WO2012089180A1 - Form c of prasugrel hydrobromide and a method for its production - Google Patents

Form c of prasugrel hydrobromide and a method for its production Download PDF

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Publication number
WO2012089180A1
WO2012089180A1 PCT/CZ2011/000127 CZ2011000127W WO2012089180A1 WO 2012089180 A1 WO2012089180 A1 WO 2012089180A1 CZ 2011000127 W CZ2011000127 W CZ 2011000127W WO 2012089180 A1 WO2012089180 A1 WO 2012089180A1
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Prior art keywords
characterized
form
prasugrel
hydrobromide
method according
Prior art date
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PCT/CZ2011/000127
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French (fr)
Inventor
Katerina Kaminska
Hana Stepankova
Josef Hajicek
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Zentiva, K.S.
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Priority to CZPV2010-999 priority Critical
Priority to CZ2010-999A priority patent/CZ305314B6/en
Application filed by Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2012089180A1 publication Critical patent/WO2012089180A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic 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
    • C07D495/04Ortho-condensed systems

Abstract

A polymorphous form of the hydrobromide of prasugrel, a well-known substance reducing blood coagulation, prasugrel of formula (I), which is characterized by high chemical stability, and a method for its production. (Formula (I))

Description

FORM C OF PRASUGREL HYDROBROMIDE AND A METHOD FOR ITS PRODUCTION Technical Field The invention relates to a new polymorphous form of the hydrobromide of prasugrel, a well-known compound reducing blood coagulability, prasugrel of formula I, which manifests high chemical stabilit and to a method for its production.

Figure imgf000002_0001

(I) Background Art

Prasugrel, a method for its preparation as well as its use as an anti-aggregation compound for patients facing the risk of platelet thrombus was first described in the EP 0 542 41 1 patent. Sankyo's EP 1 298 132 patent describes the hydrochloride and maleate of prasugrel; another patent application EP 2 003 136 of this company mentions 2 crystalline forms of prasugrel hydrochloride, characterized with physical- analytical methods. Form B of the hydrochloride according to this application is considered as highly stable. At the same time, this application also mentions a polymorphous form of the prasugrel base. The general patent application EP 0 785 205 describes production of various hydrochlorides of pharmaceutically active substances with the use of HCI generated in situ from trialkylsilyl chlorides. Prasugrel hydrochloride was also prepared by this method and characterized with physico- analytical methods.

The newly published application WO 2010/070677 of Glenmark relates to new crystalline forms of prasugrel hydrochloride, Forms G1 and G2. The application also describes an amorphous form of prasugrel hydrochloride.

Another patent application, WO 2009/066326, deals with prasugrel fumarate, benzenesulfonate, p-toluenesulfonate and malate. The Helm company has published patent application WO 2009/098142, which describes salts of alkylsulfonic and arylsulfonic acids with improved chemical stability. Application WO 2009/062044 describes new prasugrel hydrochloride crystalline forms C, B, E, as well as its amorphous form.

Another patent application, WO2009/129983 of Ratiopharm, relates again to acid addition salts of prasugrel and comprises mainly the benzenesulfonate and naphtalenesulfonate. Crystalline prasugrel hydrogen sulfate was described in Sandoz' document WO2009/130289.

Chinese patent application CN 101633662 describes a wide range of the various salts 4-acetylaminobenzoate, acetate, adipate, alginate, 4-aminosalicylate, ascorbate, aspartate, glutamate, pyroglutamate, benzoate, butyrate, camphorsulfonate.

Cyclodextrin complexes of prasugrel, which are described in Chinese patent application CN 10181061 1 , are also known. Disclosure of Invention

The present invention provides a new polymorphous Form C of 5-[2-cyclopropyl-1-(2- fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrobromide of formula I, known under the non-proprietary name prasugrel, and a method for its preparation.

Figure imgf000003_0001

(I)

The polymorphous Form C of the hydrobromide is prepared by crystallization from a solution of the base in a suitable solvent such as ethyl acetate after addition of a source of hydrogen bromide, or by heating a suspension of the polymorphous Form A or B of the hydrobromide in a suitable solvent such as ethyl acetate at an elevated temperature. The newly prepared form C of prasugrel hydrobromide has advantages of very good chemical stability and low hygroscopicity, which are properties that are strongly desirable for the manufacture of a pharmaceutical composition.

Detailed description of the invention

Prasugrel belongs to the drugs that influence blood coagulation and is indicated for suppression of platelet thrombus formation in patients having the acute coronary syndrome and is marketed under the trade name Efient. The original manufacturer uses, as the active substance for the preparation of this product, prasugrel hydrochloride in the polymorphous Form B, as referred to in the EP 2 003 136 patent. This form is described in the document as very stable and was characterized, inter alia, by X-ray patterns. By comparing the stability studies of the originally used prasugrel hydrochloride with those of the new hydrobromide Form C it has been surprisingly found out that our hydrobromide Form C exhibits better chemical stability during storage and is also less hygroscopic, as can be seen from the table below:

Stability during 4 months' storage (double PE foil, the upper one dark, desiccant, 25°C):

Figure imgf000004_0001
Already after 2 months' storage at 25°C an increase of the content of impurities occurs in the originally used hydrochloride form, while the purity of the hydrobromide Form C remains unchanged. The more stable substance brings advantages during further processing into a pharmaceutical formulation and subsequently it also provides the patient with benefits consisting in possible longer shelf life of the medicinal product.

The polymorphous Form C of the hydrobromide shows the following characteristic peaks in the X-ray powder diffraction pattern: 7.8; 8.0; 13.4; 14.5; 16.8; 22.0; 25.1 ; 27.1 and 29.9 0 2Θ. Main reflections were observed at 8.0; 14.5; 22.0; 27.1 and 29.9 ' 2Θ. The polymorphous Form C of the hydrobromide was also subjected to an equilibrium hygroscopicity test on a DVS Isotherm Plot device, namely in two cycles of 0- 90 -0 % of relative humidity. The weight increase was linear, the max. content of water was 0.29% at 90% RH. The second cycle was the same as the first one. The measurement course is well illustrated by the record in Fig. 3.

For the purpose of comparison of properties the original hydrochloride Form B was also subjected to the same test. During the testing it exhibited 40% higher increase of adsorbed water, the max. value was 0.41 % at 90% RH; the measurement record is presented in Fig. 4.

Since it was observed during the stability testing that the increase of decomposition impurities is related to the content of water in the sample, the lower amount of adsorbed water is convenient as compared to the original form.

The polymorphous Form C of the hydrobromide is prepared by crystallization from a solution or suspension of the base in a suitable solvent after addition of a hydrogen bromide source at an elevated temperature. A suitable solvent for the crystallization includes those selected from acetic acid esters or their mixtures with toluene. The hydrobromide is produced with the use of a source of hydrogen bromide, which is acetylbromide, hydrogen bromide dissolved in toluene or aqueous hydrobromic acid. The formation of the salt and crystallization thereof are performed at an elevated temperature in the range of 40 to 80°C. In the most preferable embodiment of this invention the solvent used is ethyl acetate, the source of hydrogen bromide is acetylbromide and formation of the hydrobromide is carried out at a temperature in the range of from 55 to 65°C.

The hydrobromide Form C can also be obtained by heating a suspension or solution of hydrobromides of various forms in a suitable solvent at an elevated temperature. The Form C of the hydrobromide is prepared by heating a suspension of Form A or B in a solvent selected from the group of acetic acid esters or their mixtures with methyl ethyl ketone or toluene. The heating is carried out at a temperature of from 50 to 80°C for a sufficiently long time. In accordance with the most preferable embodiment of this invention ethyl acetate is used as the solvent at a temperature of from 55 to 65°C.

The time period needed for formation of the form C by this method comprises 1 h to 24 hours. Preferably, the time period comprises about 5 hours. The Form A of the hydrobromide is prepared by crystallization of an acetone solution of the base after addition of a sufficient quantity of 48% hydrobromic acid and it exhibits the following characteristic peaks in the X-ray powder diffraction: 8.30; 10.07; 12.18; 13.71 ;18.67; 21.60; 24.39; 25.80 0 2Θ ± 0.2° 2Θ.

The Form B of the hydrobromide is prepared by crystallization from, e.g., a mixture of ethyl acetate and ethanol after addition of hydrogen bromide dissolved in toluene, or by crystallization from a solution of the base in methyl ethyl ketone after addition of a sufficient amount of 48% hydrobromic acid. In the X-ray powder diffraction, Form B exhibits the following characteristic peaks: 8.41 ; 1 1 .89; 12.93; 15.29; 24.65° 2Θ ± 0.2° 2Θ.

Brief Description of Drawings

Figure 1 a - Powder diffraction pattern of prasugrel hydrobromide Form C.

Figure 1 b - DSC record of prasugrel hydrobromide Form C.

Figure 2 - Record of equilibrium hygroscopicity measurement for prasugrel

hydrobromide Form C.

Figure 3 - Record of equilibrium hygroscopicity measurement for prasugrel

hydrochloride Form B.

Working Examples

Melting points were measured using a Kofler block. Samples of prasugrel and its salts in the following examples were evaluated by means of X-ray diffraction analysis using the following procedure:

The diffraction pattern was obtained in an X ERT PRO MPD PANalytical powder diffractometer with a graphite monochromator: used radiation CuKa (λ=1.542 A), excitation voltage: 45 kV, anodic current: 40 mA, measurement range: 2 - 40° 2Θ, increment: 0,01 ° 2Θ with residence at reflection of 50s; the measurement was carried out on a flat sample with the area/thickness of 10/0.5 mm. DSC records were produced with a Pyris 1 device (Perkin Elmer). The sample charge was 3 to 4 mg, the heating rate was 10°C/min

Temperature program:

1 ) 1 minute at 50°C 2) 50 to 200°C at the rate of 10°C/minute (except prasugrel HCI 50 to 250°C at the rate of 10°C/min).

Carrier gas: N2 20 ml/min.

Samples of prasugrel and its salts in the examples below were evaluated by means of HPLC using the following procedure:

The HPLC determination was carried out in a C8 column (250x4.6 mm; 5 pm) at the temperature of 30°C with UV detection at 228 nm. The separation was performed using gradient elution with a phosphate buffer (0.01 M KH2P04 pH 2.5) with acetonitrile at the flow rate of 1 .0 ml/min with the following gradient: 0 min 80% of the buffer; 25 min 34% of the buffer (linear gradient); 28 min 34% of the buffer. The equilibration time of the column was 10 minutes. The injection volume was 10 μΙ. The capacity factor of prasugrel is 4.3. The sample was prepared by dissolution of the corresponding substance in acetonitrile to obtain the concentration of 1 mg/ml. Example 1 : Preparation of prasugrel hydrobromide Form C from Form B

Ethyl acetate (70 ml) is added to prasugrel hydrobromide Form B (6.5 g; 14.3 mmol) and the suspension is stirred at the temperature of 60°C for 45 minutes. Subsequently, the suspension is cooled to the room temperature and stirred for another 5 h. The crystals are then aspirated, washed twice with ethyl acetate and dried in a vacuum drier at 50°C for 24 h. 5.63 g (87 %) of white crystals of Form C are obtained with the same purity as that of the starting prasugrel hydrobromide Form II. M.p. : 179-181 °C. Water content 0.15 %, residual solvents: ethyl methyl ketone < 50 ppm; ethyl acetate < 5000 ppm.

The obtained hydrobromide Form C exhibits the following characteristic peaks in the X-ray pattern:

Figure imgf000007_0001
8.02 1 1.016 41.7

13.44 6.581 40.9

14.50 6.103 100.0

16.08 5.507 8.0

16.84 5.260 13.2

19.91 4.456 8.3

20.56 4.317 1 1.1

21 .35 4.159 8.7

21.99 4.038 41.1

23.62 3.764 9.0

25.11 3.543 19.1

27.10 3.288 25.1

29.88 2.988 15.8

The record of the X-ray spectrum is presented in the Annex in Fig. 1 a, the DSC record is in Fig. 1 b. Example 2: Preparation of prasugrel hydrobromide Form C from Form A

Ethyl acetate (25 ml) is added to prasugrel hydrobromide Form A (2.02 g; 4.44 mmol) and the suspension is stirred at the temperature of 60°C for 45 minutes. Subsequently, the suspension is cooled to the room temperature and stirred for another 5 h. The crystals are then aspirated, washed twice with ethyl acetate and dried in a vacuum drier at 50°C for 24 h. 1 .8 g (89 %) of white crystals of Form C are obtained with the same purity as that of the starting prasugrel hydrobromide Form I. M. p.: 179-181 °C. Water content 0.18 %, residual solvents: ethyl methyl ketone < 50 ppm; ethyl acetate < 5000 ppm.

The X-ray spectrum is the same as the spectrum presented in Example 1 .

Example 3: Preparation of prasugrel hydrobromide Form C from the base

Prasugrel base (7.5 g; 20.08 mmol) is dissolved in ethyl acetate at 60 °C. At this temperature, acetic acid (0.95 eq.) and acetylbromide (0.95 eq.) are added dropwise at the same time and the mixture is stirred at 60°C for another 20 min. The mixture will start to crystallize spontaneously. Subsequently, the heating is stopped and the stirring continues at the room temperature for another 5 h. The separated crystals are aspirated, washed with ethyl acetate and dried at 50°C in a vacuum drier for 24 h. 8.1 5 g (89 %) of prasugrel hydrobromide are obtained with the purity of >99 % (HPLC). M. p. 178-180°C. Water content 0.25 %; residual solvents: ethyl acetate < 5000 ppm The X-ray spectrum is the same as the spectrum presented in Example 1 .

Example 4: Preparation of prasugrel hydrobromide Form C from the base

Prasugrel base (5.37 g; 14.37 mmol) is dissolved in ethyl acetate (80 ml) and a solution of gaseous HBr (0.95 eq.) in toluene is added dropwise to the solution. The mixture will become turbid and start to crystallize spontaneously and it is stirred for 18 h. The separated crystals are washed with ethyl acetate and dried at 50 °C in a vacuum drier for 24 h. 4.71 g (72%) of prasugrel hydrobromide is obtained with the purity of 98-99 % (HPLC). M. p. : 174-178 °C. Water content 0.17 %; residual solvents: ethyl acetate < 5000 ppm

The X-ray spectrum is the same as the spectrum presented in Example 1 .

Claims

Claims:
1. Prasugrel hydrobromide Form C, characterized by an X-ray powder diffraction exhibiting the following peaks 8.0; 14.5; 22.0; 27.1 and 29.9 ° 2Θ.
2. Prasugrel hydrobromide according to claim 1 , characterized by an X-ray powder diffraction exhibiting the following peaks 7.8; 8.0; 13.4; 14.5; 16.8; 22.0; 25.1 ; 27.1 and 29.9 ° 2Θ.
3. A method for the production of prasugrel hydrobromide according to claims 1 or 2, characterized in that the prasugrel base is dissolved or suspended in a solvent selected from the group consisting of acetic acid esters and their mixtures with toluene at an elevated temperature and a hydrogen bromide source is added.
4. The method according to claim 3, characterized in that the solvent is ethyl acetate.
5. The method according to claim 4, characterized in that the process is carried out at a temperature in the range of from 40 to 80°C.
6. The method according to claim 5, characterized in that the process is carried out at a temperature in the range of from 55 to 65°C.
7. The method according to claims 3-6, characterized in that the source of hydrogen bromide is acetylbromide or a solution of hydrogen bromide in toluene.
8. A method for the production of the prasugrel hydrobromide Form C according to claims 1 or 2, characterized in that prasugrel hydrobromide in crystalline Form A or B is suspended in a solvent selected from the group consisting of acetic acid esters and their mixtures with methyl ethyl ketone or toluene at an elevated temperature for a sufficient time period to produce Form C.
9. The method according to claim 8, characterized in that the solvent is ethyl acetate.
10. The method according to claims 8 or 9, characterized in that the process is carried out at a temperature in the range of from 50 to 80°C.
1 1 . The method according to claim 10, characterized in that the process is carried out at a temperature in the range of from 55 to 65°C.
PCT/CZ2011/000127 2010-12-30 2011-12-29 Form c of prasugrel hydrobromide and a method for its production WO2012089180A1 (en)

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CZ2010-999A CZ305314B6 (en) 2010-12-30 2010-12-30 Novel hydrobromide of the C 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate form known under unprotected name prasugrel and process for preparing thereof

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1728794A1 (en) 2000-07-06 2006-12-06 Sankyo Company Limited Maleate addition salt of hydropyridine derivatives

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1298132A1 (en) * 2000-07-06 2003-04-02 Sankyo Company, Limited Hydropyridine derivative acid addition salts
CN101899056A (en) * 2010-08-02 2010-12-01 江苏万全特创医药生物技术有限公司 Prasugrel hydrobromide polymorph and preparation method thereof
WO2011004392A1 (en) * 2009-07-06 2011-01-13 Glenmark Generics Limited Crystalline form of prasugrel hydrobromide, preparation and application thereof
WO2011057593A2 (en) * 2009-11-16 2011-05-19 Zentiva, K.S. New salts of prasugrel and a method of their production
WO2011127300A1 (en) * 2010-04-08 2011-10-13 Teva Pharmaceutical Industries Ltd. Crystalline forms of prasugrel salts

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101255169B (en) * 2008-03-26 2010-11-10 山东大学 Prasugrel salt and preparation method thereof
WO2010111951A1 (en) * 2009-03-31 2010-10-07 上海医药工业研究院 Crystals of prasugrel hydrobromate
CZ2009763A3 (en) * 2009-11-16 2011-05-25 Zentiva, K. S. Process for preparing extreme pure 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate known under unprotected name prasugrel and its novel pharmaceutically acceptable salts

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1298132A1 (en) * 2000-07-06 2003-04-02 Sankyo Company, Limited Hydropyridine derivative acid addition salts
WO2011004392A1 (en) * 2009-07-06 2011-01-13 Glenmark Generics Limited Crystalline form of prasugrel hydrobromide, preparation and application thereof
WO2011057593A2 (en) * 2009-11-16 2011-05-19 Zentiva, K.S. New salts of prasugrel and a method of their production
WO2011127300A1 (en) * 2010-04-08 2011-10-13 Teva Pharmaceutical Industries Ltd. Crystalline forms of prasugrel salts
CN101899056A (en) * 2010-08-02 2010-12-01 江苏万全特创医药生物技术有限公司 Prasugrel hydrobromide polymorph and preparation method thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1728794A1 (en) 2000-07-06 2006-12-06 Sankyo Company Limited Maleate addition salt of hydropyridine derivatives

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