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Publication numberCN1449286 A
Publication typeApplication
Application numberCN 01814616
PCT numberPCT/US2001/020760
Publication date15 Oct 2003
Filing date28 Jun 2001
Priority date28 Jun 2000
Also published asCA2413702A1, CN1245974C, EP1299101A1, EP1299101A4, US6699997, US7056942, US7126008, US7485663, US7605274, US20020143045, US20040152757, US20040225132, US20060030614, US20080194838, US20090326033, WO2002000216A1
Publication number01814616.3, CN 01814616, CN 1449286 A, CN 1449286A, CN-A-1449286, CN01814616, CN01814616.3, CN1449286 A, CN1449286A, PCT/2001/20760, PCT/US/1/020760, PCT/US/1/20760, PCT/US/2001/020760, PCT/US/2001/20760, PCT/US1/020760, PCT/US1/20760, PCT/US1020760, PCT/US120760, PCT/US2001/020760, PCT/US2001/20760, PCT/US2001020760, PCT/US200120760
InventorsJ希尔德谢姆, S费诺格夫, J阿伦希梅, B-Z多利茨基, S本一瓦利德, I科尔
Applicant特瓦制药工业有限公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Carvedilol
CN 1449286 A
Abstract  translated from Chinese
本发明涉及一种制备卡维地洛的改良方法、涉及卡维地洛的新结晶水合物和溶剂合物以及形态、制备它们的方法及其药用组合物。 The present invention relates to a process for preparing carvedilol improved method involving new crystalline carvedilol hydrates and solvates and forms, methods for their preparation and pharmaceutical compositions.
Claims(82)  translated from Chinese
1.一种制备卡维地洛的方法,该方法包括使式II化合物4-(环氧乙烷-2-基甲氧基)-9H-咔唑 1. A method for the preparation of carvedilol, which comprises reacting a compound of formula II 4- (2-methoxy-ethylene oxide) -9H- carbazole 与式III化合物2-(2-甲氧基苯氧基)乙胺反应的步骤, With a compound of formula III 2- (2- methoxyphenoxy) ethylamine in step, 其中式III化合物相对于式II化合物摩尔过量。 Wherein the compound of formula III with a molar excess of the compound of formula II.
2.权利要求1的方法,其中式III化合物与式II化合物的摩尔比为约1.5∶1到约100∶1。 The method of claim 1, wherein the molar ratio of the compound of formula III with a compound of formula II is from about 1.5 to about 100.
3.权利要求1的方法,其中式III化合物与式II化合物的摩尔比为约2.8∶1到约10∶1。 The method of claim 1, wherein the molar ratio of the compound of formula III with a compound of formula II is from about 2.8:1 to about 10.
4.权利要求1的方法,其中式III化合物与式II化合物的摩尔比为约2.8∶1到约6∶1。 The method of claim 1, wherein the molar ratio of the compound of formula III with a compound of formula II is from about 2.8:1 to about 6.
5.权利要求1的方法,其中所述反应步骤在一种溶剂中进行。 The method of claim 1, wherein said reaction step is performed in a solvent.
6.权利要求5的方法,其中所述溶剂选自甲苯、二甲苯和庚烷。 The method of claim 5, wherein said solvent is selected from toluene, xylene and heptane.
7.权利要求1的方法,其中所述反应步骤在包含多种溶剂的溶剂混合物中进行。 The method of claim 1, wherein said reaction step carried out in a solvent mixture containing a variety of solvents.
8.权利要求7的方法,其中所述溶剂混合物的溶剂选自甲苯、二甲苯和庚烷。 The method of claim 7, wherein said solvent mixture of a solvent selected from toluene, xylene and heptane.
9.权利要求1的方法,其中所述反应步骤在约25℃-约150℃的温度下进行。 The method of claim 1, wherein said reacting step at about 25 ℃ - at a temperature of about 150 ℃ performed.
10.权利要求1的方法,其中所述反应步骤在约60℃-约120℃的温度下进行。 10. The method of claim 1, wherein said reacting step at about 60 ℃ - at a temperature of about 120 ℃ performed.
11.权利要求1的方法,其中所述反应步骤在净条件下进行。 11. The method of claim 1, wherein said reaction step is performed at the net conditions.
12.权利要求11的方法,其中所述净条件通过将固体形态的式III化合物熔化成液体并将式II化合物溶解于该液体中形成反应混合物来获得。 The method of claim 11, wherein the net condition by reacting the compound of formula III in solid form and melted into a compound of formula II is dissolved in a liquid the liquid to form a reaction mixture obtained.
13.权利要求11的方法,还包括在溶解式II化合物后降低反应混合物温度的步骤。 13. The method of claim 11, further comprising the step of, after the reaction mixture temperature to dissolve the compound of formula II reduced.
14.权利要求13的方法,其中所述温度被降低到约70℃。 14. The method of claim 13, wherein said temperature is lowered to about 70 ℃.
15.权利要求11的方法,还包括将有机溶剂∶水混合物加入到反应混合物中的步骤。 15. The method of claim 11, further comprising an organic solvent: water mixture was added to the reaction mixture of step.
16.权利要求15的方法,其中所述有机溶剂选自乙酸乙酯、乙酸丁酯和甲乙酮。 16. The method of claim 15, wherein said organic solvent is selected from ethyl acetate, butyl acetate and methyl ethyl ketone.
17.权利要求15的方法,还包括在将有机溶剂∶水混合物加入到反应混合物中后调节加入到反应混合物的有机溶剂∶水混合物的pH的步骤。 17. The method of claim 15, further comprising an organic solvent: water mixture after the reaction mixture was added to adjust the reaction mixture was added to the organic solvent: water mixture of pH steps.
18.权利要求17的方法,其中所述pH被调节到低于约pH5。 18. The method of claim 17, wherein the pH is adjusted to less than about pH5.
19.权利要求17的方法,其中所述pH被调节到约pH3-约pH5。 19. The method of claim 17, wherein the pH is adjusted to about pH3- about pH5.
20.权利要求11的方法,还包括下面步骤:a)在调节pH后分离盐酸卡维地洛;和b)纯化卡维地洛。 20. The method of claim 11, further comprising the steps of: a) the separation of carvedilol hydrochloride after adjusting the pH; and b) purifying carvedilol.
21.权利要求20的方法,其中盐酸卡维地洛为水合物。 21. The method of claim 20, wherein the carvedilol hydrochloride hydrate.
22.结晶卡维地洛水合物。 22. The crystalline carvedilol hydrate.
23.结晶卡维地洛。 23. The crystalline carvedilol.
24.结晶卡维地洛(甲乙酮)溶剂合物。 24. The crystalline carvedilol (methyl ethyl ketone) solvate.
25.结晶卡维地洛型III。 25. The crystalline carvedilol type III.
26.权利要求25的结晶卡维地洛,特征在于其X-射线粉末衍射图在约8.40.2,17.40.2和22.00.2度2θ具有峰。 26. The crystalline carvedilol of claim 25, characterized in that X- ray powder diffraction pattern at about 8.4 0.2,17.4 0.2 and 22.0 0.2 degrees 2θ having peaks.
27.权利要求26的卡维地洛,进一步的特征在于其X-射线粉末衍射图在约9.30.2,11.60.2,13.20.2,13.50.2,14.20.2,15.30.2,15.80.2,18.40.2,19.40.2,20.60.2,21.40.2,26.50.2和27.60.2度2θ具有峰。 27. carvedilol claim 26, further characterized in that the X- ray powder diffraction pattern at about 9.3 0.2,11.6 0.2,13.2 0.2,13.5 0.2,14.2 0.2,15.3 0.2,15.8 0.2,18.4 0.2,19.4 0.2,20.6 0.2,21.4 0.2,26.5 0.2 and 27.6 0.2 degrees 2θ has peak.
28.权利要求24的结晶卡维地洛,特征在于其水含量为约2.0%(重量)。 28. The claim 24 crystalline carvedilol, characterized in that the water content of about 2.0% (by weight).
29.一种药用组合物,该组合物包含治疗有效量的权利要求24的结晶卡维地洛和药学上可接受的载体。 29. A pharmaceutical composition, which composition comprises a therapeutically effective amount of crystalline carvedilol of claim 24 and a pharmaceutically acceptable carrier.
30.一种通过给予治疗有效量的结晶卡维地洛型III来治疗充血性心力衰竭患者的方法。 30. A by administering a therapeutically effective amount of a crystalline carvedilol Form III to treat patients with congestive heart approach.
31.一种通过给予治疗有效量的结晶卡维地洛型III来治疗高血压患者的方法。 31. A by administering a therapeutically effective amount of a crystalline carvedilol in the treatment of hypertension in patients with type III approach.
32.结晶卡维地洛型IV。 32. The crystalline carvedilol type IV.
33.权利要求32的结晶卡维地洛,特征在于其X-射线粉末衍射图在约11.90.2,14.20.2,18.30.2,19.20.2,21.70.2和24.20.2度2θ具有峰。 33. The crystalline carvedilol of claim 32, characterized in that the X- ray powder diffraction pattern at about 11.9 0.2,14.2 0.2,18.3 0.2,19.2 0.2,21.7 0.2 and 24.2 0.2 degrees 2θ has peak .
34.权利要求33的结晶卡维地洛,进一步的特征在于其X-射线粉末衍射图在约15.70.2,16.50.2,17.70.2,19.60.2,22.20.2,23.90.2,24.90.2,27.40.2和28.20.2度2θ具有峰。 34. The claim 33, crystalline carvedilol, further characterized in that the X- ray powder diffraction pattern at about 15.7 0.2,16.5 0.2,17.7 0.2,19.6 0.2,22.2 0.2,23.9 0.2,24.9 0.2,27.4 0.2 and 28.2 0.2 degrees 2θ has peak.
35.结晶卡维地洛(甲乙酮)溶剂合物型V。 35. The crystalline carvedilol (methyl ethyl ketone) solvate type V.
36.权利要求35的结晶卡维地洛,特征在于其X-射线粉末衍射图在约4.10.2,10.30.2和10.70.2度2θ具有峰。 36. The crystalline carvedilol of claim 35, characterized in that X- ray powder diffraction pattern at about 4.1 0.2,10.3 0.2 and 10.7 0.2 degrees 2θ having peaks.
37.权利要求36的结晶卡维地洛,进一步的特征在于其X-射线粉末衍射图在约11.50.2,12.60.2,14.00.2,14.80.2,15.40.2,16.40.2,16.80.2,18.80.2,20.80.2,21.10.2,21.60.2和25.40.2度2θ具有峰。 37. The claim 36 crystalline carvedilol, further characterized in that the X- ray powder diffraction pattern at about 11.5 0.2,12.6 0.2,14.0 0.2,14.8 0.2,15.4 0.2,16.4 0.2,16.8 0.2,18.8 0.2,20.8 0.2,21.1 0.2,21.6 0.2 and 25.4 0.2 degrees 2θ has peak.
38.权利要求35的结晶卡维地洛,特征在于其甲乙酮含量为约14%(重量)。 38. The crystalline carvedilol of claim 35, characterized in that the content of methyl ethyl ketone (weight) of about 14%.
39.盐酸卡维地洛水合物。 39. Carvedilol hydrochloride hydrate.
40.权利要求39的结晶卡维地洛,特征在于其X-射线粉末衍射图在约6.50.2,10.20.2,10.40.2,15.80.2,16.40.2和22.20.2度2θ具有峰。 40. The crystalline carvedilol of claim 39, characterized in that the X- ray powder diffraction pattern at about 6.5 0.2,10.2 0.2,10.4 0.2,15.8 0.2,16.4 0.2 and 22.2 0.2 degrees 2θ has peak .
41.权利要求40的结晶卡维地洛,进一步的特征在于其X-射线粉末衍射图在约14.20.2,14.70.2,16.40.2,17.70.2,20.00.2,21.50.2,21.90.2,22.90.2,25.20.2,25.30.2,27.20.2,27.40.2,28.20.2,28.60.2,29.60.2度2θ具有峰。 41. The claim 40 crystalline carvedilol, further characterized in that X- ray powder diffraction pattern at about 14.2 0.2,14.7 0.2,16.4 0.2,17.7 0.2,20.0 0.2,21.5 0.2,21.9 0.2,22.9 0.2,25.2 0.2,25.3 0.2,27.2 0.2,27.4 0.2,28.2 0.2,28.6 0.2,29.6 0.2 degrees 2θ has peak.
42.权利要求39的结晶卡维地洛,特征在于其水含量为约3.5%(重量)。 42. The crystalline carvedilol of claim 39, characterized in that the water content of about 3.5% (by weight).
43.一种制备结晶卡维地洛型I的方法,包括下面步骤:a)通过加热将卡维地洛溶解于一种溶液中;b)加热所述溶液直到结晶卡维地洛完全溶解;c)降低溶液的温度;d)将溶液搅拌一段时间;e)进一步降低溶液的温度;f)进一步将溶液搅拌一段时间;和g)收集结晶卡维地洛型I。 43. A method for preparing crystalline carvedilol Form I, which comprises the following steps: a) by heating the carvedilol is dissolved in a solution; b) heating the solution until the crystalline carvedilol is completely dissolved; c) reducing the temperature of the solution; d) and the solution was stirred for a period of time; e) further reducing the temperature of the solution; f) and the solution was stirred for a further period of time; and g) collecting crystalline carvedilol type I.
44.权利要求43的方法,其中所述溶解步骤通过将溶液加热到约77℃来进行。 44. The method of claim 43, wherein said dissolving step is performed by heating the solution to about 77 ℃ performed.
45.权利要求43的方法,其中所述降低溶液温度的步骤通过在约15分钟的时间内将溶液冷却到约50℃来进行。 45. The method of claim 43, wherein said step of lowering the temperature of the solution through in about 15 minutes the solution was cooled to about 50 ℃ performed.
46.权利要求43的方法,其中所述搅拌溶液的步骤在约50℃进行约48小时。 46. The method of claim 43, wherein said step of stirring the solution is performed at about 50 ℃ about 48 hours.
47.权利要求43的方法,其中所述进一步降低溶液温度的步骤通过在约0.75小时内将溶液在搅拌下冷却到约10℃来进行。 47. The method of claim 43, wherein said step of further reducing the solution temperature by a period of about 0.75 hours the solution was cooled with stirring to about 10 ℃ performed.
48.权利要求43的方法,其中所述进一步搅拌溶液的步骤通过将悬浮液搅拌约5小时以上来进行。 48. The method of claim 43, wherein said step of further stirring the solution through the suspension was stirred for about 5 hours or more.
49.一种制备结晶卡维地洛型II的方法,包括下面步骤:a)通过将卡维地洛溶解于一种溶剂中来形成卡维地洛溶液;b)通过冷却溶液来沉淀卡维地洛型II;和c)分离结晶卡维地洛型II。 49. A method for preparing crystalline carvedilol Form II, comprising the following steps: a) by the carvedilol is dissolved in a solvent to form a solution of carvedilol; b) by cooling the solution to precipitate carvedilol Carvedilol type II; and c) isolating crystalline carvedilol type II.
50.权利要求49的方法,其中所述温度为约40℃到大约溶剂的沸点温度。 50. The method of claim 49, wherein said temperature is about 40 ℃ to about the boiling point of the solvent.
51.权利要求49的方法,其中沉淀的卡维地洛型II通过过滤分离。 51. The method of claim 49, wherein the precipitating carvedilol Form II is isolated by filtration.
52.权利要求49的方法,其中所述溶液被冷却到约-20℃到室温的温度。 52. The method of claim 49, wherein the solution is cooled to room temperature to a temperature of about -20 ℃.
53.权利要求49的方法,其中所述溶剂选自甲醇、乙醇、1-丙醇、异丙醇、正丁醇、乙二醇、乙酸丁酯、异丁基甲基酮、二氯甲烷、二氯乙烷、乙腈、丙酮、异戊醇、二甲苯和甲苯。 53. The method of claim 49, wherein said solvent is selected from methanol, ethanol, 1-propanol, isopropanol, n-butanol, ethylene glycol, butyl acetate, isobutyl methyl ketone, methylene chloride, dichloro ethane, acetonitrile, acetone, iso-amyl alcohol, xylene and toluene.
54.一种制备结晶卡维地洛型II的方法,包括下面步骤:a)通过将卡维地洛溶解于溶剂混合物中形成卡维地洛溶液;b)通过将溶液冷却到约-20℃使卡维地洛型II沉淀;和c)分离结晶卡维地洛型II。 54. A method for preparing crystalline carvedilol Form II, comprising the following steps: a) by carvedilol dissolved in a solvent mixture of carvedilol solution forms; b) by the solution is cooled to about -20 ℃ so carvedilol precipitation type II; and c) isolating crystalline carvedilol type II.
55.权利要求54的方法,其中所述溶液的温度为约40℃到大约溶剂的沸点温度。 55. The method of claim 54, wherein the temperature of the solution is about 40 ℃ to about the boiling point of the solvent.
56.权利要求54的方法,其中沉淀的卡维地洛型II通过过滤分离。 56. The method of claim 54, wherein the precipitating carvedilol Form II is isolated by filtration.
57.权利要求54的方法,其中所述溶液被冷却到约-20℃到室温的温度。 57. The method of claim 54, wherein the solution is cooled to room temperature to a temperature of about -20 ℃.
58.权利要求54的方法,其中所述溶剂混合物选自丙酮∶环己烷、氯仿∶环己烷、二氯乙烷∶环己烷、二氯甲烷∶环己烷、吡啶∶环己烷、四氢呋喃∶环己烷、二噁烷∶环己烷、丙酮∶己烷、氯仿∶己烷、二氯乙烷∶己烷、二氯甲烷∶己烷、四氢呋喃∶己烷和乙醇∶己烷。 58. The method of claim 54, wherein said solvent mixture selected from acetone: cyclohexane, chloroform: cyclohexane, dichloroethane: cyclohexane, dichloromethane: cyclohexane, pyridine: cyclohexane, tetrahydrofuran: cyclohexane, dioxane: cyclohexane, acetone: hexane, chloroform: hexane, dichloroethane: hexane, dichloromethane: hexane, tetrahydrofuran: hexane and ethanol: hexane.
59.一种制备结晶卡维地洛型III的方法,包括下面步骤:a)将卡维地洛溶解于一种溶剂中形成溶剂溶液;和b)用水作反溶剂从该溶剂溶液中沉淀结晶卡维地洛型III。 59. A method for preparing crystalline carvedilol Form III, comprising the steps of: a) the carvedilol dissolved to form a solvent solution in a solvent; and b) water as anti-solvent crystallization precipitated from the solvent solution Carvedilol type III.
60.权利要求59的方法,其中水在溶解步骤中存在于溶剂溶液中。 60. The method of claim 59, wherein in the step of dissolving water present in the solvent solution.
61.权利要求59的方法,其中所述沉淀步骤通过在卡维地洛完全溶解于溶剂中后将水加入到溶液中来进行。 61. The method of claim 59, wherein said precipitation step is performed by the after carvedilol is fully dissolved in a solvent of water was added to the solution to carry out.
62.权利要求59的方法,其中所述溶解步骤在升高的温度下进行。 62. The method of claim 59, wherein said dissolving step is performed at an elevated temperature.
63.权利要求59的方法,其中所述升高的温度为约40℃-约90℃。 63. The method of claim 59, wherein said elevated temperature is about 40 ℃ - about 90 ℃.
64.权利要求59的方法,其中所述升高的温度为约55℃。 64. The method of claim 59, wherein said elevated temperature is about 55 ℃.
65.权利要求59的方法,其中所述溶解步骤在室温下进行。 65. The method of claim 59, wherein said dissolving step is performed at room temperature.
66.权利要求59的方法,其中所述溶剂选自吡啶、二噁烷、甲醇、乙醇、异丙醇和氯仿。 66. The method of claim 59, wherein said solvent is selected from pyridine, dioxane, methanol, ethanol, isopropanol and chloroform.
67.权利要求59的方法,其中所述溶剂包括溶剂混合物。 67. The method of claim 59, wherein said solvent comprises a solvent mixture.
68.一种制备结晶卡维地洛型IV的方法,包括下面步骤:a)将卡维地洛溶解于一种溶剂中形成溶剂溶液;b)向该溶剂溶液中加入反溶剂;和c)从该溶剂溶液中沉淀结晶卡维地洛型IV。 68. A method for preparing crystalline carvedilol Form IV, which comprises the following steps: a) the carvedilol dissolved to form a solvent solution in a solvent; b) was added to the solvent, anti-solvent; and c) from the solvent solution to precipitate the crystalline carvedilol type IV.
69.权利要求68的方法,其中所述溶剂为甲乙酮。 69. The method of claim 68, wherein the solvent is methyl ethyl ketone.
70.权利要求68的方法,其中所述反溶剂为环己烷。 70. The method of claim 68, wherein the anti-solvent is cyclohexane.
71.权利要求68的方法,其中所述溶解步骤在约10℃-约50℃进行。 71. The method of claim 68, wherein the dissolution step at about 10 ℃ - for about 50 ℃.
72.权利要求68的方法,其中所述溶解步骤在约55℃进行。 72. The method of claim 68, wherein said dissolving step is performed at about 55 ℃.
73.权利要求68的方法,其中所述溶解步骤在室温下进行。 73. The method of claim 68, wherein said dissolving step is performed at room temperature.
74.一种制备结晶卡维地洛型V的方法,包括下面步骤:a)将卡维地洛溶解于一种溶剂中形成溶剂溶液;b)从该溶剂溶液中沉淀和分离结晶卡维地洛型V。 74. A method for preparing crystalline carvedilol type V, comprising the following steps: a) the carvedilol dissolved to form a solvent solution in a solvent; b) precipitation from the solvent solution, and fractional crystallization of carvedilol Los type V.
75.权利要求74的方法,其中所述溶剂为甲乙酮。 75. The method of claim 74, wherein the solvent is methyl ethyl ketone.
76.权利要求74的方法,其中所述溶解步骤通过在常温下溶解卡维地洛来进行。 76. The method of claim 74, wherein said dissolving step is performed by dissolving at room temperature for carvedilol.
77.权利要求74的方法,其中所述溶解温度为约10℃-约80℃。 77. The method of claim 74, wherein the dissolution temperature is about 10 ℃ - about 80 ℃.
78.权利要求74的方法,其中卡维地洛型V通过冷却进行沉淀。 78. The method of claim 74, wherein the carvedilol type V precipitated by cooling.
79.一种制备结晶卡维地洛型V的方法,包括下面步骤:a)将卡维地洛溶解于一种溶剂中形成溶剂溶液;和b)从该溶剂溶液中沉淀和分离结晶卡维地洛型V,其中所述沉淀步骤通过加入一种反溶剂来进行。 79. A method for preparing crystalline carvedilol type V, comprising the following steps: a) the carvedilol dissolved to form a solvent solution in a solvent; and b) precipitation from the solvent solution, and fractional crystallization of carvedilol carvedilol type V, wherein said precipitation step is performed by adding an anti-solvent.
80.权利要求79的方法,其中所述溶剂为甲乙酮。 80. The method of claim 79, wherein the solvent is methyl ethyl ketone.
81.权利要求79的方法,其中所述溶解步骤通过在常温下溶解卡维地洛来进行。 81. The method of claim 79, wherein said dissolving step is performed by dissolving at room temperature for carvedilol.
82.权利要求79的方法,其中所述反溶剂为己烷。 82. The method of claim 79, wherein the anti-solvent is hexane.
Description  translated from Chinese
卡维地洛 Carvedilol

与相关申请的相互参照本申请要求通过引用并入本文的2000年6月28日提出的美国临时专利申请60/214,356号和2000年11月7日提出的美国临时专利申请60/246,358号的权益。 CROSS-REFERENCE TO RELATED APPLICATION This application claims priority is incorporated herein by reference US Provisional Patent June 28, 2000 submitted an application No. 60 / 214,356 and US Provisional Patent November 7, 2000 on the application of the rights and interests No. 60 / 246,358 .

卡维地洛的合成通过引用并入本文的美国专利4,503,067号公开了一种通过下示反应制备卡维地洛的方法: Carvedilol synthesis is incorporated herein by reference US Patent No. 4,503,067 discloses a method shown by the following reaction of carvedilol: 其中4-(环氧乙烷-2-基甲氧基)-9H-咔唑(式II)与(2-(2-甲氧基苯氧基)乙胺(式III)反应形成卡维地洛(I)。上述方法产生低收率的卡维地洛,至少部分是因为除了卡维地洛外该方法还产生下面结构的含两个式II化合物分子的杂质(bis impurity)(式IV): Wherein 4- (oxirane-2-ylmethoxy) -9H- carbazole (formula II) with (2- (2-methoxyphenoxy) ethylamine (Formula III) to form carvedilol Rockwell (I). above method produces a low yield of carvedilol, at least in part because of carvedilol in addition to outside the method also generates the following structure containing two molecules of the compound of Formula II impurities (bis impurity) (type IV) : (参见EP918055)。 (See EP918055).

为了减少式IV的形成和提高卡维地洛的收率,EP918055提出使用2-(2-甲氧基苯氧基)乙胺(式III)的苄基保护形式。 In order to reduce the formation of type IV and improve the yield of carvedilol, EP918055 proposed using 2- (2-methoxyphenoxy) ethylamine (Formula III) benzyl protected form.

卡维地洛多晶型物通过引用并入本文的国际专利申请WO99/05105号公开了卡维地洛可根据制备方法而分离为两种多晶型物。 Carvedilol polymorph is incorporated herein by reference, the international patent application WO99 / 05105 discloses a number of carvedilol can be separated into two types according to the method for preparing polymorphs. 据报道称为型I和型II的两种多晶型物是单向转变的,可通过其红外、拉曼和X-射线粉末衍射光谱加以区分。 It has been reported is called type I and two type II polymorph is monotropic, through its IR, X- ray powder diffraction and Raman spectroscopy to differentiate. 在文献中没有发现存在卡维地洛的水合溶剂合物形态的证据。 Found no evidence of the presence of hydrated solvate forms of carvedilol in the literature.

同质多晶是一些分子和分子络合物在固态下呈现超过一种的晶型的性质。 Polymorphism is some molecules and molecular complexes exhibit more than one crystalline form in the solid state properties. 单种分子可产生多种具有不同物理性质的晶型(也称为“多晶型物”、“水合物”或“溶剂合物”)。 A single molecule can produce a variety of forms having different physical properties (also referred to as "polymorph", "hydrate" or "solvate"). 对于多晶型物和多晶型物的药物用途的综述可参见GMWall,Pharm Manuf.3,33(1986);JKHaleblian和W.McCrone,R Pharm.Sci.,58,911(1969);和JKHaleblian,J.Pharm.Sci.,64,1269(1975),这些文献均通过引用并入本文。 For a review of polymorphs and the polymorph of drug use may be found in GMWall, Pharm Manuf.3,33 (1986); JKHaleblian and W.McCrone, R Pharm.Sci, 58,911 (1969);. And JKHaleblian , J.Pharm.Sci., 64,1269 (1975), these documents are incorporated herein by reference.

不同晶型的存在和物理性质可通过各种技术如X-射线衍射光谱法、差示扫描量热法和红外光谱法来测定。 Different polymorphs of the existence and the physical properties of a variety of techniques such as by X- ray diffraction spectroscopy to measure Differential scanning calorimetry and infrared spectroscopy. 不同晶型物理性质上的差异源于在本体固体物中相邻分子(络合物)的取向和分子间相互作用。 Differences in the physical properties of the crystal stems between adjacent molecules in the bulk solids (complex) orientation and molecular interactions. 因此,多晶型物、水合物和溶剂合物是具有相同分子式但与多晶型物族中的其它形式相比具有不同的有利和/或不利物理性能的不同固体物。 Accordingly, polymorphs, hydrates and solvates are distinct solids having the same molecular formula but with the polymorph family of other forms having different advantageous and / or disadvantageous physical properties. 多晶型物、水合物和溶剂合物的存在和物理性质是不可预测的。 Existence and physical properties of polymorphs, hydrates and solvates is unpredictable.

可形成多晶型物、水合物或溶剂合物的药用化合物的最重要物理性质之一是其在水溶液中的溶解性,特别是在患者胃液中的溶解性。 One of the most important physical properties of polymorphs, hydrates or solvates may be formed is a pharmaceutical compound whose solubility in aqueous solution, particularly the solubility in gastric juices of the patient. 其它重要性质涉及将所述形式加工成药剂的难易性,诸如粉末或颗粒形式的易流动性和决定该形式的晶体是否在压成片时相互粘合的表面特性。 Other important properties related to the processing of the form to the ease of agents, such as free-flowing and determining the form of crystalline powder or granular form is pressed into a sheet in the surface properties bonded to each other.

本发明简述本发明提供了一种制备卡维地洛的方法,包括使式II化合物4-(环氧乙烷-2-基甲氧基)-9H-咔唑 SUMMARY OF THE INVENTION The present invention provides a process for preparing carvedilol, which comprises reacting a compound of formula II 4- (oxirane-2-ylmethoxy) -9H- carbazole 与式III化合物2-(2-甲氧基苯氧基)乙胺反应的步骤, With a compound of formula III 2- (2- methoxyphenoxy) ethylamine in step, 其中式III化合物相对于式II化合物摩尔过量。 Wherein the compound of formula III with a molar excess of the compound of formula II.

本发明还提供了结晶卡维地洛水合物。 The present invention also provides a crystalline carvedilol hydrate.

本发明还提供了结晶卡维地洛。 The present invention also provides a crystalline carvedilol.

本发明还提供了结晶卡维地洛(甲乙酮)溶剂合物。 The present invention also provides a crystalline carvedilol (methyl ethyl ketone) solvate.

本发明还提供了结晶卡维地洛型III,其特征在于其X-射线粉末衍射图案具有在约8.40.2,17.40.2和22.00.2度2θ的峰。 The present invention further provides crystalline carvedilol type III, characterized in that the X- ray powder diffraction pattern having about 8.4 0.2,17.4 0.2 and 22.0 0.2 degrees 2θ at the peak.

本发明还提供了结晶卡维地洛型IV,其特征在于其X-射线粉末衍射图案具有在约11.90.2,14.20.2,18.30.2,19.20.2,21.70.2和24.20.2度2θ的峰。 The present invention also provides a crystalline carvedilol type IV, characterized in that the X- ray powder diffraction pattern having at approximately 11.9 0.2,14.2 0.2,18.3 0.2,19.2 0.2,21.7 0.2 and 24.2 0.2 degrees 2θ peaks.

本发明还提供了结晶卡维地洛(甲乙酮)溶剂合物型V,其特征在于其X-射线粉末衍射图案具有在约4.10.2,10.30.2和10.70.2度2θ的峰。 The present invention further provides crystalline carvedilol (methyl ethyl ketone) solvate type V, characterized in that the X- ray powder diffraction pattern having about 4.1 0.2,10.3 0.2 and 10.7 0.2 degrees 2θ at the peak.

本发明还提供了卡维地洛HCl水合物,其特征在于其X-射线粉末衍射图案具有在约6.50.2,10.20.2,10.40.2,15.80.2,16.40.2和22.20.2度2θ的峰。 The present invention also provides a carvedilol HCl monohydrate, characterized in that the X- ray powder diffraction pattern having at approximately 6.5 0.2,10.2 0.2,10.4 0.2,15.8 0.2,16.4 0.2 and 22.2 0.2 degrees 2θ peaks.

本发明还提供了一种制备结晶卡维地洛型I的方法,包括下面步骤:通过加热将卡维地洛溶解于溶液中;加热溶液直到结晶卡维地洛完全溶解;降低溶液的温度;将溶液搅拌一段时间;进一步降低溶液温度;进一步将溶液搅拌一段时间;收集结晶卡维地洛型I。 The present invention also provides a method for preparing crystalline carvedilol Form I, which comprises the following steps: by heating the carvedilol dissolved in the solution; the solution is heated until the crystalline carvedilol is completely dissolved; lowering the temperature of the solution; The solution was stirred for a period of time; further reducing the temperature of the solution; the solution was stirred for a further period of time; collecting crystalline carvedilol type I.

本发明还提供了一种制备结晶卡维地洛型II的方法,包括下面步骤:通过将卡维地洛溶解于溶剂中形成溶液;通过冷却溶液沉淀卡维地洛型II;分离结晶卡维地洛型II。 The present invention also provides a method for preparing crystalline carvedilol Form II, comprising the steps of: by carvedilol dissolved in a solvent to form a solution; the solution precipitated by cooling carvedilol type II; fractional crystallization of carvedilol Carvedilol type II.

本发明还提供了一种制备结晶卡维地洛型II的方法,包括下面步骤:通过将卡维地洛溶解于溶剂混合物中形成卡维地洛溶液;通过冷却溶液到约-20℃沉淀卡维地洛型II;分离结晶卡维地洛型II。 The present invention also provides a method for preparing crystalline carvedilol Form II, comprising the steps of: by carvedilol dissolved in the solvent mixture to form a solution of carvedilol; by cooling the solution to about -20 ℃ precipitation card carvedilol type II; fractional crystallization of carvedilol type II.

本发明还提供了一种制备结晶卡维地洛型III的方法,包括下面步骤:将卡维地洛溶解于溶剂中形成溶剂溶液;用水作为反溶剂从所述溶剂溶液中沉淀结晶卡维地洛型III。 The present invention also provides a method for preparing crystalline carvedilol Form III includes the following steps: carvedilol dissolved in a solvent to form a solvent solution; water as anti-solvent crystallization carvedilol precipitation from the solvent solution Los type III.

本发明还提供了一种制备结晶卡维地洛型III的方法,包括下面步骤:将卡维地洛通过加热溶解于溶液中;冷却该溶液混合物;和收集结晶卡维地洛型III。 The present invention also provides a method for preparing crystalline carvedilol Form III, comprising the following steps: Carvedilol dissolved by heating the solution; cooling the solution mixture; and collecting crystalline carvedilol type III.

本发明还提供了一种制备结晶卡维地洛型IV的方法,包括下面步骤:将卡维地洛溶解于溶剂中形成溶剂溶液;将一种反溶剂加入到该溶剂溶液中;和从该溶剂溶液中沉淀结晶卡维地洛型IV。 The present invention also provides a method for preparing crystalline carvedilol Form IV, which comprises the following steps: Carvedilol is dissolved in a solvent to form a solvent solution; an anti-solvent is added to the solvent solution; and from the solvent solution to precipitate the crystalline carvedilol type IV.

本发明还提供了一种制备结晶卡维地洛型V的方法,包括将卡维地洛溶解于一种溶剂中形成溶剂溶液和从该溶剂溶液中沉淀并分离结晶卡维地洛型V的步骤。 The present invention also provides a method for preparing crystalline carvedilol type V method, including carvedilol dissolved to form a solvent solution in a solvent and precipitation from the solvent solution and fractional crystallization of carvedilol type V steps.

本发明还提供了一种制备结晶卡维地洛型V的方法,包括将卡维地洛溶解于一种溶剂中形成溶剂溶液和从该溶剂溶液中沉淀并分离结晶卡维地洛型V的步骤,其中沉淀步骤通过加入反溶剂来进行。 The present invention also provides a method for preparing crystalline carvedilol type V method, including carvedilol dissolved to form a solvent solution in a solvent and precipitation from the solvent solution and fractional crystallization of carvedilol type V step, wherein the precipitation step is performed by adding an anti-solvent.

图2显示了卡维地洛型III的DTG热曲线。 Figure 2 shows the carvedilol Form III DTG thermal profile.

图3显示了卡维地洛型IV的X-射线衍射图案。 Figure 3 shows the carvedilol Form IV X- ray diffraction pattern.

图4显示了卡维地洛型IV的DTG热曲线。 Figure 4 shows the carvedilol Form IV DTG thermal profile.

图5显示了卡维地洛型V的X-射线衍射图案。 Figure 5 shows the carvedilol type V of X- ray diffraction pattern.

图6显示了卡维地洛型V的DTG热曲线。 Figure 6 shows the carvedilol type V of DTG thermal profile.

图7显示了卡维地洛HCl的X-射线衍射图案。 Figure 7 shows the carvedilol HCl for X- ray diffraction pattern.

本发明详述此中所用的术语“卡维地洛”包括卡维地洛的水合物和溶剂合物。 The present invention is described in detail herein, the term "carvedilol" includes carvedilol hydrates and solvates. 术语“水含量”是指基于如在药典论坛(Pharmacopeia Forum)24卷1期5438页(1998年1-2月)中所述的干燥失重法(“LOD”法)、测定水含量的卡尔费歇尔测定法或热解重量分析法(TGA)的水含量。 The term "water content" refers based as in Pharmacopeial Forum (Pharmacopeia Forum) 24 Volume 1 in 5438 (January-February 1998) of the dry weight loss ("LOD" method), determination of water content Karl Fischer assays or thermal gravimetric analysis (TGA) of water content. 术语“水当量”是指水的摩尔当量。 The term "equivalents of water" means molar equivalents of water. 除非另加说明,否则本文中所有百分比均为重量百分比。 Unless otherwise stated otherwise herein, all percentages are by weight. 本领域技术人员理解术语“无水”用于指卡维地洛时是指卡维地洛基本上无水。 Skilled in the art to understand the term "anhydrous" when used to refer to carvedilol carvedilol refers substantially anhydrous. 本领域技术人员理解术语“半水合物”用于指卡维地洛时是指具有约2.2%(重量)水含量的晶体物质。 Those skilled in the art understand the term "hemihydrate" is used to refer to when carvedilol crystalline material (by weight) having a water content of about 2.2%. 本领域技术人员理解术语“水合物”是指水含量约为或高于2%(重量)的盐酸卡维地洛晶体物质。 Those skilled in the art understand the term "hydrate" refers to a water content of about or more than 2% (wt.) Carvedilol hydrochloride a crystalline material. 本领域技术人员理解术语“甲乙酮的溶剂合物”是指晶格中所含溶剂量高于1%的卡维地洛。 Those skilled in the art understand the term "methyl ethyl ketone solvate" refers to the amount of the solvent contained in the crystal lattice than 1% of the carvedilol. 本领域技术人员也理解术语含1摩尔的“甲乙酮的溶剂合物”是指甲乙酮含量为约14%(重量)的卡维地洛。 Skilled in the art also understand that the term containing 1 mole of "methyl ethyl ketone solvate" refers to methyl ethyl ketone content of about 14% (by weight) of carvedilol.

卡维地洛的水合物和溶剂合物形式为新形式并且在其特征粉末X-射线衍射图案和其热曲线上相互不同。 Hydrate and solvate forms of carvedilol for new forms and different from each other in their characteristic X- ray powder diffraction patterns and their thermal profiles.

对于本说明书来说,环境温度是指约20℃-约25℃。 For purposes of this specification, ambient temperature is from about 20 ℃ - about 25 ℃.

所有粉末X-射线衍射图均通过本领域人们熟悉的方法使用Philips X-射线粉末衍射仪获得。 All X- ray powder diffraction pattern use the Philips X- ray diffraction obtained by methods familiar in the art. 使用λ=1.5418的铜辐射线。 Using λ = 1.5418 copper radiation.

为了评价在加热样品中可能发生的物理和化学变化,进行热分析的测量。 In order to evaluate the physical and chemical changes that may occur in heating a sample, the measurement of the thermal analysis. 热反应本质上可以是吸热反应(如熔融、沸腾、升华、汽化、去溶剂化、固-固相变、化学降解等)或放热反应(如结晶、氧化分解等)。 Essentially thermal reaction may be endothermic reaction (eg molten, boiling, sublimation, vaporization, desolvation, solid - solid phase transitions, chemical degradation, etc.) or exothermic reaction (such as crystallization, oxidative decomposition, etc.). 这种方法在以多晶型物为特征的制药业上得到了广泛使用。 In this method the polymorph is characterized by the pharmaceutical industry has been widely used. 已经证明热测量可用于表征多晶型体系。 Thermal measurements have proven useful for characterizing polymorph systems. 最常用的技术是热解重量分析法(TGA)、差示热分析(DTA)和差示扫描量热法(DSC)。 The most common technique is thermal gravimetric analysis (TGA), differential thermal analysis (DTA) and differential scanning calorimetry (DSC).

此中所示的DTA和TGA曲线通过本领域人们熟悉的方法使用DTG Shimadzu model DTG-50型(结合TGA和DTA)获得。 Herein DTA and TGA curves shown DTG Shimadzu model by using familiar methods in the art DTG-50 type (combined TGA and DTA) to obtain. 样品重量为约9-13mg。 Sample weight was about 9-13mg. 将样品以10℃/min的速率扫描到约300℃或以上。 The sample rate of 10 ℃ / min to about 300 ℃ scans or more. 将样品用20ml/min流速的氮气清洗。 The sample was washed with 20ml / min flow rate of nitrogen. 标准氧化铝坩埚盖上有一个孔的盖。 Standard alumina crucibles covered with a cover hole.

热解重量分析(TGA)是作为施加温度函数的材料热致失重的度量。 Thermal gravimetric analysis (TGA) is applied as the thermal function of temperature induced weight loss metric. TGA限于涉及增失质量的转变,并且最常用于研究去溶剂化过程和化合物分解。 TGA limited change involves increased loss of quality, and most commonly used to study desolvation processes and compound decomposition.

本领域人们熟悉的卡尔费歇尔分析也用于测定样品中的水量。 People familiar with the art of Karl Fischer analysis is also used to determine the amount of water in the sample.

此中所用的溶剂是能溶解卡维地洛的任何液体物质。 As used herein the solvent is capable of dissolving carvedilol any liquid substances. 此中所用的术语“反溶剂”是指化合物难溶于其中的液体。 As used herein the term "anti-solvent" refers to a compound which is insoluble in the liquid. 向溶剂中加入反溶剂降低了化合物的溶解度。 Anti-solvent is added to the solvent to reduce the solubility of the compound. 此中所用的溶剂混合物是指包含超过一种溶剂的组合物。 The solvent mixture as used herein refers to a solvent containing more than one kind of composition.

此中所用的术语“净”条件是指其中反应的溶剂为反应物之一的反应条件。 As used herein the term "net" refers to the condition in which the reaction solvent is one of the reactants in the reaction conditions.

卡维地洛的合成按照一个实施方案,本发明是一种制备卡维地洛的方法,其包括式II化合物4-(环氧乙烷-2-基甲氧基)-9H-咔唑: Carvedilol synthesized according to one embodiment, the present invention is a method for preparing carvedilol, which comprises a compound of formula II 4- (2-methoxy-ethylene oxide) -9H- carbazole: 与式III化合物2-(2-甲氧基苯氧基)乙胺 With a compound of formula III 2- (2- methoxyphenoxy) ethylamine 的反应步骤。 Reaction step. 新方法得到比现有技术所报告的更高的卡维地洛收率。 New higher than the prior art methods reported carvedilol yield. 此外,新方法的产物几乎没有含两个式II化合物分子的杂质并且反应更快速。 In addition, the new method is almost no product with two molecules of the compound of formula II impurities and the reaction is more rapid.

优选式III化合物相对于式II化合物摩尔过量。 Preferred compounds of formula III with respect to the molar excess of the compound of formula II. 式III化合物与式II化合物的摩尔比率优选为约1.5∶1到约100∶1。 Preferably the molar ratio of the compound of formula III with a compound of formula II is from about 1.5 to about 100. 更优选式III化合物与式II化合物的摩尔比率为约2.8∶1到约10∶1。 The molar ratio of the compound of formula III with a compound of formula II is more preferably from about 2.8:1 to about 10. 最优选式III化合物与式II化合物的摩尔比率为约2.8∶1到约6∶1。 The molar ratio of the compound of formula III with a compound of formula II most preferably is from about 2.8:1 to about 6.

在本发明的一个实施方案中,所述反应步骤在溶剂中进行。 In one embodiment of the present invention, the reaction step carried out in a solvent. 所述溶剂优选选自甲苯、二甲苯和庚烷。 The solvent is preferably selected from toluene, xylene and heptane. 在另一个可选实施方案中,所述反应步骤在包含多种溶剂的溶剂混合物中进行。 In another alternative embodiment, the reaction step carried out in a solvent mixture containing a variety of solvents. 优选所述溶剂混合物中的一种溶剂选自甲苯、二甲苯和庚烷。 Preferably, the solvent mixture of a solvent selected from toluene, xylene and heptane.

所述反应步骤优选在约25℃-约150℃的温度下进行。 The reaction step is preferably from about 25 ℃ - under a temperature of about 150 ℃ performed. 最优选所述反应步骤在约60℃-约120℃的温度下进行。 Most preferably, the reaction step at about 60 ℃ - performed under a temperature of about 120 ℃.

在另一个可选实施方案中,反应步骤在净条件下进行。 In another alternative embodiment, the reaction step is performed at the net conditions. 所述净条件可通过将固态形式的式III化合物熔融成液体形式并将式II化合物溶解于该液体中而形成反应混合物来获得。 The net condition can be obtained by melt-compound of formula III in solid form to liquid form and the compound of formula II is dissolved in the liquid to form a reaction mixture was obtained.

在净条件下进行的反应还可包括在溶解式II化合物后降低反应混合物的温度的步骤。 In clear reaction conditions can also include a compound of formula II is dissolved after lowering the temperature of the reaction mixture of step. 所述温度优选降低到约70℃。 The temperature is preferably lowered to about 70 ℃.

在净条件下进行的反应还可包括向反应混合物加入有机溶剂∶水混合物的步骤。 In clear reaction conditions may also include the reaction mixture was added to the organic solvent: water mixture of step. 所述有机溶剂优选选自乙酸乙酯、甲基异丁酮、甲乙酮和乙酸丁酯。 The organic solvent is preferably selected from ethyl acetate, methyl isobutyl ketone, methyl ethyl ketone and butyl acetate.

在净条件下进行的反应还可包括在将有机溶剂∶水混合物加入到反应混合物后调节其pH的步骤。 In clear reaction conditions may also be included in the organic solvent: water mixture after step was added to adjust the pH of the reaction mixture. 所述pH优选调节到约pH5以下。 The pH is preferably adjusted to about pH5 or less. 最优选将pH调节到约3-约5。 Most preferably the pH is adjusted to about 3 to about 5.

任选所述方法还包括在调节pH后分离盐酸卡维地洛和纯化卡维地洛的步骤。 Optionally, the method further comprises, after adjusting the pH of hydrochloric acid and purified carvedilol carvedilol separate steps.

盐酸卡维地洛任选以水合物的形式分离。 Carvedilol hydrochloride optionally in the form of hydrate separation. 作为水合物分离的盐酸卡维地洛具有在约6.50.2,10.20.2,10.40.2,14.20.2,14.70.2,16.40.2,17.70.2,20.00.2,21.90.2,25.20.2度2θ的XRD峰。 As a separate hydrochloride hydrate carvedilol has about 6.5 0.2,10.2 0.2,10.4 0.2,14.2 0.2,14.7 0.2,16.4 0.2,17.7 0.2,20.0 0.2,21.9 0.2,25.2 0.2 degrees 2θ XRD peaks.

在净条件下进行的反应还可包括在调节pH后从反应混合物中分离卡维地洛并纯化卡维地洛的步骤。 Under the net reaction conditions also include the separation of carvedilol from the reaction mixture after adjusting the pH and carvedilol step purification. 卡维地洛可任选通过本领域人们熟悉的方法纯化(参见EP B 0127 099)。 Carvedilol may optionally be purified by methods familiar in the art (see EP B 0127 099).

制备型I和型II结晶卡维地洛的新方法本发明的一个方面提供了一种制备型I结晶卡维地洛的方法,该方法通过下述步骤进行:将卡维地洛溶解于一种溶剂中直到结晶卡维地洛完全溶解,降低溶液的温度并将溶液搅拌一段时间,进一步降低溶液的温度并将溶液搅拌一段时间,收集型I的结晶卡维地洛。 One aspect of the preparation of type I and type II crystalline carvedilol new method of the present invention provides a process for preparing crystalline Form I carvedilol method by the following steps: dissolving carvedilol in a solvents until crystallization of carvedilol is completely dissolved, reducing the temperature of the solution and the solution was stirred for a period of time, further reducing the temperature of the solution and the solution was stirred for a period of time, collecting crystalline Form I Carvedilol.

所述溶解步骤任选通过加热溶剂来进行。 The dissolving step is optionally heated solvent.

所述溶解步骤任选将结晶卡维地洛在约50℃-约60℃的温度加热约6小时来进行。 The dissolving step is optionally crystalline carvedilol at about 50 ℃ - a temperature of about 60 ℃ heated for about 6 hours to carry out.

所述溶解步骤任选通过将结晶卡维地洛悬浮于乙酸乙酯中来进行。 The dissolution step, optionally by crystallization of carvedilol suspended in ethyl acetate to carry out.

所述溶解步骤任选通过将溶液加热到约77℃来进行。 Optionally via the dissolution step the solution is heated to about 77 ℃ performed.

降低溶液温度的步骤任选通过在15分钟的时间内将溶液冷却到约50℃来进行。 Step optionally by reducing the temperature of the solution within 15 minutes the solution was cooled to about 50 ℃ performed.

搅拌溶液的步骤任选在约50℃进行约48小时来进行。 The solution was stirred step optionally carried out at about 50 ℃ for about 48 hours.

进一步降低溶液温度的步骤任选通过在搅拌下用约0.75小时将溶液冷却到约10℃来进行。 Step to further reduce the temperature of the solution optionally by approximately 0.75 hours the solution was cooled with stirring to about 10 ℃ performed.

进一步搅拌溶液的步骤任选通过将悬浮液搅拌5小时以上来进行。 Step further stirred solution optionally by suspension was stirred over 5 hours to carry out. 进一步搅拌的步骤可任选通过将悬浮液搅拌约24小时来进行。 Step may optionally by further stirring suspension was stirred for about 24 hours.

干燥步骤可通过在约50℃-约60℃将结晶卡维地洛加热约6小时来进行。 Drying step by about 50 ℃ - 60 ℃ about UCLA crystalline carvedilol heat for about six hours to carry out.

悬浮步骤可通过将结晶卡维地洛悬浮于乙酸乙酯中来进行。 Steps can be suspended by the crystalline carvedilol suspended in ethyl acetate to carry out.

所述加热步骤可通过将溶液加热到约77℃来进行。 The heating step may be by heating the solution to about 77 ℃ performed.

本发明的另一方面提供了一种制备型II结晶卡维地洛的方法,包括下述步骤:通过将卡维地洛溶解于一种溶剂中形成卡维地洛溶液、通过冷却溶液沉淀型II卡维地洛和分离型II结晶卡维地洛。 Another aspect of the invention provides a method for preparing crystalline carvedilol Form II, comprising the steps of: by the carvedilol is dissolved in a solvent to form a solution of carvedilol, precipitated by cooling the solution Carvedilol II and the separation of type II crystalline carvedilol.

任选所述溶解卡维地洛的步骤在从约40℃到大约溶剂沸腾温度的温度下进行。 Optional step carvedilol dissolved at from about 40 ℃ to about the boiling temperature of the solvent temperature.

任选冷却溶液的步骤通过将温度降低到约-20℃到约环境温度来进行。 Optionally cooling the solution step by lowering the temperature to about ambient temperature to about -20 ℃ performed.

任选所述溶剂选自甲醇、无水乙醇、1-丙醇、异丙醇、正丁醇、乙二醇、乙酸丁酯、异丁基甲基酮、二氯甲烷、二氯乙烷、乙腈、丙酮、异戊醇、二甲苯和甲苯。 Optionally, the solvent is selected from methanol, ethanol, 1-propanol, isopropanol, n-butanol, ethylene glycol, butyl acetate, isobutyl methyl ketone, dichloromethane, dichloroethane, acetonitrile, acetone, iso-amyl alcohol, xylene and toluene.

任选通过过滤分离沉淀的型II卡维地洛。 The precipitate was isolated by filtration, optionally type II, carvedilol.

本发明的另一方面提供了一种制备型II结晶卡维地洛的方法,包括下面步骤:通过将卡维地洛溶解于一种溶剂混合物中形成卡维地洛溶液、通过将溶液冷却到约-20℃沉淀型II卡维地洛和分离型II结晶卡维地洛。 Another aspect of the invention provides a method for preparing crystalline carvedilol Form II, comprising the following steps: by carvedilol is dissolved in a solvent mixture to form a solution of carvedilol by cooling the solution to about -20 ℃ precipitation type II carvedilol and separate type II crystalline carvedilol.

任选在约40℃到大约溶剂沸点温度的温度下将卡维地洛溶解于溶液。 Optionally at about 40 ℃ to the boiling point of the solvent at a temperature of about the carvedilol is dissolved in a solution.

任选型II卡维地洛通过过滤分离。 Optional Type II carvedilol was isolated by filtration.

任选冷却反应物的步骤通过将溶液冷却到约-20℃到环境温度的温度来进行。 Optionally cooling the reaction step by cooling the solution to about -20 ℃ to ambient temperature for.

任选所述溶剂混合物选自:丙酮∶环己烷、氯仿∶环己烷、二氯乙烷∶环己烷、二氯甲烷∶环己烷、吡啶∶环己烷、四氢呋喃∶环己烷、二噁烷∶环己烷、丙酮∶己烷、氯仿∶己烷、二氯乙烷∶己烷、二氯甲烷∶己烷、四氢呋喃∶己烷和乙醇∶己烷。 Optionally, the solvent mixture is selected from: acetone: cyclohexane, chloroform: cyclohexane, dichloroethane: cyclohexane, dichloromethane: cyclohexane, pyridine: cyclohexane, tetrahydrofuran: cyclohexane, dioxane: cyclohexane, acetone: hexane, chloroform: hexane, dichloroethane: hexane, dichloromethane: hexane, tetrahydrofuran: hexane and ethanol: hexane.

新卡维地洛多晶型物在本发明的另一方面,提供了称为型III、IV、V的新的卡维地洛结晶形式及其制备方法。 Carvedilol new polymorph in the aspect of the invention provides a new crystalline form of carvedilol and its preparation method is called type III, IV, V's. 此外,本发明提供了一种具约2%(重量)水含量的新水合形式的卡维地洛及其制备方法。 Furthermore, the present invention provides a tool for about 2% (by weight) of water content in the form of new hydration carvedilol and its preparation method. 在另一实施方案中,本发明提供了具最高约14%(重量)溶剂含量的新溶剂合物形式的卡维地洛及其制备方法,其中所述溶剂为甲基乙基酮。 In another embodiment, the present invention provides a maximum of about 14% (by weight) solvent content new solvate forms of carvedilol and its preparation method, wherein the solvent is methyl ethyl ketone. 这些卡维地洛的水合物/溶剂合物可用作合成卡维地洛药物的中间体。 These carvedilol hydrate / solvate can be used as synthetic intermediates carvedilol drug.

结晶新形式卡维地洛的方法此中提供的新水合物/溶剂合物形式任选通过从一种溶剂或溶剂混合物沉淀出结晶固体物形式的卡维地洛来形成。 New hydrate crystalline form of carvedilol new methods provided herein / solvate form optionally via a solvent or solvent mixture from the precipitation of crystalline solids in the form of carvedilol to form. 本领域技术人员理解其它方法也可用于形成此中公开的水合物/溶剂合物形式。 Skilled in the art appreciate that other methods may also be used to form the hydrate / solvates form disclosed herein. 或者所述多晶型物可通过此中所公开方法的常规修改来形成。 Alternatively the polymorphs may be formed by modifying the conventional methods disclosed herein.

型III结晶卡维地洛的形成本发明的一个实施方案提供了一种制备型III结晶卡维地洛的方法,该方法包括下述步骤:形成含卡维地洛的溶剂溶液;和用水作反溶剂从所述溶剂溶液中沉淀型III结晶卡维地洛。 Type III crystalline carvedilol forming an embodiment of the present invention provides a process for preparing crystalline carvedilol Type III method, the method comprising the steps of: forming a solvent solution containing carvedilol; and water as anti-solvent from the solvent solution to precipitate the crystalline carvedilol Form III. 本发明提供了一种溶解步骤,其中水在溶解步骤中存在于溶剂溶液中。 The present invention provides a dissolution step, wherein in the step of dissolving water present in the solvent solution. 本发明也提供了一种沉淀步骤,其中在卡维地洛完全溶解于溶剂中后将水加入到溶液中。 The present invention also provides a precipitation step, after which the carvedilol is completely dissolved in a solvent of water was added to the solution.

为了形成含卡维地洛的溶剂溶液,可任选将卡维地洛在升高的温度下溶解于溶剂中。 In order to form a solvent solution containing carvedilol, carvedilol may optionally at elevated temperature to dissolve in the solvent. 优选的升高温度是约40℃-约90℃。 The preferred elevated temperature is from about 40 ℃ - about 90 ℃. 最优选所述升高的温度为约55℃。 Most preferably the elevated temperature is about 55 ℃. 或者,可将卡维地洛在环境温度下溶解于一种溶剂中。 Alternatively, the carvedilol at ambient temperature is dissolved in a solvent.

本发明的另一个实施方案通过将卡维地洛溶解于一种溶剂中,并通过加入一种反溶剂诱导产生结晶型III卡维地洛的沉淀,形成了含卡维地洛的溶剂溶液。 Another embodiment of the invention by the carvedilol is dissolved in a solvent and by adding an anti-solvent-induced precipitation of crystalline carvedilol III, forming a solvent solution containing carvedilol. 溶剂任选选自吡啶、二噁烷、异丙醇和氯仿。 Optional solvent selected from pyridine, dioxane, isopropanol, and chloroform. 反溶剂任选选自水和己烷。 Optional anti-solvent is selected from water and hexane.

本发明的再一个实施方案通过将卡维地洛溶解于一种有机溶剂和水中而形成含卡维地洛的溶剂溶液,并沉淀型III结晶卡维地洛。 Another one by the present invention will carvedilol is dissolved in an organic solvent and water to form a solvent solution containing carvedilol embodiment, and precipitation type III crystalline carvedilol. 在该实施方案中,所述有机溶剂任选为醇。 In this embodiment, the organic solvent is optionally an alcohol. 所述醇优选选自甲醇和乙醇。 The alcohol is preferably selected from methanol and ethanol. 或者,所述有机溶剂可选自吡啶、二噁烷、乙酸乙酯和四氢呋喃。 Alternatively, the organic solvent is selected from pyridine, dioxane, ethyl acetate and tetrahydrofuran.

本发明的另一可选实施方案提供了一种制备型III结晶卡维地洛的方法,该方法包括下面步骤:在升高的温度下干燥结晶卡维地洛、将结晶卡维地洛悬浮于一种溶液混合物中、加热溶液混合物直到结晶卡维地洛完全溶解、冷却溶液混合物和收集型III结晶卡维地洛。 Another alternative embodiment of the present invention provides crystalline carvedilol preparative method III, the method comprising the following steps: at elevated temperatures dry crystalline carvedilol carvedilol crystalline suspension in a mixture of a solution, the solution was heated mixture until completely dissolved crystalline carvedilol, the solution was cooled mixture and collecting crystalline carvedilol Form III.

任选所述干燥步骤通过在约50℃-约60℃的温度下加热结晶卡维地洛约6小时来进行。 Optionally, the drying step by about 50 ℃ - heated at a temperature of about 60 ℃ of crystalline carvedilol is performed for about 6 hours.

任选所述悬浮步骤可通过将结晶卡维地洛悬浮于乙酸乙酯∶水(150∶40)的溶液混合物中来进行。 Optionally, the suspension can be obtained by crystallization step carvedilol suspended in ethyl acetate: water (150:40) solution to the mixture.

任选所述加热步骤可通过在搅拌下将溶液混合物从约60℃加热到约70℃直到结晶卡维地洛完全溶解来进行。 Optionally, the heating step can be prepared by stirring the mixture solution was heated from about 60 ℃ to about 70 ℃ until complete dissolution of the crystalline carvedilol is performed.

任选所述冷却步骤可通过在搅拌下将溶液混合物冷却到约10℃约3小时的时间来进行。 Optionally, the cooling step can be obtained by stirring the solution mixture was cooled to about 10 ℃ about 3 hours to perform.

型IV结晶卡维地洛的形成本发明也提供了一种制备型IV结晶卡维地洛的方法,其包括形成含卡维地洛的溶剂溶液并通过加入“反溶剂”诱导产生型IV结晶卡维地洛沉淀的步骤。 Type IV crystalline carvedilol formation present invention also provides a crystalline carvedilol preparative method IV, which includes the formation of a solvent solution containing carvedilol and produce type IV crystallized by adding "anti-solvent" induction Carvedilol precipitation step. 在该实施方案中,溶剂任选选自甲乙酮和甲基异丁酮。 In this embodiment, the solvent is optionally selected from methyl ethyl ketone and methyl isobutyl ketone. 反溶剂任选选自环己烷和庚烷。 Optional anti-solvent is selected from cyclohexane and heptane.

为了形成型IV结晶卡维地洛,任选在低于环境温度到升高的温度下将卡维地洛溶解于溶剂中。 In order to form crystalline carvedilol type IV, optionally in the below ambient temperature to an elevated temperature of carvedilol dissolved in the solvent. 优选的温度为约10℃-约50℃。 The preferred temperature is about 10 ℃ - about 50 ℃. 最优选温度为环境温度。 The most preferred temperature is ambient temperature.

式V结晶卡维地洛的形成本发明也提供了一种制备型V结晶卡维地洛的方法,其包括形成含卡维地洛的溶剂溶液并通过冷却或加入“反溶剂”诱导产生型V结晶卡维地洛沉淀的步骤。 Formula V to form crystalline carvedilol present invention also provides a crystalline carvedilol preparative method for V, which includes the formation of a solvent solution containing carvedilol by cooling or adding "anti-solvent" induced type V crystallization step carvedilol precipitation. 在该实施方案中,溶剂任选选自包括甲乙酮的一组溶剂。 In this embodiment, the solvent is optionally selected from a group of solvents include methyl ethyl ketone. 反溶剂任选选自环己烷和己烷。 Optional anti-solvent is selected from cyclohexane and hexane.

为了形成型V结晶卡维地洛,任选在升高的温度下将卡维地洛溶解于溶剂溶液中。 In order to form a V-type crystalline carvedilol, optionally at elevated temperature carvedilol dissolved in a solvent solution. 优选的升高的温度为约10℃-约80℃。 The preferred elevated temperature is from about 10 ℃ - about 80 ℃. 最优选的升高的温度为约55℃。 Most preferred elevated temperature of about 55 ℃. 或者,可将卡维地洛在环境温度下溶解于溶剂溶液中。 Alternatively, the carvedilol at ambient temperature is dissolved in a solvent solution.

卡维地洛的新水合物和溶剂合物结晶形式本发明提供了称为型III、IV和V以及盐酸卡维地洛的新的卡维地洛结晶形式。 The new crystalline form hydrates and solvates of carvedilol The present invention provides a called type III, IV and V and the new crystalline form of carvedilol carvedilol hydrochloride. 这些形式可通过特征粉末X-射线衍射图和热曲线与卡维地洛的现有技术形式相区分以及相互区分。 These forms can be distinguished from each other and are distinguished by the characteristic X- ray powder diffraction pattern and thermal profile of the prior art in the form of carvedilol.

不同的结晶形式也可通过其各自的溶剂合状态表征。 Different crystalline forms may also be their respective engagement state characterized by the solvent. 在药物中最常见的溶剂合物为1∶1化学计量的那些溶剂合物。 In the most common drug solvates are those stoichiometric solvates 1:1. 偶尔也遇到混合的溶剂合物类型。 Occasionally encountered mixed solvate type. 当水或溶剂以化学计量比例结合到化合物的晶格中时,形成的分子加合物称为水合物或溶剂合物。 When water or solvent is in a stoichiometric ratio of the compound bound to the crystal lattice, the molecular adduct formation is called a hydrate or solvate thereof.

型III的结晶卡维地洛型III卡维地洛(“型III”)通过其X-射线衍射图表征,其峰在约8.40.2,9.30.2,11.60.2,13.20.2,13.50.2,14.20.2,15.30.2,15.80.2,17.40.2,18.40.2,19.40.2,20.60.2,21.40.2,22.00.2,26.50.2和27.60.2度2θ。 Type III, type III crystalline carvedilol carvedilol ("Type III"), through its X- ray diffraction pattern characterized by its peak at about 8.4 0.2,9.3 0.2,11.6 0.2,13.2 0.2,13.5 0.2,14.2 0.2,15.3 0.2,15.8 0.2,17.4 0.2,18.4 0.2,19.4 0.2,20.6 0.2,21.4 0.2,22.0 0.2,26.5 0.2 and 27.6 0.2 degrees 2θ. 型III的最具特征的峰在约8.40.2,17.40.2,和22.00.2度2θ。 The most characteristic peaks of Form III at about 8.4 0.2,17.4 0.2, and 22.0 0.2 degrees 2θ. 图1复制了其衍射图。 Figure 1 copy of its diffraction diagram.

图2显示了型IV的DTG热曲线。 Figure 2 shows the DTG thermal profile of Form IV. 型III的差示扫描量热法(DSC)热曲线显示出取决于样品和粒径的在100℃附近(96℃-110℃)的一个熔融峰。 Form III Differential scanning calorimetry (DSC) thermal curve shows the particle size depending on the sample and a melting peak near 100 ℃ (96 ℃ -110 ℃) of. 该熔融峰伴随着如通过热解重量分析(TGA)测得的约2%的干燥损失。 The melting peak accompanied by such analysis (TGA) as measured by thermogravimetric about 2% loss on drying. 通过卡尔费歇尔分析测得的样品中的水含量与由TGA获得的值高度一致,从而证实干燥损失是由于脱水并且表明该材料为a。 By Karl Fischer analysis measured water content of the sample is consistent with the value of the height obtained by TGA, thus confirming the loss on drying is due to dehydration and indicating that the material is a.

型IV结晶卡维地洛卡维地洛型IV(“型IV”)由X-射线衍射图表征,其峰在约11.90.2,14.20.2,15.70.2,16.50.2,17.70.2,18.30.2,19.20.2,19.60.2,21.70.2,22.20.2,23.90.2,24.20.2,24.90.2,27.40.2和28.20.2度2θ。 Type IV crystalline carvedilol carvedilol Luoka Wei type IV ("Type IV") by X- ray diffraction pattern characterized by its peak at about 11.9 0.2,14.2 0.2,15.7 0.2,16.5 0.2,17.7 0.2 , 18.3 0.2,19.2 0.2,19.6 0.2,21.7 0.2,22.2 0.2,23.9 0.2,24.2 0.2,24.9 0.2,27.4 0.2 and 28.2 0.2 degrees 2θ. 型IV的最具特征的峰在约11.90.2,14.20.2,18.30.2,19.20.2,21.70.2和24.2+0.2度2θ。 Type IV is the most characteristic peak at about 11.9 0.2,14.2 0.2,18.3 0.2,19.2 0.2,21.7 0.2 and 24.2 + 0.2 degrees 2θ. 图3复制了该衍射图。 Figure 3 copy of the diffraction pattern.

图4显示了型IV的DTG热曲线。 Figure 4 shows the DTG thermal profile of Form IV. 型IV的DSC热曲线显示了在约104℃的一个熔融峰。 The DSC thermal profile of Form IV at about 104 ℃ shows a melting peak.

型V结晶卡维地洛型V卡维地洛("型V")通过X-射线衍射图表征,其峰在约4.10.2,10.30.2,10.70.2,11.50.2,12.60.2,14.00.2,14.80.2,15.40.2,16.40.2,16.80.2,18.80.2,20.80.2,21.10.2,21.60.2和25.40.2度2θ。 Type V Type V crystalline carvedilol carvedilol ("Type V") by X- ray diffraction pattern characterized by its peak at about 4.1 0.2,10.3 0.2,10.7 0.2,11.5 0.2,12.6 0.2 , 14.0 0.2,14.8 0.2,15.4 0.2,16.4 0.2,16.8 0.2,18.8 0.2,20.8 0.2,21.1 0.2,21.6 0.2 and 25.4 0.2 degrees 2θ. 型V的最具特征的峰在约4.10.2,10.30.2,10.70.2和11.50.2度2θ。 The most characteristic peaks at approximately V-type 4.1 0.2,10.3 0.2,10.7 0.2 and 11.5 0.2 degrees 2θ. 图5复制了其衍射图。 5, the copy of its diffraction diagram.

型V的DTG热曲线显示于图6。 Type V, DTG thermal profile is shown in Figure 6. 型V的DSC热曲线显示在约67℃的溶剂解吸吸热,接着是重结晶和在115℃的熔融峰。 The DSC thermal profile of V-type display in a solvent desorption endotherm of about 67 ℃, followed by recrystallization and the melting peak at 115 ℃. 解吸吸热伴随着由TGA测得的约14%的干燥损失。 With desorption endotherm measured by TGA of about 14% loss on drying. 该特征与每分子卡维地洛一分子MEK的损失相符(计算的单MEK的化学计量值为15%)。 This feature is part of carvedilol loss per molecule MEK match (single MEK stoichiometric calculations is 15%).

盐酸卡维地洛水合物结晶的盐酸卡维地洛由在约6.50.2,10.20.2,10.40.2,14.20.2,14.70.2,15.80.2,16.40.2,17.70.2,20.00.2,21.50.2,21.90.2,22.20.2,22.90.2,25.20.2,25.30.2,27.20.2,27.40.2,28.20.2,28.60.2,29.60.2度2θ具有峰的X-射线衍射图所表征。 Carvedilol hydrochloride hydrate crystalline hydrochloride carvedilol by about 6.5 0.2,10.2 0.2,10.4 0.2,14.2 0.2,14.7 0.2,15.8 0.2,16.4 0.2,17.7 0.2,20.0 0.2,21.5 0.2,21.9 0.2,22.2 0.2,22.9 0.2,25.2 0.2,25.3 0.2,27.2 0.2,27.4 0.2,28.2 0.2,28.6 0.2,29.6 0.2 2θ with a peak The X- ray diffraction pattern characterized. 结晶盐酸卡维地洛的最具特征的峰在约6.50.2,10.20.2,10.40.2,15.80.2,16.40.2和22.20.2度2θ。 The most characteristic crystalline hydrochloride carvedilol peak at about 6.5 0.2,10.2 0.2,10.4 0.2,15.8 0.2,16.4 0.2 and 22.2 0.2 degrees 2θ. 其衍射图见图7。 Diffraction shown in Figure 7.

盐酸卡维地洛的DTG热曲线显示了两个吸热峰。 Carvedilol hydrochloride DTG thermal profile shows two endothermic peaks. 在118℃的峰是脱水峰。 Peak is at 118 ℃ dehydration peak. 在135℃的第二个吸热峰是由于样品熔化。 At 135 ℃ second endothermic peak is due to sample melting. 该样品的LOD为3.5%。 LOD of the sample was 3.5%. 卡尔费歇尔分析测得的该样品的水含量为3.7%。 Karl Fischer analysis measured water content of the sample was 3.7%. 因此卡尔费歇尔分析与LOD值一致,证实了该样品中水合物的存在。 So Karl Fischer analysis and LOD values match, the samples confirmed the presence of hydrates. 盐酸卡维地洛一水合物的预期值是3.9%。 The expected value of carvedilol hydrochloride monohydrate is 3.9%.

含卡维地洛的药用组合物按照另一方面,本发明涉及含一种或多种此中公开的新晶形卡维地洛和至少一种药学上可接受的赋形剂的药用组合物。 Pharmaceutical compositions containing carvedilol According to another aspect, the invention relates to contain one or more of which open new crystalline carvedilol acceptable pharmaceutical excipients and at least one pharmaceutical composition thereof. 这种药用组合物可以一种剂型对哺乳动物患者给药。 Such pharmaceutical compositions may be administered one dosage form of a mammalian patient.

所述剂型可包含一种或多种新的卡维地洛形式,或者可包含一种或多种作为组合物一部分的新形式的卡维地洛。 The dosage form may contain one or more new forms of carvedilol, or may contain one or more as part of a new form of the composition of carvedilol. 无论是以纯形式还是以组合物形式给药,卡维地洛都可以是粉末、颗粒、聚集体或任何其它固体形式。 Either in pure form or in the form of a composition administered carvedilol can be a powder, granules, aggregates or any other solid form. 本发明的组合物包括片剂组合物。 Compositions of the invention include tablets compositions. 片剂组合物可根据所用的制片方法、所需的释放速率和其它因素具有几种或许多组分。 The tablet composition may be used in the method according to the producer, the desired release rate and other factors have several or many of the components. 例如,本发明的组合物可包含稀释剂诸如纤维素源材料如粉末纤维素、微晶纤维素、超细纤维素、甲基纤维素、乙基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素盐以及其它取代和未取代纤维素;淀粉;预凝胶化淀粉;无机稀释剂诸如碳酸钙和二磷酸钙以及其它本领域技术人员熟知的稀释剂。 For example, the compositions of the present invention may contain diluents such as cellulose source material, such as powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted cellulose; starch; pregelatinized starch; inorganic diluents such as calcium carbonate and calcium diphosphate and other skilled in the art known diluent. 其它适用的稀释剂包括蜡、糖(如乳糖)和糖醇象甘露糖醇和山梨糖醇,丙烯酸酯聚合物和共聚物,以及果胶、糊精和明胶。 Other suitable diluents include waxes, sugars (e.g., lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.

本发明拟采用的其它赋形剂包括粘合剂诸如阿拉伯胶、预凝胶化淀粉、藻酸钠、葡萄糖和其它用于干湿制粒和直接压片方法的粘合剂;崩解剂诸如淀粉羟基乙酸钠、聚乙烯聚吡咯烷酮、低取代羟丙基纤维素等;润滑剂诸如硬脂酸镁和硬脂酸钙和硬脂酰基富马酸钠;调味剂;甜味剂、防腐剂;药学上可接受的染料和助流剂诸如二氧化硅。 Other excipients present invention is intended to be employed include a binder such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders wet and dry granulation and direct compression method used; disintegrating agents such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and the like; a lubricant such as magnesium stearate and calcium stearate and sodium stearyl fumarate; flavoring agents; sweeteners, preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

剂型可以是适合于经口、颊、非肠道、眼、直肠和经皮途径对患者给药。 Dosage form may be suitable for oral, buccal, parenteral, ophthalmic, rectal and transdermal routes of administration to the patient. 口服剂型包括片剂、丸剂、胶囊、锭剂、小袋、悬浮液、粉剂、锭剂、酏剂等。 Oral dosage forms include tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like. 此中公开的卡维地洛的新形式也可以作为通过其它途径给药的栓剂、眼膏和悬浮剂以及非肠道用悬浮剂给药。 New forms disclosed herein carvedilol can also be administered by other routes as suppositories, ointments and suspensions, and parenteral suspensions administration. 本发明的卡维地洛形式的最优选给药途径为经口给药。 Carvedilol in the form of the most preferred route of administration of the invention is administered orally.

胶囊剂包含可涂覆明胶的胶囊中的固体组合物。 Capsules may be coated with gelatin capsules containing the solid composition. 片剂和粉末也可用肠溶衣包覆。 Tablets and powders may also be coated with an enteric coating. 肠溶衣包覆的粉末形式可具有包衣,所述包衣包括邻苯二甲酸纤维素乙酸酯、羟丙基甲基纤维素邻苯二甲酸酯、聚乙烯醇邻苯二甲酸酯、羧甲基乙基纤维素、苯乙烯和马来酸的共聚物、甲基丙烯酸和甲基丙烯酸甲酯的共聚物和类似材料,如果需要,它们可连同适合的增塑剂和/或补充剂一起使用。 Enteric-coated powder forms may have a coating, said coating comprising cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalate ester, carboxymethyl ethyl cellulose, copolymers of styrene and maleic acid, methacrylic acid and methyl methacrylate copolymers and the like, if desired, they may, together with suitable plasticizers and / or used with supplements. 包衣片剂可在片剂的表面具有一层包衣或者可以是由具肠溶衣的粉末或颗粒组成的片剂。 Coated tablet may have a coating layer on the surface of the tablet or may be a tablet consisting of a powder or granules with an enteric coating composition.

目前的卡维地洛商品形式是3.125mg、6.25mg、12.5mg和25mg片剂,其包括下述非活性成分:胶体二氧化硅、聚乙烯聚吡咯烷酮、羟丙基甲基纤维素、乳糖、硬脂酸镁、聚乙二醇、聚山梨醇酯八十、聚维酮、蔗糖和二氧化钛。 The current form of carvedilol commodity 3.125mg, 6.25mg, 12.5mg and 25mg tablets, which includes the following inactive ingredients: colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, polysorbate eighty, povidone, sucrose, and titanium dioxide.

本发明的各种实施方案的功能和优点可从下面的实施例更全面地理解。 Features and advantages of the various embodiments of the present invention can be more fully understood from the following examples. 下面的实施例将用于说明本发明的益处,但是并不例证本发明的整个范围。 The following examples serve to illustrate the benefits of the invention, but not the entire scope of the present invention is exemplified.

将得到的材料在乙酸乙酯(50ml)和含5%碳酸钠的水(20ml)中重新打浆直到pH达到7.5。 The resulting material was partitioned between ethyl acetate (50ml) and water containing 5% sodium carbonate (20ml) re-pulping until the pH reaches 7.5. 分离有机相并经硫酸钠干燥。 Organic phase was separated and dried over sodium sulfate. 将干燥的溶液浓缩成浑浊溶液并彻夜冷却到约4℃。 The dried solution was concentrated to a turbid solution and cooled overnight to about 4 ℃. 通过过滤分离沉淀的卡维地洛并从异丙醇重结晶。 The precipitate was isolated by filtration of carvedilol and recrystallized from isopropanol.

实施例2在净条件下卡维地洛的制备将2-(2-甲氧基苯氧基)乙胺(III)(4.89g)加热到约100℃,此后分部分加入4-(环氧乙烷-2-基甲氧基)-9H-咔唑(II)(3.31g)。 Example 2 In clear conditions for preparing carvedilol 2- (2-methoxyphenoxy) ethylamine (III) (4.89g) was heated to about 100 ℃, after which sub-section 4- (epoxy ethane-2-ylmethoxy) -9H- carbazole (II) (3.31g). 约20分钟后,将反应混合物冷却到约70℃,然后加入水(25ml)和乙酸乙酯(15ml)。 After about 20 minutes, the reaction mixture was cooled to about 70 ℃, then water (25ml) and ethyl acetate (15ml). 然后将该两相混合物的pH用2N盐酸调节到5。 The two-phase mixture is then pH adjusted to 5 with 2N hydrochloric acid. 将所形成的盐酸卡维地洛水合物固体物过滤、用水(20ml)洗涤并接着用乙酸乙酯(15ml)洗涤。 The formed hydrochloride hydrate carvedilol solid was filtered, washed, and then (15ml) washed with ethyl acetate washed with water (20ml).

将得到的材料在乙酸乙酯(50ml)和含5%碳酸钠的水(20ml)中重新打浆直到pH达到7.5。 The resulting material was partitioned between ethyl acetate (50ml) and water containing 5% sodium carbonate (20ml) re-pulping until the pH reaches 7.5. 分离有机相并经硫酸钠干燥。 Organic phase was separated and dried over sodium sulfate. 将干燥的溶液浓缩成浑浊溶液并彻夜冷却到约4℃。 The dried solution was concentrated to a turbid solution and cooled overnight to about 4 ℃. 通过过滤分离沉淀的卡维地洛并从甲醇重结晶。 The precipitate was isolated by filtration of carvedilol and recrystallized from methanol.

实施例3制备型I卡维地洛的方法按照实施例3的步骤制备结晶卡维地洛。 Example 3 Preparation of type I carvedilol following the procedure of Example 3 Preparation of crystalline carvedilol. 然后将结晶物质在50-60℃干燥6小时。 The crystalline material is then dried at 50-60 ℃ 6 hours. 将干燥后的结晶卡维地洛(220g卡维地洛)溶解于2200ml乙酸乙酯中。 The dried crystalline carvedilol (220g carvedilol) 2200ml dissolved in ethyl acetate. 在搅拌下将乙酸乙酯溶液加热到77℃直到固体物完全溶解。 The ethyl acetate solution was under stirring heated to 77 ℃ until completely dissolved solids. 然后在搅拌下将乙酸乙酯溶液用15分钟的时间冷却到约50℃。 Then ethyl acetate solution under stirring over 15 minutes was cooled to about 50 ℃. 将冷却后的溶液搅拌48小时。 The cooled solution was stirred for 48 hours. 然后在搅拌下用0.75小时将溶液冷却到10℃。 Then under stirring 0.75 hours the solution was cooled to 10 ℃. 再将悬浮液搅拌24小时后,过滤产物。 The suspension was then stirred for 24 hours, the product was filtered. 获得型I的纯结晶卡维地洛(170g)。 Obtain pure crystalline Form I Carvedilol (170g).

实施例4型II结晶卡维地洛的制备通过使卡维地洛从表I所列溶剂中结晶来形成型II结晶卡维地洛。 Example 4 Preparation of type II crystalline carvedilol carvedilol by crystallization from solvents listed in Table I, type II crystals formed carvedilol. 通过形成溶液并加热达到透明溶液(通常接近于溶剂沸点温度)来使卡维地洛结晶。 And heated to form a solution reached through a transparent solution (usually close to the boiling temperature of the solvent) to make carvedilol crystals. 然后将溶液冷却到环境温度并过滤沉淀物而形成型II的卡维地洛。 The solution was then cooled to ambient temperature and the precipitate was filtered to form type II carvedilol.

表I Table I

实施例5通过在-20℃过滤制备型II结晶卡维地洛通过使卡维地洛从表II所列溶剂中结晶来形成型II的结晶卡维地洛。 Example 5 was prepared by filtering at -20 ℃ type II crystalline carvedilol carvedilol by forming solvent crystallization listed in Table II from type II crystalline carvedilol. 通过形成加热至大约溶剂沸点温度的卡维地洛溶液来使卡维地洛结晶。 By forming the boiling temperature of the solvent is heated to about carvedilol carvedilol solution to make crystals. 然后将溶液冷却到-20℃,过滤沉淀物并干燥而得到卡维地洛型II。 The solution was then cooled to -20 ℃, the precipitate was filtered and dried to obtain carvedilol type II.

表2 Table 2

实施例6在溶剂混合物中制备结晶卡维地洛型II Example 6 was prepared in a solvent mixture of type II crystalline carvedilol

通过使卡维地洛从表III所列溶剂混合物中结晶来制备结晶卡维地洛型II。 By carvedilol to prepare crystalline carvedilol Form II crystal from the solvent mixture listed in Table III. 通过形成加热至成为透明溶液(通常接近于溶剂混合物的沸点温度)的卡维地洛溶液来使卡维地洛结晶。 By forming the heating to a transparent solution (usually close to the boiling temperature of the solvent mixture) of carvedilol carvedilol solution to make crystals. 然后将溶液冷却到环境温度并过滤。 The solution was then cooled to ambient temperature and filtered. 通过过滤收集结晶并干燥而得到卡维地洛型II。 The crystals were collected by filtration and dried to obtain carvedilol type II.

表III Table III

实施例7结晶卡维地洛型III的制备:通过在55℃水浴中、在搅拌下加热而将卡维地洛(4g)溶解于45mL 96%乙醇和4%水的混合物中。 Example 7 Preparation of crystalline carvedilol Form III: through a water bath at 55 ℃, heating and stirring the carvedilol (4g) was dissolved in 45mL 96% mixture of ethanol and 4% water. 将溶液冷却并在没有搅拌下置于室温下约14小时,将结晶通过布氏漏斗过滤、用约10ml冷(4℃)的96%乙醇洗涤两次并于室温下在干燥器中干燥(连接到空气泵)直到恒重而获得卡维地洛型III。 The solution was cooled and left at room temperature without stirring for about 14 hours, the crystals filtered through a Buchner funnel, with about 10ml of cold (4 ℃) was washed twice in 96% ethanol at room temperature and dried in a desiccator (connected to air pump) until constant weight was obtained carvedilol type III.

实施例8结晶卡维地洛型III的制备通过在55℃水浴中、在搅拌下加热而将卡维地洛(4g)溶解于195mL水/甲醇(分别为1∶3的比率)的混合物中。 Preparation Example 8 crystalline carvedilol Form III by 55 ℃ water bath, stirring heated to carvedilol (4g) dissolved in 195mL of water / methanol (1:3 ratio, respectively) is a mixture of . 将溶液冷却到室温并在没有搅拌下置于室温下约15小时,将结晶通过布氏漏斗过滤、并在室温下在干燥器中干燥(连接到空气泵)直到恒重而获得卡维地洛型III。 The solution was cooled to room temperature and left at room temperature without stirring for about 15 hours, the crystals filtered through a Buchner funnel, and dried at room temperature in a desiccator (connected to air pump) until constant weight to obtain carvedilol type III.

实施例9结晶卡维地洛型III的制备通过在室温下搅拌将卡维地洛(4g)溶解于39mL吡啶中。 Example 9 Preparation of crystalline carvedilol Form III by stirring at room temperature for Carvedilol (4g) was dissolved in 39mL of pyridine. 然后逐滴加入70mL水直到开始结晶。 70mL of water was then added dropwise until crystallization began. 在没有搅拌下在室温下将溶液放置约80小时,然后将结晶通过布氏漏斗过滤,并在室温下在干燥器中干燥(连接到空气泵)直到恒重而获得卡维地洛型III。 Without stirring the solution at room temperature for about 80 hours, and then through a Buchner funnel and the crystalline carvedilol Form III obtained by filtration, and dried at room temperature in a desiccator (connected to air pump) until constant weight.

实施例10结晶卡维地洛型III的制备在室温下将卡维地洛(4g)溶解于76mL二噁烷中,将110mL水分成约10mL的部分加入到经搅拌的溶液中。 Example 10 Preparation of crystalline carvedilol Form III at room temperature Carvedilol (4g) was dissolved in 76mL dioxane, at approximately 10mL to 110mL of water was added to the stirred part of the solution. 将所得溶液在没有搅拌下在室温下放置约15小时,然后将形成的结晶沉淀通过布氏漏斗过滤,并在室温下在干燥器中干燥(连接到空气泵)直到恒重而获得与卡维地洛型II相混合的卡维地洛型III。 The resulting solution was allowed to stand without stirring at room temperature for about 15 hours, and the resulting crystalline precipitate was filtered through a Buchner funnel, and dried at room temperature in a desiccator (connected to air pump) until constant weight was obtained with carvedilol type II mixed carvedilol carvedilol type III.

实施例11结晶卡维地洛型III的制备通过在搅拌下、在55℃水浴中加热将卡维地洛(4g)溶解于267mL分别为1∶1.4比率的二噁烷/水中。 Example 11 Preparation of crystalline carvedilol Form III by stirring and heated in a water bath at 55 ℃ in the carvedilol (4g) were dissolved in 267mL 1:1.4 ratio of dioxane / water. 将所得溶液在没有搅拌下在室温下放置约15小时,然后将结晶通过布氏漏斗过滤,并在干燥器中干燥(连接到空气泵)直到恒重而获得与卡维地洛型II混合的卡维地洛型III。 The resulting solution was left for about 15 hours without stirring at room temperature, and then crystallized by Buchner filtration, and dried in a desiccator (connected to air pump) until constant weight was obtained by mixing with carvedilol Form II Carvedilol type III.

实施例12结晶卡维地洛型III的制备通过在搅拌下、在55℃水浴中加热将卡维地洛(4g)溶解于180mL 1∶1比率的己烷/IPA中。 Example 12 Preparation of crystalline carvedilol Form III by stirring and heated in a water bath at 55 ℃ in the carvedilol (4g) was dissolved in 180mL 1:1 ratio of hexane / IPA in. 将溶液在没有搅拌下在室温下放置约15小时,然后将得到的结晶通过布氏漏斗过滤,并在室温下在干燥器中干燥(连接到空气泵)直到恒重而获得卡维地洛型III。 The solution was allowed to stand without stirring for about 15 hours at room temperature, and then the resulting crystals through a Buchner funnel and filtered to obtain carvedilol type, and at room temperature in a desiccator (connected to air pump) until constant weight III.

实施例13制备卡维地洛型III的方法将卡维地洛(40g)溶解于150ml乙醇和40ml水中。 The method of Example 13 was prepared carvedilol Form III will carvedilol (40g) was dissolved in 150ml of ethanol and 40ml water. 搅拌下将溶液加热到60-70℃直到固体物完全溶解。 The solution was heated with stirring to 60-70 ℃ until the solids were completely dissolved. 然后在搅拌下将溶液用3小时冷却到10℃。 The solution was then stirred for 3 hours cooled to 10 ℃. 再将悬浮液搅拌2.75小时后,将产物过滤。 The suspension was then stirred for 2.75 hours, the product was filtered. 获得纯的卡维地洛型III(35g)。 Obtain pure carvedilol type III (35g).

实施例14结晶卡维地洛型IV的制备通过在室温下搅拌将卡维地洛(1g)溶解于35ml甲乙酮中,并逐滴加入202mL环己烷。 Example 14 Preparation of crystalline carvedilol Form IV by stirring carvedilol (1g) was dissolved in 35ml of methyl ethyl ketone at room temperature, and added dropwise 202mL cyclohexane. 将溶液在没有搅拌下置于室温下约15小时,然后将得到的结晶通过布氏漏斗过滤,并在室温下在干燥器中干燥(连接到空气泵)直到恒重而获得卡维地洛型IV。 The solution was left at room temperature for about 15 hours in the absence of stirring, and then the resulting crystals were obtained carvedilol type filtration through a Buchner funnel, and dried at room temperature in a desiccator (connected to air pump) until constant weight IV.

实施例15结晶卡维地洛型V的制备通过在室温下搅拌将卡维地洛(1g)溶解于70ml甲乙酮中,并逐滴加入138mL己烷。 Example 15 Preparation of crystalline carvedilol type V by stirring carvedilol (1g) was dissolved in 70ml of methyl ethyl ketone at room temperature, and added dropwise 138mL hexane. 在没有搅拌下将溶液置于室温下约15小时,然后将得到的结晶通过布氏漏斗过滤,并在室温下在干燥器中干燥(连接到空气泵)直到恒重而获得卡维地洛型V。 Without stirring and the solution was left at room temperature for about 15 hours, and then the resulting crystals were filtered through a Buchner funnel, and dried at room temperature (connected to air pump) until constant weight to obtain carvedilol in the dryer type V.

实施例16结晶卡维地洛型V的制备通过在搅拌下、在55℃水浴中加热将卡维地洛(2g)溶解于45mL甲乙酮中,然后将溶液冷却,并在没有搅拌下在室温下放置约14小时,将结晶通过布氏漏斗过滤,并在室温下在干燥器中干燥(连接到空气泵)直到恒重而获得卡维地洛型V。 Example 16 Preparation of crystalline carvedilol Los type V by stirring, heating carvedilol (2g) was dissolved in 45mL of methyl ethyl ketone at 55 ℃ water bath, and then the solution was cooled, and at room temperature without stirring to stand for about 14 hours, the crystals filtered through a Buchner funnel, and dried at room temperature in a desiccator (connected to air pump) until constant weight to obtain carvedilol type V.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
CN101389605B31 Aug 200620 Apr 2011安国药品株式会社Process for the preparation of highly optical pure carvedilol
CN102190613A *14 Mar 201021 Sep 2011浙江华海药业股份有限公司Method for preparing carvedilol
Classifications
International ClassificationA61P9/12, A61K31/403, A61K31/40, C07D209/88, A61P9/10, A61P9/00, A61P43/00, C07D209/82
Cooperative ClassificationC07D209/88
European ClassificationC07D209/88
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