KR100729701B1 - Crystal of (±)2-(Dimethylamino)-1-{[O-(m-methoxyphenethyl)phenoxy]methyl}ethyl Hydrogen Succinate Hydrochloride - Google Patents

Abstract

The present invention provides novel crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride.

According to the present invention, a specific diffraction peak in powder X-ray diffraction spectrum, a specific endothermic peak in differential scanning calorimetry, a specific peak in solid ¹³ C-NMR spectrum and a specific peak in infrared absorption spectrum are selected. Form II crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride characterized by one or more physicochemical properties and Type I crystals are provided.

Crystals, (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride, powder X-ray diffraction, differential scanning thermal analysis, infrared absorption spectrum Chemical stability

Description

Crystals of (±) 2- (dimethylamino) -1-｛[O- (m-methoxyphenethyl) phenoxy] methyl｝ ethyl hydrogen succinate hydrochloride {Crystal of (±) 2- (Dimethylamino) -1- O [O- (m-methoxyphenethyl) phenoxy] methyl｝ ethyl Hydrogen Succinate Hydrochloride}

1 is a diagram showing a powder X-ray diffraction pattern of Form II crystals.

2 is a diagram showing a powder X-ray diffraction pattern of Form I crystals.

3 is a diagram illustrating a powder X-ray diffraction pattern of SPG.

4 shows the differential scanning thermal analysis curve of Form II crystals.

Fig. 5 shows the differential scanning thermal analysis curve of Form I crystals.

6 is a diagram showing the differential scanning thermal analysis curve of SPG.

Fig. 7 shows the solid ¹³ C-NMR spectra of Form II crystals.

8 shows a solid ¹³ C-NMR spectrum of a Form I crystal.

9 shows a solid ¹³ C-NMR spectrum of SPG.

10 shows the infrared absorption spectrum of Form II crystals.

11 shows the infrared absorption spectrum of Form I crystals.

13 is a diagram comparing the chemical stability of Form II crystals and SPG.

[Patent Document 1] Japanese Unexamined Patent Publication No. 58-32847

[Patent Document 2] Japanese Patent Application Laid-Open No. 2-304022

The present invention relates to crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride and to pharmaceutical compositions comprising the same as active ingredients .

(±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride can be prepared based on the description of Example 2 of Patent Document 1 have. Patent Document 1 also describes that the compound has a platelet aggregation inhibitory effect, and Patent Document 2 describes that the compound has a serotonin antagonism. However, these documents do not describe or suggest that a plurality of crystal polymorphs exist in the compound.

The problem of this invention is the novel crystal | crystallization of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride (Hereinafter, In the present invention, one of the two crystal forms is called Form I crystal and the other is Form II crystal.

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining in view of the said subject, the present inventors determined the crystal | crystallization of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride. It was found that Form II crystals and Form I crystals exist and have completed the present invention.

That is, the summary of this invention is as follows.

1. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy characterized by one or more physicochemical properties selected from (1) to (4) below ] Methyl} ethyl hydrogen succinate hydrochloride crystals.

(1) The powder X-ray diffraction spectrum has one or more diffraction peaks selected from Bragg angles (2θ) of 9.5 ± 0.1 °, 11.0 ± 0.1 ° and 19.15 ± 0.1 °.

(2) In the differential scanning calorimetry, it has an endothermic peak near about 157 ° C.

(3) In the solid ¹³ C-NMR spectrum, it has at least one peak selected from 146.4 ± 0.5, 131.0 ± 0.5, and 110.4 ± 0.5 ppm.

(4) The infrared absorption spectrum has one or more absorption peaks selected from 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0, and 792 ± 2.0 cm ⁻¹ .

2. The crystal according to 1 above, characterized by two or more physicochemical properties selected from (1) to (4).

3. The crystal according to 1 or 2 above, characterized by the physicochemical properties of (1) and (2).

4. The crystal according to any one of 1 to 3 above, having a diffraction peak at a Bragg angle (2θ) of 9.5 ± 0.1 °, 11.0 ± 0.1 ° and 19.15 ± 0.1 ° in the powder X-ray diffraction spectrum.

5. The crystal according to the above 4, wherein the powder X-ray diffraction pattern also has a diffraction peak at a Bragg angle (2θ) of 16.2 ± 0.1 °, 19.7 ± 0.1 °, 22.8 ± 0.1 °, or 23.8 ± 0.1 °.

6. The crystal according to the above 4, wherein the powder X-ray diffraction pattern also has diffraction peaks at Bragg angles (2θ) of 16.2 ± 0.1 °, 19.7 ± 0.1 °, 22.8 ± 0.1 ° and 23.8 ± 0.1 °.

7. The crystal according to any one of 1 to 6, wherein in the powder X-ray diffraction pattern, none of the Bragg angles (2θ) of 9.3 ± 0.1 °, 10.7 ± 0.1 ° and 16.5 ± 0.1 ° have diffraction peaks.

8. The crystal according to 1 or 2 above, having a peak at 146.4 ± 0.5, 131.0 ± 0.5 and 110.4 ± 0.5 ppm in the solid ¹³ C-NMR spectrum.

9. The crystal according to 8 above, which also has 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. Crystal according to the above 8, having a peak in the solid ¹³ C-NMR spectrum also at 128.5 ± 0.5, 58.3 ± 0.5 and 37.3 ± 0.5 ppm.

11. The crystal according to 1 or 2 above, having an absorption peak at 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0 and 792 ± 2.0 cm ⁻¹ in the infrared absorption spectrum.

12. The crystal according to the above 11, which has an absorption peak in the infrared absorption spectrum and also at 1725 ± 2.0, 1076 ± 2.0 or 1048 ± 2.0 cm ⁻¹ .

13. The crystal according to ^{11 above} , which has an absorption peak in the infrared absorption spectrum and also at 1725 ± 2.0, 1076 ± 2.0 and 1048 ± 2.0 cm ⁻¹ .

14. In the powder X-ray diffraction pattern, at least one selected from Bragg angle (2θ) of 9.5 ± 0.2 °, 11.0 ± 0.2 ° and 19.15 ± 0.2 °, and has a diffraction peak of 1593 ± 2.0 in infrared absorption spectrum. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy having at least one absorption peak selected from 1163 ± 2.0, 1040 ± 2.0 and 792 ± 2.0 cm ⁻¹ Crystals of c.methyl} ethyl hydrogen succinate hydrochloride.

15. The powder X-ray diffraction pattern according to the above 14, which has diffraction peaks at Bragg angles (2θ) of 9.5 ± 0.2 °, 11.0 ± 0.2 ° and 19.15 ± 0.2 °, and also 16.2 ± 0.2 ° and 19.7 ± 0.2 ° , Crystals having diffraction peaks at 22.8 ± 0.2 ° or 23.8 ± 0.2 °.

16. The powder X-ray diffraction pattern according to the above 14, which has diffraction peaks at Bragg angles (2θ) of 9.5 ± 0.2 °, 11.0 ± 0.2 ° and 19.15 ± 0.2 °, and also 16.2 ± 0.2 ° and 19.7 ± 0.2 ° , Crystals having diffraction peaks at 22.8 ± 0.2 ° and 23.8 ± 0.2 °.

17. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy characterized by one or more physicochemical properties selected from (5) to (8) below ] Methyl} ethyl hydrogen succinate hydrochloride crystals.

(5) The powder X-ray diffraction spectrum has one or more diffraction peaks selected from Bragg angles (2θ) of 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 °.

(6) In the differential scanning calorimetry, it has an endothermic peak near about 152 ° C.

(7) Solid ¹³ C-NMR spectrum with at least one peak selected from 117.3 ± 0.5 and 106.3 ± 0.5 ppm.

(8) In the infrared absorption spectrum, it has at least one absorption peak selected from 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 and 780 ± 2.0 cm ^-1 .

18. The crystal according to the above 17, characterized by two or more physicochemical properties in (5) to (8).

19. The crystal according to the above 17 or 18, characterized by the physicochemical properties of (5) and (6).

20. The crystal according to any one of 17 to 19, having a diffraction peak at a Bragg angle (2θ) of 10.7 ± 0.1 ° and 16.5 ± 0.1 ° in the powder X-ray diffraction pattern.

21. The powder X-ray diffraction spectrum of 20 above, further having diffraction peaks at a Bragg angle (2θ) of 9.3 ± 0.1 °, 12.8 ± 0.1 °, 13.0 ± 0.1 °, 18.1 ± 0.1 °, or 24.1 ± 0.1 °. decision.

22. The powder X-ray diffraction spectrum of 20 above, further having diffraction peaks at Bragg angles (2θ) of 9.3 ± 0.1 °, 12.8 ± 0.1 °, 13.0 ± 0.1 °, 18.1 ± 0.1 °, and 24.1 ± 0.1 °. decision.

23. The crystal according to any one of 17 to 19, wherein the powder X-ray diffraction pattern has diffraction peaks at Bragg angles (2θ) of 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 °.

24. The crystal according to the above 23, wherein the powder X-ray diffraction pattern further has diffraction peaks at a Bragg angle (2θ) of 12.8 ± 0.1 ° or 13.0 ± 0.1 °.

25. The crystal according to the above 23, wherein the powder X-ray diffraction pattern also has diffraction peaks at Bragg angles (2θ) of 12.8 ± 0.1 ° and 13.0 ± 0.1 °.

26. The crystal according to any one of 17 to 25, wherein in the powder X-ray diffraction pattern, none of the Bragg angles (2θ) of 11.0 ± 0.1 ° and 19.15 ± 0.1 ° have diffraction peaks.

27. The crystal according to 17 or 18, having a peak at 117.3 ± 0.5 and 106.3 ± 0.5 ppm in the solid ¹³ C-NMR spectrum.

28. The crystal according to 27 above, which also has a peak in the solid ¹³ C-NMR spectrum and also at 145.0 ± 0.5 or 129.7 ± 0.5 ppm.

29. The crystal according to 27 above, which also has peaks at 145.0 ± 0.5 and 129.7 ± 0.5 ppm in the solid ¹³ C-NMR spectrum.

30. The absorption peak according to 17 or 18 above, wherein the absorption peak is measured 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 in the infrared absorption spectrum. Having a decision.

31. The crystal according to ^{30 above} , which has an absorption peak in the infrared absorption spectrum and also at 3021 ± 2.0, 1729 ± 2.0, 1195 ± 2.0, 1152 ± 2.0 or 918 ± 2.0 cm ⁻¹ .

32. The crystal according to 30, wherein the infrared absorption spectrum further has an absorption peak at 3021 ± 2.0, 1729 ± 2.0, 1195 ± 2.0, 1152 ± 2.0, and 918 ± 2.0 cm ⁻¹ .

33. In the powder X-ray diffraction pattern, the Bragg angle (2θ) has diffraction peaks at one or more selected from 9.3 ± 0.2 °, 10.7 ± 0.2 °, and 16.5 ± 0.2 °, and in the infrared absorption spectrum, 1612 ± 2.0 (±) 2- (dimethylamino) -1- {with one or more absorption peaks selected from 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 and 780 ± 2.0 cm ^-1 Crystals of [O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride.

34. The powder X-ray diffraction pattern according to 33 above, having a diffraction peak at Bragg angles (2θ) of 10.7 ± 0.2 ° and 16.5 ± 0.2 °, and also 9.3 ± 0.2 °, 12.8 ± 0.2 ° or 13.0 ± 0.2 ° Crystals with diffraction peaks in.

35. The powder X-ray diffraction pattern according to the above 33, which has diffraction peaks at Bragg angles (2θ) of 10.7 ± 0.2 ° and 16.5 ± 0.2 °, and also 9.3 ± 0.2 °, 12.8 ± 0.2 °, and 13.0 ± 0.2 ° , Crystals having diffraction peaks at 18.1 ± 0.2 ° and 24.1 ± 0.2 °.

36. A pharmaceutical composition comprising the crystal according to any one of 1 to 16 as an active ingredient.

37. A prophylactic and / or therapeutic agent for chronic arterial occlusion, which contains the crystal according to any one of 1 to 16 as an active ingredient.

38. An agent for improving ischemic symptoms of ulcers, pain, and coldness caused by chronic arterial occlusion, which contains the crystal according to any one of 1 to 16 as an active ingredient.

39. An agent for improving intermittent lameness, comprising the crystal according to any one of 1 to 16 as an active ingredient.

40. An inhibitor of thrombus / embolism formation in ischemic cerebrovascular disorder containing the crystal according to any one of 1 to 16 as an active ingredient.

41. The inhibitor according to the above 40, wherein the ischemic cerebrovascular disorder is a transient cerebral ischemic attack and / or cerebral infarction.

42. A reducer of pain according to neuralgia after shingles containing the crystal according to any one of 1 to 16 as an active ingredient.

43. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl, using the crystal according to any one of 1 to 16 above as a seeding crystal. Process for the preparation of Form II crystals of hydrogen succinate hydrochloride.

44. (±) 2- (dimethylamino, using crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride A method for producing Form II crystals of) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride.

45. The crystal of 44 above, wherein the crystal of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride is crystallized at a crystal transition temperature of 160 ° C. The manufacturing method including the process of stirring at any temperature of the process.

46. The crystal transition temperature of 44 above, wherein the crystal of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride is crystallized in the presence of a solvent; A manufacturing method including the process of stirring at the temperature of the boiling point of a solvent.

47. The crystal of 44 above, wherein the crystal of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride is crystallized at a crystal transition temperature of 160 ° C. The manufacturing method including the process of crystallizing at any temperature of this.

48. The crystal transition temperature of 44 above, wherein the crystal of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride is crystallized in the presence of a solvent; To a process for crystallizing at any temperature at the boiling point of the solvent.

49. The method according to any one of 45 to 48, wherein the crystal transition temperature is 20 ° C to 40 ° C.

50. The production method according to any one of 43 to 49, wherein the Form II crystal is the crystal according to any one of 1 to 16 above.

51. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl, using the crystal according to any one of 17 to 35 above as a seeding crystal. Process for producing Form I crystals of hydrogen succinate hydrochloride.

52. (±) 2- (dimethylamino, using crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride ) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride A method for producing Form I crystals.

53. The crystal of 52 above, wherein the crystal of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride is crystallized from -10 deg. A manufacturing method comprising the step of crystallizing at any temperature of the temperature.

54. The crystal of 52 above, wherein the crystal of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride is dissolved in the presence of a solvent. A process for crystallization at any temperature from the freezing point to the crystal transition temperature.

55. The process according to 52 above, wherein the solvent is water.

56. The method according to any one of 53 to 55, wherein the crystal transition temperature is 20 ° C to 40 ° C.

57. (±) comprising a step of blowing hydrogen chloride into a solution of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate A method for producing Form I crystals of 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride.

58. The production method according to any one of 51 to 57, wherein the Form I crystal is the crystal according to any one of 17 to 35 above.

59. A pharmaceutical composition comprising the crystal according to any one of 1 to 16 above and the crystal according to any one of 17 to 35 as an active ingredient.

60. A prophylactic and / or therapeutic agent for chronic artery occlusion, comprising the crystal according to any one of 1 to 16 above and the crystal according to any one of 17 to 35 as an active ingredient.

61. An agent for improving ischemic symptoms of ulcers, pain and coldness according to chronic arterial occlusion, comprising the crystal according to any one of 1 to 16 above and the crystal according to any one of 17 to 35 as an active ingredient.

62. An agent for improving intermittent claudication, comprising the crystal according to any one of 1 to 16 above and the crystal according to any one of 17 to 35 as an active ingredient.

63. An inhibitor of thrombus / embolism formation in ischemic cerebrovascular disorder comprising the crystal according to any one of 1 to 16 above and the crystal according to any one of 17 to 35 as an active ingredient.

64. The inhibitor of thrombus / embolism according to 63 above, wherein the ischemic cerebrovascular disorder is a transient cerebral ischemic attack and / or cerebral infarction.

65. A pain-reducing agent according to neuralgia after shingles containing the crystal according to any one of 1 to 16 above and the crystal according to any one of 17 to 35 as an active ingredient.

71. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride having a powder X-ray diffraction spectrum having the pattern shown in FIG. Form II crystals.

72. (±) 2- (dimethylamino having a pattern of the powder X-ray diffraction spectrum shown in FIG. 1 and having no diffraction peaks at any of the Bragg angles (2θ) of 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 ° Form II crystals of) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride.

73. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate, with the powder X-ray diffraction spectrum having the pattern shown in FIG. Form I crystals of hydrochloride.

74. (±) 2- (dimethylamino) -1- {with a powder X-ray diffraction spectrum having the pattern shown in FIG. 1 and having no diffraction peaks at any of the Bragg angles (2θ) of 11.0 ± 0.1 ° and 19.15 ± 0.1 ° Form I crystals of [O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride.

101. Crystallization of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride.

102. The crystal according to 101 above, characterized by any of the following physical and chemical properties.

(1) the powder X-ray diffraction pattern, having a diffraction peak (2θ) at 9.5 ± 0.1 °, 11.0 ± 0.1 ° or 19.2 ± 0.1 °;

(2) for differential scanning calorimetry, having an endothermic peak near about 157 ° C;

(3) for a solid ¹³ C-NMR spectrum, having a peak of chemical shift of 146.4 ± 0.5, 131.0 ± 0.5 or 110.4 ± 0.5 ppm; And / or

(4) The infrared absorption spectrum has an absorption peak at 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0 or 792 ± 2.0 cm ⁻¹ .

103. A powder X-ray diffraction pattern having a diffraction peak (2θ) at 9.5 ± 0.2 °, 11.0 ± 0.2 ° or 19.2 ± 0.2 °, and in an infrared absorption spectrum, 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0 Or the crystal of 102 above having an absorption peak at 792 ± 2.0 cm ⁻¹ .

104. The crystal according to 102 above, having a diffraction peak (2θ) at 9.5 ± 0.1 °, 11.0 ± 0.1 ° and 19.2 ± 0.1 ° in the powder X-ray diffraction pattern.

105. The crystal according to 102 above, wherein in the powder X-ray diffraction pattern, the diffraction peak (2θ) cannot be confirmed at any of 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 °.

106. The powder X-ray diffraction pattern according to 102 above, having a diffraction peak (2θ) at 9.5 ± 0.1 °, 11.0 ± 0.1 ° and 19.2 ± 0.1 °, and also 16.2 ± 0.1 °, 19.7 ± 0.1 °, and 22.8. Crystal with diffraction peak (2θ), either ± 0.1 ° or 23.8 ± 0.1 °.

107. The powder X-ray diffraction pattern according to 102 above, having a diffraction peak (2θ) at 9.5 ± 0.2 °, 11.0 ± 0.2 ° and 19.2 ± 0.2 °, and also 16.2 ± 0.2 °, 19.7 ± 0.2 °, and 22.8. A crystal having a diffraction peak (2θ) at either ± 0.2 ° or 23.8 ± 0.2 ° and having an absorption peak at 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0 or 792 ± 2.0 cm ⁻¹ in the infrared absorption spectrum.

108. The crystal according to 102 above, having a peak in the powder X-ray diffraction pattern shown in FIG. 1.

109. The crystal according to 102 above, having a characteristic thermal analysis pattern in differential scanning calorimetry shown in FIG. 4.

110. The crystal of 102 above, having a peak of chemical shifts of 146.4 ± 0.5, 131.0 ± 0.5 and 110.4 ± 0.5 ppm in the solid ¹³ C-NMR spectrum.

111. The compound of 102, having a peak of chemical shifts of 146.4 ± 0.5, 131.0 ± 0.5 and 110.4 ± 0.5 ppm in the solid ¹³ C-NMR spectrum, and also in 128.5 ± 0.5, 58.3 ± 0.5 or 37.3 ± 0.5 ppm Determine where the peak of the chemical shift is.

112. The crystal according to 102 above, having a characteristic peak of chemical shift in the solid ¹³ C-NMR spectrum shown in FIG.

113. The crystal according to 102 above, having an absorption peak at 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0 and 792 ± 2.0 cm ⁻¹ in the infrared absorption spectrum.

114. The above-mentioned 102, having an absorption peak at 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0 and 792 ± 2.0 cm ⁻¹ in the infrared absorption spectrum, and also having 1725 ± 2.0, 1076 ± 2.0 or 1048 ± 2.0 cm ^The crystal having an absorption peak of ^-1 .

115. The crystal according to 102 above, which shows a characteristic peak in the infrared absorption spectrum shown in FIG.

116. The crystal according to 101 above, characterized by any of the following physical and chemical properties.

(1) in the powder X-ray diffraction spectrum, having a diffraction peak (2θ) at 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 °;

(2) in differential scanning calorimetry, having an endothermic peak near about 152 ° C;

(3) for the solid ¹³ C-NMR spectrum, have chemical shifts at 117.3 ± 0.5 and 106.3 ± 0.5 ppm; And / or

(4) The infrared absorption spectrum has absorption peaks 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 .

117. The powder X-ray diffraction pattern of 116, having a diffraction peak (2θ) at 9.3 ± 0.2 °, 10.7 ± 0.2 °, or 16.5 ± 0.2 °, and in an infrared absorption spectrum, 1612 ± 2.0, 1585 ±. Crystals with an absorption peak at 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 or 780 ± 2.0 cm ^-1 .

118. The crystal according to 116 above, having a diffraction peak (2θ) at 10.7 ± 0.1 ° and 16.5 ± 0.1 ° in the powder X-ray diffraction pattern.

119. The powder X-ray diffraction pattern of 116, having a diffraction peak (2θ) at 10.7 ± 0.2 ° and 16.5 ± 0.2 °, and also any one of 9.3 ± 0.2 °, 12.8 ± 0.2 °, or 13.0 ± 0.2 ° Crystals with diffraction peaks (2θ) and absorption peaks in the infrared absorption spectrum at 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 or 780 ± 2.0 cm ^-1 .

120. The powder X-ray diffraction pattern according to 116, having a diffraction peak (2θ) at 10.7 ± 0.1 ° and 16.5 ± 0.1 °, and also 9.3 ± 0.1 °, 12.8 ± 0.1 °, 13.0 ± 0.1 °, and 18.1. Crystal with diffraction peak (2θ), either ± 0.1 ° or 24.1 ± 0.1 °.

121. The powder X-ray diffraction pattern according to 116, having a diffraction peak (2θ) at 10.7 ± 0.2 ° and 16.5 ± 0.2 °, and also 9.3 ± 0.2 °, 12.8 ± 0.2 °, 13.0 ± 0.2 °, and 18.1. Having a diffraction peak (2θ), either ± 0.2 ° or 24.1 ± 0.2 °, and in the infrared absorption spectrum, 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 or 780 ± Crystals with an absorption peak at 2.0 cm ^-1 .

122. The crystal according to 116 above, having a diffraction peak (2θ) at 9.3 ± 0.1 °, 10.7 ± 0.1 ° and 16.5 ± 0.1 ° in the powder X-ray diffraction pattern.

123. The crystal according to 116 above, having a diffraction peak (2θ) at 9.3 ± 0.1 °, 10.7 ± 0.1 °, 12.8 ± 0.1 ° and 16.5 ± 0.1 ° in the powder X-ray diffraction pattern.

124. The crystal according to the above 116, having a diffraction peak (2θ) at 9.3 ± 0.1 °, 10.7 ± 0.1 °, 13.0 ± 0.1 ° and 16.5 ± 0.1 ° in the powder X-ray diffraction pattern.

125. The crystal according to 116 above, having a diffraction peak (2θ) at 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.

126. The crystal according to the above 116, wherein in the powder X-ray diffraction pattern, the diffraction peak (2θ) cannot be confirmed at any of 9.5 ± 0.1 °, 11.0 ± 0.1 °, and 19.2 ± 0.1 °.

127. The crystal of 116 above having a peak in a powder X-ray diffraction pattern shown in FIG.

128. The crystal of 116 above having a characteristic thermal analysis pattern in differential scanning calorimetry shown in FIG. 5.

129. The crystal according to 116 above, having a peak of chemical shifts of 117.3 ± 0.5 and 106.3 ± 0.5 ppm in the solid ¹³ C-NMR spectrum.

130. The crystal according to 116 above, having a peak of chemical shift of 117.3 ± 0.5 and 106.3 ± 0.5 ppm in the solid ¹³ C-NMR spectrum and having a peak of chemical shift of 145.0 ± 0.5 or 129.7 ± 0.5 ppm .

131. The crystal according to 116 above, having a characteristic peak of chemical shift in the solid ¹³ C-NMR spectrum shown in FIG.

132. The crystal of 116 above, having an absorption peak 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 in the infrared absorption spectrum.

133. The absorption peak of 116, having an absorption peak 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 in the infrared absorption spectrum, Crystals with an absorption peak at 3021 ± 2.0, 1729 ± 2.0, 1195 ± 2.0, 1152 ± 2.0 or 918 ± 2.0 cm ^-1 .

134. The crystal according to 116 above, which shows a characteristic peak in the infrared absorption spectrum shown in FIG.

135. A pharmaceutical composition comprising the crystal according to any one of 102 to 115 as an active ingredient.

136. A prophylactic and / or therapeutic agent for chronic artery occlusion, which contains the crystal according to any one of 102 to 115 as an active ingredient.

137. An agent for improving the ischemic symptoms of ulcers, pain and coldness caused by chronic arterial occlusion containing the crystal according to any one of 102 to 115 as an active ingredient.

138. An agent for improving intermittent lameness, comprising the crystal according to any one of 102 to 115 as an active ingredient.

139. An inhibitor of thrombus and embolism in ischemic cerebrovascular disorder containing the crystal according to any one of 102 to 115 as an active ingredient.

140. The inhibitor of thrombosis / embolism according to item 139, wherein the ischemic cerebrovascular disorder is a transient cerebral ischemic attack and / or cerebral infarction.

141. A pain reducing agent according to neuralgia after shingles containing the crystal according to any one of 102 to 115 as an active ingredient.

142. The method for producing a crystal according to any one of 102 to 115 above.

143. The method for producing a crystal according to 142 above, wherein the crystal according to any one of 102 to 115 is used as a seeding crystal.

144. The crystal of (142) above, wherein the crystal of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride is crystallized at a crystal transition temperature of 160 ° C. The manufacturing method of the crystal | crystallization containing the process of stirring at any temperature.

145. The crystal according to the above 142, wherein the crystal of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride is determined from the crystal transition temperature to the solvent. The manufacturing method of the crystal | crystallization including the process of stirring at the temperature of boiling point.

146. The crystal of (142) is dissolved in (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride, A method for producing a crystal comprising the step of crystallizing at any temperature from to 160 ° C.

147. The crystal of (142), wherein (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride is dissolved A process for producing a crystal comprising the step of crystallizing at any temperature from the temperature of the boiling point to the solvent.

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. The method for producing a crystal according to any one of 116 to 134.

150. The method for producing a crystal according to the above 149, wherein the crystal according to any one of 116 to 134 is used as a seeding crystal.

151. The crystal of (149) above according to (149), dissolving the crystal of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride, -10 deg. To crystallization at a certain temperature of the crystal transition temperature.

152. The crystal according to the above 149, wherein the crystal of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride is dissolved and the solidification point of the solvent To crystallization at a certain temperature of the crystal transition temperature.

153. 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. The method for producing a crystal according to any one of 151 to 154, wherein the solvent is water.

155. The process according to 151 or 152, wherein the hydrogen chloride is blown into the (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate solution The manufacturing method of the crystal containing.

According to the invention, Form II crystals and Form I, which are novel crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride It is possible to provide a method for producing a crystal.

Best Mode for Carrying Out the Invention

Hereinafter, the present invention will be described in detail.

First, Form II crystals and Form I crystals 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 succinic acid represented by the following general formula (1): It is a crystalline polymorph of nate hydrochloride, both of which have different physicochemical characteristics. Here, the crystalline polymorph means a crystalline form of one of a plurality of different crystalline forms of the same compound.

Form II crystals in the present invention have the following physical and chemical characteristics specific to Form II crystals, which do not exist in Form I crystals.

(1) The powder X-ray diffraction spectrum has one or more diffraction peaks selected from Bragg angles (2θ) of 9.5 ± 0.1 °, 11.0 ± 0.1 ° and 19.15 ± 0.1 °.

(2) In the differential scanning calorimetry, it has an endothermic peak around about 157 ° C.

(3) In the solid ¹³ C-NMR spectrum, it has one or more diffraction peaks selected from 146.4 ± 0.5, 131.0 ± 0.5, or 110.4 ± 0.5 ppm.

(4) The infrared absorption spectrum has one or more diffraction peaks selected from 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0 or 792 ± 2.0 cm ⁻¹ .

What is necessary is just to provide 1 type or more of said physicochemical characteristics as type II crystal | crystallization, Preferably at least 2 or more types of said (1)-(4), More preferably, the physicochemical characteristics of (1) and (2) It is provided.

As type II crystals, crystals having one or more (preferably two or more) of the following physical and chemical characteristics are particularly preferable, and the characteristics are substantially ultrapure in excess of 95%, preferably 98% or more. It can be confirmed that it is a type II crystal.

(11) In the powder X-ray diffraction spectrum, the Bragg angles (2θ) have diffraction peaks at 9.5 ± 0.1 °, 11.0 ± 0.1 °, and 19.15 ± 0.1 °.

(12) In the differential scanning calorimetry, it has an endothermic peak near about 157 ° C.

(13) Solid ¹³ C-NMR spectrum with peaks at 146.4 ± 0.5, 131.0 ± 0.5 or 110.4 ± 0.5 ppm.

(14) The infrared absorption spectrum has an absorption peak at 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0, or 792 ± 2.0 cm ⁻¹ .

In addition, in the powder X-ray diffraction spectrum, type II crystals also have diffraction peaks at one or more selected from Bragg angles (2θ) of 16.2 ± 0.1 °, 19.7 ± 0.1 °, 22.8 ± 0.1 °, and 23.8 ± 0.1 °. In order to more reliably form a high-purity type II crystal, it is preferable not to have a diffraction peak in any of the Bragg angles (2θ) of 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 °. Furthermore, in the solid ¹³ C-NMR spectrum, it may have one or more peaks selected from 128.5 ± 0.5, 58.3 ± 0.5 or 37.3 ± 0.5 ppm, and also in the infrared absorption spectrum, 1725 ± 2.0, 1076 ± 2.0 or 1048. It may have one or more absorption peaks selected from ± 2.0 cm ⁻¹ .

In addition, in the powder X-ray diffraction spectrum, Form II crystal has a diffraction peak at one or more selected from Bragg angles (2θ) of 9.5 ± 0.2 °, 11.0 ± 0.2 °, and 19.15 ± 0.2 °, For example, it may have one or more absorption peaks selected from 1593 ± 2.0, 1163 ± 2.0, 1040 ± 2.0 or 792 ± 2.0 cm ⁻¹ . In this case, in the powder X-ray diffraction spectrum, the Bragg angles (2θ) have diffraction peaks at 9.5 ± 0.2 °, 11.0 ± 0.2 °, and 19.15 ± 0.2 °, and also 16.2 ± 0.2 °, 19.7 ± 0.2 °, and 22.8 ± 0.2 Having diffraction peaks at ° and 23.8 ± 0.2 °, or for powder X-ray diffraction spectra, also having diffraction peaks at Bragg angles (2θ) of 9.5 ± 0.2 °, 11.0 ± 0.2 ° and 19.15 ± 0.2 ° It is desirable to have diffraction peaks at ± 0.2 °, 19.7 ± 0.2 °, 22.8 ± 0.2 ° and 23.8 ± 0.2 °.

(±) 2- (dimethylamino) -1 obtained by the method of Example 2 of Unexamined-Japanese-Patent No. 58-32847, as shown in the following Example Compared with the crystal of-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride, the production rate of hydrolyzate is low and it is suitable for use as a medicine. The corresponding action of the type II crystal is (±) 2- (dimethylamino) -1-{[O- (m-meth) obtained according to the method described in Example 2 of JP-A-58-32847. It is unexpected in the determination of oxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride.

In addition, Form I crystals in the present invention have the following physical and chemical characteristics specific to Form I crystals not present in Form II crystals.

(5) The powder X-ray diffraction spectrum has one or more diffraction peaks selected from Bragg angles (2θ) of 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 °.

(6) In the differential scanning calorimetry, it has an endothermic peak around about 152 ° C.

(7) in the solid ¹³ C-NMR spectrum, has one or more peaks selected from 117.3 ± 0.5 or 106.3 ± 0.5 ppm.

(8) In the infrared absorption spectrum, it has one or more absorption peaks selected from 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 or 780 ± 2.0 cm ⁻¹ .

What is necessary is just to provide 1 type or more of the following physicochemical characteristics as Form I crystal, Preferably it is at least 2 or more types of said (5)-(8), More preferably, the physicochemical characteristic of (5) and (6) It is to be provided.

As the type I crystal, a crystal having one or more (preferably two or more) of the following physical and chemical properties is particularly preferable, and the ultrapure is more than 95% pure, preferably 98% or more pure by this feature. It can be confirmed that it is a type I crystal.

(15) In the powder X-ray diffraction spectrum, the Bragg angles (2θ) have diffraction peaks at 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 °.

(16) In the differential scanning calorimetry, the endothermic peak is only around 152 占 폚.

(17) In the solid ¹³ C-NMR spectrum, it has a diffraction peak at 117.3 ± 0.5 or 106.3 ± 0.5 ppm.

(18) In the infrared absorption spectrum, it has an absorption peak at 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 or 780 ± 2.0 cm ^-1 .

In the powder X-ray diffraction spectrum, Form I crystal preferably has diffraction peaks at Bragg angles (2θ) of 10.7 ± 0.1 ° and 16.5 ± 0.1 °, in which case Bragg angle (2θ) of 9.3 ± 0.1 °, One or more selected from 12.8 ± 0.1 °, 13.0 ± 0.1 °, 18.1 ± 0.1 °, and 24.1 ± 0.1 ° may have diffraction peaks, and the Bragg angle (2θ) may be used to more reliably form a high-purity type I crystal. It is preferable not to have a diffraction peak at any of 11.0 ± 0.1 ° and 19.2 ± 0.1 °. Furthermore, in the solid ¹³ C-NMR spectrum, it may also have one or more peaks selected from 145.0 ± 0.5 and 129.7 ± 0.5 ppm, and also in the infrared absorption spectrum, 3021 ± 2.0, 1729 ± 2.0, 1195 ± 2.0 , 1152 ± 2.0 and 918 ± 2.0 cm ⁻¹ .

In the powder X-ray diffraction spectrum, Form I crystal has a diffraction peak at one or more selected from Bragg angles (2θ) of 9.3 ± 0.2 °, 10.7 ± 0.2 °, and 16.5 ± 0.2 °, and in the infrared absorption spectrum, It may have one or more absorption peaks selected from 1612 ± 2.0, 1585 ± 2.0, 1434 ± 2.0, 1054 ± 2.0, 932 ± 1.0, 918 ± 2.0 and 780 ± 2.0 cm ⁻¹ . In that case, in the powder X-ray diffraction spectrum, it has diffraction peaks at Bragg angles (2θ) of 10.7 ± 0.1 ° and 16.5 ± 0.1 °, and also shows diffraction peaks at 9.3 ± 0.2 °, 12.8 ± 0.2 ° and 13.0 ± 0.2 °. Having, or having a diffraction peak (2θ) at Bragg angles (2θ) of 10.7 ± 0.2 ° and 16.5 ± 0.2 ° in the powder X-ray diffraction spectrum, and also has 9.3 ± 0.2 °, 12.8 ± 0.2 °, and 13.0 ± 0.2 ° , 18.1 ± 0.2 ° and 24.1 ± 0.2 ° preferably have diffraction peaks.

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

Crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride according to the present invention are determined according to the physicochemical properties described herein. Although each spectrum data may be changed somewhat in its nature, it is not to be interpreted strictly.

In the present invention, the powder X-ray diffraction spectrum refers to a spectrum measured under the following conditions using a RINT2500 type powder X-ray diffraction apparatus (Rigaku Denki Co., Ltd.).

X-ray source: Cu

Filter: Ni

Tube voltage: 40 kV

Tube current: 300 mA

Divergence Slit: 1/2 °

Scattering Slit: 1/2 °

Receiving Slit: 0.15 mm

Scanning range: 3 to 40 ° 2θ

Step Width: 0.02 °

Sampling time: 1.00 seconds

Sample rotation speed: 60 rpm

Scan Rate: 0.02 ° / sec

In addition, the endothermic peak in differential scanning calorimetry (henceforth "DSC") means the endothermic peak measured on condition of the following using DSC6200 (Seiko Instruments Inc.).

Temperature rise rate: 20 ℃ / min

Atmosphere: 40 ml / min nitrogen

Measurement temperature: 30 to 200 ℃ / min

In addition, a solid ¹³ C-NMR spectrum refers to a spectrum measured under the following conditions using Infinity CMX-400 (Chemagnetics).

Probe: Probe for 7.5 mmφ CP / MAS

¹³ C observation frequency: 100 MHz

MAS revolutions: 5.0 to 5.8 kHz

¹ H decoupling frequency: 50 kHz

¹ H 90 ° pulse width: 5.0 microseconds

Contact time: 3 milliseconds

Repeat time: 20 seconds

Total count: 1000 to 100,000

The infrared absorption (hereinafter also referred to as "IR") spectrum refers to a spectrum measured under the following conditions using a Spectrum One (Perkin Elmer).

Measuring Method: KCl Purification

Measuring range: 4000 to 400 cm ^-1

Resolution: 2.00 cm ^-1

Scan count: 4

In the case where the crystals are analyzed using these devices, the similarities of the respective data and the patterns as a whole are included in the crystals of the present invention. Mixed type II crystals are also included in the "type II crystals" of the present invention. Similarly, Form I crystals in which Form II crystals are mixed in amounts which cannot be detected by a conventional measurement method are also included in the "Form I crystals" of the present invention.

In addition, due to the nature of powder X-ray diffraction spectral data, the diffraction angle (2θ) or the overall pattern is important in confirming the identity of crystals, and the relative intensity may change slightly depending on the direction of crystal growth, particle size, and measurement conditions. have. Even in DSC, solid ¹³ C-NMR spectra or IR spectra, the overall pattern is important in the identification of crystals and can be changed somewhat by measurement conditions.

Therefore, the similarity of the data and pattern of the powder X-ray diffraction spectrum, the DSC, the solid ¹³ C-NMR spectrum, or the IR spectrum of the crystal of the present invention are generally included in the crystal of the present invention.

Particularly, in the powder X-ray diffraction spectrum, it is included in the crystal of the present invention that diffraction peaks are identified at the same plane interval.

As the powder X-ray diffraction spectrum of the type II crystal in the present invention, crystals in which the diffraction peak (2θ) cannot be confirmed at any of the vicinity of 9.3 °, 10.7 ° and 16.5 ° which are the diffraction angles derived from the type I crystal are also the type II of the present invention. It is included in the decision.

As a powder X-ray diffraction spectrum of Form I crystals in the present invention, crystals in which the diffraction peak (2θ) cannot be confirmed in any of the diffraction angles derived from Form II crystals in the vicinity of 9.5 °, 11.0 ° and 19.2 ° are also Form I of the present invention. It is included in the decision.

In the DSC, an endothermic peak derived from Form I crystals is detected at about 152 ° C. In the present invention, "about 152 ° C" is slightly different depending on the measurement sample. it means. Similarly, in the type II crystals, the term "nearly about 157 ° C" means approximately 157 ± 2.0 ° C.

Although it does not specifically limit as a manufacturing method of the crystal | crystallization of this invention, For example, as shown to the following example, the substance obtained by the method of Example 2 of Unexamined-Japanese-Patent No. 58-32847 is stirred. And a step of dissolving the substance in a solvent and crystallizing it, including a step of concentrating and crystallizing the substance, and solidifying the substance from a molten state. Preferably, the thing including the process of stirring in a solvent is mentioned. Moreover, the method of using the type I or II crystal shown above as a seeding crystal | crystallization is mentioned. Thereby, a substantially ultrapure crystalline polymorph of more than 95% purity, preferably 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 is acetonitrile, acetone, ethyl acetate, hexane, 1-propanol, 2-propanol, methanol, ethanol, water, toluene, tetrahydrofuran, diisopropyl ether, chloroform, cyclohexane, heptane, octane, Although xylene, chlorobenzene, etc. are mentioned, Preferably, acetone, ethyl acetate, water, methanol, ethanol, 1-propanol, 2-propanol, toluene, tetrahydrofuran, hexane, heptane, octane, xylene are mentioned.

As a more preferable solvent for obtaining type II crystal | crystallization, acetone, water, ethyl acetate, toluene, hexane, heptane, octane, xylene are mentioned. Especially, acetone, ethyl acetate, and xylene are preferable. Moreover, the combination of these solvent is also preferable.

More preferable solvents for obtaining Form I crystals include acetone, water, methanol, ethanol, 1-propanol and 2-propanol. Especially, water, methanol, and 2-propanol are preferable. Moreover, the combination of these solvent is also preferable.

The boiling point and solidification point of each solvent are described in the "New Solvent Pocket Book" (issued by Ohm Co., Ltd., an organic synthetic chemistry association on June 10, 1994).

In the present invention, stirring means (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen described in Japanese Patent Application Laid-Open No. 58-32847. (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl as described in the process of suspending succinate hydrochloride or in JP-A-58-32847 } The process of dissolving and crystallizing ethyl hydrogen succinate hydrochloride shall be included.

Japanese Patent Laid-Open No. 58-32847 discloses (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride There is no description as to what type II crystals and type I crystals are obtained, and sufficient information for distinguishing and producing type II crystals and type I crystals having different crystal forms of the present invention is not disclosed. This is due to the fact that the mutual crystal transition temperature of Form II crystals and Form I crystals, which became apparent for the first time in the present invention, exists at about 20 ° C. to about 40 ° C., so that they could not be produced separately under ordinary conditions. Is considered.

As a method of producing type II crystals, More preferably

Crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride are dissolved in a solvent, and the crystal transition temperature to the boiling point of the solvent Method for producing type II crystals comprising the step of crystallizing at any one of the temperatures,

Crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride are dissolved in a solvent, and the crystal transition temperature to the boiling point of the solvent Method for producing type II crystals comprising the step of adding a seeding crystal at any one of the temperature, then cooling and crystallizing,

Crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride are dissolved in a solvent and at about 45 ° C. to about 60 ° C. Method for producing type II crystals comprising the step of adding the seeding crystals, followed by cooling to crystallize,

Crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride are dissolved in a solvent and at about 50 ° C to about 55 ° C Method for producing type II crystals comprising the step of adding the seeding crystals, followed by cooling to crystallize,

Crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride are dissolved in a solvent, and from about 40 ° C. to about 65 in a solvent A method for producing type II crystals comprising the step of adding a seeding crystal suspended at any temperature in the range of about 45 ° C. to about 60 ° C., followed by cooling to crystallize,

Crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride are dissolved in a solvent, and from about 50 ° C. to about 65 in a solvent A method for producing type II crystals comprising the step of adding the seeding crystals suspended at 0 ° C. at about 45 ° C. to about 60 ° C., followed by cooling and crystallization

Crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride are dissolved in a solvent, and the solvent is about 55 ° C. to about 65 And a method for producing type II crystals comprising the step of adding the seeding crystals suspended at 0 ° C. at about 50 ° C. to about 56 ° C., followed by cooling to crystallize.

As a method for producing type I crystals, More preferably

Crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride are dissolved in a solvent, and the temperature is -10 deg. Method for producing Form I crystals comprising the step of cooling and crystallizing at any one of the temperatures,

Crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride are dissolved in a solvent, and the freezing point to crystal transition temperature of the solvent A method for producing Form I crystals comprising the step of crystallizing at any one of the temperatures of

Method for producing Form I crystals comprising the step of blowing hydrogen chloride into a solution of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate Can be mentioned.

In the present invention, it is possible to obtain a mixed crystal in which the II type crystal and the I type crystal are mixed in an arbitrary ratio, and for example, the ultrapure type II crystal and the I type crystal obtained by the above production method are obtained. It can manufacture by mixing so that it may become a desired ratio.

In the pharmaceutical composition containing the crystal of the present invention as an active ingredient, the crystal component of each of the type II crystals and the type I crystals is not particularly limited, but for example, an herbal medicine containing about 75% or more of the type II crystals of the present invention Pharmaceutical compositions produced using i) are preferred. Moreover, the pharmaceutical composition manufactured using the original medicine containing about 85% or more type II crystal | crystallization is more preferable, and the pharmaceutical composition manufactured using the original medicine containing about 98% or more type II crystal | crystallization is the most preferable.

When the crystal of the present invention is used as a medicament, it may be administered alone, but it is preferable to prepare and administer a pharmaceutical composition containing the compound as an active ingredient using an pharmaceutically acceptable additive for preparation. desirable. The composition of the pharmaceutical composition is determined by the solubility of the compound, the chemical nature, the route of administration, the dosing schedule and the like. For example, granules, granules, powders, tablets, hard syrups, soft capsules, troches, syrups, emulsions, soft gelatin capsules, gels, pastes, suspensions, liposomes, and the like, are administered orally. Or intravenously, intramuscularly, or subcutaneously, as an injection. Moreover, it can also be manufactured and used at the time of use as a powder for injection.

Pharmaceutically acceptable additives for the preparation may be organic or inorganic solid or liquid carriers suitable for oral, enteral, parenteral or topical administration. The pharmaceutical composition may contain, in addition to the carrier, an adjuvant such as a humectant, a suspending aid, a sweetener, a fragrance, a coloring agent, and a preservative. Liquid formulations may also be incorporated into capsules of absorbable materials such as gelatin. A solvent, a suspending agent, etc. are used for preparation of parenteral preparation administration, ie, injection. In addition, manufacture of each said formulation can be performed according to a conventional method.

The crystal of the present invention is useful as an active ingredient of medicine, and specifically, for treating chronic arterial occlusion, ulcers due to chronic arterial occlusion, for improving ischemic symptoms of pain and coldness, for improving intermittent claudication, for thrombosis in ischemic cerebrovascular disorders. It is useful as an active ingredient of an inhibitor of embolism and an alleviator of pain following neuralgia after shingles.

Dosage is determined by taking these or other factors into account, depending on age, weight, general state of health, sex, diet, time of administration, method of administration, rate of excretion, combination of drugs, and the severity of the patient being treated. . The compounds of the present invention, their optical isomers or their pharmaceutically acceptable salts are low toxic and can be used safely, and the daily dosage depends on the patient's condition or body weight, the type of compound, route of administration, etc. Parenteral is administered subcutaneously, intravenously, intramuscularly or rectally from about 0.01 to 50 mg / 1 person / 1 day, preferably from 0.01 to 20 mg / 1 person / 1 day, and also orally from about 0.01 to 150 mg / 1 person / 1 day, preferably 0.1 to 100 mg / 1 person / day is preferred.

<Example>

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

Example  One

(±) 2- (dimethylamino) -1-{[O, wherein the molar ratio of Form II crystals and Form I crystals obtained in accordance with the method described in Example 2 of JP-A-58-32847 is 3: 7 A mixture of 1 kg of-(m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride (hereinafter sometimes referred to as "SPG") and 10 liters of acetone was stirred under conditions of 55 ° C for 12 hours. . After cooling to 25 ° C., the crystals were filtered off and washed with 1.00 L of acetone. Then, it dried under reduced pressure and obtained 0.95 kg of Form 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 filtered 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, filtered, and then 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 at elevated temperature, and concentrated to about 180 ml at normal pressure. After stirring for about 2 hours at about 55 ℃, it was cooled to room temperature. The crystals were filtered off and washed with 8 ml of acetone. Then, it dried under reduced pressure and obtained 1.74 g of Form 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 warmed to dissolve, and the internal temperature was cooled to 50 ° C. To this solution was added a suspension prepared from 0.7 L of acetone and 0.05 kg of Form II crystals obtained in Example 1, and 0.5 L of acetone was added. After cooling to 10 ° C. or less, the crystals were filtered off, washed with 1 L of acetone, and dried under reduced pressure to obtain 0.9 kg of Form 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 warmed to dissolve, and the internal temperature was cooled to 50 ° C. 0.05 kg of type II crystals obtained in Example 1 were added to this solution, and 1.2 L of acetone was added, followed by cooling to 10 ° C or lower. The crystals were filtered off, washed with 1 L of acetone, and dried under reduced pressure to obtain 0.9 kg of Form 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, and the mixture was warmed to dissolve, and the internal temperature was cooled to about 50 ° C. A suspension prepared from 0.7 L of acetone and 0.05 kg of Form II crystals was added to this solution after heating and stirring at about 55 ° C. After adding 0.5 L of acetone, the mixture was cooled to 10 DEG C or lower, and the crystals were filtered off. The crystals were washed with 1 L of acetone and dried under reduced pressure to obtain 0.9 kg of Form II crystals. The purity was 98% or more.

Example  8

A solution obtained by 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 off. 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- () obtained according to the method described in Example 1 of JP-A-58-32847. (±) -1- [O- [2- (m-methoxyphenyl) ethyl] phenoxy] -3-, obtained by extracting dimethylamino) -2-propanol hydrochloride with toluene as a free base in aqueous sodium hydroxide solution. To the toluene solution containing about 1.0 kg of (dimethylamino) -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 to 30 ° C, 8.5 L of acetone was added and cooled to around 10 ° C. A small amount of SPG was added thereto as a seeding crystal, 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 [deg.] C. or less, it is aged for 2-3 hours and filtered rinsed (2 L of acetone). It dried under reduced pressure and obtained about 1.4 kg of Form I crystals. The purity was 98% or more.

Example  10

When a small amount of Form II crystals were detected in Example 9, the following steps were added. A mixture of 50 g of crystals obtained in Example 9 and 500 ml of isopropanol was stirred at 25 ° C. for 30 hours. The crystals were filtered off and washed in 200 ml of isopropanol. Then, it dried under reduced pressure and obtained 48.9 g of Form I crystals. The purity was 98% or more.

Example  11

The internal temperature of the solution obtained by heating and dissolving a mixture of 100 g of SPG, 880 ml of acetone and 55 ml of water was cooled to about 50 ° C, and 5 g of Form I crystals obtained in Examples 8 to 9 were added, followed by addition of 120 ml of acetone. . Then, it cooled to 10 degrees C or less. The crystals were filtered off, washed with 100 ml of acetone, and dried under reduced pressure to obtain 90 g of Form I crystals. Purity was 98% or more.

Experimental Example 1 Powder X-ray Diffraction Measurement

Powder X-ray diffraction of Form II crystals, Form I crystals, and SPG was measured under the following conditions.

(Measuring conditions)

Equipment: RINT2500 type powder X-ray diffractometer (Rigaku Denki Co., Ltd.)

X-ray: Cu

Filter: Ni

Tube voltage: 40 kV

Tube current: 300 mA

Divergence Slit: 1/2 °

Scattering Slit: 1/2 °

Receiving Slit: 0.15 mm

Scanning range: 3 to 40 ° 2θ

Step Width: 0.02 °

Sampling time: 1.00 seconds

Sample rotation speed: 60 rpm

Detection limit: 2%

Scan Rate: 0.02 ° / sec

Powder X-ray diffraction patterns of Form II crystals, Form I crystals, and SPG are shown in Figs. 1, 2, and 3, respectively. The diffraction peak value (2θ) of the powder X-ray diffraction pattern of the Form II crystal is shown in Table 1 below, and the diffraction peak value (2θ) of the powder X-ray diffraction pattern of the Form I crystal is shown in Table 2 below. The diffraction peak values 2θ of the pattern are shown in Table 3 below, respectively.

As a result of the measurement, it became clear that Form I crystal, Form II crystal and SPG exhibited different powder X-ray diffraction patterns.

Experimental Example 2 DSC Measurement

1 mg of each sample of Form II crystal, Form I crystal, and SPG was weighed, placed in an aluminum open pan, and measured under the following conditions.

(Measuring conditions)

Device: DSC6200 (Seiko Instruments)

Temperature rise rate: 20 ℃ / min

Atmosphere: 40 ml / min nitrogen

Measurement temperature: 30 to 200 ℃ / min

The SPG curves of Form II crystals, Form I crystals, and SPG are shown in FIGS. 4, 5, and 6. 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 Spectral Measurement

Solid ¹³ C-NMR spectra of Form II crystals, Form I crystals, and SPG were measured.

(Measuring conditions)

Device: Infiniti CMX-400 (Kematics)

Probe: Probe for 7.5 mmφ CP / MAS

¹³ C observation frequency: 100 MHz

MAS revolutions: 5.0 to 5.8 kHz

¹ H decoupling frequency: 50 kHz

¹ H 90 ° pulse width: 5.0 microseconds

Contact time: 3 milliseconds

Repeat time: 20 seconds

Total count: 1000 to 100,000

Solid ¹³ C-NMR spectra of Form II crystals, Form I crystals, and SPG are shown in FIGS. 7, 8, and 9. The solid ¹³ C-NMR chemical shift values of the spectrum of the II-form crystal are shown in Table 4 in, II-type solid-state ¹³ C-NMR chemical shift values of the spectrum of the crystal is shown in Table 5, the SPG solid ¹³ C-NMR spectra chemical shift values of the Are shown in Table 6, respectively.

As a result of the measurement, it became clear that Form I crystal, Form II crystal, and SPG exhibit mutually different powder solid ¹³ C-NMR spectra.

Experimental Example 4 IR Spectrum Measurement

About the Form II crystal, Form I crystal, and SPG, the infrared absorption spectrum by KCl purification method was measured on condition of the following.

(Measuring conditions)

Device: Spectrum Circle (Perkin Elmer)

Measuring range: 4000 to 400 cm ^-1

Resolution: 2.00 cm ^-1

Scan count: 4

Infrared absorption spectra of Form II crystals, Form I crystals, and SPG are shown in FIGS. 10, 11, and 12. Form II crystals, Form I crystals, and SPG showed different spectra.

Experimental Example 5 Chemical Stability

The chemical stability of Form II crystals prepared by the present invention and SPG were compared. Chemical stability evaluated the production amount of BP-984 (Table 1 No. 3 compound of Unexamined-Japanese-Patent No. 58-32847) which is a main decomposition product of SPG by high performance liquid chromatography. In addition, BP-984 can be synthesized according to Example 1 described in JP-A-58-32847.

(Stability condition)

Preservation conditions: 40 ℃ / 75% RH

Preservation form: glass chalet opening

Retention period: 2 weeks, 4 weeks, 8 weeks

(High-speed liquid chromatography measurement conditions)

About 20 mg of Form II crystals and SPG were dissolved in 10 ml of the mobile phase and made into a sample solution. 2 ml of the sample solution was accurately weighed and the mobile phase was further precisely set to 200 ml to obtain a 1% dilution standard solution. 10 µl of the sample solution and 1% dilution standard solution were injected, and the respective peak areas were determined by the automatic integration method. The amount of BP-984 was calculated by the following equation.

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)

Device: 10A-VP system (Shimazu Seisakusho)

Detector: UV visible spectrophotometer (wavelength 272 nm)

Mobile phase: water / acetonitrile / trifluoroacetic acid = 65: 35: 0.05

Column: Inertsil ODS-3 V 4.6 mmφ × 150 cm

Flow rate: 1.1 ml / min

The stability test results of Form II crystals and SPG are shown in FIG. 13. The amount of BP-984 produced by Type II crystals was less than half the amount of BP-984 produced by SPG.

From these results, it was found that the type II crystal according to the present invention has an advantageous property that the chemical stability is higher than that of the conventional SPG.

Experimental Example 6 Physically Stable

The physically stable forms were examined for Form I crystals and Form II crystals. Equivalent mixtures of Form I crystals and Form II crystals were prepared, which were suspended in ethanol at respective temperatures of 5 ° C., 15 ° C., 25 ° C., 35 ° C. and 40 ° C. and stirred. This was filtered by suction and dried under reduced pressure, and powder X-ray diffraction measurement was performed. Measurement conditions were the same as in Example 1. As a result, the peak intensities of Form I crystals were relatively increased at 5 ° C, 15 ° C and 25 ° C, and the peak intensities of Form II crystals were relatively increased at 35 ° C and 40 ° C. Accordingly, it was found that Form I crystals are physically stable at temperatures lower than 25 ° C, and Form II crystals are physical and chemical stable at temperatures higher than 35 ° C.

That is, the temperature before the crystal, which is the temperature at which the physicochemical stable forms of the crystals of Form I and Form II are exchanged, ranges from 25 ° C to 35 ° C.

Form I crystals can be transferred to Form II crystals by suspending and stirring mixed crystals in a solvent at a temperature higher than the crystal transition temperature. Conversely, the mixed crystals are suspended in a solvent at a temperature lower than the crystal transition temperature and then stirred. Form I crystals can be transferred to Form II crystals.

According to the invention, Form II crystals and Form I, which are novel crystals of (±) 2- (dimethylamino) -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride It is possible to provide a method for producing a crystal.

In addition, this application is based on the JP Patent application 2005-044896 of an application on February 22, 2005 in Japan, The content is altogether included in this specification.

Claims (3)

(±) 2- (dimethylamino) -1 in which the powder X-ray diffraction spectrum has the pattern shown in FIG. 1 and has diffraction peaks at Bragg angles (2θ) of 9.5 ± 0.1 °, 11.0 ± 0.1 ° and 19.15 ± 0.1 ° Form II crystals of-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride. (±) 2- (dimethylamino) in which the powder X-ray diffraction spectrum has the pattern shown in FIG. 1 and does not have a diffraction peak at any of the Bragg angles (2θ) of 9.3 ± 0.1 °, 10.7 ± 0.1 °, and 16.5 ± 0.1 ° Form II crystals of -1-{[O- (m-methoxyphenethyl) phenoxy] methyl} ethyl hydrogen succinate hydrochloride. 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 °, and Bragg angles (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, having no diffraction peaks in any of °.

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