FORM 2
THE PATENT ACT 1970
(39 of l970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION (See section 10 and rule 13)
CRYSTALLINE FORM OF PRASUGREL HYDROBROMIDE AND PROCESS FOR THE PREPARATION THEREOF"


Glenmark Generics Limited an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenmark House.
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Giakala. Andheri (East), Mumbai - 400 099
The following specification describes the nature of the invention:


FIELD OF THE INVENTION
The present invention relates to crystalline form of prasugrel hydrobromide and process for the preparation thereof. The present invention also relates to a pharmaceutical composition comprising crystalline form of prasugrel hydrobromide.
BACKGROUND OF THE INVENTION
Description of the Related Art
Prasugrel is a P2Y12 (P2T) antagonist which has been filed for regulatory approval in the U.S, and approved in Europe for the secondary prevention of thrombotic cardiovascular complications. Prasugrel hydrochloride is chemically described as 5-[2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6J-tetrahydrothieno[3;2-c]pyridin-2-yl acetate and is represented by the structural formula below;

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Prasugrel hydrobromide is chemically described as 2-acetoxy-5-(.alpha. cyclopropylcarbony)-2-fluorobenzy))-4,5.6.7-tetrahydrothieno[3,2-c]pyndine hydrobromide and can be represented by structural formula:


U.S. Patent No. 5,288.726 describes tetrahydrothienopyridine derivatives, including prasugrel and their pharmaceutically acceptable salts, a pharmaceutical composition and method of treatment.
U.S. Patent No. 6,693,115 discloses crystal A. crystal Bl and crystal B2 of prasugrel hydrochloride and processes for the preparation thereof
E.P. Patent No. 2003136 describes crystal A, cryStal Bl and crystal B2 of prasugrel hydrochloride and processes for the preparation thereof.
The present invention provides crystalline form of prasugrel hydrobromide and a process for the preparation thereof.
The process of present invention is simple, ecofriendly, robust, and well suited on commercial scale.
SUMMARY OF THE INVENTION
The present invention relates to prasugrel hydrobromide and a process for the preparation thereof. More particularly, the present invention relates to a crystalline form of prasugrel hydrobromide.
In one aspect, the present invention provides a trvstalline form of prasusrel hydrobromide characterized by an X- ray powder diffraction pattern with characteristic peaks at about 7.06 ; 8.31, 10.08, 11.46, 12.19, 12.82, 13.73, 14.17, 15.8, 16.7, 16.98, 17.23, 17.73, 18.36, 18.70, 21.60, 23.42, 23.69, 24.21, 24.39. 24.9. 25.14, 25.82. 26.50. 27.0, 29.89, 30.31 and 37.2 ± 0.2 degrees two-theta, which is substantially in accordance with Figure 1.
The crystalline form of prasugrel hydrobromide of the present invention is further characterized by differentia! scanning calorimetry with an endotherm curve at about 138.25°C with an onset at about 128.29°C and an endset at about 146.34°C. which is substantially in accordance with Figure 2.
The crystalline form of prasugrel hydrobromide of the present invention is further characterized by infrared absorption spectrum which is substantial I v in accordance with Figure 3.
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In vet another aspect, the present invention provides a process for preparing crystalline form of Prasugrel Hydrobromide comprising:
a) providing a solution of prasugrel and hydrobromic acid in one or more solvents or aqueous mixtures thereof; and
(b) precipitating the solid by cooling or by adding a solvent; and
(c) recovering the prasugrel hydrobromide substantially in crystalline form.
In a further aspect, the present invention provides a pharmaceutical composition comprising crystalline form of prasugrel hydrobromide and at least a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES
Fig. 1: X-ray powder diffraction pattern of Prasugrel hydrobromide crystalline form
prepared by Example I. Fig. 2: Differential scanning calorimetry of Prasugrel hydrobromide crystalline form
prepared by Example 1. Fig. 3: is an infrared absorption spectrum of Prasugrel hydrobromide crystalline form
prepared by Example 1. Fig. 4 : is a MASS spectrum of Prasugrel hydrobromide prepared by Example I.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to prasugrel hydrobromide and a process for the preparation thereof. More particularly, the present invention relates to a crystalline form of prasugrel hydrobromide.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug.
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including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form, Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as. infrared spectrometry.
Such discoveries enlarge the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.
The present invention provides crystalline form of prasugrel HBr and process for preparation thereof, which is simple, ecofriendly, inexpensive, reproducible, robust and well suited on commercial scale.
The present invention provides a crystalline form of prasugrel hydrobromide characterized by an X- ray powder diffraction pattern with characteristic peaks at about 7.06 , 8.31, 10.08, 11.46, 12.19, 12.82, 13.73, 14.17, 15.8. 16.7, 16.98, 17.23, 17.73, 18.36, 18.70, 21.60, 23.42, 23.69, 24.21, 24.39, 24.9. 25.14, 25.82, 26.50, 27.0, 29.89. 30.31 and 37,2 ± 0.2 degrees two-theta, which is substantially in accordance with Figure I. The crystalline form of prasugrel hydrobromide of the present invention is further characterized by differential scanning calorimetry with an endotherm curve at about ]38.25°C with an onset at about I28.29°C and an endset at about !46,34°C, which is substantially in accordance with Figure 2.
The crystalline form of prasugrel hydrobromide of the present invention is further characterized by infrared absorption spectrum which is substantially in accordance with Figure 3.
In yet another aspect, the present invention provides a process for preparing crystalline form of Prasugrel Hydrobromide comprising:
a) providing a solution of prasugrel and hydrobromic acid in one or more solvents or aqueous mixtures thereof; and
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(b) precipitating the solid by cooling or by adding a solvent; and
(c) recovering the prasugrel hydrobromide substantially in crystalline form.
The solution of prasugrel and hydrobromic acid can be obtained by dissolving prasugrel and hydrobromic acid either separately or together in a solvent or mixture of solvents or their aqueous mixtures, either by agitation at room temperature or at elevated temperatures.
As used herein, a solvent is any liquid substance capable of dissolving prasugrel and hydrobromic acid.
As used herein a mixture of solvents refers to a composition comprising more than one solvent.
The solvents that can be used include: but are not limited to water, alcohols such as methanol, ethanol, n-propanol. isopropanol, n-butanol, isobutanoh and tertiary butyl alcohol and the like; ketonic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-butanone and the like; nitrile solvents such as acetonitrile, propionitrile and the like; or mixtures thereof or their aqueous mixtures in various proportions without limitation. Preferably, acetone or acetonitrile or their aqueous mixtures.
The volume of the solvent used to solubilize prasugrel and hydrobromic acid can range from about 2 volumes to about 20 volumes to the weight of the prasugrel free base taken, preferably from about 15 volumes to about 18 volumes.
The molar ratio of hydrobromic acid to prasugrel is preferably about 1:1 to about 1:1.2.
The hydrobromic acid used herein can be of any percentage and in any form, either as a gas or in solution.
The temperature for obtaining a clear and homogenous solution can range from about 25°C to about 75°C or the boiling point of the solvent/s used, preferably from about 25°C to about 40°C.
The solution obtained is optionally filtered through celite or diatomaceous earth to separate the extraneous matter present or formed in the solution by using conventional filtration techniques known in the art.
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Recovery of crystalline form of prasugrel hydrobromide obtained by the above process, can be performed by any conventional method, such as nitration, decantation and centrifugation, known in the art.
Preferably, recovery comprises filtering, washing, and drying the solid. Washing is usually done with the same solvent used in the reaction.
The crystalline form of prasugrel hydrobromide obtained by the above process may be further dried in. for example, vacuum tray dryer, rotocon vacuum dryer, vacuum paddle dryer or pilot plant rotavapor, to further lower residual solvents. When implemented, the preferred instrument is a vacuum tray dryer.
The temperature for drying can range from about 25°C to about 60°C, preferably from about 50°C to about 60°C under vacuum.
The drying can be carried out for any desired time, till a constant weight is obtained and time periods can range from about 1 hour to about 50 hours, preferably from about 40 hours to about 50 hours.
The prasugrel freebase used as starting material In the processes described herein above, may be of indefinite morphology, i.e. crystalline or crystalline or mixture thereof or may be crude prasugrel resulting from synthetic processing step known in the art. Illustratively, these processes are disclosed in U.S. Patent Nos. 5288726 and 6693115, both of which are incorporated herein in their entirety by reference.
The characterization of the crystalline form of prasugrel hydrobromide of the present invention is analyzed by X-ray powder diffraction were performed on a Philips X'pert PRO Diffractometer using Cu Ka radiation (Cu Kal = l .54060A). The X-ray source is operated at 45 kV and 40mA. Spectra are recorded in the 20 range of 2-50°, a step size 0.0167° with a ;'time-per-step" optimized to 1000 seconds.
The crystalline form of prasugrel hydrobromide is further characterized by Differential scanning calorimetry (DSC) by the method as follows:
Approximately l-2mg sample was accurately weighed into an Aluminum DSC pan with pin hole lid and the sample was placed into the Mettler Toledo DSC822e equipped with a nitrogen cooling unit and allowed to equilibrate at 30°C until the stable heat flow reference was seen. A dry nitrogen purge gas at a flow rate of 50ml/minute was used to produce inert atmosphere to prevent oxidation of sample during the heating. The
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sample was scanned from 30-350°C at rate of 10°C/min and resulting heat flow response was measured against temperature.
FTFR method : IR is measured by using instrument Perkin Elmer by KBr mode.
Specifically, substantially pure crystalline form of prasugrel hydrobromide may have less than 20%, more preferably less than 10%: even more preferably less than about 5%. and most preferably less than 1 %, of any crystalline forms and amorphous form of prasugrel hydrobromide. In one example, the PXRD pattern of the pure crystalline form of prasugrel hydrobromide is substantially in accordance with Figure l.The crystalline prasugrel hydrobromide of the present invention has a purity, as measured by HPLC. of at least about 98%, more preferably, at least about 99% and most preferably at least about 99.5%. Preferably, the chemical purity of the prasugrel hydrobromide is about 99% or more, more preferably about 99.5% or more, more preferably about 99.8% or more, more preferably about 99.9% or more, as measured by area under HPLC.
In one embodiment, the present invention encompasses prasugrel hydrobromide having less than about 0.20% of any single impurity as measured by area under HPLC peaks. Preferably, the prasugrel or a pharmaceutical!)' acceptable salt thereof has less than about 0.15% of any single chemical impurity as measured by area under HPLC peaks.
Advantageously the prasugrel HBr is converted into hydrochloride salt of prasugre] by general methods known in the art for example neutralizing Ihe HBr salt of prasugrel by using a base to give prasugrel freebase and then reaction of freebase with hydrochloric acid to give the hydrochloride salt of prasugrel which is herein described in the example 2.
Prasugrel hydrobromide obtained by the process described above, has residual organic solvents or organic volatile impurities comprises less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. pharmacopoeia; less than about 600ppm of dichloromethane, less than about 5000ppm of ethanol, acetone, ethyl acetate, isopropyl alcohol, less than about 890 ppm of toluene and less than about 290ppm of n-hexane.
Accordingly, D90 particle size of the unformulated crystalline prasugrel hydrobromide salt obtained by the process of present invention is used as starting
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material in preparing a pharmaceutical composition generally is less than 400 microns preferably less than about 200 microns, more preferably less than 150 microns, still more preferably less than about 50 microns and still more preferably less than about 15 microns.
Any milling, grinding micronizing or other particle size reduction method known in the art can be used to bring the crystalline prasugrel hydrobromide into any desired particle size range as set forth above.
In another embodiment the present invention provides a pharmaceutical composition comprising crystalline form of prasugrel hydrobromide and at least a pharmaceutical!}' acceptable carrier.
Such pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes. Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The prasugrel or its pharmaceutical acceptable salts obtained by the process disclosed herein also may be administered as suppositories, ophthalmic ointments and suspensions. and parenteral suspensions, which are administered by other routes. The most preferred route of administration of the prasugrel or its pharmaceutically acceptable salts is oral. The dosage forms may contain the prasugrel or its pharmaceutically acceptable salts as part of a composition. The pharmaceutical compositions may further contain one or more pharmaceutical!)' acceptable excipients.
Capsule dosages will contain the prasugrel or its pharmaceutically acceptable salts which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. The enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcelluiose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric-coating.
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Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials iike powdered cellulose, microcrystalline cellulose, microflne cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Other excipients contemplated by the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone: low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl hydrobromide; flavorings; sweeteners; preservatives; pharmaceutical^ acceptable dyes and glidants such as silicon dioxide.
The process for the preparation of crystalline prasugrel hydrobromide of the present invention is simple, eco-friendly and easily scaleable.
The following examples are provided to enable one skilled in the art to practice the invention and is merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
EXAMPLE I: PREPARATION OF CRYSTALLINE FORM OF PRASUGREL HYDROBROMIDE 75.0 ml of acetone and 5.0 g prasugrel base were charged in a clean and dry 4 neck round-bottom-flask (RBF) follovved by stirring for about 15 minutes. 2.7 g of Hydrobromic acid (48%v/v) was added drop wisely at about 25-30°C over about 10 minutes. The resultant reaction solution was stirred at about 25-30°C for about 3 hours. The separated solid was filtered and the solid obtained was vvashed with 2*20 ml of
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acetone. The solid obtained was dried at about 50-60°C under vacuum for about 48 hours
to afford 4.7 g of the title compound.
Purity by HPLC: 99.5%
All known and Unknown impurities = 0.5%.
MASS (M/S): 374.15 a.m.u
Content of HBr (%w/w by titrimetry): 17%w/w.
Target compound has an X- ray powder diffraction pattern with characteristic peaks at
about 7.06 , 8.3L 10.08, 11.46, 12.19, 12.82, 13.73, 14.17, 15.8, 16.7, 16.98, 17.23,
17.73, 18.36, 18.70, 21.60, 23.42. 23.69, 24.21, 24.39, 24.9, 25.14, 25.82, 26.50, 27.0,
29.89, 30.31 and 37.2 ± 0.2 degrees two-theta, which is substantially in accordance with
Figure I.
And differential scanning calorimetry endotherm curve at about 138.25°C with an onset at about 128.29°C and an endset at about ]46.34°C, which is substantially in accordance with Figure 2.
And FTIR frequencies by infrared absorption which is substantially in accordance with Figure 3.
EXAMPLE-2 : PROCESS FOR CONVERSION OF PRASUGREL
HYDROBROM1DE TO PRASUGREL HYDROCHLORIDE 10 gm of prasugrel hydrobromide and 100ml of ethyl acetate in a clean and dry 4 neck RBF followed by stirring for about 15 minutes. 12 ml of triethyl amine was added slowly over about 10 minutes. Organic layer was washed with 20 ml of water followed by 20 ml of brine solution. Organic layer was separated and the dried over 2gm of anhydrous sodium sulphate. Organic layer was distilled completely at about 45°C under vacuum of about 700mm of Hg. 50ml of methanol was charged and distilled completely. 10 ml of methanol was charged and stirred for about 1 hour. The solid separated was filtered and the solid was washed with 2x10ml of methanol. The solid obtained was dried at about 55°C under vacuum over about 12 hours. To the solid (6.5gm) obtained 97.5 ml of Acetone was charged and stirred for about 15 minutes to obtain clear solution. 1.5ml of cone HCI was added followed by stirring 4 hrs. Solid separated was filtered and the
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solid was washed with 2x10ml of acetone. The solid obtained was dried at about 55°C under vacuum for about 12 hrs to afford ~ 4gm-5.5gm of the title compound.
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The present invention particularly provides:
A. A crystalline form of prasugrel HBr.
B. Crystalline form of prasugrel HBr as described in A. is characterized by X- ray
powder diffraction pattern with characteristic peaks at about 7.06 . 8.31. 10.08, 11.46,
12.19. 12.82, 13.73, 14.17. 15.8, 16.7, 16.98, 17.23, 17.73, 18.36, 18.70,21.60,23.42.
23.69. 24.21, 24.39, 24.9, 25.14, 25.82, 26.50, 27.0, 29.89, 30.31 and 37.2 ± 0.2
degrees two-theta.
C. The crystalline form of prasugrel HBr as described in A, characterized by an PXRD
spectrum, which is substantially in accordance with Figure 1.
D. The crystalline prasugrel hydrobromide as described in A, is further characterised by
differential scanning calorimetry endotherm substantially in accordance with Figure 2.
E. The crystalline prasugrel hydrobromide as described in A, is further characterized by
Infrared absorption spectrum substantially in accordance with
Figure 3.
F. A process for preparing crystalline form of prasugrel hydrobromide comprising:
(a) providing a solution of prasugrel and hydrobromic acid in one or more solvents or aqueous mixtures thereof; and
(b) precipitating the solid by cooling or by adding a solvent: and
(c) recovering the prasugrel hydrobromide substantially in crystalline form.
G. The process as described in F, wherein the crystalline form of prasugrel hydrobromide
has an X- ray powder diffraction pattern 2-theta peaks as described in B.
H. The process as described in F. wherein the solvent is selected from alcoholic solvents
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like methanol, ethanol, isopropyl alcohol, n-
butanol, tertiary butyl alcohol, ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone, nitriles like acetonitrile, propionitrile, and mixtures and aqueous mixtures thereof.
I. The process as described in H. wherein the solvents used is acetone or acetonitrile.
J. The process described in F, wherein the crystalline prasugrel hvdrobromide obtained has a chemical purity of at least about 99 area % and 0.15 area % of any individual impurity by HPLC. K. A process for conversion of prasugrel hvdrobromide into prasugrel hydrochloride comprising:
(a) providing a suspension of prasugrel hvdrobromide in one or more solvents or aqueous mixtures thereof; and
b) adding a base to the suspension of step a) to obtain clear solution; and
c) adding hydrochloric acid to the clear solution of step b);
(d) recovering the prasugrel hydrochloride substantially in solid state. L) The process as described in K, wherein the solvent used is ethyl acetate. M) The process as described in K. wherein the base used is tri ethyl amine. N) The process as described in M. wherein the solvent used for isolation is acetone.
O). A pharmaceutical composition, comprising crystalline form of prasugrel hvdrobromide and at least one pharmaceutical^ acceptable excipient.

(Signed).
DR. MADHAVI KARNIK
DEPUTY GENERAL MANAGER - IPM
GLENMARK GENERICS LIMITED.
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