JP2010077155A - CRYSTAL OF (±)2-(DIMETHYLAMINO)-1-{[O-(m-METHOXYPHENETYL)PHENOXY]METHYL}ETHYL HYDROGEN SUCCINATE HYDROCHLORIDE - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide new crystals of (±)2-(dimethylamino)-1-ä[O-(m-methoxyphenetyl)phenoxy]methyl}ethyl hydrogen succinate hydrochloride. <P>SOLUTION: There are provided type II crystals and type I crystals of (±)2-(dimethylamino)-1-ä[O-(m-methoxyphenetyl)phenoxy]methyl}ethyl hydrogen succinate hydrochloride characterized by at least one physicochemical property selected from a specific diffraction peak in X-ray powder diffraction spectrum, a specific endothermic peak in differential scanning calorimetry, a specific peak in solid<SP>13</SP>C-NMR spectrum, and a specific peak in infrared absorption spectrum. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a novel crystal of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride and a pharmaceutical composition containing the same as an active ingredient. is there.

  (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride can be produced based on the description in Example 2 of Patent Document 1. A compound. Patent Document 1 describes that the compound has a platelet aggregation inhibitory action, and Patent Document 2 describes that the compound has a serotonin antagonistic action. However, these documents neither describe nor suggest that a plurality of crystal polymorphs exist in the above compound.

JP 58-32847 A Japanese Patent Laid-Open No. 2-304022

  An object of the present invention is to provide a novel crystal of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride (hereinafter referred to as 2 One of the crystal forms of the seeds is called type I crystal and the other is called type II crystal).

  As a result of intensive studies in view of the above problems, the present inventors have found that (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride has crystals. The present inventors have found that Form II crystals and Form I crystals exist, and have completed the present invention.

That is, the gist of the present invention is as follows.
1. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl characterized by at least one physicochemical property selected from the following (1) to (4) Hydrogen succinate hydrochloride crystals.
(1) In a powder X-ray diffraction spectrum, a diffraction peak appears in at least one selected from Bragg angle (2θ) 9.5 ± 0.1 °, 11.0 ± 0.1 °, and 19.15 ± 0.1 °. Have
(2) In differential scanning calorimetry, it has an endothermic peak in the vicinity of about 157 ° C.
(3) The solid ¹³ C-NMR spectrum has a peak at at least one selected from 146.4 ± 0.5, 131.0 ± 0.5, and 110.4 ± 0.5 ppm.
(4) In the infrared absorption spectrum, at least one selected from 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0 and 792 ± 2.0 cm ⁻¹ has an absorption peak.
2. 2. The crystal according to 1 above, characterized by at least two physicochemical properties selected from (1) to (4) above.
3. 3. The crystal according to 1 or 2 above, characterized by the physicochemical properties of (1) and (2) above.

4). Any of the above 1 to 3 having diffraction peaks at a Bragg angle (2θ) of 9.5 ± 0.1 °, 11.0 ± 0.1 ° and 19.15 ± 0.1 ° in a powder X-ray diffraction spectrum The crystal of crab.
5). Further, in the powder X-ray diffraction pattern, the Bragg angle (2θ) is 16.2 ± 0.1 °, 19.7 ± 0.1 °, 22.8 ± 0.1 °, or 23.8 ± 0.1 °. 5. The crystal according to 4 above, having a diffraction peak.
6). In the powder X-ray diffraction pattern, the Bragg angle (2θ) is 16.2 ± 0.1 °, 19.7 ± 0.1 °, 22.8 ± 0.1 °, and 23.8 ± 0.1 °. 5. The crystal according to 4 above, having a diffraction peak.
7). In the powder X-ray diffraction pattern, the Bragg angle (2θ) of 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 ° has no diffraction peak, 1 above The crystal | crystallization in any one of -6.
8). 3. The crystal according to 1 or 2 above, having peaks at 146.4 ± 0.5, 131.0 ± 0.5, and 110.4 ± 0.5 ppm in a solid ¹³ C-NMR spectrum.
9. 9. The crystal according to 8 above, further having a peak at 128.5 ± 0.5, 58.3 ± 0.5, or 37.3 ± 0.5 ppm in the solid ¹³ C-NMR spectrum.
10. 9. The crystal according to 8 above, further having peaks at 128.5 ± 0.5, 58.3 ± 0.5, and 37.3 ± 0.5 ppm in a solid ¹³ C-NMR spectrum.
11. 3. The crystal according to 1 or 2 above, which has absorption peaks at 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0, and 792 ± 2.0 cm ⁻¹ in an infrared absorption spectrum.
12 12. The crystal according to 11 above, further having an absorption peak at 1725 ± 2.0, 1076 ± 2.0, or 1048 ± 2.0 cm ⁻¹ in the infrared absorption spectrum.
13. 12. The crystal according to 11 above, further having absorption peaks at 1725 ± 2.0, 1076 ± 2.0, and 1048 ± 2.0 cm ⁻¹ in the infrared absorption spectrum.
14 In the powder X-ray diffraction pattern, at least one selected from Bragg angle (2θ) 9.5 ± 0.2 °, 11.0 ± 0.2 ° and 19.15 ± 0.2 ° has a diffraction peak And having an absorption peak in at least one selected from 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0 and 792 ± 2.0 cm ⁻¹ in the infrared absorption spectrum, (±) 2 -(Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride crystals.
15. The powder X-ray diffraction pattern has diffraction peaks at Bragg angles (2θ) of 9.5 ± 0.2 °, 11.0 ± 0.2 ° and 19.15 ± 0.2 °, and 16.2 15. The crystal according to the above 14, having a diffraction peak at ± 0.2 °, 19.7 ± 0.2 °, 22.8 ± 0.2 °, or 23.8 ± 0.2 °.
16. In the powder X-ray diffraction pattern, there are diffraction peaks at Bragg angles (2θ) of 9.5 ± 0.2 °, 11.0 ± 0.2 ° and 19.15 ± 0.2 °, and 16.2 15. The crystal according to the above 14, having diffraction peaks at ± 0.2 °, 19.7 ± 0.2 °, 22.8 ± 0.2 °, and 23.8 ± 0.2 °.

17. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl characterized by at least one physicochemical property selected from the following (5) to (8) Hydrogen succinate hydrochloride crystals.
(5) In the powder X-ray diffraction spectrum, the diffraction peak is at least one selected from Bragg angle (2θ) 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 °. Have
(6) In differential scanning calorimetry, it has an endothermic peak near about 152 ° C.
(7) A solid ¹³ C-NMR spectrum has a peak at at least one selected from 117.3 ± 0.5 and 106.3 ± 0.5 ppm.
(8) In the infrared absorption spectrum, 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 and 780 ± 2.0 cm ^At least one selected from ^-1 has an absorption peak.
18. 18. The crystal according to 17 above, characterized by at least two physicochemical properties among the above (5) to (8).
19. 19. The crystal according to 17 or 18 above, characterized by the physicochemical properties of (5) and (6) above.

20. 20. The crystal according to any one of 17 to 19 above, which has diffraction peaks at Bragg angles (2θ) of 10.7 ± 0.1 ° and 16.5 ± 0.1 ° in a powder X-ray diffraction pattern.
21. In the powder X-ray diffraction spectrum, a Bragg angle (2θ) of 9.3 ± 0.1 °, 12.8 ± 0.1 °, 13.0 ± 0.1 °, 18.1 ± 0.1 ° or 21. The crystal according to the above 20, having a diffraction peak at 24.1 ± 0.1 °.
22. In the powder X-ray diffraction spectrum, a Bragg angle (2θ) of 9.3 ± 0.1 °, 12.8 ± 0.1 °, 13.0 ± 0.1 °, 18.1 ± 0.1 ° and 21. The crystal according to the above 20, having a diffraction peak at 24.1 ± 0.1 °.
23. Any of 17 to 19 above, which has diffraction peaks at a Bragg angle (2θ) of 9.3 ± 0.1 °, 10.7 ± 0.1 ° and 16.5 ± 0.1 ° in a powder X-ray diffraction pattern The crystal of crab.
24. 24. The crystal according to 23, further having a diffraction peak at a Bragg angle (2θ) of 12.8 ± 0.1 ° or 13.0 ± 0.1 ° in a powder X-ray diffraction pattern.
25. 24. The crystal according to 23 above, further having diffraction peaks at a Bragg angle (2θ) of 12.8 ± 0.1 ° and 13.0 ± 0.1 ° in a powder X-ray diffraction pattern.
26. In the powder X-ray diffraction pattern, the crystal according to any one of the above 17 to 25, which has no diffraction peak at any of Bragg angle (2θ) 11.0 ± 0.1 ° and 19.15 ± 0.1 °. .
27. The crystal according to 17 or 18 above, which has peaks at 117.3 ± 0.5 and 106.3 ± 0.5 ppm in a solid ¹³ C-NMR spectrum.
28. 28. The crystal according to 27 above, further having a peak at 145.0 ± 0.5 or 129.7 ± 0.5 ppm in the solid ¹³ C-NMR spectrum.
29. 28. The crystal according to 27 above, further having peaks at 145.0 ± 0.5 and 129.7 ± 0.5 ppm in a solid ¹³ C-NMR spectrum.
30. In the infrared absorption spectrum, at 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 and 780 ± 2.0 cm ⁻¹ 19. The crystal according to 17 or 18 above, which has an absorption peak.
31. 30. The crystal according to 30 above, further having an absorption peak at 3021 ± 2.0, 1729 ± 2.0, 1195 ± 2.0, 1152 ± 2.0, or 918 ± 2.0 cm ⁻¹ in an infrared absorption spectrum. .
32. 30. The crystal according to 30 above, further having absorption peaks at 3021 ± 2.0, 1729 ± 2.0, 1195 ± 2.0, 1152 ± 2.0, and 918 ± 2.0 cm ⁻¹ in an infrared absorption spectrum. .

33. The powder X-ray diffraction pattern has a diffraction peak in at least one selected from Bragg angle (2θ) 9.3 ± 0.2 °, 10.7 ± 0.2 °, and 16.5 ± 0.2 °. In the infrared absorption spectrum, 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 and 780 ± 2.0 cm A crystal of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride having an absorption peak in at least one selected from ^-1 .
34. In the powder X-ray diffraction pattern, there are diffraction peaks at Bragg angles (2θ) of 10.7 ± 0.2 ° and 16.5 ± 0.2 °, and 9.3 ± 0.2 °, 12.8 ±. 34. The crystal according to the above 33, which has a diffraction peak at 0.2 ° or 13.0 ± 0.2 °.
35. In the powder X-ray diffraction pattern, there are diffraction peaks at Bragg angles (2θ) of 10.7 ± 0.2 ° and 16.5 ± 0.2 °, and 9.3 ± 0.2 °, 12.8 ±. 34. The crystal according to the above 33, which has diffraction peaks at 0.2 °, 13.0 ± 0.2 °, 18.1 ± 0.2 °, and 24.1 ± 0.2 °.

36. The pharmaceutical composition which uses the crystal | crystallization in any one of said 1-16 as an active ingredient.
37. A preventive and / or therapeutic agent for chronic arterial occlusion containing the crystal according to any one of 1 to 16 as an active ingredient.
38. An agent for improving ischemic symptoms of ulcer, pain and cold sensation associated with chronic arterial occlusion, comprising the crystal according to any one of 1 to 16 as an active ingredient.
39. The improvement agent of the intermittent claudication which contains the crystal | crystallization in any one of said 1-16 as an active ingredient.
40. An inhibitor of thrombus / embolization in ischemic cerebrovascular disorder comprising the crystal according to any one of 1 to 16 as an active ingredient.
41. 41. The thrombus / embolization inhibitor as described in 40 above, wherein the ischemic cerebrovascular disorder is a transient ischemic attack and / or cerebral infarction.
42. An agent for reducing pain associated with postherpetic neuralgia comprising the crystal according to any one of 1 to 16 as an active ingredient.

43. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride, wherein the crystal according to any one of 1 to 16 above is used as a seed crystal. Method for producing type II crystals.
44. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride crystals are used, (±) 2- (dimethylamino) -1- { [O- (m-methoxyphenethyl) phenoxy] methyl} ethyl A method for producing hydrogen succinate hydrochloride, form II crystals.
45. (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Step of stirring hydrogen succinate hydrochloride crystals at any temperature from the crystal transition temperature to 160 ° C 45. The manufacturing method of said 44 containing.
46. (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride in the presence of a solvent, either from the crystal transition temperature to the boiling point of the solvent 45. The production method according to the above item 44, comprising a step of stirring at a temperature.
47. Crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride are crystallized at any temperature from the crystal transition temperature to 160 ° C. 45. The method according to 44 above, comprising a step.
48. (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride in the presence of a solvent, either from the crystal transition temperature to the boiling point of the solvent 45. The method according to 44 above, comprising a step of crystallizing at a temperature.
49. 49. The production method according to any one of 45 to 48, wherein the crystal transition temperature is from 20C to 40C.
50. 50. The production method according to any one of 43 to 49, wherein the type II crystal is the crystal according to any one of 1 to 16 above.

51. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride, wherein the crystal according to any one of 17 to 35 is used as a seed crystal. A method for producing an I-type crystal.
52. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride crystals are used, (±) 2- (dimethylamino) -1- { [O- (m-methoxyphenethyl) phenoxy] methyl} ethyl A process for producing Form I crystals of hydrogen succinate hydrochloride.
53. Crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride are crystallized at any temperature from −10 ° C. to the crystal transition temperature. 53. The production method according to 52 above, comprising a step of causing
54. (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride in the presence of a solvent, either from the freezing point of the solvent to the crystal transition temperature 53. The method according to 52 above, which comprises a step of crystallizing at a temperature of
55. 55. The method according to 54 above, wherein the solvent is water.
56. 56. The production method according to any of 53 to 55, wherein the crystal transition temperature is 20 ° C to 40 ° C.
57. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl including a step of blowing hydrogen chloride into a solution of hydrogen succinate.
(±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl A process for producing Form I crystals of hydrogen succinate hydrochloride.
58. 58. The production method according to any one of 51 to 57, wherein the I-form crystal is the crystal according to any one of 17 to 35.

59. A pharmaceutical composition comprising the crystal according to any one of 1 to 16 and the crystal according to any one of 17 to 35 as active ingredients.
60. A preventive and / or therapeutic agent for chronic arterial occlusion comprising the crystal according to any one of 1 to 16 and the crystal according to any one of 17 to 35 as an active ingredient.
61. An agent for improving ischemic symptoms of ulcer, pain and cold feeling associated with chronic arterial occlusion, comprising the crystal according to any one of 1 to 16 and the crystal according to any one of 17 to 35 as an active ingredient.
62. The improvement agent of the intermittent lameness which contains the crystal | crystallization in any one of said 1-16, and the crystal | crystallization in any one of said 17-35 as an active ingredient.
63. An inhibitor of thrombus / embolization in ischemic cerebrovascular disorder comprising the crystal according to any one of 1 to 16 and the crystal according to any one of 17 to 35 as an active ingredient.
64. 64. The thrombus / embolization inhibitor according to the above 63, wherein the ischemic cerebrovascular disorder is a transient cerebral ischemic attack and / or cerebral infarction.
65. The relief agent of the pain accompanying postherpetic neuralgia which contains the crystal | crystallization in any one of said 1-16, and the crystal | crystallization in any one of said 17-35 as an active ingredient.

71. (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride Form II crystals, whose powder X-ray diffraction spectrum has the pattern shown in FIG.
72. The powder X-ray diffraction spectrum has the pattern shown in FIG. 1 and has a Bragg angle (2θ) of 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 °. Form II crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride without a diffraction peak.
73. (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride Form I crystal having the powder X-ray diffraction spectrum shown in FIG.
74. The powder X-ray diffraction spectrum has the pattern shown in FIG. 1, and has no diffraction peak at either Bragg angle (2θ) 11.0 ± 0.1 ° or 19.15 ± 0.1 °, (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Form I crystals of hydrogen succinate hydrochloride.

101. (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride crystals.
102. 102. The crystal of 101, characterized by any of the following physicochemical properties:
(1) In a powder X-ray diffraction pattern, it has a diffraction peak (2θ) at 9.5 ± 0.1 °, 11.0 ± 0.1 ° or 19.2 ± 0.1 °;
(2) In differential scanning calorimetry, it has an endothermic peak around 157 ° C .;
(3) having a chemical shift peak of 146.4 ± 0.5, 131.0 ± 0.5 or 110.4 ± 0.5 ppm in the solid ¹³ C-NMR spectrum; and / or
(4) In the infrared absorption spectrum, it has an absorption peak at 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0 or 792 ± 2.0 cm ⁻¹ .

103. In the powder X-ray diffraction pattern, it has a diffraction peak (2θ) at 9.5 ± 0.2 °, 11.0 ± 0.2 ° or 19.2 ± 0.2 °, and in the infrared absorption spectrum, 1593 105. The crystal according to the above 102, which has an absorption peak at ± 2.0, 1163 ± 2.0, 1040 ± 2.0, or 792 ± 2.0 cm ⁻¹ .
104. 105. The crystal according to the above item 102, which has diffraction peaks (2θ) at 9.5 ± 0.1 °, 11.0 ± 0.1 °, and 19.2 ± 0.1 ° in a powder X-ray diffraction pattern.
105. 103. The powder X-ray diffraction pattern according to 102, wherein no diffraction peak (2θ) is observed at any of 9.3 ± 0.1 °, 10.7 ± 0.1 ° and 16.5 ± 0.1 °. crystal.
106. In the powder X-ray diffraction pattern, it has diffraction peaks (2θ) at 9.5 ± 0.1 °, 11.0 ± 0.1 ° and 19.2 ± 0.1 °, and further, 16.2 ± 0 101. The crystal according to the above 102, which has a diffraction peak (2θ) at any one of 1 °, 19.7 ± 0.1 °, 22.8 ± 0.1 °, or 23.8 ± 0.1 °.
107. In the powder X-ray diffraction pattern, it has diffraction peaks (2θ) at 9.5 ± 0.2 °, 11.0 ± 0.2 ° and 19.2 ± 0.2 °, and further, 16.2 ± 0 .2 °, 19.7 ± 0.2 °, 22.8 ± 0.2 °, or 23.8 ± 0.2 °, having a diffraction peak (2θ), and in the infrared absorption spectrum, 1593 105. The crystal according to the above 102, which has an absorption peak at ± 2.0, 1163 ± 2.0, 1040 ± 2.0, or 792 ± 2.0 cm ⁻¹ .

108. 102. The crystal according to the above item 102, which has a peak in the powder X-ray diffraction pattern shown in FIG.
109. 105. The crystal according to the above item 102, which has a characteristic thermal analysis pattern in the differential scanning calorimetry shown in FIG.
110. 103. The crystal according to 102, having chemical shift peaks of 146.4 ± 0.5, 131.0 ± 0.5, and 110.4 ± 0.5 ppm in the solid state ¹³ C-NMR spectrum.
111. In the solid ¹³ C-NMR spectrum, it has chemical shift peaks of 146.4 ± 0.5, 131.0 ± 0.5 and 110.4 ± 0.5 ppm, and further 128.5 ± 0.5, 58 103. The crystal according to 102, which has a chemical shift peak at either 3 ± 0.5 or 37.3 ± 0.5 ppm.
112. 102. The crystal according to the above item 102, which has a characteristic peak of chemical shift in the solid state ¹³ C-NMR spectrum shown in FIG.
113. 105. The crystal according to 102, which has absorption peaks at 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0 and 792 ± 2.0 cm ⁻¹ in the infrared absorption spectrum. 114. In the infrared absorption spectrum, it has absorption peaks at 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0 and 792 ± 2.0 cm ⁻¹ , and further 1725 ± 2.0, 1076 ± 2.0. Or the crystal | crystallization of the said 102 which has an absorption peak in any of 1048 +/- 2.0cm < ^-1 >.
115. The crystal according to 102, which shows a characteristic peak in the infrared absorption spectrum shown in FIG.

116. 102. The crystal of 101, characterized by any of the following physicochemical properties:
(1) In a powder X-ray diffraction pattern, it has a diffraction peak (2θ) at 9.3 ± 0.1 °, 10.7 ± 0.1 ° or 16.5 ± 0.1 °;
(2) In differential scanning calorimetry, it has an endothermic peak around 152 ° C;
(3) having a chemical shift peak of 117.3 ± 0.5 or 106.3 ± 0.5 ppm in the solid ¹³ C-NMR spectrum; and / or
(4) In infrared absorption spectrum, 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 or 780 ± 2.0 cm ^-1 has an absorption peak.

117. In the powder X-ray diffraction pattern, it has a diffraction peak (2θ) at 9.3 ± 0.2 °, 10.7 ± 0.2 ° or 16.5 ± 0.2 °, and in the infrared absorption spectrum, 1612 In the above 116 having an absorption peak at ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 or 780 ± 2.0 cm ⁻¹ The described crystals.
118. 116. The crystal according to the above item 116, which has diffraction peaks (2θ) at 10.7 ± 0.1 ° and 16.5 ± 0.1 ° in a powder X-ray diffraction pattern.
119. In the powder X-ray diffraction pattern, there are diffraction peaks (2θ) at 10.7 ± 0.2 ° and 16.5 ± 0.2 °, and 9.3 ± 0.2 °, 12.8 ± 0. It has a diffraction peak (2θ) at either 2 ° or 13.0 ± 0.2 °, and in the infrared absorption spectrum, 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 116. The crystal according to the above 116, having an absorption peak at 2.0, 932 ± 1.0, 918 ± 2.0 or 780 ± 2.0 cm ⁻¹ .
120. In the powder X-ray diffraction pattern, there are diffraction peaks (2θ) at 10.7 ± 0.1 ° and 16.5 ± 0.1 °, and 9.3 ± 0.1 °, 12.8 ± 0. 116. The crystal according to the above 116, which has a diffraction peak (2θ) at any of 1 °, 13.0 ± 0.1 °, 18.1 ± 0.1 °, or 24.1 ± 0.1 °.
121. In the powder X-ray diffraction pattern, there are diffraction peaks (2θ) at 10.7 ± 0.2 ° and 16.5 ± 0.2 °, and 9.3 ± 0.2 °, 12.8 ± 0. It has a diffraction peak (2θ) at 2 °, 13.0 ± 0.2 °, 18.1 ± 0.2 °, or 24.1 ± 0.2 °, and in the infrared absorption spectrum, 1612 ± 119, which has an absorption peak at 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 or 780 ± 2.0 cm ⁻¹ Crystal.
122. 116. The crystal according to the above item 116, which has diffraction peaks (2θ) at 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 ° in a powder X-ray diffraction pattern.
123. In the powder X-ray diffraction pattern, there are diffraction peaks (2θ) at 9.3 ± 0.1 °, 10.7 ± 0.1 °, 12.8 ± 0.1 ° and 16.5 ± 0.1 °. The crystal according to 116 above.
124. In the powder X-ray diffraction pattern, there are diffraction peaks (2θ) at 9.3 ± 0.1 °, 10.7 ± 0.1 °, 13.0 ± 0.1 ° and 16.5 ± 0.1 °. The crystal according to 116 above.
125. 9.3 ± 0.1 °, 10.7 ± 0.1 °, 12.8 ± 0.1 °, 13.0 ± 0.1 ° and 16.5 ± 0.1 in the powder X-ray diffraction pattern 116. The crystal according to the above 116, which has a diffraction peak (2θ) at °.
126. 116. The powder X-ray diffraction pattern according to 116, wherein a diffraction peak (2θ) is not observed at any of 9.5 ± 0.1 °, 11.0 ± 0.1 ° and 19.2 ± 0.1 °. crystal.

127. 116. The crystal according to the above 116, which has a peak in the powder X-ray diffraction pattern shown in FIG.
128. 116. The crystal according to the above 116, which has a characteristic thermal analysis pattern in the differential scanning calorimetry shown in FIG.
129. 116. The crystal according to the above 116, having chemical shift peaks of 117.3 ± 0.5 and 106.3 ± 0.5 ppm in a solid state ¹³ C-NMR spectrum.
130. In the solid ¹³ C-NMR spectrum, it has chemical shift peaks of 117.3 ± 0.5 and 106.3 ± 0.5 ppm, and either 145.0 ± 0.5 or 129.7 ± 0.5 ppm 116. The crystal according to the above item 116, which has a chemical shift peak.
131. 116. The crystal according to the above 116, which has a characteristic peak of chemical shift in the solid state ¹³ C-NMR spectrum shown in FIG.
132. In the infrared absorption spectrum, at 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 and 780 ± 2.0 cm ⁻¹ 116. The crystal according to the above 116, having an absorption peak.
133. In the infrared absorption spectrum, at 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 and 780 ± 2.0 cm ⁻¹ 116. The crystal according to the above 116, which has an absorption peak and further has an absorption peak at 3021 ± 2.0, 1729 ± 2.0, 1195 ± 2.0, 1152 ± 2.0, or 918 ± 2.0 cm ⁻¹ .
134. 116. The crystal according to the above 116, which shows a characteristic peak in the infrared absorption spectrum shown in FIG.

135. 116. A pharmaceutical composition comprising the crystal according to any one of 102 to 115 as an active ingredient. 136. 116. A preventive and / or therapeutic agent for chronic arterial occlusion comprising the crystal according to any one of 102 to 115 as an active ingredient.
137. 116. An agent for improving ischemic symptoms of ulcer, pain and cold feeling associated with chronic arterial occlusion, comprising the crystal according to any one of 102 to 115 as an active ingredient.
138. 115. An agent for improving intermittent claudication comprising the crystal according to any one of 102 to 115 as an active ingredient.
139. 115. An inhibitor of thrombus / embolization in ischemic cerebrovascular disorder comprising the crystal according to any one of 102 to 115 as an active ingredient.
140. 140. The thrombus / embolization inhibitor according to the above 139, wherein the ischemic cerebrovascular disorder is a transient cerebral ischemic attack and / or cerebral infarction.
141. 114. An agent for reducing pain associated with postherpetic neuralgia comprising the crystal according to any one of 102 to 115 as an active ingredient.

142. 116. The method for producing a crystal according to any one of the above 102 to 115.
143. 142. The method for producing a crystal according to 142, wherein the crystal according to any one of 102 to 115 is used as a seed crystal.
144. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl The step of stirring the crystals of hydrogen succinate hydrochloride at any temperature from the crystal transition temperature to 160 ° C. 145. The manufacturing method of the crystal | crystallization of said 142 containing.
145. (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl The crystals of hydrogen succinate hydrochloride are stirred at any temperature from the crystal transition temperature to the boiling point of the solvent. 145. A method for producing a crystal according to 142, comprising a step.
146. (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride crystals are dissolved and crystallized at any temperature from the crystal transition temperature to 160 ° C. 145. A method for producing a crystal according to 142, comprising a step of analyzing.
147. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Any one of the temperatures from the crystal transition temperature to the boiling point of the solvent, dissolving the crystals of hydrogen succinate hydrochloride 142. The method for producing a crystal according to 142, comprising a step of crystallizing at a temperature of 150 ° C.
148. 148. The method for producing a crystal according to any one of 144 to 147, wherein the crystal transition temperature is 20 ° C to 40 ° C.
149. 135. A method for producing a crystal according to any one of 116 to 134.
150. 145. The method for producing a crystal according to 149, wherein the crystal according to any one of 116 to 134 is used as a seed crystal.
151. (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Any temperature from −10 ° C. to the crystal transition temperature after dissolving the crystals of hydrogen succinate hydrochloride 149. The method for producing a crystal according to 149, which comprises a step of crystallizing at 149.
152. (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Any temperature from the freezing point of the solvent to the crystal transition temperature after dissolving the crystals of hydrogen succinate hydrochloride 149. The method for producing a crystal according to 149, which comprises a step of crystallizing at 149.
153. 155. The method for producing a crystal according to any one of 151 to 154, wherein the crystal transition temperature is 20 ° C. to 40 ° C.
154. 151. The method for producing a crystal according to 151 or 152, wherein the solvent is water.
155. (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl The method for producing a crystal according to the above 151 or 152, comprising a step of blowing hydrogen chloride into a hydrogen succinate solution.

  According to the present invention, (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride is a new crystalline polymorph of Form II crystals and I Shape crystals can be provided.

It is a figure which shows the powder X-ray-diffraction pattern of a type II crystal. It is a figure which shows the powder X-ray-diffraction pattern of a type I crystal. It is a figure which shows the powder X-ray-diffraction pattern of SPG. It is a figure which shows the differential scanning calorimetry curve of a type II crystal. It is a figure which shows the differential scanning calorimetry curve of a type I crystal. It is a figure which shows the differential scanning calorimetry curve of SPG. It is a figure which shows the solid ¹³ C-NMR spectrum of a type II crystal. It is a figure which shows the solid ¹³ C-NMR spectrum of a type I crystal. It is a figure which shows the solid ¹³ C-NMR spectrum of SPG. It is a figure which shows the infrared absorption spectrum of a type II crystal. It is a figure which shows the infrared absorption spectrum of a type I crystal. It is a figure which shows the infrared absorption spectrum of SPG. It is the figure which compared the chemical stability of a type II crystal and SPG.

Hereinafter, the present invention will be described in detail.
First, the II type crystal and the I type crystal according to the present invention will be described.
Form II crystals and Form I crystals of the present invention are (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride represented by the following formula: Crystal polymorphs, both having different physicochemical characteristics. Here, the crystal polymorph means one crystal form among a plurality of different crystal forms of the same compound.

The type II crystal in the present invention has the following physicochemical characteristics unique to the type II crystal that are not present in the type I crystal.
(1) In a powder X-ray diffraction spectrum, a diffraction peak appears in at least one selected from Bragg angle (2θ) 9.5 ± 0.1 °, 11.0 ± 0.1 °, and 19.15 ± 0.1 °. Have
(2) In differential scanning calorimetry, it has an endothermic peak in the vicinity of about 157 ° C.
(3) The solid ¹³ C-NMR spectrum has a peak at at least one selected from 146.4 ± 0.5, 131.0 ± 0.5, and 110.4 ± 0.5 ppm.
(4) In the infrared absorption spectrum, at least one selected from 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0 and 792 ± 2.0 cm ⁻¹ has an absorption peak.
As the type II crystal, it is sufficient to have at least one of the above physicochemical characteristics, preferably at least two of the above (1) to (4), more preferably (1) and (2). ) Physicochemical properties.

As the type II crystal, a crystal having at least one (preferably two or more) of the following physicochemical characteristics is particularly preferable, and due to this characteristic, a substance having a purity of more than about 95%, preferably about 98% or more. Can be confirmed to be pure II crystal.
(11) The powder X-ray diffraction spectrum has diffraction peaks at Bragg angles (2θ) of 9.5 ± 0.1 °, 11.0 ± 0.1 °, and 19.15 ± 0.1 °.
(12) In differential scanning calorimetry, it has an endothermic peak only at about 157 ° C.
(13) The solid ¹³ C-NMR spectrum has peaks at 146.4 ± 0.5, 131.0 ± 0.5, and 110.4 ± 0.5 ppm.
(14) In the infrared absorption spectrum, it has absorption peaks at 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0, and 792 ± 2.0 cm ⁻¹ .

In the powder X-ray diffraction spectrum, the type II crystal further has a Bragg angle (2θ) of 16.2 ± 0.1 °, 19.7 ± 0.1 °, 22.8 ± 0.1 °, and 23. At least one selected from 8 ± 0.1 ° may have a diffraction peak, and in order to obtain a high-purity type II crystal more reliably, the Bragg angle (2θ) is 9.3 ± 0.1 °. Those having no diffraction peak at any of 10.7 ± 0.1 ° and 16.5 ± 0.1 ° are desirable. Furthermore, the solid ¹³ C-NMR spectrum may further have a peak in at least one selected from 128.5 ± 0.5, 58.3 ± 0.5, and 37.3 ± 0.5 ppm. In addition, the infrared absorption spectrum may further have an absorption peak in at least one selected from 1725 ± 2.0, 1076 ± 2.0, and 1048 ± 2.0 cm ⁻¹ .

Further, the type II crystal has at least one selected from Bragg angle (2θ) 9.5 ± 0.2 °, 11.0 ± 0.2 ° and 19.15 ± 0.2 ° in the powder X-ray diffraction pattern. And has an absorption peak in at least one selected from 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0, and 792 ± 2.0 cm ⁻¹ in the infrared absorption spectrum. It may have. In that case, the powder X-ray diffraction pattern has diffraction peaks at Bragg angles (2θ) of 9.5 ± 0.2 °, 11.0 ± 0.2 °, and 19.15 ± 0.2 °, and 16 .2 ± 0.2 °, 19.7 ± 0.2 °, 22.8 ± 0.2 ° or 23.8 ± 0.2 ° having a diffraction peak, or in a powder X-ray diffraction pattern, Bragg It has diffraction peaks at angles (2θ) of 9.5 ± 0.2 °, 11.0 ± 0.2 ° and 19.15 ± 0.2 °, and 16.2 ± 0.2 °, 19. Those having diffraction peaks at 7 ± 0.2 °, 22.8 ± 0.2 ° and 23.8 ± 0.2 ° are preferred.

  Form II crystals in the present invention are obtained according to the method described in Example 2 of JP-A No. 58-32847 as shown in the following Examples (±) 2- (dimethylamino) -1-{[O- (M-Methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride has the advantage of a low hydrolyzate production rate and is very convenient for use as a pharmaceutical product. The action of the type II crystal is (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy obtained according to the method described in Example 2 of JP-A-58-32847. ] Methyl} ethyl Hydrogen succinate hydrochloride mixed crystal is unexpected.

In addition, the I-type crystal in the present invention has the following physicochemical characteristics unique to the I-type crystal that are not present in the II-type crystal.
(5) In the powder X-ray diffraction spectrum, the diffraction peak is at least one selected from Bragg angle (2θ) 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 °. Have
(6) In differential scanning calorimetry, it has an endothermic peak near about 152 ° C.
(7) A solid ¹³ C-NMR spectrum has a peak at at least one selected from 117.3 ± 0.5 and 106.3 ± 0.5 ppm.
(8) In the infrared absorption spectrum, 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 and 780 ± 2.0 cm ^At least one selected from ^-1 has an absorption peak.
The I-type crystal may have at least one of the above physicochemical characteristics, preferably at least two of the above (5) to (8), more preferably (5) and (6 ) Physicochemical properties.

As the I-type crystal, a crystal having at least one (preferably two or more) of the following physicochemical characteristics is more preferable, and by this characteristic, a purity of more than about 95%, preferably about 98% or more It can be confirmed that the crystal is pure I form crystal.
(15) The powder X-ray diffraction spectrum has diffraction peaks at Bragg angles (2θ) of 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 °.
(16) In differential scanning calorimetry, it has an endothermic peak only at about 152 ° C.
(17) The solid ¹³ C-NMR spectrum has peaks at 117.3 ± 0.5 and 106.3 ± 0.5 ppm.
(18) In the infrared absorption spectrum, 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 and 780 ± 2.0 cm ^-1 has an absorption peak.

In addition, in the powder X-ray diffraction spectrum, the I-type crystal preferably has diffraction peaks at Bragg angles (2θ) of 10.7 ± 0.1 ° and 16.5 ± 0.1 °. Bragg angle (2θ) from 9.3 ± 0.1 °, 12.8 ± 0.1 °, 13.0 ± 0.1 °, 18.1 ± 0.1 ° and 24.1 ± 0.1 ° At least one selected may have a diffraction peak, and in order to obtain a high-purity type I crystal more reliably, the Bragg angle (2θ) 11.0 ± 0.1 ° and 19.15 ± 0. Those having no diffraction peak at 1 ° are desirable. Furthermore, in the solid ¹³ C-NMR spectrum, it may further have a peak in at least one selected from 145.0 ± 0.5 and 129.7 ± 0.5 ppm. Furthermore, at least one selected from 3021 ± 2.0, 1729 ± 2.0, 1195 ± 2.0, 1152 ± 2.0, and 918 ± 2.0 cm ⁻¹ may have an absorption peak. .

Further, the Form I crystal has at least one selected from Bragg angles (2θ) of 9.3 ± 0.2 °, 10.7 ± 0.2 °, and 16.5 ± 0.2 ° in the powder X-ray diffraction pattern. In the infrared absorption spectrum, 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2. It may have an absorption peak in at least one selected from 0 and 780 ± 2.0 cm ⁻¹ . In that case, the powder X-ray diffraction pattern has diffraction peaks at Bragg angles (2θ) of 10.7 ± 0.2 ° and 16.5 ± 0.2 °, and further 9.3 ± 0.2 °, 12 One having a diffraction peak at 8 ± 0.2 ° or 13.0 ± 0.2 °, or a powder X-ray diffraction pattern, Bragg angle (2θ) 10.7 ± 0.2 ° and 16.5 ± 0 Has a diffraction peak (2θ) at .2 ° and is further 9.3 ± 0.2 °, 12.8 ± 0.2 °, 13.0 ± 0.2 °, 18.1 ± 0.2 ° and Those having a diffraction peak at 24.1 ± 0.2 ° are preferred.

  Form I crystals in the present invention are (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] obtained according to the method described in Example 2 of JP-A-58-32847. Compared with the mixed crystal of methyl} ethyl hydrogen succinate hydrochloride, there is an advantage that it exhibits high solubility at a temperature higher than the crystal transition temperature.

  The crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride according to the present invention are produced according to the physicochemical properties described herein. Although specified, each spectral data can vary somewhat in its nature and should not be interpreted strictly.

In the present invention, the powder X-ray diffraction spectrum refers to a spectrum measured under the following conditions using a RINT 2500 type powder X-ray diffraction apparatus (Rigaku Corporation).
X-ray source: Cu
Filter: Ni
Tube voltage: 40 kV
Tube current: 300mA
Divergent slit: 1/2 °
Scattering slit: 1/2 °
Receiving slit: 0.15mm
Scanning range: 3-40 ° 2θ
Step width: 0.02 °
Sampling time: 1.00 seconds Sample rotation speed: 60 rpm
Scan speed: 0.02 ° / sec

The endothermic peak in differential scanning calorimetry (hereinafter sometimes referred to as “DSC”) refers to an endothermic peak measured under the following conditions using DSC6200 (Seiko Instruments Inc.).
Temperature increase rate: 20 ° C./min Atmosphere: nitrogen 40 mL / min Measurement temperature range: 30 to 200 ° C.

Further, the solid ¹³ C-NMR spectrum refers to a spectrum measured under the following conditions using Infinity CMX-400 (Chemologicals).
Probe: 7.5mmφ CP / MAS probe
¹³ C observation frequency: 100 MHz
MAS rotation speed: 5.0 to 5.8 kHz
¹ H decoupling frequency: 50 kHz
¹ H90 ° pulse width: 5.0 microseconds Contact time: 3 milliseconds Repeat time: 20 seconds Integration number: 1000 to 100,000 times

The infrared absorption (hereinafter sometimes referred to as “IR”) spectrum refers to a spectrum measured under the following conditions using Spectrum One (Perkin Elmer).
Measuring method: KCl tablet method Measuring range: 4000 to 400 cm ⁻¹
Resolution: 2.00cm ^-1
Number of scans: 4

  In addition, when the crystal is analyzed using these apparatuses, the data and the patterns that are generally similar to each other are included in the crystal of the present invention and, for example, cannot be detected by a normal measurement method. Form II crystals mixed with the amount of Form I crystals are also included in the “Form II crystals” of the present invention. Similarly, Form I crystals mixed with an amount of Form II crystals that cannot be detected by ordinary measurement methods are also included in the “Form I crystals” of the present invention.

In addition, due to the nature of powder X-ray diffraction spectrum data, the Bragg angle (2θ) and the overall pattern are important in the identification of crystal identity, and the relative intensity is the crystal growth direction, particle size, and measurement. May vary slightly depending on conditions. Also in DSC, solid state ¹³ C-NMR spectrum, and IR spectrum, the overall pattern is important in the identification of crystal identity, and may vary somewhat depending on the measurement conditions.
Therefore, the crystal of the present invention includes a pattern similar to the powder X-ray diffraction spectrum, DSC, solid ¹³ C-NMR spectrum or IR spectrum of the crystal of the present invention.
In particular, in the powder X-ray diffraction spectrum, those having diffraction peaks at the same interplanar spacing are included in the crystal of the present invention.

As a powder X-ray diffraction spectrum of the II type crystal in the present invention, a diffraction peak (2θ) is observed at any of 9.3 °, 10.7 ° and 16.5 ° which are diffraction angles derived from the I type crystal. Unacceptable crystals are also included in Form II crystals of the present invention.
The powder X-ray diffraction spectrum of the I-form crystal in the present invention has a diffraction peak (2θ) at any of the diffraction angles derived from the II-form crystal of 9.5 °, 11.0 ° and 19.2 °. Unacceptable crystals are also included in Form I crystals of the present invention.
In DSC, an endothermic peak derived from the type I crystal is detected at around 152 ° C., but in the present invention, “around 152 ° C.” is about 152 ± 2.0 although there is a slight variation depending on the measurement sample. Means ℃. Similarly, in the II type crystal, “around 157 ° C.” means approximately 157 ± 2.0 ° C.

  The method for producing the crystal of the present invention is not particularly limited. For example, as shown in the following examples, a step of stirring the substance obtained by the method described in Example 2 of JP-A-58-32847 is provided. And a step of crystallizing after dissolving the substance in a solvent, a step of concentrating and crystallizing a solution of the substance, and a step of solidifying the substance from a molten state. Preferably, what includes the process of stirring in a solvent is mentioned. Moreover, the method of using the crystal | crystallization of I form or II form shown above as a seed crystal is also mentioned. Thereby, a substantially pure crystal polymorph having a purity of about 95% or more, preferably about 98% or more can be easily obtained.

  In the present invention, the crystal transition temperature refers to about 20 ° C. to about 40 ° C., preferably about 25 ° C. to about 35 ° C.

In the present invention, the solvent includes acetonitrile, acetone, ethyl acetate, hexane, 1-propanol, 2-propanol, methanol, ethanol, water, toluene, tetrahydrofuran, diisopropyl ether, chloroform, cyclohexane, heptane, octane, xylene, chlorobenzene and the like. Preferred examples include acetone, ethyl acetate, water, methanol, ethanol, 1-propanol, 2-propanol, toluene, tetrahydrofuran, hexane, heptane, octane, and xylene.
More preferred solvents for obtaining type II crystals include acetone, water, ethyl acetate, toluene, hexane, heptane, octane, and xylene, with acetone, ethyl acetate, and xylene being particularly preferred. A combination of these solvents is also suitable.
More preferable solvents for obtaining the I-form crystals include acetone, water, methanol, ethanol, 1-propanol, and 2-propanol. Among these, water, methanol, and 2-propanol are preferable. A combination of these solvents is also suitable.
The boiling point and freezing point of each solvent are described in the “New Edition Solvent Pocket Book” (published by Ohm, edited by the Society of Synthetic Organic Chemistry, June 10, 1994). Is possible.

  In the present invention, stirring means (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride described in JP-A-58-32847. A step of suspending, or (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride described in JP-A-58-32847. A step of dissolving and crystallizing in a solvent is included.

  JP-A-58-32847 discloses (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride with type II crystals and I There is no description about obtaining a shaped crystal, and there is no disclosure of sufficient information for making different Form II crystals and Form I crystals having different crystal forms of the present invention. This can be made under normal conditions because the crystal transition temperature of the type II crystal and the type I crystal whose existence has been clarified for the first time in the present invention is about 20 ° C. to about 40 ° C. It is thought that it came from not having.

More preferably, as a method for producing a type II crystal,
(±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Dissolves hydrogen succinate hydrochloride crystals in a solvent and adjusts the temperature from the crystal transition temperature to the boiling point of the solvent. A method for producing a type II crystal comprising a step of crystallizing at any temperature;
(±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Dissolves hydrogen succinate hydrochloride crystals in a solvent and adjusts the temperature from the crystal transition temperature to the boiling point of the solvent. A method for producing a type II crystal comprising a step of adding a seed crystal at any temperature and then cooling to crystallize,
(±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride crystals are dissolved in a solvent, and seed crystals are obtained at about 45 ° C. to about 60 ° C. A method for producing a type II crystal comprising a step of cooling and crystallizing after the addition,
(±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride crystals are dissolved in a solvent, and seed crystals are obtained at about 50 ° C. to about 55 ° C. A method for producing a type II crystal comprising a step of cooling and crystallizing after the addition,
(±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride crystals are dissolved in a solvent, and any of about 40 ° C. to about 65 ° C. in the solvent is used. A method of producing a type II crystal comprising a step of adding a seed crystal suspended at a temperature of about 45 ° C. to about 60 ° C. and then cooling to crystallize the seed crystal,
(±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride crystals are dissolved in a solvent and suspended in a solvent at about 50 ° C. to about 65 ° C. A method for producing a type II crystal comprising a step of adding a turbid seed crystal at about 45 ° C. to about 60 ° C., followed by cooling and crystallization, and (±) 2- (dimethylamino) -1-{[ O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride crystals dissolved in a solvent and suspended in a solvent at about 55 ° C. to about 65 ° C. were seeded at about 50 ° C. to about 56 ° C. And a method for producing a type II crystal, which includes a step of cooling and crystallizing after addition.

More preferably, as a method for producing the type I crystal,
(±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Any solution from −10 ° C. to the crystal transition temperature by dissolving hydrogen succinate hydrochloride crystals in a solvent. A method for producing Form I crystals, comprising a step of cooling to the temperature of crystallization and
(±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride crystals are dissolved in a solvent, and any of the solvent from the freezing point to the crystal transition temperature A method for producing Form I crystals comprising a step of crystallizing at any temperature, and a solution of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate A method for producing I-type crystals including a step of blowing hydrogen chloride is mentioned.

  In the present invention, it is possible to obtain a mixed crystal containing an arbitrary proportion of Form II crystals and Form I crystals. For example, pure Form II crystals and Form I crystals obtained by the above-described production method are obtained as desired. It can prepare by mixing so that it may become a ratio.

In the pharmaceutical composition containing the crystal of the present invention as an active ingredient, the content ratio of each of the type II crystal and the type I crystal is not particularly limited, but for example, contains about 75% or more of the type II crystal of the present invention. A pharmaceutical composition produced using the active drug substance is preferred. More preferably, the pharmaceutical composition is prepared using a drug substance containing about 85% or more of Form II crystals, and the pharmaceutical composition is prepared using a drug substance containing about 98% or more of Form II crystals. Is most preferred.
When the crystal of the present invention is used as a medicine, it may be administered alone, but a pharmaceutical composition containing the above crystal as an active ingredient is produced and administered using a pharmaceutically acceptable additive for pharmaceutical preparations. It is preferable to do this. The composition of the pharmaceutical composition is determined by crystal solubility, chemical characteristics, route of administration, dosing schedule, and the like. For example, granules, fine granules, powders, tablets, hard syrups, soft capsules, troches, syrups, emulsions, soft gelatin capsules, gels, pastes, suspensions, liposomes, etc. Can be administered orally, or can be administered intravenously, intramuscularly, or subcutaneously as an injection. Moreover, it can also be prepared and used at the time of use by making powder for injection.

  As the pharmaceutically acceptable pharmaceutical additive, an organic or inorganic solid or liquid carrier suitable for oral, enteral, parenteral or topical administration can be used. In addition to the carrier described above, the pharmaceutical composition may also contain adjuvants such as wetting agents, suspending aids, sweeteners, fragrances, coloring agents, preservatives and the like. Liquid formulations may also be used in capsules of absorbable substances such as gelatin. Solvents or suspending agents are used for the preparation of parenteral preparations, that is, injections and the like. In addition, preparation of each said formulation can be performed in accordance with a conventional method.

The crystal of the present invention is useful as an active ingredient of a medicine, specifically, a therapeutic agent for chronic arterial occlusion, an ulcer associated with chronic arterial occlusion, an agent for improving ischemic symptoms of pain and cold, intermittent It is useful as an active ingredient for lameness improving agents, inhibitors of thrombus / embolization in ischemic cerebrovascular disorders, and pain relieving agents associated with postherpetic neuralgia.
Dosage depends on age, weight, general health, sex, diet, administration time, administration method, excretion rate, combination of drugs, patient's condition being treated at the time, or other factors. It is decided in consideration. The crystals of the present invention, optical isomers thereof or pharmaceutically acceptable salts thereof can be safely used with low toxicity, and the daily dose depends on the patient's condition and body weight, the type of compound, the route of administration. For example, parenterally, about 0.01 to 50 mg / person / day, preferably 0.01 to 20 mg / person / day is administered subcutaneously, intravenously, intramuscularly or rectally. Specifically, it is desirable to administer about 0.01 to 150 mg / person / day, preferably 0.1 to 100 mg / person / day.

  EXAMPLES Hereinafter, although an Example and an experiment example demonstrate this invention concretely, this invention is not limited to these description.

Example 1
(±) 2- (dimethylamino) -1-, obtained by following the method described in Example 2 of JP-A-58-32847, wherein the molar ratio of Form II crystals to Form I crystals is about 3: 7. {[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl A mixture of 1 kg of a mixed crystal of hydrogen succinate hydrochloride (hereinafter sometimes referred to as “SPG”) and 10 L of acetone at 55 ° C. for 12 hours. Stir. Thereafter, the mixture was cooled to 25 ° C., and the crystals were collected by filtration and washed with 1.00 L of acetone. Thereafter, it was dried under reduced pressure to obtain 0.95 kg of type II crystals. The purity was 98% or more.

Example 2
10 g of SPG and 200 ml of xylene were stirred and heated to about 134 ° C., stirred for about 3 hours, cooled, and the crystals were collected by filtration and washed with acetone. After drying under reduced pressure, 8 g of Form II crystals were obtained. The purity was 98% or more.

Example 3
20 g of SPG and 200 ml of xylene were stirred and heated to about 139 ° C., stirred for about 2 hours, cooled, and the crystals were collected by filtration and washed with acetone. After drying under reduced pressure, 8.8 g of Form II crystals were obtained. The purity was 98% or more.

Example 4
2 g of SPG and 750 ml of acetone were dissolved by stirring and heating, and concentrated to about 180 ml at normal pressure. After stirring at about 55 ° C. for about 2 hours, the mixture was cooled to room temperature. The crystals were collected by filtration and washed with 8 ml of acetone. Thereafter, it was dried under reduced pressure to obtain 1.74 g of type II crystals. The purity was 98% or more.

Example 5
1 kg of SPG, 8.8 L of acetone and 0.55 L of water were mixed and the mixture was dissolved by heating, and then the internal temperature was cooled to 50 ° C. A suspension prepared from 0.7 L of acetone and 0.05 kg of the type II crystal obtained in Example 1 was added to this liquid, and 0.5 L of acetone was added. After cooling to 10 ° C. or lower, the crystals were collected by filtration, washed with 1 L of acetone, and dried under reduced pressure to obtain 0.9 kg of type II crystals. The purity was 98% or more.

Example 6
1 kg of SPG, 8.8 L of acetone and 0.55 L of water were mixed and the mixture was dissolved by heating, and then the internal temperature was cooled to 50 ° C. To this solution, 0.05 kg of the type II crystal obtained in Example 1 was added, and 1.2 L of acetone was added, followed by cooling to 10 ° C. or lower. The crystals were collected by filtration, washed with 1 L of acetone, and dried under reduced pressure to obtain 0.9 kg of type II crystals. The purity was 98% or more.

Example 7
1 kg of SPG, 8.8 L of acetone and 0.55 L of water were mixed, the mixture was heated and dissolved, and then the internal temperature was cooled to about 50 ° C. A suspension prepared from 0.7 L of acetone and 0.05 kg of type II crystals was added to this liquid after heating and stirring at about 55 ° C. After adding 0.5 L of acetone, the mixture was cooled to 10 ° C. or lower, and the crystals were collected by filtration. The crystals were washed with 1 L of acetone and dried under reduced pressure to obtain 0.9 kg of type II crystals. The purity was 98% or more.

Example 8
A solution obtained by heating and dissolving a mixture of 70 g of SPG and 467 mL of water at 55 ° C. was placed in a refrigerator at 0 ° C. and allowed to stand. After about 24 hours, the crystals were filtered. After drying under reduced pressure, 65.96 g of Form I crystals were obtained. The purity was 98% or more.

Example 9
(±) -1- [O- [2- (m-methoxyphenyl) ethyl] phenoxy] -3- (dimethylamino) -2-obtained according to the method described in Example 1 of JP-A-58-32847 (±) -1- [O- [2- (m-methoxyphenyl) ethyl] phenoxy] -3- (dimethyl) obtained by extracting propanolic hydrochloride with a sodium hydroxide aqueous solution as a free base with toluene and then concentrating. To a toluene solution containing about 1.0 kg of amino) -2-propanol, 2.1 L of acetone and about 0.34 kg of succinic anhydride were added and reacted at 35 to 45 ° C. for about 2 hours. After cooling to 20-30 ° C., 8.5 L of acetone was added and cooled to around 10 ° C. A small amount of SPG was added here as seed crystals, and crystals were precipitated by blowing 1.0 to 1.2 equivalents of hydrochloric acid gas at about 15 ° C. or lower. After cooling to about 6 ° C. or lower, the mixture was aged for 2 to 3 hours and filtered and washed (acetone 2 L). About 1.4 kg of Form I crystals were obtained by drying under reduced pressure. The purity was 98% or more.

Example 10
When a small amount of Form II crystals is detected in Example 9, the following steps are added.
A mixture of 50 g of the crystals obtained in Example 9 and 500 mL of isopropanol was stirred at 25 ° C. for 30 hours. The crystals were collected by filtration and washed with 200 mL of isopropanol. Thereafter, it was dried under reduced pressure to obtain 48.9 g of Form I crystals. The purity was 98% or more.

Example 11
A solution in which a mixture of SPG (100 g), acetone (880 mL) and water (55 mL) was dissolved by heating was cooled to an internal temperature of about 50 ° C., and after adding 5 g of Form I crystals obtained in Examples 8 to 9, 120 mL of acetone was added. Thereafter, it was cooled to 10 ° C. or lower. The crystals were collected by filtration, washed with 100 mL of acetone, and then dried under reduced pressure to obtain 90 g of Form I crystals. The purity was 98% or more.

Experimental Example 1 Powder X-ray diffraction measurement
Powder X-ray diffraction of Form II crystal, Form I crystal and SPG was measured under the following conditions.
(Measurement condition)
Apparatus: RINT2500 powder X-ray diffractometer (Rigaku)
X-ray source: Cu
Filter: Ni
Tube voltage: 40 kV
Tube current: 300mA
Divergent slit: 1/2 °
Scattering slit: 1/2 °
Receiving slit: 0.15mm
Scanning range: 3-40 ° 2θ
Step width: 0.02 °
Sampling time: 1.00 seconds Sample rotation speed: 60 rpm
Detection limit: 2%
Scan speed: 0.02 ° / sec
The powder X-ray diffraction patterns of type II crystal, type I crystal and SPG are shown in FIG. 1, FIG. 2 and FIG. 3, respectively. The diffraction peak value (2θ) of the powder X-ray diffraction pattern of type II crystal is shown in Table 1, the diffraction peak value (2θ) of the powder X-ray diffraction pattern of type I crystal is shown in Table 2, and the powder X-ray diffraction pattern of SPG The diffraction peak values (2θ) are shown in Table 3, respectively.

  As a result of measurement, it was clarified that type II crystal, type I crystal and SPG show different powder X-ray diffraction patterns.

Experimental example 2 DSC measurement
Each 1 mg sample of Form II crystal, Form I crystal and SPG was weighed and placed on an aluminum open pan, and measured under the following conditions.
(Measurement condition)
Equipment: DSC6200 (Seiko Instruments)
Temperature increase rate: 20 ° C./min Atmosphere: nitrogen 40 mL / min Measurement temperature: 30-200 ° C.
The DSC curves for Form II, Form I and SPG are shown in FIGS. 4, 5 and 6, respectively. Form II showed an endothermic peak of melting at 157.1 ° C., and Form I showed an endothermic peak of melting at 152.2 ° C.

Experimental Example 3 Solid ¹³ C-NMR spectrum measurement
Solid ¹³ C-NMR spectra of Form II crystals, Form I crystals and SPG were measured.
(Measurement condition)
Apparatus: Infinity CMX-400 (Chemologicals)
Probe: 7.5mmφ CP / MAS probe
¹³ C observation frequency: 100 MHz
MAS rotation speed: 5.0 to 5.8 kHz
¹ H decoupling frequency: 50 kHz
¹ H90 ° pulse width: 5.0 microseconds Contact time: 3 milliseconds Repeat time: 20 seconds Integration number: 1000 to 100,000 times
The solid ¹³ C-NMR spectra of Form II crystal, Form I crystal and SPG are shown in FIGS. 7, 8 and 9, respectively. The chemical shift values of the solid ¹³ C-NMR spectrum of form II crystal in Table 4, the chemical shift values of the solid ¹³ C-NMR spectrum of form II crystal in Table 5, SPG solid ¹³ C-NMR spectrum of the chemical shift values Are shown in Table 6.

As a result of the measurement, it was revealed that the II-type crystal, the I-type crystal and the SPG show different solid ¹³ C-NMR spectra.

Experimental Example 4 IR spectrum measurement
The IR spectrum by the KCl tablet method was measured under the following conditions for Form II crystals, Form I crystals and SPG.
(Measurement condition)
Apparatus: Spectrum One (Perkin Elmer)
Measurement range: 4000 to 400 cm ⁻¹
Resolution: 2.00cm ^-1
Number of scans: 4
Infrared absorption spectra of type II crystal, type I crystal and SPG are shown in FIGS. 10, 11 and 12, respectively. Form II crystal, Form I crystal and SPG showed different spectra.

Experimental Example 5 Chemical Stability For the type II crystal produced according to the present invention and SPG, the chemical stability of both was compared. The chemical stability was evaluated by high-performance liquid chromatography for the amount of BP-984 (Table-1 No. 3 compound described in JP-A No. 58-32847), which is the main decomposition product of SPG. BP-984 can be synthesized according to Example 1 described in JP-A-58-32847 as described in JP-A-58-32847.
(Stability condition)
Storage conditions: 40 ° C / 75% RH
Storage form: Glass petri dish open Storage period: 2 weeks, 4 weeks, 8 weeks (high-performance liquid chromatography measurement conditions)
Form II crystals and about 20 mg of SPG were dissolved in 10 mL of mobile phase to prepare a sample solution. The sample solution was accurately weighed in 2 mL, and the mobile phase was added to make exactly 200 mL to obtain a 1% diluted standard solution. About 10 μL of the sample solution and the 1% diluted standard solution were injected, and the respective peak areas were determined by an automatic integration method. The amount of BP-984 was determined by the following calculation formula.

Amount of BP-984 (%) = peak area of BP-984 obtained from sample solution / peak area of SPG obtained from standard solution × 0.78 (sensitivity coefficient of BP-984)
Equipment: 10A-VP system (Shimadzu Corporation)
Detector: UV-visible spectrophotometer (measurement wavelength: 272 nm)
Mobile phase: water / acetonitrile / trifluoroacetic acid = 65: 35: 0.05
Column: Inertsil ODS-3V 4.6 mmφ × 150 cm
Flow rate: 1.1 mL / min
The stability test results for Form II crystals and SPG are shown in FIG. The amount of BP-984 produced (-Δ-) of the type II crystal was less than half of the amount of BP-984 produced (-■-) of SPG.
From this result, it was found that the type II crystal according to the present invention has an advantageous property that its chemical stability is higher than that of the conventional SPG.

Experimental Example 6 Physically stable form
The physical stable form was investigated about the type I crystal and the type II crystal. An equal mixture of Form I and Form II crystals was prepared and suspended in ethanol at 5 ° C, 15 ° C, 25 ° C, 35 ° C and 40 ° C and stirred. The powder was subjected to suction filtration and dried under reduced pressure, and the powder X-ray diffraction spectrum was measured. The measurement conditions are the same as in Example 1. As a result, the peak intensity of Form I crystals increased relatively at 5 ° C., 15 ° C., and 25 ° C., and the peak intensity of Form II crystals increased relatively at 35 ° C. and 40 ° C. As a result, it was found that Form I crystals were physically stable at temperatures below 25 ° C., and Form II crystals were physicochemically stable at temperatures above 35 ° C.
That is, the crystal transition temperature, which is the temperature at which the physicochemical stable forms of the I-form crystal and the II-form crystal are interchanged, is in the range of 25 to 35 ° C.
By suspending and stirring the mixed crystal in a solvent at a temperature higher than this crystal transition temperature, the Form I crystal can be transferred to the Form II crystal, and conversely, the mixed crystal in a solvent at a temperature lower than the crystal transition temperature. Can be transferred to form II crystals by suspending and stirring.

According to the present invention, there are provided (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride Form II crystals and Form I crystals. it can.
In addition, this application is based on Japanese Patent Application No. 2005-044896 for which it applied on February 22, 2005 in Japan, The content is altogether included in this specification.

Claims (10)

  (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Hydrogen succinate hydrochloride Form I crystal having the powder X-ray diffraction spectrum shown in FIG.   The powder X-ray diffraction spectrum has the pattern shown in FIG. 2, and has no diffraction peak at either Bragg angle (2θ) 11.0 ± 0.1 ° or 19.15 ± 0.1 °, (±) 2- (Dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl Form I crystals of hydrogen succinate hydrochloride.   3. The (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride crystal according to claim 1 or 2, and pharmacologically acceptable A pharmaceutical composition comprising the resulting pharmaceutical additive.   The pharmaceutical composition according to claim 3, which is a granule, fine granule, powder or tablet. The (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride form I crystal according to claim 1 or 2, and the powder X-ray diffraction spectrum (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride type II crystals having the pattern shown in FIG. A method for producing a mixed crystal of the Form I crystal and the Form II crystal.   The type II crystal has no diffraction peak at any of Bragg angles (2θ) of 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 °. A method for producing a mixed crystal.   A pharmaceutical composition comprising the form I crystal and the mixed crystal of the form II crystal produced by the method according to claim 5 and 6, and a pharmacologically acceptable pharmaceutical additive.   The pharmaceutical composition according to claim 7, which is a granule, a fine granule, a powder or a tablet.   A mixed crystal of the I-type crystal and the II-type crystal produced by the method according to claim 5 or 6.   A standard reagent comprising a mixed crystal of the Form I crystal and the Form II crystal produced by the method according to claim 5 or 6.

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