WO2011016686A2 - Prasugrel disulfonate or crystalline forms thereof, method for preparing same, and pharmaceutical composition containing same - Google Patents

Prasugrel disulfonate or crystalline forms thereof, method for preparing same, and pharmaceutical composition containing same Download PDF

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Publication number
WO2011016686A2
WO2011016686A2 PCT/KR2010/005149 KR2010005149W WO2011016686A2 WO 2011016686 A2 WO2011016686 A2 WO 2011016686A2 KR 2010005149 W KR2010005149 W KR 2010005149W WO 2011016686 A2 WO2011016686 A2 WO 2011016686A2
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Prior art keywords
prasugrel
disulfonate
acid
disulfonic acid
pharmaceutical composition
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PCT/KR2010/005149
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French (fr)
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WO2011016686A3 (en
Inventor
Chang Hee Park
Jong Ouk Baek
Hee Sook Oh
Mi Kyoung Lee
Chang Ju Choi
Tae Hee Ha
Kwee Hyun Suh
Gwan Sun Lee
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Hanmi Holdings Co., Ltd.
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Publication of WO2011016686A2 publication Critical patent/WO2011016686A2/en
Publication of WO2011016686A3 publication Critical patent/WO2011016686A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4743—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a prasugrel disulfonate and a crystalline form thereof, a method for preparing same, and a pharmaceutical composition comprising same.
  • Prasugrel (2-acetoxy-5-( ⁇ -cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine) was first described in European Patent No. 0,542,411 as an antagonist of purinergic adenosine 5 '-diphosphate receptor P2Y 12 .
  • Prasugrel is a pharmacological antithrombotic agent which inhibits the platelet- aggregation, and accordingly, it has been acknowledged as one of therapeutic agents for preventing or treating ischemic diseases such as acute coronary artery syndrome.
  • An active ingredient of a pharmaceutical composition is required to be stable during the preparation process which involves grinding, mixing, granulating, and compressing steps and good storage stability. Also, such active ingredient is required to be non-hygroscopic, fluidic, and non-electrostatic and can be a rapidly released so as to provide quick absorbance thereof by the body after its administration to a mammal.
  • prasugrel does not have all such physical and pharmaceutical properties required of an active ingredient. Therefore, there have been conducted many studies to use various acid-addition salts or crystalline forms of prasugrel as the active ingredient of a pharmaceutical composition.
  • European Patent No. 0,542,411 disclosed thieno[3,2- c]pyridine derivatives having platelet-aggregation inhibition activity or i pharmaceutically acceptable salts thereof together with prasugrel.
  • the pharmaceutically acceptable salts include acid-addition salts of inorganic acids, low alkylsulfonic acids, and carboxylic acids.
  • prasugrel acid-addition salts have been disclosed.
  • International Publication No. WO 2002/04461 has disclosed acid-addition salts of prasugrel prepared by adding an inorganic acid such as sulfonic acid, hydrochloric acid, nitric acid, and phosphoric acid; or an organic acid such as trifluoroacetic acid, maleic acid, methansulfonic acid, and p- toluensulfonic acid.
  • an inorganic acid such as sulfonic acid, hydrochloric acid, nitric acid, and phosphoric acid
  • organic acid such as trifluoroacetic acid, maleic acid, methansulfonic acid, and p- toluensulfonic acid.
  • the preparation examples have disclosed only prasugrel hydrochloride and maleate salts.
  • WO 2007/114526 disclosed a method for preparing highly pure prasugrel and acid-addition salts thereof.
  • the disclosed salts of prasugrel are acid-addition salts derived using an inorganic acid such as sulfonic acid, hydrochloric acid, nitric acid, and phosphoric acid; or an organic acid such as trifluoroacetic acid, maleic acid, methansulfonic acid, and p- toluensulfonic acid.
  • an inorganic acid such as sulfonic acid, hydrochloric acid, nitric acid, and phosphoric acid
  • organic acid such as trifluoroacetic acid, maleic acid, methansulfonic acid, and p- toluensulfonic acid.
  • prasugrel hydrochloride alone has been described in the example reaction.
  • International Publication No. WO 2009/066326 disclosed a method for preparing prasugrel and acid-addition salts thereof.
  • the disclosed salts of prasugrel are acid-addition salts derived using hydrochloric acid, bromic acid, benzenesulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p- toluensulfonic acid, and malic acid.
  • the preparation examples describe only prasugrel fumarate, maleate, hydrochloride, benzenesulfonate, and p-toluensulfonate.
  • China Patent Publication No. 1,255,169 has disclosed a method for preparing prasugrel and conventional salts thereof.
  • the disclosed conventional salts of prasugrel are acid-addition salts of methansulfonic acid, fumaric acid, acetic acid, oxalic acid, succinic acid, tartaric acid, 2- hydroxybenzoic acid, acetylsalicylic acid, hydrobromic acid, hydroiodic acid, sulfonic acid, and phosphoric acid.
  • the preparation examples describe only prasugrel methansulfonate, hydrobromoride, hydroiodide, and 2- hydroxybenzoate.
  • the present inventors have endeavored to develop a prasugrel acid- addition salt or a crystalline form thereof having the required properties, and have found that a novel prasugrel disulfonate or a crystalline form thereof obtained by treating prasugrel with 1,2-ethane disulfonic acid or 1,5-naphthalene disulfonic acid exhibits markedly improved physical and pharmaceutical properties.
  • a prasugrel disulfonate or a crystalline form thereof having improved physical and pharmaceutical properties.
  • It is a further object of the present invention to provide a pharmaceutical composition comprising said compound as an active ingredient.
  • HA is 1,2-ethane disulfonic acid (or ethane- 1,2-disulfonic acid; hereinafter, referred to "ethane disulfonic acid”) or 1,5-naphthalene disulfonic acid (or naphthalene- 1,2-disulfonic acid; hereinafter, referred to "naphthalene disulfonic acid”).
  • a method for preparing said compound which comprises a step of treating prasugrel with a disulfonic acid in an organic solvent.
  • a pharmaceutical composition for preventing or treating an ischemic disease which comprises said compound as an active ingredient, together with a pharmaceutically acceptable carrier, diluent or excipient.
  • Figs. 1 to 3 an X-ray diffraction (XRD) spectrum, a differential scanning calorimeter (DSC) scan, and a dynamic vapor sorption (DVS) scan of the inventive prasugrel 1,2-ethane disulfonate obtained in Example 1, respectively; and
  • Figs. 4 to 6 an XRD spectrum, DSC scan, and DVS scan of prasugrel 1,5- naphthalene disulfonate obtained in Example 6, respectively.
  • the structure of the inventive prasugrel disulfonate of formula (I) or a crystalline form thereof is composed of two molecules of prasugrel and one molecule of disulfonic acid in a molar ratio of 2:1, which can be confirmed by proton nuclear magnetic resonance ( 1 H-NMR) spectrum analysis.
  • the prasugrel disulfonate composed of prasugrel and disulfonic acid in a molar ratio of 2:1 has not yet been reported previously.
  • the inventive prasugrel disulfonate of formula (I) includes both (i) prasugrel ethane disulfonate and (ii) prasugrel naphthalene disulfonate, and each prasugrel disulfonate is described in detail as follows, (i) prasugrel ethane disulfonate
  • the X-ray diffraction (hereinafter, referred to XRD) spectrum obtained using Cu-Ka radiation of the inventive crystalline form of prasugrel ethane disulfonate shows major peaks at diffraction angles (2 ⁇ ) of 8.3 ⁇ 0.2°, 12.5 ⁇ 0.2°, 13.8 ⁇ 0.2°, 15.2 ⁇ 0.2°, 17.8 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.2 ⁇ 0.2°, 22.0 ⁇ 0.2°, 23.8 ⁇ 0.2°, and 24.8 ⁇ 0.2° (see, Fig. 1).
  • the melting point of the inventive crystalline form of prasugrel ethane disulfonate is in the range of 184 ° C to 192°C determined by thermogravity capillary analysis.
  • the differential scanning calorimetry (hereinafter, referred to DSC) scan of the inventive crystalline form of prasugrel ethane disulfonate shows endothermic peak with an onset point at 189 ⁇ 2 ° C and a minimum point at 194 ⁇ 2°C which corresponds to said melting point (see, Fig. 2).
  • the difference of water content of the inventive crystalline form of prasugrel ethane disulfonate measured by dynamic vapor sorption (hereinafter, referred to DVS) of less than 0.5% was determined at a relative humidity ranging from 0 to 90%, which represents the fact that the inventive compound exhibits a very low hygroscopicity (see, Fig. 3).
  • the XRD spectrum obtained using Cu-Ka radiation of the inventive crystalline form of prasugrel napthalane disulfonate shows major peaks at diffraction angles (2 ⁇ ) of l l.l ⁇ 0.2°, 11.5 ⁇ 0.2°, 12.1 ⁇ 0.2°, 15.9 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.1 ⁇ 0.2°, 19.4 ⁇ 0.2°, 22.1 ⁇ 0.2°, 22.4 ⁇ 0.2°, and 26.9 ⁇ 0.2° (see, Fig. 4).
  • the melting point v of the inventive crystalline form of prasugrel napthalane disulfonate is in the range of 216 ° C to 222 ° C , preferably 218 ° C to
  • the difference of water content of the inventive crystalline form of prasugrel naphthalane disulfonate measured by DVS of less than 1.0% was determined at a relative humidity ranging from 0 to 90%, which represents the fact that the inventive compound exhibits a very low hygroscopicity ⁇ see, Fig. 6).
  • the crystalline form of the pharmaceutical ingredients can be determined by at least one selected from the group consisting of the melting point, the spectrum of XRD, DSC, solid state nuclear magnetic resonance spectroscopy, infrared (IR) spectroscopy and raman spectroscopy, and hydrates.
  • XRD spectrum are a major factor to determine the crystalline form of the pharmaceutical ingredients.
  • the inventive crystalline form of the prasugrel disulfonate characterized by XRD spectrum, DSC scan and melting point will be identified as a uniform state within the margin of error, regardless of preparation arrangement, drying time, storage period, storage method and measurement method.
  • the inventive prsugrel disulfonate of formula (I) or a crystalline form thereof may be prepared by a method which comprises the step of treating prasugrel with a disulfonic acid in an organic solvent.
  • the organic solvent used in the inventive reaction may be an organic solvent which not reacts with prasugrel or disulfonic acid and does not cause a reverse effect on a crystallization of the prasugrel disulfonate.
  • the organic solvent is selected from the group consisting of acetone, methylethylketone, methylisobutylketone, diethylketone, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, isopropyl ether, and ethyl ether, preferably, acetone, isopropanol, tetrahydrofuran, and acetonitrile.
  • the amount of the organic solvent used in the reaction is ranging from 1 ml to 50 ml, preferably 5 ml to 15 ml based on one
  • the disulfonic acid used in the reaction may be ethane disulfonic acid or naphthalane disulfonic acid, and the amount of the disulfonic acid is ranging from 0.4 to 1.2 mole, preferably, 0.5 to 0.6 mole based on 1 mole of prasugrel.
  • the prasugrel used in the inventive method may be prepared by any one of the conventional methods (European Patent No. 0,542,411 or International Application Publication No. WO 2002/04461) or others, and it may be a purified or crude one.
  • the prasugrel may be treated with the disulfonic acid at a temperature of 0 °C to a melting point of the organic solvent used in the reaction, preferably 10 ° C to 50°C . And the mixture thus obtained may be induced to precipitate a crystal at a temperature of -20 ° C to 50 °C, preferably, 0°C to room temperature. Also, in order to induce for precipitating the crystal, a seed crystal prepared separately may be seeded thereto.
  • the prasugrel disulfonate or the crystalline form thereof prepared in the present invention has a high chemical purity of 98.5% or higher which meets the purity requirement of the pharmaceutical ingredient.
  • the prasugrel is an antithrombotic agent which strongly inhibits purinergic adenosine 5 '-diphosphate receptor P2Yi 2 involved in the platelet- aggregation, and is useful for preventing and treating an ischemic disease such as acute coronary artery syndrome.
  • an ischemic disease such as acute coronary artery syndrome.
  • a pharmaceutical composition for preventing or treating an ischemic disease which comprises the prasugrel disulfonate of formula (I) or a crystalline form thereof as an active ingredient, together with a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition comprising the prasugrel disulfonate or a crystalline form thereof in a specific amount may be administered via various routes including oral or parental administration, preferably an oral administration.
  • the composition for oral administration may be in the form of capsules, tablets, dispersions, suspensions and the like.
  • the capsule or tablet may include enteric coated capsules or tablets, or enteric coated pellet-containing capsules or tablets.
  • the pharmaceutical composition of the present invention may be prepared by admixing prasugrel disulfonate or a crystalline form thereof together with a pharmaceutically acceptable carrier, diluent or excipient.
  • suitable carrier are saline solution, poly ethylenegly col, ethanol, vegetable oil, and isopropyl myristearate
  • suitable diluent are lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and glycine
  • suitable excipient are starch, sugar, lactose, dextrin, mannitol, sorbitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, Arabia gum, amylopectin, light anhydrous silicic acid, and synthetic aluminum silicate.
  • the pharmaceutical composition may further include pharmaceutically acceptable additives including fillers and bulking agents such as calcium phosphate and silicic acid derivatives; binding agents such as starch, sugar, mannitol, trehalose, dextrin, amylopectin, sucrose, glutin, Arabia gum, cellulose derivatives (e.g., methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, hydroxypropyl cellulose and hydroxypropyl cellulose), gelatin, alginate, and polyvinylpyrrolidone; lubricants such as talc, calcium or magnesium stearate, hydrogenated castor oil, talcum powder and solid-phase polyethylene glycol; disintergents such as povidone, croscarmellose sodium and crospovidone; and surfactants such as polysorbate, cetyl alcohol and glycerol monostearate.
  • pharmaceutically acceptable additives including fillers and bulking agents such as calcium phosphate and silicic acid derivatives;
  • compositions comprising the prasugrel disulfonate or a crystalline form thereof in a specific amount as an active ingredient together with optional additives such as carriers, diluents or excipients may be prepared according to conventional methods (see, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 19 th Edition, 1995).
  • the pharmaceutical composition of the present invention may comprise the prasugrel disulfonate of formula (I) or a crystalline form thereof in an amount ranging from 0.1 to 95% by weight, preferably from 1 to 70% by weight based on the total weight thereof.
  • a proposed daily dose of the prasugrel disulfonate or crystalline forms thereof as an active ingredient for administration to a mammal including human is about from 0.5 to 250 mg/kg body weight, preferably about from 1 to 150 mg/kg body weight, which may be administered in a single dose or in divided doses.
  • UV spectorphotometer 225 nm
  • the melting point of the inventive prasugrel disulfonate was determined using a capillary digital melting point recorder (Barnstead Electrothermal, Great Britain).
  • the water content of the inventive prasugrel disulfonate was measured using 795 KFT water meter (Metrohm, Switzerland), and the infrared absorption spectrum (IR) was obtained using MB- 100 infrared spectrometer (Bomen, Canada).
  • 1 H nuclear magnetic resonance ( 1 H-NMR) spectrum was measured using Avance DPX 300 (Bruker, Germany).
  • Differential scanning calorimeter (DSC) scan was obtained using STA S-1000 (Scinco, Korea) with a temperature programming rate of 10 " C per a minute.
  • the water content was determined by performing dynamic vapor sorption (DVS) twice, are, moisture sorption and the other, adsorption under the conditions of 25 "C and relative humidity of 0 to 90%, using DVS Advantage 1 dynamic vapor sorption system (Surface Measurement System, Great Britain).
  • Combination ratio of ethane disulfonic acid 0.5 molecules to one molecule of prasugrel ( 1 H-NMR).
  • IR (KBr, cm “1 ): 3413, 2944, 2570, 1761, 1707, 1614, 1589, 1496, 1444, 1420, 1390, 1376, 1231, 1205, 1167, 1021, 766, 545.
  • a DSC (10°C/min) scan showed endothermic peak with an onset point at 188.52°C and a minimum point at 193.7 ° C which corresponds to the melting point of said compound as shown in Fig. 2.
  • the difference of the water content by DVS of less than 0.5% was determined at a relative humidity ranging from 0 to 90%, as shown in Fig. 3.
  • Example 2 Preparation of prasugrel 1,2-ethane disulfonate 2.O g of prasugrel (5.35 mmol) was dissolved in 20 ml of acetone, 1.06 g of 1,2-ethane disulfonic acid (5.55 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hrs. The solid formed was filtered, washed with 5 ml of acetone, and dried at 40 "C to obtain 1.80 g of the title compound as a white-colored crystal (72%).
  • Combination ratio of ethane disulfonic acid 0.5 molecules to one molecule of prasugrel ( 1 H-NMR).
  • Combination ratio of ethane disulfonic acid 0.5 molecules to one molecule of prasugrel ( 1 H-NMR).
  • Combination ratio of naphthalane disulfonic acid 0.5 molecules to one molecule of prasugrel ( 1 H-NMR).
  • Combination ratio of naphthalane disulfonic acid 0.5 molecules to one molecule of prasugrel ( 1 H-NMR).
  • Example 6 Preparation of prasugrel 1,5-naphthaIa ⁇ e disulfonate
  • Combination ratio of naphthalane disulfonic acid 0.5 molecules to one molecule of prasugrel ( 1 H-NMR).
  • the inventive prasugrel disulfonate and crystalline forms thereof can be characterized by the melting point, diffraction angle peaks and the distances between crystal facets in XRD spectrum analysis, and the temperature in endothermic peaks exhibited by DSC scan.
  • the inventive prasugrel disulfonate and crystalline forms thereof exhibited a minimized water-content increase as a value of less than 0.5% (ethane disulfonate) or less than 1.0% (naphthalane disulfonate), which represents the fact the compounds are non-hyposcopic.

Abstract

The present invention provides a stable and non-hygroscopic prasugrel disulfonate or a crystalline form thereof; a method for preparing same, and a pharmaceutical composition comprising same.

Description

PRASUGREL DISULFONATE OR CRYSTALLINE FORMS THEREOF,
METHOD FOR PREPARING SAME, AND PHARMACEUTICAL
COMPOSITION CONTAINING SAME
FIELD OF THE INVENTION
The present invention relates to a prasugrel disulfonate and a crystalline form thereof, a method for preparing same, and a pharmaceutical composition comprising same.
BACKGROUND OF THE INVENTION
Prasugrel (2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine) was first described in European Patent No. 0,542,411 as an antagonist of purinergic adenosine 5 '-diphosphate receptor P2Y12. Prasugrel is a pharmacological antithrombotic agent which inhibits the platelet- aggregation, and accordingly, it has been acknowledged as one of therapeutic agents for preventing or treating ischemic diseases such as acute coronary artery syndrome.
An active ingredient of a pharmaceutical composition is required to be stable during the preparation process which involves grinding, mixing, granulating, and compressing steps and good storage stability. Also, such active ingredient is required to be non-hygroscopic, fluidic, and non-electrostatic and can be a rapidly released so as to provide quick absorbance thereof by the body after its administration to a mammal.
However, prasugrel does not have all such physical and pharmaceutical properties required of an active ingredient. Therefore, there have been conducted many studies to use various acid-addition salts or crystalline forms of prasugrel as the active ingredient of a pharmaceutical composition.
For example, European Patent No. 0,542,411 disclosed thieno[3,2- c]pyridine derivatives having platelet-aggregation inhibition activity or i pharmaceutically acceptable salts thereof together with prasugrel. The pharmaceutically acceptable salts include acid-addition salts of inorganic acids, low alkylsulfonic acids, and carboxylic acids. However, no examples of prasugrel acid-addition salts have been disclosed.
In addition, International Publication No. WO 2002/04461 has disclosed acid-addition salts of prasugrel prepared by adding an inorganic acid such as sulfonic acid, hydrochloric acid, nitric acid, and phosphoric acid; or an organic acid such as trifluoroacetic acid, maleic acid, methansulfonic acid, and p- toluensulfonic acid. However, the preparation examples have disclosed only prasugrel hydrochloride and maleate salts.
International Publication No. WO 2007/114526 disclosed a method for preparing highly pure prasugrel and acid-addition salts thereof. The disclosed salts of prasugrel are acid-addition salts derived using an inorganic acid such as sulfonic acid, hydrochloric acid, nitric acid, and phosphoric acid; or an organic acid such as trifluoroacetic acid, maleic acid, methansulfonic acid, and p- toluensulfonic acid. However, the preparation of prasugrel hydrochloride alone has been described in the example reaction.
Also, International Publication No. WO 2009/066326 disclosed a method for preparing prasugrel and acid-addition salts thereof. The disclosed salts of prasugrel are acid-addition salts derived using hydrochloric acid, bromic acid, benzenesulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p- toluensulfonic acid, and malic acid. However, the preparation examples describe only prasugrel fumarate, maleate, hydrochloride, benzenesulfonate, and p-toluensulfonate.
Further, China Patent Publication No. 1,255,169 has disclosed a method for preparing prasugrel and conventional salts thereof. The disclosed conventional salts of prasugrel are acid-addition salts of methansulfonic acid, fumaric acid, acetic acid, oxalic acid, succinic acid, tartaric acid, 2- hydroxybenzoic acid, acetylsalicylic acid, hydrobromic acid, hydroiodic acid, sulfonic acid, and phosphoric acid. However, the preparation examples describe only prasugrel methansulfonate, hydrobromoride, hydroiodide, and 2- hydroxybenzoate. The above-mentioned acid-addition salts of prasugrel are not easy to prepare, or the acid-addition salts of prasugrel prepared are often non-crystalline or highly hygroscopic, and thus, there is a need for developing a prasugrel salt having improved physical and pharmaceutical properties.
The present inventors have endeavored to develop a prasugrel acid- addition salt or a crystalline form thereof having the required properties, and have found that a novel prasugrel disulfonate or a crystalline form thereof obtained by treating prasugrel with 1,2-ethane disulfonic acid or 1,5-naphthalene disulfonic acid exhibits markedly improved physical and pharmaceutical properties.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a prasugrel disulfonate or a crystalline form thereof having improved physical and pharmaceutical properties.
It is another object of the present invention to provide a method for preparing said compound.
It is a further object of the present invention to provide a pharmaceutical composition comprising said compound as an active ingredient.
In accordance with one aspect of the present invention, there is provided a prasugrel disulfonate of formula (I) or a crystalline form thereof:
Figure imgf000004_0001
wherein,
HA is 1,2-ethane disulfonic acid (or ethane- 1,2-disulfonic acid; hereinafter, referred to "ethane disulfonic acid") or 1,5-naphthalene disulfonic acid (or naphthalene- 1,2-disulfonic acid; hereinafter, referred to "naphthalene disulfonic acid").
In accordance with another aspect of the present invention, there is provided a method for preparing said compound which comprises a step of treating prasugrel with a disulfonic acid in an organic solvent.
In accordance with a further aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating an ischemic disease, which comprises said compound as an active ingredient, together with a pharmaceutically acceptable carrier, diluent or excipient. BRIEF DESCRIPTION OF DRAWINGS
The above and other objects and features of the present invention will become apparent from the following description of the invention taken in conjunction with the following accompanying drawings, which respectively show:
Figs. 1 to 3: an X-ray diffraction (XRD) spectrum, a differential scanning calorimeter (DSC) scan, and a dynamic vapor sorption (DVS) scan of the inventive prasugrel 1,2-ethane disulfonate obtained in Example 1, respectively; and
Figs. 4 to 6: an XRD spectrum, DSC scan, and DVS scan of prasugrel 1,5- naphthalene disulfonate obtained in Example 6, respectively.
DETAILED DESCRIPTION OF THE INVENTION The structure of the inventive prasugrel disulfonate of formula (I) or a crystalline form thereof is composed of two molecules of prasugrel and one molecule of disulfonic acid in a molar ratio of 2:1, which can be confirmed by proton nuclear magnetic resonance (1H-NMR) spectrum analysis. The prasugrel disulfonate composed of prasugrel and disulfonic acid in a molar ratio of 2:1 has not yet been reported previously.
The inventive prasugrel disulfonate of formula (I) includes both (i) prasugrel ethane disulfonate and (ii) prasugrel naphthalene disulfonate, and each prasugrel disulfonate is described in detail as follows, (i) prasugrel ethane disulfonate In accordance with one aspect of the present invention, the X-ray diffraction (hereinafter, referred to XRD) spectrum obtained using Cu-Ka radiation of the inventive crystalline form of prasugrel ethane disulfonate shows major peaks at diffraction angles (2Θ) of 8.3±0.2°, 12.5±0.2°, 13.8±0.2°, 15.2±0.2°, 17.8±0.2°, 19.4±0.2°, 20.2±0.2°, 22.0±0.2°, 23.8±0.2°, and 24.8±0.2° (see, Fig. 1).
The melting point of the inventive crystalline form of prasugrel ethane disulfonate is in the range of 184°C to 192°C determined by thermogravity capillary analysis. The differential scanning calorimetry (hereinafter, referred to DSC) scan of the inventive crystalline form of prasugrel ethane disulfonate shows endothermic peak with an onset point at 189±2°C and a minimum point at 194±2°C which corresponds to said melting point (see, Fig. 2).
The difference of water content of the inventive crystalline form of prasugrel ethane disulfonate measured by dynamic vapor sorption (hereinafter, referred to DVS) of less than 0.5% was determined at a relative humidity ranging from 0 to 90%, which represents the fact that the inventive compound exhibits a very low hygroscopicity (see, Fig. 3).
(ii) prasugrel napthalane disulfonate In accordance with one aspect of the present invention, the XRD spectrum obtained using Cu-Ka radiation of the inventive crystalline form of prasugrel napthalane disulfonate shows major peaks at diffraction angles (2Θ) of l l.l±0.2°, 11.5±0.2°, 12.1±0.2°, 15.9±0.2°, 17.9±0.2°, 18.1±0.2°, 19.4±0.2°, 22.1±0.2°, 22.4±0.2°, and 26.9±0.2° (see, Fig. 4).
The melting point v of the inventive crystalline form of prasugrel napthalane disulfonate is in the range of 216 °C to 222 °C , preferably 218°C to
220 °C determined by thermogravity capillary analysis. The DSC scan of the inventive crystalline form of prasugrel napthalane disulfonate shows endothermic peak with an onset point at 206±20C and a minimum point at 223±2 °C which corresponds to said melting point {see, Fig. 5).
The difference of water content of the inventive crystalline form of prasugrel naphthalane disulfonate measured by DVS of less than 1.0% was determined at a relative humidity ranging from 0 to 90%, which represents the fact that the inventive compound exhibits a very low hygroscopicity {see, Fig. 6).
Generally, the crystalline form of the pharmaceutical ingredients can be determined by at least one selected from the group consisting of the melting point, the spectrum of XRD, DSC, solid state nuclear magnetic resonance spectroscopy, infrared (IR) spectroscopy and raman spectroscopy, and hydrates. Preferably, the diffraction angles (2Θ) and distance between crystal facets (d value) in the
XRD spectrum are a major factor to determine the crystalline form of the pharmaceutical ingredients.
In the present invention, the inventive crystalline form of the prasugrel disulfonate characterized by XRD spectrum, DSC scan and melting point will be identified as a uniform state within the margin of error, regardless of preparation arrangement, drying time, storage period, storage method and measurement method.
The inventive prsugrel disulfonate of formula (I) or a crystalline form thereof may be prepared by a method which comprises the step of treating prasugrel with a disulfonic acid in an organic solvent.
The organic solvent used in the inventive reaction may be an organic solvent which not reacts with prasugrel or disulfonic acid and does not cause a reverse effect on a crystallization of the prasugrel disulfonate. For example, the organic solvent is selected from the group consisting of acetone, methylethylketone, methylisobutylketone, diethylketone, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, isopropyl ether, and ethyl ether, preferably, acetone, isopropanol, tetrahydrofuran, and acetonitrile. The amount of the organic solvent used in the reaction is ranging from 1 ml to 50 ml, preferably 5 ml to 15 ml based on one gram of the prasugrel.
The disulfonic acid used in the reaction may be ethane disulfonic acid or naphthalane disulfonic acid, and the amount of the disulfonic acid is ranging from 0.4 to 1.2 mole, preferably, 0.5 to 0.6 mole based on 1 mole of prasugrel.
The prasugrel used in the inventive method may be prepared by any one of the conventional methods (European Patent No. 0,542,411 or International Application Publication No. WO 2002/04461) or others, and it may be a purified or crude one.
In the present invention, the prasugrel may be treated with the disulfonic acid at a temperature of 0 °C to a melting point of the organic solvent used in the reaction, preferably 10°C to 50°C . And the mixture thus obtained may be induced to precipitate a crystal at a temperature of -20 °C to 50 °C, preferably, 0°C to room temperature. Also, in order to induce for precipitating the crystal, a seed crystal prepared separately may be seeded thereto.
The prasugrel disulfonate or the crystalline form thereof prepared in the present invention has a high chemical purity of 98.5% or higher which meets the purity requirement of the pharmaceutical ingredient.
The prasugrel is an antithrombotic agent which strongly inhibits purinergic adenosine 5 '-diphosphate receptor P2Yi2 involved in the platelet- aggregation, and is useful for preventing and treating an ischemic disease such as acute coronary artery syndrome. When the inventive prasugrel disulfonate is introduced to gastrointestinal tract or in vivo, the prasugrel is released from the prasugrel disulfonate, accordingly, the inventive prasugrel disulfonate can be useful in preventing and treating the ischemic disease caused by the platelet- aggregation.
In accordance with still further aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating an ischemic disease, which comprises the prasugrel disulfonate of formula (I) or a crystalline form thereof as an active ingredient, together with a pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutical composition comprising the prasugrel disulfonate or a crystalline form thereof in a specific amount may be administered via various routes including oral or parental administration, preferably an oral administration. The composition for oral administration may be in the form of capsules, tablets, dispersions, suspensions and the like. The capsule or tablet may include enteric coated capsules or tablets, or enteric coated pellet-containing capsules or tablets.
The pharmaceutical composition of the present invention may be prepared by admixing prasugrel disulfonate or a crystalline form thereof together with a pharmaceutically acceptable carrier, diluent or excipient. The representative examples of suitable carrier are saline solution, poly ethylenegly col, ethanol, vegetable oil, and isopropyl myristearate; the representative examples of suitable diluent are lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and glycine; and the representative examples of suitable excipient are starch, sugar, lactose, dextrin, mannitol, sorbitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, Arabia gum, amylopectin, light anhydrous silicic acid, and synthetic aluminum silicate. In the present invention, the pharmaceutical composition may further include pharmaceutically acceptable additives including fillers and bulking agents such as calcium phosphate and silicic acid derivatives; binding agents such as starch, sugar, mannitol, trehalose, dextrin, amylopectin, sucrose, glutin, Arabia gum, cellulose derivatives (e.g., methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, hydroxypropyl cellulose and hydroxypropyl cellulose), gelatin, alginate, and polyvinylpyrrolidone; lubricants such as talc, calcium or magnesium stearate, hydrogenated castor oil, talcum powder and solid-phase polyethylene glycol; disintergents such as povidone, croscarmellose sodium and crospovidone; and surfactants such as polysorbate, cetyl alcohol and glycerol monostearate.
Further, the pharmaceutical composition comprising the prasugrel disulfonate or a crystalline form thereof in a specific amount as an active ingredient together with optional additives such as carriers, diluents or excipients may be prepared according to conventional methods (see, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 19th Edition, 1995).
The pharmaceutical composition of the present invention may comprise the prasugrel disulfonate of formula (I) or a crystalline form thereof in an amount ranging from 0.1 to 95% by weight, preferably from 1 to 70% by weight based on the total weight thereof.
In the present invention, a proposed daily dose of the prasugrel disulfonate or crystalline forms thereof as an active ingredient for administration to a mammal including human is about from 0.5 to 250 mg/kg body weight, preferably about from 1 to 150 mg/kg body weight, which may be administered in a single dose or in divided doses.
The following Examples are intended to further illustrate the present invention without limiting its scope.
The purities shown in the following Examples were calculated by percentage (%) of the peak area of prasugrel to the total peak area (except for the peak area of solvent) based on the chromatograpic analysis performed under the following conditions:
Column: Capcell PCK MG C 18™ (diameter 4.6 mm x length 150 mm, particle size: 5 μm);
Detector and wavelength: UV spectorphotometer (225 nm);
Mobile phase: 0.02M phosphate buffered saline/acetonitrile = 30/70 (v/v %); and
Flow rate: 1.0 ml/min.
The melting point of the inventive prasugrel disulfonate was determined using a capillary digital melting point recorder (Barnstead Electrothermal, Great Britain). The water content of the inventive prasugrel disulfonate was measured using 795 KFT water meter (Metrohm, Switzerland), and the infrared absorption spectrum (IR) was obtained using MB- 100 infrared spectrometer (Bomen, Canada). 1H nuclear magnetic resonance (1H-NMR) spectrum was measured using Avance DPX 300 (Bruker, Germany). Differential scanning calorimeter (DSC) scan was obtained using STA S-1000 (Scinco, Korea) with a temperature programming rate of 10 "C per a minute. The water content was determined by performing dynamic vapor sorption (DVS) twice, are, moisture sorption and the other, adsorption under the conditions of 25 "C and relative humidity of 0 to 90%, using DVS Advantage 1 dynamic vapor sorption system (Surface Measurement System, Great Britain). X-ray diffraction (XRD) spectra were obtained using CuKa radiation (wavelength λ=1.54056A) according to a conventional method described in [U.S. Pharmacopeia 31 NF26] using D8 Advance X-ray diffraction analyzer (Bruker, Germany).
Example 1: Preparation of prasugrel 1,2-ethane disulfonate
2.0 g of prasugrel (5.35 mmol) was dissolved in 20 ml of acetone, 0.6 g of 1,2-ethane disulfonic acid (3.15 mmol) was added thereto, and the mixture was stirred at room temperature for 6 hrs. The solid formed was filtered, washed with 5 ml of acetone, and dried at 400C to obtain 2.15 g of the title compound as a white-colored crystal (86%).
Melting point: 187 °C to 189°C (melting)
Water content: 0.32%
Chemical purity: 99.3%
Combination ratio of ethane disulfonic acid: 0.5 molecules to one molecule of prasugrel (1H-NMR).
1H-NMR (CDCl3, ppm): δ 7.7(br. m, IH), 7.5(q, IH), 7.4(t, IH), 7.2(t, IH), 7.2(m, IH), 6.4(bs, IH), 5.8(bs, IH), 4.8(m, IH), 4.1(m, IH), 4.0-3.5(m, 2H), 3.3(s, 2H, edisilate), 3.1(m, IH), 2.9(m, IH), 2.3(s, 3H), 1.7(m, IH), 1.3(m, IH), l.l(m, IH), 1.0(m, IH), 0.9(m, IH).
IR (KBr, cm"1): 3413, 2944, 2570, 1761, 1707, 1614, 1589, 1496, 1444, 1420, 1390, 1376, 1231, 1205, 1167, 1021, 766, 545.
An XRD spectrum of the above was obtained using CuKa radiation and determined 2 theta (20) major peaks having relative peak intensity of at least 30% (1/I0; I: the peak intensity; and I0: the peak intensity of the maximum peak), and the distances between crystal facets (d) are shown in Table 1. Said major peaks are shown in Fig. 1.
<Table 1>
Figure imgf000012_0001
A DSC (10°C/min) scan showed endothermic peak with an onset point at 188.52°C and a minimum point at 193.7 °C which corresponds to the melting point of said compound as shown in Fig. 2.
The difference of the water content by DVS of less than 0.5% was determined at a relative humidity ranging from 0 to 90%, as shown in Fig. 3.
Example 2: Preparation of prasugrel 1,2-ethane disulfonate 2.O g of prasugrel (5.35 mmol) was dissolved in 20 ml of acetone, 1.06 g of 1,2-ethane disulfonic acid (5.55 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hrs. The solid formed was filtered, washed with 5 ml of acetone, and dried at 40 "C to obtain 1.80 g of the title compound as a white-colored crystal (72%).
Melting point: 188 °C to 190 °C (melting)
Water content: 0.25%
Chemical purity: 99.1% Combination ratio of ethane disulfonic acid: 0.5 molecules to one molecule of prasugrel (1H-NMR).
The results of 1H-NMR, IR, XRD, DSC and DVS are identical to those of Example 1.
Example 3: Preparation of prasugrel 1,2-ethane disulfonate
2.0 g of prasugrel (5.35 mmol) was dissolved in 20 ml of isopropanol, 0.6 g of 1,2-ethane disulfonic acid (3.15 mmol) was added thereto, and the mixture was heated to 50 °C . The resulting mixture was slowly cooled to room temperature and stirred for 12 hrs. The solid formed was filtered, washed with 5 ml of isopropanol, and dried at 40 °C to obtain 2.23 g of the title compound as a white-colored crystal (89%).
Melting point: 186°C to 1880C (melting)
Water content (KF): 0.20%
Chemical purity: 98.9%
Combination ratio of ethane disulfonic acid: 0.5 molecules to one molecule of prasugrel (1H-NMR).
The results of 1H-NMR, IR, XRD, DSC and DVS are identical to those of Example 1.
Example 4: Preparation of prasugrel 1,2-ethane disulfonate
2.0 g of prasugrel (5.35 mmol) was dissolved in 15 ml of tetrahydrofuran, 0.6 g of 1,2-ethane disulfonic acid (3.15 mmol) was added thereto, and the mixture was stirred at room temperature for 6 hrs. The solid formed was filtered, washed with 5 ml of tetrahydrofuran, and dried at 40 °C to obtain 2.1O g of the title compound as a white-colored crystal (84%).
Melting point: 187°C to 190 °C (melting)
Water content: 0.10%
Chemical purity: 99.0% Combination ratio of ethane disulfonic acid: 0.5 molecules to one molecule of prasugrel (1H-NMR).
The results of 1H-NMR, IR, XRD, DSC and DVS are identical to those of Example 1.
Example 5: Preparation of prasugrel 1,2-ethane disulfonate
2.0 g of prasugrel (5.35 mmol) was dissolved in 10 ml of acetonitrile, 0.6 g of 1,2-ethane disulfonic acid (3.15 mmol) was added thereto, and the mixture was stirred at room temperature for 6 hrs. The solid formed was filtered, washed with 5 ml of acetonitrile, and dried at 40 °C to obtain 1.95 g of the title compound as a white-colored crystal (78%).
Melting point: 188 °C to 190°C (melting)
Water content: 0.30%
Chemical purity: 99.1 %
Combination ratio of ethane disulfonic acid: 0.5 molecules to one molecule of prasugrel (1H-NMR).
The results of 1H-NMR, IR, XRD, DSC and DVS are almost identical to those of Example 1.
Example 6: Preparation of prasugrel 1,5-naphthalene disulfonate
2.0 g of prasugrel (5.35 mmol) was dissolved in 20 ml of acetone, 1.0 g of 1,5-naphthalane disulfonic acid tetrahydrate (2.78 mmol) was added thereto, and the mixture was stirred at room temperature for 6 hrs. The solid formed was filtered, washed with 5 ml of acetone, and dried at 40 °C to obtain 2.65 g of the title compound as a white-colored crystal (96%).
Melting point: 218 "C to 220 °C (melting)
Water content: 0.25%
Chemical purity: 99.0%
Combination ratio of naphthalane disulfonic acid: 0.5 molecules to one molecule of prasugrel (1H-NMR). 1H-NMR (DMSO-d6, ppm): δ 8.9(d, IH), 7.9(d, IH), 7.6(m, IH), 7.4~7.5(m, 4H), 6.6(s, IH), 6.0(s, IH), 4.0(m, 2H), 3.0(m, 2H), 2.4(m, IH), 2.2(s, 3H), 2.1(m, IH), 1.9(m, IH), l.l(m, 2H), 0.9(m, 2H).
IR (KBr, cm"1): 3458, 2011, 2917, 2556, 2363, 1770, 1711, 1615, 1587, 1496, 1451, 1370, 1248, 1222, 1171, 1131, 1026, 766, 612.
An XRD spectrum of the above was obtained using CuKa radiation and determined 2 theta (2Θ) major peaks having relative peak intensity of at least 30% (1/I0; I: the peak intensity; and I0: the peak intensity of the maximum peak), and the distances between crystal facets (d) are shown in Table 2. Said major peaks are shown in Fig. 4.
<Table 2>
Figure imgf000015_0001
A DSC (10 °C/min) scan showed endothermic peak with an onset point at
206.33 °C and a minimum point at 223.38 "C which corresponds to the melting point of said compound as shown in Fig. 5.
The difference of the water content by DVS of less than 1.0% was determined at a relative humidity ranging from 0 to 90%, as shown in Fig. 6. Example 7: Preparation of prasugrel 1,5-naphthalane disulfonate
2.0 g of prasugrel (5.35 mmol) was dissolved in 20 ml of acetone, 2.0 g of 1,5-naphthalane disulfonic acid tetrahydrate (5.55 mmol) was added thereto, and the mixture was stirred at room temperature for 4 hrs. The solid formed was filtered, washed with 5 ml of acetone, and dried at 40 °C to obtain 2.35 g of the title compound as a white-colored crystal (85%).
Melting point: 219 °C to 221 °C (melting)
Water content: 0.2%
Chemical purity: 98.7%
Combination ratio of naphthalane disulfonic acid: 0.5 molecules to one molecule of prasugrel (1H-NMR).
The results of 1H-NMR, IR, XRD, DSC and DVS are identical to those of Example 6.
Example 8: Preparation of prasugrel 1,5-naphthalane disulfonate
2.0 g of prasugrel (5.35 mmol) was dissolved in 15 ml of isopropanol, 1.0 g of 1,5-naphthalane disulfonic acid tetrahydrate (2.78 mmol) was added thereto, and the mixture was heated to 50 "C . The resulting mixture was slowly cooled to room temperature and stirred for 12 hrs. The solid formed was filtered, washed with 5 ml of isopropanol, and dried at 40 °C to obtain 2.50 g of the title compound as a white-colored crystal (90%).
Melting point: 2190C to 22 TC (melting)
Water content: 0.2%
Optical purity: 98.5%
Combination ratio of naphthalane disulfonic acid: 0.5 molecules to one molecule of prasugrel (1H-NMR).
The results of 1H-NMR, IR, XRD, DSC and DVS are identical to those of
Example 6. Example 9: Preparation of prasugrel 1,5-naphthaIaπe disulfonate
2.0 g of prasugrel (5.35 mmol) was dissolved in 10 ml of acetonitrile, 1.0 g of 1,5-naphthalane disulfonic acid tetrahydrate (2.78 mmol) was added thereto, and the mixture was stirred at room temperature for 6 hrs. The solid formed was filtered, washed with 5 ml of acetonitrile, and dried at 40 °C to obtain 2.55 g of the title compound as a white-colored crystal (92%).
Melting point: 218 °C to 220 °C (melting)
Water content: 0.2%
Chemical purity: 99.1 %
Combination ratio of naphthalane disulfonic acid: 0.5 molecules to one molecule of prasugrel (1H-NMR).
The results of 1H-NMR, IR, XRD, DSC and DVS are identical to those of Example 6.
The inventive prasugrel disulfonate and crystalline forms thereof can be characterized by the melting point, diffraction angle peaks and the distances between crystal facets in XRD spectrum analysis, and the temperature in endothermic peaks exhibited by DSC scan. The inventive prasugrel disulfonate and crystalline forms thereof exhibited a minimized water-content increase as a value of less than 0.5% (ethane disulfonate) or less than 1.0% (naphthalane disulfonate), which represents the fact the compounds are non-hyposcopic.
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes of the invention also fall within the scope of the present invention defined by the claims that follow.

Claims

What is claimed is:
1. A prasugrel disulfonate of formula (I) or a crystalline form thereof:
Figure imgf000018_0001
wherein,
HA is 1,2-ethane disulfonic acid or 1,5-naphthalane disulfonic acid.
2. The prasugrel disulfonate of claim 1, which is prasugrel 1,2-ethane disulfonate.
3. The prasugrel disulfonate of claim 2, whose X-ray diffraction spectrum obtained using Cu-Ka radiation shows major peaks at diffraction angles (2Θ) of 8.3±0.2°, 12.5±0.2°, 13.8±0.2°, 15.2±0.2°, 17.8±0.2°, 19.4±0.2°, 20.2±0.2°, 22.0±0.2°, 23.8±0.2°, and 24.8±0.2°.
4. The prasugrel disulfonate of claim 2, whose melting point is in the range of l84°C to l92 °C .
5. The prasugrel disulfonate of claim 4, whose differential scanning calorimetry (DSC) scan shows an endothermic peak with an onset point at 189±2 °C and a minimum peak point at 194±2°C, which corresponds to said melting point.
6. The prasugrel disulfonate of claim 1, which is prasugrel 1,5-naphthalane disulfonate.
7. The prasugrel disulfonate of claim 6, whose X-ray diffraction spectrum obtained using Cu-Ka radiation shows major peaks at diffraction angles (2Θ) of ll.l±0.2°, 11.5±0.2°, 12.1±0.2°, 15.9±0.2°, 17.9±0.2°, 18.1±0.2°, 19.4±0.2°, 22.1±0.2°, 22.4±0.2°, and 26.9±0.2°.
8. The prasugrel disulfonate of claim 6, whose melting point is in the range of216°C to 222°C .
9. The prasugrel disulfonate of claim 8, whose differential scanning calorimetry (DSC) scan shows an endothermic peak with an onset point at 206±2°C and a minimum peak point at 223±2°C, which corresponds to said melting point.
10. A method for preparing the prasugrel disulfonate of claim 1, which comprises the step of treating prasugrel with a disulfonic acid in an organic solvent.
11. The method of claim 10, wherein the organic solvent is selected from the group consisting of acetone, methylethylketone, methylisobutylketone, diethylketone, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, isopropyl ether, and ethyl ether.
12. The method of claim 11, wherein the organic solvent is selected from the group consisting of acetone, isopropanol, tetrahydrofuran, and acetonitrile.
13. The method of claim 10, wherein the disulfonic acid is 1,2-ethane disulfonic acid or 1,5-naphthalane sulfonic acid.
14. A pharmaceutical composition for preventing or treating an ischemic disease, which comprises the prasugrel disulfonate of claim 1 as an active ingredient, together with a pharmaceutically acceptable carrier, diluent or excipient.
15. The pharmaceutical composition of claim 14, which is formulated for oral administration.
16. The pharmaceutical composition of claim 14, wherein the prasugrel disulfonate is employed in an amount ranging from 0.1 to 95 % by weight based on the total weight of the composition.
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