviating, ameliorating or preventing) thrombotic disorders.

By "pharmaceutically acceptable preparation" it is meant that the excipient matrix component or components must be compatible with amorphous clopidogrel of the preparation, and not be deleterious to the recipient thereof.

By "pharmaceutically acceptable composition" it is meant that the carrier, diluent or excipient must be compatible with amorphous clopidogrel of the composition, and not be deleterious to the recipient thereof. Pharmaceutical compositions can be prepared by procedures known in the art. For example, amorphous clopidogrel of this invention can be formulated with common carriers, diluents or excipients, and formed into tablets, capsules, and the like.

Examples of carriers, diluents or excipients that are suitable for such compositions include the following: fillers and extenders; binding agents; moisturising agents; surface active agents; and lubricants. Final pharmaceutical forms may be: pills, tablets, powders, lozenges, sachets, cachets, or sterile packaged powders, and the like, depending on the type of excipient used.

The particular dosage of amorphous clopidogrel required to treat, inhibit, or prevent thrombotic disorders as described herein in an animal patient, including humans, will depend upon the particular thrombotic disease or condition, and the symptoms, and severity thereof.

Dosage, routes of administration, and frequency, of dosing is best decided by an attending physician. When the compositions of the invention are administered to an animal patient by the oral or parenteral route, it is typically preferable that the daily dose of amorphous clopidogrel is in the range of 50 and 100 ma.

Compositions according to the present invention are, however, preferably made so as to be administrable by the oral or parenteral route.

Pharmaceutical compositions of the present invention may be administered in unit forms, for example the forms for oral administration include tablets, gelatin capsules, powders, granules and oral solutions or suspensions.

When a solid composition in the form of tablets is prepared, amorphous clopidogrel can be mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arable and the like. The tablets can be coated with sucrose or other appropriate materials or alternatively they can be treated such that they have a prolonged or delayed activity and that they continuously liberate a predetermined quantity of amorphous clopidogrel. A preparation in the form of gelatin capsules can be obtained by mixing amorphous clopidogrel with a diluent and by pouring the mixture obtained into soft or hard gelatin capsules. The water-dispersible granules or powders may contain amorphous clopidogrel mixed with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as sweeteners or flavour enhancers.

For parenteral administration, aqueous suspensions, isotonic saline solutions, or sterile and injectable solutions, can be used which contain dispersing agents and/or wetting agents which are pharmacologically compatible, for example propylene glycol or butylene glycol.

Amorphous clopidogrel can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.

As a further embodiment of the invention, amorphous clopidogrel may be administered along with an effective amount of an additional therapeutic agent, including one or more further antithrombotic agents that might exhibit synergistic activity with amorphous clopidogrel according to the present invention. The different forms of these additional antithrombotic therapeutic agents available and the applicable dosing regimens are well known to those of skill in the art. The present invention, therefore, further provides a product containing amorphous clopidogrel and one or more further antithrombotic agents, for simultaneous, separate or sequential use in the treatment of thrombotic disorders, wherein suitably amorphous clopidogrel may be provided by a pharmaceutically acceptable preparation substantially as hereinbefore described for inclusion in the product.

The present invention further provides amorphous clopidogrel for use in the manufacture of a medicament for the treatment of thrombotic disorders as described herein. Again, the amorphous clopidogrel may suitably be present in a pharmaceutically acceptable preparation substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of thrombotic disorders as described herein.

The present invention also provides a method of treating thrombotic disorders in an animal patient in need of such treatment, which method comprises administering to the animal patient an effective amount of amorphous clopidogrel for treating thrombotic disorders in the animal patient. The amorphous clopidogrel employed in such a method may suitably be present in a pharmaceutically acceptable preparation or composition substantially as hereinbefore described.

Still further provided by way of the present invention are processes for the preparation of amorphous clopidogrel as herein described.

Amorphous clopidogrel according to the present invention is conveniently prepared by a process which constitutes a further feature of the present invention, and which comprises recovering clopidogrel from a solution thereof under conditions whereby an amorphous product is obtained.

The amorphous clopidogrel of the instant invention can be prepared by dissolving a crystalline form of clopidogrel in a suitable solvent or solvent mixture, such as, for example, methanol and / or water, followed by recovery of the material by any suitable means.

Techniques which may be employed to recover amorphous clopidogrel from the solution include those wherein the solvent is removed from the solution, preferably rapidly, and the product deposited. Methods involving the use of these procedures which have been found to be satisfactory include spray drying, roller drying, solvent precipitation, rotary evaporation, and freeze drying. Particularly preferred for the practice of the present invention are the methods of spray drying or rotary evaporation.

A preferred process according to the present invention comprises dissolving a first salt of clopidogrel (for example, clopidogrel (-) camphor-10-sulfonate) in crystalline form in a solvent or solvent mixture, converting the first clopidogrel salt (for example, clopidogrel (-) camphor-10-sulfonate) to the free base and subsequently to a second salt of clopidogrel (for example clopidogrel bisulfate) and recovering the second clopidogrel salt from the solution thereof under conditions whereby an amorphous product is obtained.

There is also provided by the present invention clopidogrel (-) camphor10-sulfonate in crystalline form, suitably for use as an intermediate in the preparation of amorphous clopidogrel, or a pharmaceutically acceptable salt thereof.

Solvents which may be employed in the practice of the present invention will be chosen according to the technique and conditions to be employed, and include water, methanol, ethanol, and the like, including mixtures thereof, if desired.

The concentration of crystalline clopidogrel in the solvent is typically in the range of about I to 300 mg/ml, preferably about 10 to 200 mg/ml. The solvents may, if desired, be heated as an aid to solubility and solvent removal.

Clopidogrel exhibits sufficient heat stability to withstand spray drying and the like, and accordingly, spray drying is the preferred method of recovery. Spray drying systems may be operated in a known manner to obtain an amorphous product essentially free from crystalline material as well as free from particulate contaminants.

The drying gas employed in a spray drying process according to the present invention can suitably be air, but other drying gases such as, for example, nitrogen, argon and carbon dioxide may be employed. The gas inlet temperature to the spray dryer is chosen according to the solvent employed, but would be, for example, in the range of from about 75 C to about 1 50 C, preferably in the range of from about 85 C to about 115 C.

Amorphous clopidogrel may also be combined with a number of other materials prior to or after spray drying, or otherwise processed to provide amorphous clopidogrel, which may in turn be further formulated for processing.

The present invention also provides a process of preparing a preparation substantially as hereinbetore described, which process comprises complexing an effective amount of amorphous clopidogrel substantially as hereinbefore described, with at least a homopolymer or copolymer of Nvinyl pyrrolidone.

Suitably, either or both of amorphous clopidogrel and the homopolymer or copolymer of N-

vinyl pyrrolidone is or are present in solution.

When amorphous clopidogrel is present in solution, we prefer to use a suitable organic solvent such as methanol, ethanol, isopropanol, acetone, ethyl acetate or any suitable solvent.

When the homopolymer or copolymer of N-vinyl pyrrolidone is in solution, suitable solvents include methanol, ethanol, isopropanol or any other suitable solvent.

When a complex present in a preparation according to the present invention is formed in solution, it is advantageously recovered from the solution for storage or use in solid form.

Thus, for example, solvent can be removed from the solution such as by evaporation, to cause the complex to precipitate. Other recovery methods can also be used such as, for example, spray drying. However, care needs to be taken not to expose the complex to temperatures at which amorphous clopidogrel might be degraded.

The present invention will now be further illustrated by the following Figure and Examples, which do not limit the scope of the invention in any way.

Figure I shows the powder X-ray diffraction pattern of amorphous clopidogrel prepared according to the present invention.

Example I

Preparation of Amorphous Clopidogrel Bisulfate Crystalline Clopidogrel bisulfate Form-2, 25g, was stirred in 100ml of methanol to obtain a clear solution. This solution was spray dried in a Lab Plant Spray Drier SD 05 with an inlet temperature of 90 C, outlet temperature of 70 C, compressed air rate of 0.3m3/hr and a teed rate of 8ml/min to obtain 1 8g of the title product.

The amorphous title product was characterised by powder X-ray diffraction.

Example 2

Preparation of Amorphous Clopidogrel Bisulfate Crystalline Clopidogrel bisulfate Form-1, 25g, was stirred in 500ml of water to obtain a clear solution. This solution was spray dried in a Lab Plant Spray Drier SD 05 with inlet temperature of 110 C, outlet temperature of 80 C, compressed air rate of 0.3m3/hr and a feed rate of 8ml/min to obtain 1 9g of the title product.

The amorphous title product was characterised by powder X-ray diffraction.

Example 3

Preparation of Amorphous Clopidogrel Bisulfate 20g of crystalline Clopidogrel Bisulfate Form-1 was dissolved in 60ml of methanol under stirring. Methanol was distilled off on a rotary evaporator under vacuum of 1-4 mbar at a temperature in the range of 50 - 55 C to obtain a foam. The foam was further dried on the rotary evaporator for 2 hours at a temperature in the range of 50 - 55 C, I mbar vacuum and the product unloaded.

The amorphous title product was characterised by powder X-ray diffraction.

Example 4

Preparation of Amorphous Clopidogrel Bisulfate 20g of crystalline Clopidogrel Bisulfate Form-2 was dissolved in 60ml of methanol under stirring. Methanol was distilled off on a rotary evaporator under vacuum of I - 4 mbar at a temperature in the range of 50 - 55 C, to obtain a foam. The foam was further dried on the rotary evaporator for 2 hours at a temperature in the range of 50 - 55 C, Imbar vacuum and the product unloaded.

The amorphous title product was characterised by powder X-ray diffraction.

Example 5

Preparation of Amorphous Clopidogrel Bisulfate 20g of Clopidogrel (-) camphor-10-sulfonate was taken in 100 ml of water and 100 ml of dichloromethane. To this was added 10% aq. sodium bicarbonate solution and the organic layer was separated. Concentration of the solvent yielded the base, which was dissolved in 100 ml of methanol and sulphuric acid 3g was added and the solution spray-dried as in Example 1 to obtain 11.5g of the title product.

The amorphous product was characterised by powder x-ray diffraction.

Example 6

Amorphous Clopidogrel base complex l Og of (+)Clopidogrel was dissolved in 50ml of methanol. To this was added a solution of 20g of polyvinyl pyrrolidone in lOOml of methanol, and the solvent was evaporated on a rotary evaporator under vacuum at about 50 C. After complete removal of the solvent, the residue was further kept under vacuum at 50 C for further 2 hours, when the title compound was obtained as a white foamy solid, which was removed and packed as a free flowing solid, assay 32%. The solid was characterized by x-ray diffraction.

Example 7

Preparation of a Pharmaceutical Formulation of Amorphous Clopidogrel Bisulfate A solid oral pharmaceutical formulation according to the present invention can be manufactured by any granulation process known in the art. The following is illustrative of one such process.

Ingredient Quantity/tablet (mg) Clopidogrel bisulfate 97.854 Pregelatinised starch 40.000 Microcrystalline cellulose 23.000 Lactose 95. 146 Colloidal silicon dioxide 3.000 Stearic acid 6.000 Coating material Hydroxypropyl methyl cellulose 6.475 Polyethylene glycol - 6000 0.700 Titanium dioxide 0.800

Red oxide of iron 0.025 Methylene chloride q.s.

Isopropyl alcohol q.s.

The amorphous Clopidogrel bisulfate was blended with the excipients and then lubricated with stearic acid. The resulting mixture was then compressed to form tablets and the resulting tablets were film coated.

Claims

CLAIMS:

1 Clopidogrel, or a pharmaceutically acceptable salt thereof, in an amorphous form.

2 The bisulfate salt of the (+) form of clopidogrel, in an amorphous form.

3 Amorphous clopidogrel bisulfate having an X-ray diffraction pattern as shown in Figure 1.

4 Amorphous clopidogrel according to any of claims 1 to 3, essentially free from any crystalline form of clopidogrel.

5 Amorphous clopidogrel according to any of claims I to 4, having a solubility in methanol in the range of about 0.2 to 0.3 g/ml.

6 Amorphous clopidogrel according to any of claims 1 to 5, having a density in the range of about 0.2 to 0.5g/ml.

7 A pharmaceutically acceptable preparation comprising an effective amount of amorphous clopidogrel according to any of claims 1 to 6, together with an excipient matrix comprising at least a homopolymer or copolymer of N-vinyl pyrrolidone, wherein said homopolymer or copolymer of N-vinyl pyrrolidone is complexed with said amorphous clopidogrel. 8 A pharmaceutically acceptable preparation according to claim 7, wherein said homopolymer or copolymer of N-vinyl pyrrolidone is selected from the group consisting of PVP K-12, PVP K-15, PVP K-17, PVP K-25, PVP K-30, PVP K-60, PVP K-90 and PVP K-

120.

9 A pharmaceutically acceptable preparation according to claim 8, wherein said homopolymer or copolymer of N-vinyl pyrrolidone is PVP K-30.

10 A pharmaceutically acceptable composition for administering to an animal patient in need of treatment for thrombotic disorders, which composition comprises an effective amount of amorphous clopidogrel according to any of claims l to 6, or as provided by a preparation according to any of claims 7 to 9, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

11 A pharmaceutically acceptable composition according to claim l O. wherein the thrombotic disorder to be treated is selected from the group consisting of prior and acute myocardial infarction, unstable and stable angina, acute reocclusion after percutaneous transluminal coronary angioplasty, restenosis, thrombotic stroke, prior transient ischemic attack and reversible ischemic neurological deficit.

12 A product containing amorphous clopidogrel according to any of claims l to 6, or as provided by a preparation according to any of claims 7 to 9, and one or more further antithrombotic agents, for simultaneous, separate or sequential use in the treatment of thrombotic disorders.

13 A product according to claim 12, wherein the thrombotic disorder to be treated is selected from the group consisting of prior and acute myocardial infarction, unstable and stable angina, acute reocclusion after percutaneous transluminal coronary angioplasty' restenosis, thrombotic stroke, prior transient ischemic attack and reversible ischemic neurological deficit.

14 Amorphous clopidogrel according to any of claims I to 6, or a preparation according to any of claims 7 to 9, for use in the manufacture of a medicament for the treatment of thrombotic disorders.

15 Use according to claim 14, wherein the thrombotic disorder to be treated is selected from the group consisting of prior and acute myocardial infarction, unstable and stable

angina, acute reocclusion after percutaneous transluminal coronary angioplasty, restenosis, thrombotic stroke, prior transient ischemic attack and reversible ischemic neurological deficit. 16 A method of treating thrombotic disorders in an animal patient in need of such treatment, which method comprises administering to the animal patient an effective amount of amorphous clopidogrel according to any of claims 1 to 6, or as provided by a preparation according to any of claims 7 to 9, for treating thrombotic disorders in the animal patient.

17 A process of preparing amorphous clopidogrel according to any of claims I to 6, which process which comprises recovering clopidogrel from a solution thereof under conditions whereby an amorphous product is obtained.

18 A process according to claim 17, which comprises dissolving a crystalline form of clopidogrel in a solvent or solvent mixture, followed by recovery of amorphous clopidogrel according to any of claims I to 6.

19 A process according to claim 18, which comprises dissolving a first salt of clopidogrel in crystalline form in a solvent or solvent mixture, converting the first clopidogrel salt to the free base and subsequently to a second salt of clopidogrel and recovering the second clopidogrel salt from the solution thereof under conditions whereby an amorphous product is obtained. 20 A process according to claim 19, wherein the first salt is clopidogrel (-) camphor-10-

sulfonate and the second salt is clopidogrel bisulfate.

21 A process according to claim 17, wherein recovery is by spray drying or rotary evaporation. 22 A process according to claim 18, wherein the solvent or solvent mixture comprises water and / or methanol.

23 A process according to claim 18, wherein the concentration of crystalline clopidogrel in the solvent or solvent mixture is in the range of about I to 300mg/ml.

24 A process according to claim 23, wherein the concentration of crystalline clopidogrel in the solvent or solvent mixture is in the range of about 10 to 200mg/ml.

25 A process of preparing a preparation according to any of claims 7 to 9, which process comprises complexing an effective amount of amorphous clopidogrel according to any of claims 1 to 6, with at least a homopolymer or copolymer of N-vinyl pyrrolidone.

26 Amorphous clopidogrel substantially as described in any of the Examples.