DESC:

The following specification particularly describes the invention and the manner in which it is to be performed.

INTRODUCTION

Aspect of the present invention relates to an improved process for the preparation of crystalline Form 1 of clopidogrel bisulphate.

BACKGROUND

The drug compound having the adopted name “clopidogrel bisulfate” can be represented by structural formula (I), and is a thienopyridine class inhibitor of P2Y12 ADP platelet receptors.

(I)
Chemically it is methyl (+)-(S)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)acetate sulfate (1:1) and it is the active ingredient in Plavix® (clopidogrel bisulfate) tablets, for the treatment of acute coronary syndrome (ACS) and recent MI, recent stroke, or established peripheral arterial disease.
U.S. Patent No. 4,529,596 discloses racemic clopidogrel and related compounds, including their pharmaceutically acceptable salts and enantiomers thereof, pharmaceutical compositions thereof and their use.

U.S. Patent No. 4,847,265 discloses dextro-rotatory isomer of clopidogrel and pharmaceutically acceptable salts thereof and its pharmaceutical composition.

The processes for the preparation of crystalline Form 1 of Clopidogrel bisulphate have been described in a number of references, including: (I) U.S. patent 6,429,210B1; (II) U.S. patent 6,767,913B2; (III) U.S. patent 7,714,133B2; (IV) U.S. patent 7,999,106B2; (V) U.S. patent 7,772,398B2; (VI) U.S. patent 7,291,735B2; (VII) U.S. patent application US20060047121A1; (VIII) U.S. patent application 20070142637A1 and (IX) U.S. patent application 2009093635A1.

The methods for the preparation of crystalline Form 1 of clopidogrel bisulphate described in the literature suffer from one or more drawbacks such as reproducibility and less yield which does not result an industrially feasible process.

Therefore, there is a need to provide simple, reproducible, environment friendly, cost effective, industrially feasible processes for the preparation of crystalline Form 1 of clopidogrel bisulphate.

SUMMARY

In an aspect, the present invention provides an improved process for the preparation of crystalline Form 1 of clopidogrel bisulphate comprising:

a) providing a solution of clopidogrel freebase in an alcoholic solvent;

b) treating the solution obtained in step a) with charcoal;

c) adding sulfuric acid to the solution obtained in step b);

d) adding halogenated hydrocarbon to the solution obtained in step c);

e) optionally seeding the solution obtained in step (d) with crystalline Form 1 of clopidogrel bisulphate; and

i) isolating the crystalline Form 1 of Clopidogrel bisulphate.

In an aspect, the present invention provides a process for packaging and storing clopidogrel bisulfate Form I with increased stability and shelf life, which includes placing clopidogrel bisulfate Form I in a sealed polythene bag along with a moisture adsorbent.

In an aspect, the invention provides packing conditions of crystalline Form 1 of clopidogrel bisulfate, which comprise the steps of:

a) placing crystalline Form 1 of clopidogrel bisulfate in innermost clear polythene bag under nitrogen atmosphere and tied with tag/plastic strip;

b) placing the innermost bag in a middle black polythene bag along with molecular sieves under nitrogen atmosphere and sealed;

c) placing the middle bag in triple laminated bag along with molecular sieves and sealed with a vacuuming nitrogen flushing & sealing machine sealer;

d) placing the above mentioned triple laminated bag in triple laminated bag along with molecular sieves and sealed with a vacuuming nitrogen flushing & sealing machine sealer; and

e) finally placing the triple laminated bag in High-density polyethylene (HDPE) container.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 depicts a PXRD pattern of a crystalline Form 1 of clopidogrel bisulfate.

Fig. 2 depicts a spherical particles of clopidogrel bisulfate.

DETAILED DESCRIPTION

In an aspect, the present invention provides an improved process for the preparation of crystalline Form 1 of Clopidogrel bisulphate comprising:

a) providing a solution of clopidogrel freebase in an alcoholic solvent;

b) treating the solution obtained in step a) with charcoal;

c) adding sulfuric acid to the solution obtained in step b);

d) adding halogenated hydrocarbon to the solution obtained in step c);

e) optionally seeding the solution obtained in step (d) with crystalline Form 1 of clopidogrel bisulphate; and

i) isolating the crystalline Form 1 of Clopidogrel bisulphate.

In embodiments, the clopidogrel freebase solution can be prepared by dissolving clopidogrel freebase in an alcoholic solvents. The suitable alcoholic solvents that may be used for the preparation of clopidogrel freebase solution include, but are not limited to, methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol; or mixtures thereof.
Clopidogrel freebase solution can also be obtained from the reaction mass of the previous stage.

In embodiments, the clopidogrel freebase solution can be prepared at any suitable temperatures, such as from about 0°C to about the reflux temperature of the solvent used.

In embodiments, clopidogrel freebase solution can be treated with charcoal, or any other suitable material to remove water, impurities and to improve the colour. In specific embodiment the clopidogrel freebase solution can be treated with degassed charcoal.

The solution obtained above may be filtered to remove insoluble particles if any. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

In embodiments, any source of sulfuric acid may be used for the preparation of clopidogrel bisulfate from clopidogrel free base. The source may be concentrated sulfuric acid, aqueous sulfuric acid or sulfuric acid in a solvent etc.

In embodiments, the sulfuric acid in a solvent can be prepared by adding alcoholic solvent to the sulfuric acid, alcoholic solvents that may be used for the preparation of sulfuric acid solution include, but are not limited to, methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol; or any mixtures of two or more thereof.

In embodiments, the sulfuric acid in a solvent can be prepared at any suitable temperatures, such as from about 0°C to about the room temperature of the solvent used. In specific embodiments, the sulfuric acid solution can be prepared at the temperature below 5°C.

In embodiments, clopidogrel bisulfate can be prepared by adding sulfuric acid to the clopidogrel freebase solution.

In embodiments, the sulfuric acid added to the clopidogrel free base solution at any suitable temperatures, such as from about 0°C to about 50°C for about 5 minutes to 2 hours or longer.

In embodiments, halogenated hydrocarbons can be added to the above obtained solution. The halogenated hydrocarbons can be added drop-wise or lot wise in one lot or more lots or rapidly. The halogenated hydrocarbons may be selected from the group consisting of dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene, or any mixtures thereof.

In embodiments, optionally the reaction mass can be seeded with clopidogrel bisulfate Form 1. The reaction mass maintained at about 0°C to about 50°C for about 30 minutes to about 18 hours, or longer for obtaining the suspension.

In embodiments, the clopidogrel bisulfate suspension can be further maintained at a temperature from about 0°C to about 30°C, the maintenance time may vary from about 30 minutes to about 8 hours, or longer. In general, yields of the crystalline product will be improved by maintaining the lowest temperatures that are above the freezing point of the solution, and by increasing the solute content of the solution.

In embodiments, crystalline clopidogrel bisulfate can be isolated using any techniques, such as decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the solid can be washed with a solvent, to reduce the amount of entrained impurities.

In embodiments, crystalline clopidogrel bisulfate may be washed with suitable solvent. Solvents that are useful in the reaction include, but are not limited to: C1-6 alcohols and saturated or unsaturated, linear or branched, cyclic or acyclic, C1 to C8 hydrocarbons; examples of such solvents include alcohols such as methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol; examples of such solvents include cycloalkanes, such as cyclopropane, cylobutane, cyclopentane and cyclohexane, n-pentane, n-hexane, n-heptane, methylcyclohexane, petroleum ether, or any mixtures thereof.

In embodiments, crystalline clopidogrel bisulfate can be dried in step-wise manner at about 25oC to about 110oC under atmospheric or reduced pressures for about 10 minutes to about 50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. Drying temperatures and times will be sufficient to achieve desired product purity. In specific embodiments, the crystalline clopidogrel bisulfate dried under vacuum for 3-8 hours at 40-50°C followed 3-8 hours at 55-65°C and then further dried for 3-8 hours at 85-100°C.

Fig. 1 provides the PXRD pattern of crystalline Form 1 of clopidogrel bisulfate obtained by the process of the present application.

In embodiments, crystalline Form 1 of clopidogrel bisulfate prepared according to the process of the present application can be substantially pure having a chemical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, by weight, as determined using high performance liquid chromatography (HPLC). Crystalline Form 1 of clopidogrel bisulfate produced by a method of present application can be chemically pure crystalline Form 1 of clopidogrel bisulfate having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC. Crystalline Form 1 of clopidogrel bisulfate produced by the methods of present application can be chemically pure crystalline Form 1 of clopidogrel bisulfate having purity greater than about 99.8% and containing no single impurity in amounts greater than about 0.1%, by HPLC.

In embodiments, the process described in this application can be useful to enhance the chemical purity of the crystalline Form 1 of clopidogrel bisulfate. In embodiments, the chemical purity of the crystalline Form 1 of clopidogrel bisulfate can be enhanced by initially converting the clopidogrel bisulfate into clopidogrel free base followed by adopting the same process described herein.

Crystalline Form 1 of clopidogrel bisulfate obtained according to a process of the present disclosure can be milled or micronized using any processes known in the art, such as ball milling, jet milling, wet milling, etc., to produce a desired particle size distribution and spherical shape. Spherical particle of clopidogrel bisulfate obtained according to certain processes of the present disclosure has a particle size distribution wherein: d(0.1) is less than about 100 µm or less than about 60 µm; d(0.5) is less than about 125 µm or less than about 95 µm; and d(0.9) is less than about 200 µm or less than about 160 µm. Particle size distributions can be determined using any means, including laser light diffraction equipment, coulter counters, microscopic procedures, etc. The term d(x) in a distribution means that a particular fraction has particles with a maximum size being the value given, 0.5 representing 50% of the particles and 0.9 representing 90% of the particles. Particle shape and size often has a significant influence on final product performance parameters such as flowability, abrasive efficiency, bioavailability etc, the crystalline polymorphic form I clopidogrel hydrogen sulfate having a bulk density is less than 0.8 gm/ml and tapped bulk density is less than 1 gm/ml.

In an aspect, the present invention provides a process for packaging and storing clopidogrel bisulfate Form I with increased stability and shelf life, which includes placing clopidogrel bisulfate Form I in a polythene bag along with a moisture adsorbent.

In an aspect, the invention provides packing conditions of crystalline Form 1 of clopidogrel bisulfate, which comprise the steps of:

a) placing Clopidogrel bisulfate form I in innermost clear polythene bag under nitrogen atmosphere and tied with tag/plastic strip;

b) placing the innermost bag in a middle black polythene bag along with molecular sieves under nitrogen atmosphere and sealed;

c) placing the middle bag in triple laminated bag along with molecular sieves and sealed with a vacuuming nitrogen flushing & sealing machine sealer;

d) placing the above mentioned triple laminated bag again in triple laminated bag along with molecular sieves and sealed with a vacuuming nitrogen flushing & sealing machine sealer; and

e) finally placing the triple laminated bag in HDPE container.

In embodiments, clopidogrel freebase which is used as the starting material can be prepared by any method, including methods known in the art. In embodiments, clopidogrel freebase which is used as the starting material can be a residue, any crystalline form, anhydrous or amorphous.

In embodiments, the present application provides pharmaceutical compositions containing a therapeutically effective amount of clopidogrel bisulfate, together with one or more pharmaceutically acceptable excipients. The pharmaceutical compositions comprising crystalline Form 1 of clopidogrel bisulfate of the application together with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms, such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze-dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate-controlling substances to form matrix or reservoir systems, or combinations of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated powder coated, enteric coated, or modified release coated.

Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to, any one or more of: diluents such as starches, pregelatinized starches, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic, cationic, and neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film-formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.

DEFINITIONS

The following definitions are used in connection with the disclosure of the present application, unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.

The following abbreviations and acronyms are used herein and have the indicated definitions:
An “alcoholic solvent” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.

"Clopidogrel freebase" is a free species of S enantiomer of (2-chlorophenyl) 6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester. It should be understood that there exist equilibrium between a free species and an acid addition salt form of a compound capable of forming acid addition salts. Thus, the presence of small amount of a salt form of clopidogrel in the starting solution described herein cannot be excluded.

“Petroleum ether” is a group of various volatile, liquid hydrocarbon mixtures used chiefly as nonpolar solvents. Chemically, it is not ether like diethyl ether, but a light hydrocarbon. Petroleum ether is commonly available as 30 to 40°C, 40 to 60°C, 60 to 80°C, 80 to 100°C, 80 to 120°C, and sometimes 100 to 120°C boiling fractions. The 60 to 80°C fraction is often used as a replacement for hexane. Petroleum ether is mostly used by pharmaceutical companies in the manufacturing process. The 30-40°C fraction of petroleum ether consists mainly of pentane, and is sometimes used instead of pentane due to its lower cost. Petroleum ether should not be confused with the class of organic compounds called ethers, which contain the R-O-R functional group.

The term "isolating" is used to indicate separation of the compound being isolated regardless of the purity of the isolated compound from any unwanted substance which presents with the compound as a mixture. Thus, degree of the purity of the isolated or separated compound does not affect the status of "isolating".
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES

Example 1: Preparation of a clopidogrel bisulfate Form-1
Clopidogrel freebase (40 g), 2-butanol (360 ml) and degassed charcoal (4 gm) were charged into a round bottom flask at 26°C. The reaction mass was stirred for 2 hours at 26°C and filtered. The filtrate was charged into reactor at 26°C and stirred at the same temperature for 15 minutes. The solution of sulfuric acid (6.3 gm) in 2-butanol (40 ml) was added slowly to the filtrate at 24°C for 30 minutes.

Dichloromethane (2 ml) and Clopidogrel bisulphate Form-1 (230 mg) as seeding materials were added to the filtrate and stirred for 6 hours at 24°C. The suspension was cooled to 19°C and stirred for 2 hours at the same temperature. The precipitated solid product was obtained by filtration and washed with 2-butanol (40 ml) and cyclohexane (15 ml). The compound was dried under vacuum for 5 hours at 45°C then for 5 hours at 60°C and further dried for 5 hours at 90°C. Yield: 11.5 g; HPLC purity: 99.90%.

Example 2: Preparation of a clopidogrel bisulfate Form-1
Clopidogrel freebase (40 g), 2-butanol (360 ml) and degassed charcoal (4 gm) were charged into a round bottom flask at 26°C. The reaction mass was stirred for 2 hours at 26°C and filtered. The filtrate was charged into reactor at 26°C and stirred at the same temperature15 minutes. The solution of sulfuric acid (6.3 gm) in 2-butanol (40 ml) was added slowly to the filtrate at 24°C for 20 minutes. Dichloromethane (2 ml) and Clopidogrel bisulphate Form-1 (230 mg) as seeding materials were added to the filtrate and stirred for 6 hours at 24°C. The suspension was cooled to 19°C and stirred for 1 hour. The precipitated solid product was obtained by filtration and washed with 2-butanol (40 ml) and cyclohexane (15 ml). The compound was dried under vacuum for 5 hours at 45°C then for 5 hours at 60°C and further dried for 5 hours at 90°C. Yield: 12.1 g; HPLC purity: 99.92%. ,CLAIMS:We Claim:

1. A process for the preparation of crystalline Form 1 of clopidogrel bisulphate comprising:

a) providing a solution of clopidogrel freebase in an alcoholic solvent;

b) treating the solution obtained in step a) with charcoal;

c) adding sulfuric acid to the solution obtained in step b);

d) adding halogenated hydrocarbon to the solution obtained in step c);

e) optionally seeding the solution obtained in step d) with crystalline Form 1 of clopidogrel bisulphate; and

i) isolating the crystalline Form 1 of clopidogrel bisulphate.

2. The process according to claim 1, wherein the alcoholic solvent is selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol; or mixtures thereof.

3. The process according to claims 1 and 2, wherein the alcoholic solvent is 2-butanol.

4. The process according to claim 1, wherein the halogenated hydrocarbon solvent is selected from dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene; or mixtures thereof.

5. The process according to claims 1 and 4, wherein the halogenated hydrocarbon solvent is dichloromethane.

6. A process for packing of clopidogrel bisulfate Form I comprising:

a) placing crystalline Form 1 of clopidogrel bisulfate in innermost clear polythene bag under nitrogen atmosphere and tied;

b) placing the innermost bag in a middle black polythene bag along with molecular sieves under nitrogen atmosphere and sealed;

c) placing the middle bag in triple laminated bag along with molecular sieves and sealed with a vacuuming nitrogen flushing and sealing machine sealer;

d) placing the above mentioned triple laminated bag in triple laminated bag along with molecular sieves and sealed with a vacuuming nitrogen flushing and sealing machine sealer; and

e) finally placing the triple laminated bag in High-density polyethylene (HDPE) container.

7. A spherical particle of clopidgrel bisulfate having a 10% volume particle diameter (d0.1) is less than 60 µm and 50% volume particle diameter (d0.5) is less than 90 µm and 90% volume particle diameter (d0.9) is less than 130 µm.

8. A process for the preparation of crystalline Form 1 of clopidogrel bisulphate comprising:

a) providing a solution of clopidogrel freebase in 2-butanol;

b) treating the solution obtained in step a) with charcoal;

c) adding sulfuric acid to the solution obtained in step b);

d) adding dichloromethane to the solution obtained in step c);

e) optionally seeding the solution obtained in step d) with crystalline Form 1 of clopidogrel bisulphate; and

i) isolating the crystalline Form 1 of clopidogrel bisulphate.