JP2007217333A - Crystal form of sarpogrelate hydrochloride and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide sarpogrelate hydrochloride of a crystal form suitable for formulation of a solid pharmaceutical preparation and to provide a method for producing the sarpogrelate hydrochloride of crystal form with good reproducibility and simpler operation in high yield. <P>SOLUTION: The crystal form B of the sarpogrelate hydrochloride having a powder X-ray diffraction spectrum represented as substantially the same in the figure is produced by a method for recrystallization from one kind of solvent or a mixed solvent of two or more kinds thereof selected from the group consisting of acetone, acetonitrile, methanol, ethanol, isopropyl alcohol, N,N-dimethylformamide and tetrahydrofuran or a mixed solvent of the solvents with water. Thereby, the crystal form B is provided. Hydrous acetone or hydrous acetonitrile is preferable in the solvents. The hydrous acetone with 1-10 wt.% moisture content or the hydrous acetonitrile with 1-7 wt.% moisture content is especially preferred. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to ((±) -2- (dimethylamino) -1-[[o- (m-methoxyphenethyl) phenoxy] methyl] ethyl hydrogen succinate hydrochloride, ie, crystals of sarpogrelate hydrochloride (generic name). The present invention relates to a shape and a manufacturing method thereof.

Sarpogrelate hydrochloride has been found as a compound having an excellent 5-HT ₂ antagonism, and has been used clinically as an effective drug for the improvement of ischemic symptoms such as ulcers, pain and coldness associated with chronic arterial occlusion. It is used.

Japanese Patent Publication No. 63-13427 “Journal of Medicinal Chemistry”, Vol. 33 (No. 6), 1818-1823 (1990)

The present inventor tried to produce sarpogrelate hydrochloride by a known method (patent document 1 and non-patent document 1) in order to use the drug substance of sarpogrelate hydrochloride for formulation study. During examination of conditions for improving the yield and purification efficiency, the powder X-ray diffraction measurement results and thermal analysis of the obtained crystals were conducted, and it was found that crystal polymorphs exist.
When an additional test was carried out by changing the conditions within the range described in Patent Document 1, it was easy to obtain a mixture of two crystal forms, the mixing ratio was not constant, and one of the two crystal forms was commercially available. It was found that it was used in this formulation, and that the other one was not disclosed yet.
When the physical properties differ depending on the difference in crystal form, it is not rare that the difference affects the stability of the crystal with respect to temperature, humidity, etc., making it difficult to set the production conditions for obtaining a preparation of constant quality. Therefore, if crystalline polymorphs are present, it is advantageous in the industrial production of the preparation if only the more preferred crystalline form can be selectively produced with good reproducibility, but detailed information on crystals of sarpogrelate hydrochloride is available. Not yet disclosed.
Therefore, the present inventor studied the problem of finding a method for taking out crystals having industrially advantageous physical properties with good reproducibility and substantially purely from crystals of sarpogrelate hydrochloride.

  As a result of diligent research to solve the above-mentioned problems, the present inventor has a known crystal form (hereinafter referred to as A-form crystal) used in commercially available tablets among the two crystal forms of sarpogrelate hydrochloride. And another novel type (hereinafter referred to as “B-type crystal”) have been found with high reproducibility and high yield, and the present invention has been completed.

That is, according to the present invention, the following (1) crystal form and the methods (2), (3) and (4) relating to the production of the crystal form can be provided, respectively.
(1) B-form crystal of sarpogrelate hydrochloride having a powder X-ray diffraction spectrum shown substantially the same as FIG.
(2) Sarpogrelate hydrochloride is a kind of solvent selected from the group consisting of acetone, acetonitrile, methanol, ethanol, isopropyl alcohol, N, N-dimethylformamide, and tetrahydrofuran, or a mixed solvent of two or more kinds, or those solvents and water. A method for producing a B-form crystal of sarpogrelate hydrochloride having a powder X-ray diffraction spectrum substantially the same as that shown in FIG.
(3) The method according to claim 2, wherein the mixed solvent is water-containing acetone or water-containing acetonitrile.
(4) The method according to claim 3, wherein the water-containing acetone is acetone containing 1 to 10% by weight of water or the water-containing acetonitrile is acetonitrile containing 1 to 7% by weight of water.

  According to the present invention, sarpogrelate hydrochloride having a crystalline polymorph can be produced and supplied in a high yield with a reproducible, simpler operation and in a substantially single form (form B crystal) that is easy to formulate. be able to.

The B-form crystals of sarpogrelate hydrochloride according to the present invention can be produced by recrystallization from a hydrous polar solvent. Examples of solvents that can be selectively obtained include acetone, acetonitrile, methanol, ethanol, isopropyl alcohol. , N, N-dimethylformamide and tetrahydrofuran, one kind of solvent selected from the group consisting of two or more kinds, a mixed solvent of these solvents and water, and the like. Among them, water-containing acetone or water-containing acetonitrile is preferable, and the water content is preferably about 1 to 10% by weight in the case of water-containing acetone, more preferably about 2 to 8% by weight, and about 1 to 7% by weight in the case of water-containing acetonitrile. Preferably, it is about 2 to 5% by weight.
When the crude crystals of sarpogrelate hydrochloride are dissolved in, for example, water-containing acetone or water-containing acetonitrile, depending on the type of solvent and the water content ratio, approximately 3 to 10 times the volume of the solvent is used with respect to 1 part by weight of the solute, and 50 C. to 70.degree. C. with stirring while warming. The solution is gradually cooled to room temperature or lower within 1 to 24 hours with stirring, preferably 3 to 8 hours, whereby the desired form of sarpogrelate hydrochloride B-form is obtained in a high yield. It is obtained by.
Incidentally, the A-type crystal (powder X-ray diffraction pattern: FIG. 2), which is one of the crystal forms, can be obtained in high yield by operating in the same manner as described above using 1 to 9% by weight of hydrous methyl ethyl ketone.

The crude crystals of sarpogrelate hydrochloride used in the following examples were produced according to the method described in Patent Document 1 (excluding the final recrystallization step).

なお、粉末Ｘ線回折スペクトルを図１に示した。 Example 1 4 g of crude sarpogrelate hydrochloride crystals were added to 30 ml of 5% water-containing acetone, dissolved under heating, crystallized at 50 ° C., and cooled to room temperature. The precipitated crystals were collected by filtration, washed with a small amount of acetone, and then dried to obtain 3.5 g of sarpogrelate hydrochloride B-form crystals.
Melting point: 150-151 ° C
FAB-MS (m / z): 430 (M + 1) ⁺
IR (cm ⁻¹ ; KBr): 698, 758, 1245, 1404, 1495, 1742, 2936
Powder X-ray diffraction (Device used: Bruker AXS D8 DISCOVER with
GADDS CS. Measurement conditions: Tube Cu Tube voltage 45 KV Tube current 40 mA):

The powder X-ray diffraction spectrum is shown in FIG.

[Example 2] 4 g of crude sarpogrelate hydrochloride crystals were added to 30 ml of 3% aqueous acetonitrile, dissolved under heating, and gradually cooled to room temperature. The precipitated crystals were collected by filtration, washed with a small amount of acetonitrile, and then dried to obtain 3.7 g of sarpogrelate hydrochloride B-form crystals. The melting point, IR, and powder X-ray diffraction spectrum data substantially coincided with the data of Example 1, respectively.

なお、粉末Ｘ線回折スペクトルを図２に示した。 The crude crystals of sarpogrelate hydrochloride used in the following Reference Examples were produced according to the method described in Patent Document 1 (excluding the final recrystallization step).
[Reference Example 1] 200 g of crude sarpogrelate hydrochloride crystals were added to 1000 ml of 6% aqueous methyl ethyl ketone and dissolved at 65 ° C. The solution was allowed to cool to 60 ° C., and 2 g of A-type crystals were added to cause crystallization. The temperature was gradually lowered while stirring, and the mixture was stirred at room temperature for 5 hours. The precipitated crystals were collected by filtration, washed with methyl ethyl ketone, and then dried to obtain 157.5 g of A-form crystals of sarpogrelate hydrochloride.
Melting point: 154-155 ° C
FAB-MS (m / z): 430 (M + 1) ⁺
IR (cm ⁻¹ ; KBr): 698, 758, 793, 1163, 1246, 1406, 1464, 1497, 1603, 1742, 2937
Powder X-ray diffraction (Device used: D8 DISCOVER with GADDS CS. Manufactured by Bruker AXS, Inc. Measurement conditions: tube Cu tube voltage 45 KV tube current 40 mA):

The powder X-ray diffraction spectrum is shown in FIG.

[Reference Example 2] 200 g of crude sarpogrelate hydrochloride crystals were added to 1000 ml of 4% hydrous methyl ethyl ketone and dissolved at 65 ° C. After allowing the solution to cool to 60 ° C., 2 g of A-type crystals were added for crystallization, and when the liquid temperature reached 50 ° C., 1000 ml of 50 ° C. methyl ethyl ketone was added. Thereafter, the liquid temperature was gradually lowered, and the mixture was stirred overnight at room temperature. The precipitated crystals were collected by filtration, washed with methyl ethyl ketone, and then dried to obtain 185.4 g of Form A crystals of sarpogrelate hydrochloride. The melting point, IR, and powder X-ray diffraction spectrum data substantially matched the respective data of Reference Example 1.

  INDUSTRIAL APPLICABILITY The present invention can be used for industrial production of a crystalline drug substance suitable for formulation of sarpogrelate hydrochloride.

3 shows a powder X-ray diffraction spectrum of sarpogrelate hydrochloride B-type crystals. 2 shows a powder X-ray diffraction spectrum of sarpogrelate hydrochloride type A crystal.

Claims (4)

B-form crystals of sarpogrelate hydrochloride having a powder X-ray diffraction spectrum shown substantially identical to FIG. Sarpogrelate hydrochloride is one or more solvents selected from the group consisting of acetone, acetonitrile, methanol, ethanol, isopropyl alcohol, N, N-dimethylformamide and tetrahydrofuran, or a mixed solvent of these solvents and water. A method for producing a B-form crystal of sarpogrelate hydrochloride having a powder X-ray diffraction spectrum substantially identical to that shown in FIG.   The method according to claim 2, wherein the mixed solvent is hydrous acetone or hydrous acetonitrile. The method according to claim 3, wherein the water-containing acetone is acetone containing 1 to 10% by weight of water or the water-containing acetonitrile is acetonitrile containing 1 to 7% by weight of water.

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