Novel forms of pravastatin sodium

• US 20010041809A1
• Filed: 12/14/2000
• Published: 11/15/2001
• Est. Priority Date: 12/14/1999
• Status: Active Grant

• Current Assignee: Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag (Teva Pharmaceutical Industries Limited)
• Original Assignee: Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag (Teva Pharmaceutical Industries Limited)
• Inventors: Aronhime, Judith, Szabo, Csaba, Kéri, Vilmos, Nagyne, Edit Arvai
• Granted Patent: US 7,001,919 B2
• Time in Patent Office: Days
• US Class Current: 560/256
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 2602/28 Hydrogenated naphthalenes
• CPC Class Codes: C07C 67/52 by change in the physical state, e.g. crystallisation
• CPC Class Codes: C07C 69/33 esterified with hydroxy compounds having more than three hydroxy groups esters of sugars C07H

Abstract

New polymorphic forms of pravastatin sodium are provided. Each of the new forms is selectively obtained by crystallization from different solvent systems, each solvent system having a protic component, and by controlling the rate of crystallization through temperature. The new polymorphic forms are suitable for use as active substances of pharmaceutical dosage forms for reduction of serum cholesterol levels in the bloodstream.

Claims

1. Crystalline pravastatin sodium and hydrates thereof having an X-ray powder diffraction pattern comprising characteristic peaks at 3.9, 4.5, 6.2, 7.2, and 20.0±

0.2 degrees measured at reflection angle 2θ

.

2. Crystalline pravastatin sodium of

claim 1

wherein the X-ray powder diffraction pattern further comprises peaks at 8.6, 9.2, 10.0, 11.6, 12.0, and 17.0±

0.2 degrees measured at reflection angle 2θ

.

5. A pharmaceutical composition comprising the crystalline polymorph of

claim 1

and a pharmaceutically acceptable carrier.

6. A method for treating a patient suffering from atherosclerosis or hypercholesteremia by administering a therapeutically effective amount of the pharmaceutical composition of

claim 5

.

3. Crystalline pravastatin sodium and hydrates thereof having an infrared spectrum obtained in Nujol Moll comprising absorption bands at 826, 842, 864, 1156, 1184 and 1576±

4 cm<sup>−

1</sup>.

4. Crystalline pravastatin sodium of

claim 3

wherein the infrared spectrum further comprises absorption bands at 686, 842, 864, 917, 939, 965, 1013, 1040, 1092, 1111, 1156, 1265, 1310, 1330, and 1726±

2 cm<sup>−

1</sup>.

11. Crystalline pravastatin sodium of

claim 3

wherein the infrared spectrum further comprises absorption bands at 614, 692, 739, 824, 842, 854, 868, 901, 914, 936, 965, 1011, 1028, 1039, 1072, 1091, 1111, 1129, 1185, 1232, 1245, 1318, 1711 and 1730±

2 cm<sup>−

1</sup>.

7. Pravastatin sodium Form A.

8. Crystalline pravastatin sodium and hydrates thereof having an X-ray powder diffraction pattern comprising characteristic peaks at 3.6, 6.1 and 6.6 ±

0.2 degrees measured at reflection angle 2θ

.

9. Crystalline pravastatin sodium of

claim 8

wherein the X-ray powder diffraction pattern further comprises peaks at 9.0, 9.6, 10.1, 16.4, 16.8 and 18.6±

0.2 degrees measured at reflection angle 2θ

.

12. A pharmaceutical composition comprising the crystalline polymorph of

claim 8

and a pharmaceutically acceptable carrier.

13. A method for treating a patient suffering from atherosclerosis or hypercholesteremia by administering a therapeutically effective amount of the pharmaceutical composition of

claim 12

.

10. Crystalline pravastatin sodium and hydrates thereof having an infrared spectrum obtained in Nujol Moll comprising absorption bands at 1149, 1161, 1563 and 1606±

2 cm<sup>−

1</sup>.

14. Pravastatin sodium Form B.

15. Crystalline pravastatin sodium and hydrates thereof having an X-ray powder diffraction pattern comprising characteristic peaks at 13.0, 15.5, 16.0 and 21.0±

0.2 degrees measured at reflection angle 2θ

.

16. Crystalline pravastatin sodium of

claim 15

wherein the X-ray powder diffraction pattern further comprises peaks at 4.8, 7.6, 8.7, 10.0, 11.8, 12.4, 17.4, 17.9, 18.4, 19.7, 21.8 and 22.8±

0.2 degrees measured at reflection angle 2θ

.

19. A pharmaceutical composition comprising the crystalline pravastatin sodium of

claim 15

and a pharmaceutically acceptable carrier.

20. A method for treating a patient suffering from atherosclerosis or hypercholesteremia by administering a therapeutically effective amount of the pharmaceutical composition of

claim 19

.

17. Crystalline pravastatin sodium and hydrates thereof having an infrared spectrum obtained in Nujol Moll comprising absorption bands at 829, 851, 1078, 1090, 1567, and 1728 ±

2 cm<sup>−

1</sup>.

18. Crystalline pravastatin sodium of

claim 17

wherein the infrared spectrum further comprises absorption bands at 742, 870, 926, 940, 964, 1013, 1038, 1146, 1166, 1174, 1194, 1257, 1268, 1313 and 1328±

2 cm<sup>−

1</sup>.

21. Pravastatin sodium Form C.

22. Crystalline pravastatin sodium and hydrates thereof having an X-ray powder diffraction pattern comprising characteristic peaks at 6.3 and 9.8±

0.2 degrees measured at reflection angle 2θ

.

23. Crystalline pravastatin sodium of

claim 22

wherein the X-ray powder diffraction pattern further comprises peaks at 3.6 and 17.1±

0.2 degrees measured at reflection angle 2θ

.

26. A pharmaceutical composition comprising the crystalline pravastatin sodium of

claim 22

and a pharmaceutically acceptable carrier.

27. A method for treating a patient suffering from atherosclerosis or hypercholesteremia by administering a therapeutically effective amount of the pharmaceutical composition of

claim 26

.

24. Crystalline pravastatin sodium and hydrates thereof having an infrared spectrum obtained in Nujol Moll comprising absorption bands at 824, 842, 854, 1157, 1186, 1566, and 1606±

2 cm<sup>−

1</sup>.

25. Crystalline pravastatin sodium of

claim 24

wherein the infrared spectrum further comprises absorption bands at 854, 914, 939, 965, 1013, 1041, 1079, 1091, 1266, and 1728±

2 cm<sup>−

1</sup>.

28. Pravastatin sodium Form D.

29. Crystalline pravastatin sodium and hydrates thereof having an X-ray powder diffraction pattern comprising characteristic peaks at 4.6, 10.3, 12.1, and 16.6±

0.2 degrees measured at reflection angle 2θ

.

30. Crystalline pravastatin sodium of

claim 29

wherein the X-ray powder diffraction pattern further comprises peaks at 9.2, 11.2, 18.3 and 20.6±

0.2 degrees measured at reflection angle 2θ

.

33. A pharmaceutical composition comprising the crystalline pravastatin sodium of

claim 29

and a pharmaceutically acceptable carrier.

34. A method for treating a patient suffering from atherosclerosis or hypercholesteremia by administering a therapeutically effective amount of the pharmaceutical composition of

claim 33

.

31. Crystalline pravastatin sodium and hydrates thereof having an infrared spectrum obtained in Nujol Moll comprising absorption bands at 1016, 1043, 1158, 1179, 1573 and 1727±

2 cm<sup>−

1</sup>.

32. Crystalline pravastatin sodium of

claim 31

wherein the infrared spectrum further comprises absorption bands at 781, 829, 853, 939, 964, 1078, 1266, 1300, 1329 and 1401±

2 cm<sup>−

1</sup>.

35. Pravastatin sodium Form E.

36. Amorphous pravastatin sodium and hydrates thereof having an X-ray powder diffraction pattern comprising a characteristic peak at 4.6±

0.2 degrees measured at reflection angle 2θ

.

39. A pharmaceutical composition comprising the amorphous pravastatin sodium of

claim 36

and a pharmaceutically acceptable carrier.

41. A method for treating a patient suffering from atherosclerosis or hypercholesteremia by administering a therapeutically effective amount of the pharmaceutical composition of

claim 39

.

37. Amorphous pravastatin sodium and hydrates thereof having an infrared spectrum obtained in Nujol Moll comprising absorption bands at 1157, 1181, 1576, and 1727±

2 cm<sup>−

1</sup>.

38. Amorphous pravastatin sodium of

claim 37

wherein the infrared spectrum further comprises absorption bands at 781, 829, 853, 939, 964, 1016, 1043, 1079, 1265, 1300, 1330 and 1400±

2 cm<sup>−

1</sup>.

40. A pharmaceutical composition comprising amorphous pravastatin sodium and a pharmaceutically acceptable carrier.

42. Pravastatin sodium Form F.

43. Amorphous pravastatin.

44. Crystalline pravastatin sodium and hydrates thereof having an X-ray powder diffraction pattern comprising characteristic peak at 4.5, 9.2, 10.0, 12.2, 16.0, 16.5, 17.6, 18.6, 19.5, 20.5 and 22.8±

0.2 degrees measured at reflection angle 2θ

.

45. A pharmaceutical composition comprising the crystalline pravastatin sodium of

claim 44

and a pharmaceutically acceptable carrier.

46. A method for treating a patient suffering from atherosclerosis or hypercholesteremia by administering a therapeutically effective amount of the pharmaceutical composition of

claim 45

.

47. Pravastatin sodium Form G.

48. Crystalline pravastatin sodium and hydrates thereof having an X-ray powder diffraction pattern comprising characteristic peaks at 3.5, 5.9, 9.0, 10.1 and 17.0±

0.2 degrees measured at reflection angle 2θ

.

49. Crystalline pravastatin sodium of

claim 48

wherein the X-ray powder diffraction pattern further comprises peaks at 11.7, 12.1, 14.7, 19.0, 19.9, 20.6, 21.8 and 22.9±

0.2 degrees measured at reflection angle 2θ

.

50. A pharmaceutical composition comprising the crystalline pravastatin sodium of

claim 48

and a pharmaceutically acceptable carrier.

51. A method for treating a patient suffering from atherosclerosis or hypercholesteremia by administering a therapeutically effective amount of the pharmaceutical composition of

claim 50

.

52. Pravastatin sodium Form H.

55. A pharmaceutical composition comprising the crystalline pravastatin sodium of

claim 52

and a pharmaceutically acceptable carrier.

53. Crystalline pravastatin sodium and hydrates thereof having an X-ray powder diffraction pattern comprising characteristic peaks at 3.5, 5.9, 8.9, 10.1, 17.6, 18.8 and 20.8±

0.2 degrees measured at reflection angle 2θ

.

54. Crystalline pravastatin sodium of

claim 53

wherein the X-ray powder diffraction pattern further comprises peaks at 6.8, 11.7, 12.3, 13.3, 14.8, 20.0 and 22.9±

0.2 degrees measured at reflection angle 2θ

.

56. A method for treating a patient suffering from atherosclerosis or hypercholesteremia by administering a therapeutically effective amount of the pharmaceutical composition of

claim 53

.

60. A pharmaceutical composition comprising the crystalline pravastatin sodium of

claim 56

and a pharmaceutically acceptable carrier.

57. Pravastatin sodium Form H1.

58. Crystalline pravastatin sodium and hydrates thereof having an X-ray powder diffraction pattern comprising characteristic peaks at 4.4, 5.2, 5.8, 6.5, 13.2, and 14.0±

0.2 degrees measured at reflection angle 2θ

.

59. Crystalline pravastatin sodium of

claim 58

wherein the X-ray powder diffraction pattern further comprises peaks at 7.5, 8.3, 9.8, 10.2, 11.2, 16.5, 17.5, 18.3, 18.6, 19.5, 20.5, 21.5 and 23.0±

0.2 degrees measured at reflection angle 2θ

.

61. A method for treating a patient suffering from atherosclerosis or hypercholesteremia by administering a therapeutically effective amount of the pharmaceutical composition of

claim 58

.

62. Pravastatin sodium Form I.

65. A pharmaceutical composition comprising the crystalline pravastatin sodium of

claim 62

and a pharmaceutically acceptable carrier.

63. Crystalline pravastatin sodium and hydrates thereof having an X-ray powder diffraction pattern comprising characteristic peaks at 3.8, 6.0, and 16.3±

0.2 degrees measured at reflection angle 2θ

.

64. Crystalline pravastatin sodium of

claim 63

wherein the X-ray powder diffraction pattern further comprises peaks at 3.3, 6.8, 7.5, 8.8, 9.3, 10.2, 11.2, 11.7, 13.5, 13.9, 14.5, 15.6, 17.7, 18.1, 18.7, 19.5, 20.0, 20.3, 21.7, 22.3, 24.2, and 26.1±

0.2 degrees measured at reflection angle 2θ

.

66. A method for treating a patient suffering from atherosclerosis or hypercholesteremia by administering a therapeutically effective amount of the pharmaceutical composition of

claim 63

.

67. Pravastatin sodium Form J.

68. Crystalline pravastatin sodium and hydrates thereof having an X-ray powder diffraction pattern comprising a broad peak between 15 and 25±

0.2 degrees measured at reflection angle 2θ

.

69. A pharmaceutical composition comprising the crystalline pravastatin sodium of

claim 68

and a pharmaceutically acceptable carrier.

70. A method for treating a patient suffering from atherosclerosis or hypercholesteremia by administering a therapeutically effective amount of the pharmaceutical composition of

claim 68

.

71. Pravastatin sodium Form K.

72. Crystalline pravastatin sodium and hydrates thereof having an X-ray powder diffraction pattern comprising characteristic peaks at 16.6, 17.6, and 18.5±

0.2 degrees measured at reflection angle 2θ

.

73. Crystalline pravastatin sodium of

claim 72

wherein the X-ray powder diffraction pattern further comprises peaks at 4.5, 5.0, 9.0, 10.1, 12.3, 13.4, 15.0, 19.5, 20.2, and 22.7±

0.2 degrees measured at reflection angle 2θ

.

74. A pharmaceutical composition comprising the crystalline pravastatin sodium of

claim 72

and a pharmaceutically acceptable carrier.

75. A method for treating a patient suffering from atherosclerosis or hypercholesteremia by administering a therapeutically effective amount of the pharmaceutical composition of

claim 72

.

76. Pravastatin sodium Form L.

77. A process for preparing pravastatin sodium Form A comprising the steps of:

(a) dissolving any solid form of pravastatin sodium in a protic solvent to form a solution;

(b) diluting the solution of pravastatin sodium with an aprotic solvent; and

(c) crystallizing the pravastatin sodium Form A from the solution of pravastatin sodium.

78. The process of

claim 77

wherein the protic solvent is a mixture of ethanol and water.

79. The process of

claim 77

wherein the aprotic solvent is a polar aprotic solvent.

80. The process of

claim 78

wherein the polar aprotic solvent is acetonitrile.

81. The process of

claim 77

wherein the aprotic solvent is a non-polar solvent.

82. The process of

claim 81

wherein the non-polar solvent is selected from the group consisting hexane, petroleum, ether and carbon tetrachloride.

83. The process of

claim 77

wherein crystallizing pravastatin sodium is performed at a temperature of between about −

10°

C. and 10°

C.

84. The process of

claim 83

wherein the temperature is about −

10°

C.

85. The process of

claim 83

wherein the temperature is about 10°

C.

86. The process of

claim 83

wherein the temperature is about 5°

C.

87. The process of

claim 77

further comprising cooling the solution of pravastatin sodium.

88. The process of

claim 77

further comprising cooling the solution of pravastatin sodium at a rate of about 5.8°

C. per hour to about 35°

C. per hour.

89. The process of

claim 77

further comprising cooling the solution of pravastatin sodium at a rate of about 2°

C. per hour.

90. The process of

claim 77

wherein pravastatin sodium is at a concentration of about 0.05 to 0.5 M after dilution with the protic solvent.

91. The process of

claim 77

further comprising heating the solution of pravastatin sodium to a temperature above 40°

C. prior to the addition of the aprotic solvent.

92. The process of

claim 91

wherein the temperature is about 60°

C.

93. A process for preparing pravastatin sodium Form B comprising the steps of:

(a) dissolving any solid form of pravastatin sodium in a protic solvent to form a solution;

(b) diluting the solution of pravastatin sodium with an aprotic solvent; and

(c) crystallizing the pravastatin sodium Form B from the solution of pravastatin sodium.

94. The process of

claim 93

wherein the protic solvent is ethanol.

95. The process of

claim 93

wherein the aprotic solvent is a polar aprotic solvent.

96. The process of

claim 95

wherein the polar aprotic solvent is acetonitrile.

97. The process of

claim 95

wherein the polar aprotic solvent is a mixture of solvents selected from the group consisting of acetonitrile, acetone, and ethyl acetate.

98. The process of

claim 93

wherein the aprotic solvent is a non-polar solvent.

99. The process of

claim 98

wherein the non-polar solvent is selected from the group consisting hexane, petroleum, ether and carbon tetrachloride.

100. The process of

claim 93

wherein crystallizing pravastatin sodium is performed at a temperature of between about −

10°

C. and 10°

C.

101. The process of

claim 100

wherein the temperature is about −

10°

C.

102. The process of

claim 100

wherein the temperature is about 10°

C.

103. The process of

claim 100

wherein the temperature is about 5°

C.

104. The process of

claim 93

further comprising cooling the solution of pravastatin sodium.

105. The process of

claim 93

further comprising cooling the solution of pravastatin sodium at a rate of about 5.8°

C. per hour to about 35°

C. per hour.

106. The process of

claim 93

further comprising cooling the solution of pravastatin sodium at a rate of about 2°

C. per hour.

107. The process of

claim 93

wherein pravastatin sodium is at a concentration of about 0.05 to 0.5 M after dilution with the protic solvent.

108. The process of

claim 93

further comprising heating the solution of pravastatin sodium to a temperature above 40°

C. prior to the addition of the aprotic solvent.

109. The process of

claim 108

wherein the temperature is about 60°

C.

121. The process of

claim 101

further comprising cooling the solution of pravastatin sodium.

110. A process for preparing pravastatin sodium Form C comprising the steps of:

(a) dissolving a solid form of pravastatin sodium in a protic solvent to form a solution;

(b) diluting the solution of pravastatin sodium with an aprotic solvent; and

(c) crystallizing the pravastatin sodium Form C from the solution of pravastatin sodium.

111. The process of

claim 110

wherein the protic solvent is water.

112. The process of

claim 110

wherein the aprotic solvent is a polar aprotic solvent.

113. The process of

claim 112

wherein the polar aprotic solvent is a mixture of solvents selected from the group consisting of acetonitrile, acetone, and ethyl acetate.

114. The process of

claim 112

wherein the polar aprotic solvent is a mixture of acetonitrile and acetone.

115. The process of

claim 110

wherein the aprotic solvent is a non-polar solvent.

116. The process of

claim 115

wherein the non-polar solvent is selected from the group consisting hexane, petroleum, ether and carbon tetra chloride.

117. The process of

claim 110

wherein crystallizing pravastatin sodium is performed at a temperature of between about −

10°

C. and 10°

C.

118. The process of

claim 117

wherein the temperature is about −

10°

C.

119. The process of

claim 117

wherein the temperature is about 10°

C.

120. The process of

claim 117

wherein the temperature is about 5°

C.

122. The process of

claim 110

further comprising cooling the solution of pravastatin sodium at a rate of about 5.8°

C. per hour to about 35°

C. per hour.

123. The process of

claim 110

further comprising cooling the solution of pravastatin sodium at a rate of about 2°

C. per hour.

124. The process of

claim 110

wherein pravastatin sodium is at a concentration of about 0.05 to 0.5 M after dilution with the protic solvent.

125. The process of

claim 110

further comprising heating the solution of pravastatin sodium to a temperature above 40°

C. prior to the addition of the aprotic solvent.

126. The process of

claim 125

wherein the temperature is about 60°

C.

127. A process for preparing pravastatin sodium Form D comprising the steps of:

(a) dissolving any solid form of pravastatin sodium in a protic solvent to form a solution;

(b) diluting the solution of pravastatin sodium with an aprotic solvent; and

(c) crystallizing the pravastatin sodium Form D from the solution of pravastatin sodium.

128. The process of

claim 127

wherein the protic solvent is water.

129. The process of

claim 127

wherein the aprotic solvent is a polar aprotic solvent.

130. The process of

claim 129

wherein the polar aprotic solvent is acetonitrile or acetone.

131. The process of

claim 130

wherein the polar aprotic solvent is a mixture of acetonitrile and acetone.

132. The process of

claim 127

wherein the aprotic solvent is a non-polar solvent.

133. The process of

claim 132

wherein the non-polar solvent is selected from the group consisting hexane, petroleum, ether and carbon tetrachloride.

134. The process of

claim 127

wherein crystallizing pravastatin sodium is performed at a temperature of between about −

10°

C. and 10°

C.

135. The process of

claim 134

wherein the temperature is about −

10°

C.

136. The process of

claim 134

wherein the temperature is about 10°

C.

137. The process of

claim 134

wherein the temperature is about 5°

C.

138. The process of

claim 127

further comprising cooling the solution of pravastatin sodium.

139. The process of

claim 127

further comprising cooling the solution of pravastatin sodium at a rate of about 5.8°

C. per hour to about 35°

C. per hour.

140. The process of

claim 127

further comprising cooling the solution of pravastatin sodium at a rate of about 2°

C. per hour.

141. The process of

claim 127

wherein pravastatin sodium is at a concentration of about 0.05 to 0.5 M after dilution with the protic solvent.

142. The process of

claim 127

further comprising heating the solution of pravastatin sodium to a temperature above 40°

C. prior to the addition of the aprotic solvent.

143. The process of

claim 142

wherein the temperature is about 60°

C.

144. A process for preparing pravastatin sodium Form E comprising the steps of:

(a) dissolving any solid form of pravastatin sodium in a protic solvent to form a solution;

(b) diluting the solution of pravastatin sodium with an aprotic solvent; and

(c) crystallizing the Form E pravastatin sodium from the solution of pravastatin sodium.

145. The process of

claim 144

wherein the protic solvent is a mixture of ethanol and water.

146. The process of

claim 144

wherein the aprotic solvent is a polar aprotic solvent.

147. The process of

claim 144

wherein the polar aprotic solvent is a mixture of solvents selected from the group consisting of acetonitrile, acetone, and ethyl acetate.

148. The process of

claim 144

wherein the aprotic solvent is a non-polar solvent.

149. The process of

claim 148

wherein the non-polar solvent is ethyl acetate.

150. The process of

claim 149

wherein the non-polar solvent is selected from the group consisting hexane, petroleum, ether and carbon tetrachloride.

151. The process of

claim 144

wherein crystallizing pravastatin sodium is performed at a temperature of between about −

10°

C. and 10°

C.

152. The process of

claim 151

wherein the temperature is about −

10°

C.

153. The process of

claim 151

wherein the temperature is about 10°

C.

154. The process of

claim 151

wherein the temperature is about 5°

C.

155. The process of

claim 144

further comprising cooling the solution of pravastatin sodium.

156. The process of

claim 144

further comprising cooling the solution of pravastatin sodium at a rate of about 5.8°

C. per hour to about 35°

C. per hour.

157. The process of

claim 144

further comprising cooling the solution of pravastatin sodium at a rate of about 2°

C. per hour.

158. The process of

claim 144

wherein pravastatin sodium is at a concentration of about 0.05 to 0.5 M after dilution with the protic solvent.

159. The process of

claim 144

further comprising heating the solution of pravastatin sodium to a temperature above 40°

C. prior to the addition of the aprotic solvent.

160. The process of

claim 159

wherein the temperature is about 60°

C.

161. A process for preparing pravastatin sodium Form F comprising the steps of:

(a) dissolving any solid form of pravastatin sodium in a protic solvent to form a solution;

(b) diluting the solution of pravastatin sodium with an aprotic solvent; and

(c) crystallizing the pravastatin sodium Form F from the solution of pravastatin sodium.

162. The process of

claim 161

where the protic solvent is water.

163. The process of

claim 161

wherein the aprotic solvent is a polar aprotic solvent.

164. The process of

claim 163

wherein the polar aprotic solvent is acetonitrile or acetone.

165. The process of

claim 164

wherein the polar aprotic solvent is a mixture of solvents selected from the group consisting of acetonitrile, acetone, and ethyl acetate.

166. The process of

claim 161

wherein the aprotic solvent is a non-polar solvent.

167. The process of

claim 166

wherein the non-polar solvent is selected from the group consisting hexane, petroleum, ether and carbon tetrachloride.

168. The process of

claim 161

wherein crystallizing pravastatin sodium is performed at a temperature of between about −

10°

C. and 10°

C.

169. The process of

claim 166

wherein the temperature is about −

10°

C.

170. The process of

claim 166

wherein the temperature is about 10°

C.

171. The process of

claim 166

wherein the temperature is about 5°

C.

172. The process of

claim 161

further comprising cooling the solution of pravastatin sodium.

173. The process of

claim 161

further comprising cooling the solution of pravastatin sodium at a rate of about 5.8°

C. per hour to about 35°

C. per hour.

174. The process of

claim 161

further comprising cooling the solution of pravastatin sodium at a rate of about 2°

C. per hour.

175. The process of

claim 161

wherein pravastatin sodium is at a concentration of about 0.05 to 0.5 M after dilution with the protic solvent.

176. The process of

claim 161

further comprising heating the solution of pravastatin sodium to a temperature above 40°

C. prior to the addition of the aprotic solvent.

177. The process of

claim 176

wherein the temperature is about 60°

C.

178. A process for preparing pravastatin sodium Form G comprising exposing pravastatin Form F to a relative humidity of between about 40 to about 80%.

179. A process for crystallizing pravastatin sodium as polymorph Form A, comprising exposing polymorph Form D or polymorph Form F to the vapors of ethanol for three weeks.

180. A process for crystallizing pravastatin sodium as polymorph Form H, comprising exposing polymorph Form D or polymorph Form F to the vapors of ethanol for three weeks.

181. A process for crystallizing pravastatin sodium as polymorph Form H1, comprising suspending polymorph Form D in methanol.

182. A process for crystallizing pravastatin sodium as polymorph Form I, comprising exposing polymorph Form D or polymorph Form F to the vapors of isopropanol.

183. A process for crystallizing pravastatin sodium as polymorph Form J, comprising exposing polymorph Form D or polymorph Form F to the vapors of butanol.

184. A process for crystallizing pravastatin sodium as a polymorph Form K, comprising suspending pravastatin in a solvent.

185. The process of

claim 184

wherein the solvent is selected from the group consisting of ethanol, isopropyl alcohol and butanol.

186. A process for crystallizing pravastatin Form D and hydrates thereof by heating pravastatin to a temperature above room temperature.

187. The process of

claim 186

wherein pravastatin is a crystalline pravastatin form.

188. The process of

claim 186

wherein the crystalline pravastatin form is Form D, Form A, Form C, Form D, Form E, Form G, Form H or Form H1.

189. The process of

claim 186

wherein pravastatin is amorphous pravastatin.

190. The process of

claim 189

wherein the amorphous pravastatin is Form F.

191. The process of

claim 186

wherein the temperature is 120°

C.

192. The process of

claim 186

wherein the heating is performed for 2 hours.

193. A process for crystallizing pravastatin Form C by incubating pravastatin at 100% relative humidity.

194. The process of

claim 193

wherein the incubation is performed for 1 week.

195. Pravastatin sodium with water content of at least 30%.

196. Pravastatin sodium with a water content of at least 20%.

197. A process for preparing pravastatin sodium Form L comprising the steps of:

(a) dissolving any solid form of pravastatin sodium in a protic solvent to form a solution;

(b) diluting the solution of pravastatin sodium with an aprotic solvent; and

(c) crystallizing the pravastatin sodium Form L from the solution of pravastatin sodium.

198. The process of

claim 197

wherein the protic solvent is water.

199. The process of

claim 197

wherein the aprotic solvent is acetone.

200. The process of

claim 197

further comprising cooling a solution of pravastatin sodium at a rate of about 2°

C.h<sup>−

1</sup>.

201. A process for preparing pravastatin sodium Form D comprising the steps of:

(a) dissolving any solid form of pravastatin sodium in a protic solvent to form a solution;

(b) diluting the solution of pravastatin sodium with an aprotic solvent;

(c) crystallizing the pravastatin sodium Form L from the solution of pravastatin sodium; and

(d) drying pravastatin sodium Form L to produce Form D.

202. The process of

claim 201

wherein drying pravastatin Form L comprises gradual heating to about 60°

C.

203. The process of

claim 201

further comprising cooling a solution of pravastatin sodium at a rate of about 2°

C.h<sup>−

1</sup>.