Claims
- 1. Risedronate sodium in crystalline form B characterized by X-ray peaks at 6.0, 14.4, 19.6, 24.9 and 25.4 degrees two-theta.
- 2. The risedronate sodium in crystalline form B of claim 1, that is pure form B, comprising less than about 1 weight % risedronate sodium in crystalline form A.
- 3. The substantially pure risedronate sodium in crystalline form B of claim 2, comprising less than about 0.5 weight % risedronate sodium in crystalline form A.
- 4. The substantially pure risedronate sodium in crystalline form B of claim 2, stable against transformation to risedronate sodium in crystalline form A.
- 5. The Risedronate sodium of claim 4 wherein less than about 20% of form B is converted to form A during storage for two years at room temperature.
- 6. Risedronate sodium in crystalline form B stable against transformation to risedronate sodium in crystalline form A when exposed to 75% RH at 40° C. for at least about three months.
- 7. The risedronate sodium form B of claim 6 stable against transformation to risedronate sodium in crystalline form A when exposed to 75% RH at 40° C. for at least about 5 months.
- 8. The risedronate sodium form B of claim 7 stable against transformation to risedronate sodium in crystalline form A when exposed to 75% RH at 40° C. for at least about 6 months.
- 9. Risedronate sodium form B wherein not more that about 20% by weight of the form B transforms to form A when exposed to 75% RH at 40° C. for at least 3 months.
- 10. The risedronate sodium form B of claim 9 wherein not more than about 10% by weight of the form B transforms to form A when exposed to 75% RH at 40° C. for at least 3 months.
- 11. The risedronate sodium form B of claim 10 wherein not more than about 5% by weight of the form B transforms to form A when exposed to 75% RH at 40° C. for at least 3 months.
- 12. Risedronate sodium in a crystalline form characterized by x-ray diffraction peaks at 6.0, 14.4, 19.6, 24.9 and 25.4 degrees two-theta.
- 13. The risedronate sodium of claim 12 characterized by an x-ray diffraction diagram substantially as shown in FIG. 4.
- 14. Risedronate sodium in a crystalline form characterized by FTIR absorption bands at 624, 951, 796, 912, 931, 1046, 1105, 1123, 1373, and 1641 cm−1.
- 15. The risedronate sodium of claim 14 characterized by a FTIR spectrum substantially as shown in FIG. 6.
- 16. A method for preparing risedronate sodium having at least one characteristic of form B comprising the steps of:
refluxing a mixture of risedronic acid, a sodium base, and a liquid comprising about 40% to about 60% v/v lower alkanol in water, and isolating risedronate sodium having at least one characteristic of form B from the resulting mixture.
- 17. The method of claim 16 further comprising the step of, before isolating risedronate sodium having at least one characteristic of form B, cooling the mixture.
- 18. The method of claim 17 wherein the cooling is to a temperature of about room temperature.
- 19. The method of claim 17 wherein the cooling is to a temperature of about 5° C. or less.
- 20. The method of claim 16 wherein the molar ratio between risedronic acid and the sodium base is between about 1:0.8 and about 1:1.2.
- 21. Method of claim 20 wherein the molar ratio between risedronic acid and the sodium base is between about 1:1 and about 1:1.2.
- 22. The method of claim 20 wherein the sodium base is sodium hydroxide.
- 23. The method of claim 16 wherein the lower alkanol is selected from the group consisting of methanol, ethanol and isopropanol.
- 24. The method of claim 16 wherein the liquid consists essentially of a mixture of about 50% ethanol and about 50%, v/v, water.
- 25. The method of claim 16 wherein the liquid consists essentially of a mixture of about 50% methanol and about 50% water, v/v.
- 26. The method of claim 16 wherein the risedronate sodium having at least one characteristic of form B is pure form B.
- 27. The method of claim 16 wherein the risedronate sodium having at least one characteristic of form B is stable form B.
- 28. A method for preparing risedronate sodium having at least one characteristic of form B comprising the steps of:
refluxing a mixture of risedronic acid, a sodium base, and a liquid comprising about 20% to about 70%, v/v, methanol in water, and isolating risedronate having at least one characteristic of form B from the resulting mixture.
- 29. The method of claim 28 further comprising the step of, prior to isolating risedronate sodium having at least one characteristic of form B, cooling the mixture.
- 30. The method of claim 29 wherein the cooling is to a temperature of about room temperature.
- 31. The method of claim 29 wherein the cooling is to a temperature of about 5° C. or less.
- 32. The method of claim 28 wherein the molar ratio between risedronic acid and the sodium base is between about 1:0.8 and about 1:1.2.
- 33. The method of claim 32 wherein the molar ratio between risedronic acid and the sodium base is between about 1:1 and about 1:1.2.
- 34. The method of claim 28 wherein the sodium base is sodium hydroxide.
- 35. The method of claim 28 wherein the risedronate sodium having at least one characteristic of form B is pure form B.
- 36. The method of claim 28 wherein the risedronate sodium having at least one characteristic of form B is stable form B.
- 37. Risedronate sodium in a crystalline form characterized by x-ray peaks at about 8.5, 9.1, 9.5, and 12.2+/−0.2 degrees two-theta.
- 38. The risedronate sodium of claim 37 characterized by additional x-ray peaks at about 14.3, 16.9, 19.7, 23.5, 28.8, and 33.6+/−0.2 degrees two-theta.
- 39. The risedronate sodium of claim 38 characterized by an x-ray diffraction diagram substantially as shown in FIG. 7.
- 40. Risedronate sodium in form BB.
- 41. A method of making risedronate sodium having at least one characteristic of form BB comprising the steps of:
a) providing a solution of risedronate sodium in water at a temperature of about 70° C. or more, b) adding iso-propanol to the solution to obtain a solid-in-liquid suspension, c) isolating the solid from the suspension, d) refluxing the isolated solid in suspension in iso-propanol for at least about 10 hours, and e) isolating risedronate sodium having at least one characteristic of form BB from the suspension.
- 42. Risedronate sodium having at least one characteristic of form BB made by the method of claim 41.
- 43. A method of making risedronate sodium having at least one characteristic of form BB comprising the step of exposing risedronate sodium having at least one characteristic of form F to an atmosphere having a relative humidity of at least about 80%.
- 44. The method of claim 43 wherein the risedronate sodium having at least one characteristic of form F is exposed for a period of time of at least about 1 week.
- 45. Risedronate sodium having at least one characteristic of form BB made by the method of claim 43.
- 46. Risedronate disodium salt in a crystalline form characterized by x-ray diffraction peaks at about 6.5, 14.7, 21.2, 27.7, and 32.4+/−0.2 degrees two-theta.
- 47. The risedronate disodium salt of claim 46 having an x-ray diffraction diagram substantially as shown in FIG. 9.
- 48. A method of making risedronate sodium in crystalline form B in admixture with crystalline form B1 comprising the steps of:
refluxing a combination of risedronic acid and a sodium base in a liquid comprising between about 5% and about 25%, v/v, ethanol, the remainder consisting essentially of water, and isolating the risedronate sodium form B from the combination.
- 49. The method of claim 48 further comprising the step, prior to the isolation step, of cooling the combination.
- 50. The method of claim 49 wherein the cooling is to a temperature of about room temperature.
- 51. The method of claim 49 wherein the cooling is to a temperature of about 5° C. or less.
- 52. The method of claim 48 wherein the sodium base is sodium hydroxide.
- 53. A method of making risedronate disodium in a crystalline form having at least one characteristic of form B1 comprising the steps of;
refluxing a mixture of risedronic acid, at least about two equivalents of a sodium base, and a liquid comprising water and ethanol, 50/50 v/v, and isolating risedronate disodium having at least one characteristic of form B1 from the mixture.
- 54. The method of claim 53 further comprising the step, before the isolating step, of cooling the combination.
- 55. The method of claim 54 wherein the cooling is to a temperature of about room temperature.
- 56. The method of claim 54 wherein the cooling is to a temperature of about 5° C. or less.
- 57. The method of claim 53 wherein the sodium base is sodium hydroxide.
- 58. Risedronate sodium having at least one characteristic of form B1 made by the method of claim 52.
- 59. Risedronate sodium in a crystalline form characterized by X-ray peaks at about 5.6, 10.3, 12.9, 26.5, and 30.9°+/−0.2 degrees two-theta.
- 60. The risedronate sodium of claim 59 characterized by an x-ray diffraction diagram substantially as shown in FIG. 11.
- 61. Risedronate sodium in a crystalline form characterized by absorption bands at about 615, 666, 1089, 1563 and 1615 cm−1 in FTIR spectroscopy.
- 62. The risedronate sodium of form 61 characterized by an FTIR spectrum substantially as shown in FIG. 13.
- 63. A method of making risedronate sodium having at least one characteristic of form C comprising the step of refluxing a mixture of risedronic acid, a sodium base, and a liquid comprising about 3%, v/v, ethanol, the remainder of the mixture by volume consisting essentially of water.
- 64. The method of claim 63 further comprising the steps of:
cooling the mixture to about room temperature, isolating risedronate sodium having at least one characteristic of form C.
- 65. The method of claim 64 further comprising the step of, before isolating risedronate sodium having at least one characteristic of form C, further cooling the mixture to a temperature of about 5° C. or less.
- 66. The method of claim 63 wherein the sodium base is sodium hydroxide.
- 67. Risedronate sodium having at least one characteristic of form C made by the method of claim 63.
- 68. Risedronate sodium in a crystalline form characterized by x-ray diffraction peaks at about 9.9, 17.2, 22.1, 27.9, and 29.2+/−0.2 degrees two-theta.
- 69. The risedronate sodium of claim 68 characterized by an x-ray diffraction diagram substantially as shown in FIG. 14.
- 70. Risedronate sodium in a crystalline form characterized by absorption bands at 697, 807, 854, 955, 1187, 1218, 1576, 1646, and 1719 cm−1 in FTIR spectroscopy.
- 71. The risedronate sodium of claim 70 characterized by an FTIR spectrum substantially as shown in FIG. 16.
- 72. A method of making risedronate sodium having at least one characteristic of form D comprising the step of refluxing a mixture of risedronic acid, a sodium base, and a liquid that is selected from the group consisting of ethanol, methanol, and mixtures of methanol and water having up to about 11%, v/v, water.
- 73. The method of claim 72 further comprising the steps of:
cooling the mixture to a temperature of about room temperature, and isolating risedronate sodium having at least one characteristic form D.
- 74. The method of claim 73 further comprising the step of, prior to isolating risedronate sodium having at least one characteristic of form D, further cooling the mixture to a temperature of about 5° C. or less.
- 75. Risedronate sodium having at least one characteristic of form D made by the method of claim 72.
- 76. A method of making risedronate sodium comprising crystalline form B comprising the step of exposing risedronate sodium crystalline form D to an atmosphere of 80% to 100% relative humidity.
- 77. The method of claim 76 wherein the risedronate sodium having at least one characteristic form B is pure form B.
- 78. Risedronate sodium in a crystalline form characterized by x-ray peaks at about 8.4, 8.9, 13.6, 27.6, and 27.9+/−0.2 degrees two-theta.
- 79. The method of claim 76 wherein the risedronate sodium having at least one characteristic of form B is stable form B.
- 80. The risedronate sodium of claim 79 characterized by an x-ray diffraction diagram substantially as shown in FIG. 17.
- 81. Risedronate sodium in crystalline a crystalline form characterized by absorption bands at 801, 890, 935, 1656, and 1689 cm−1 in FTIR spectroscopy.
- 82. The risedronate sodium of claim 81 characterized by an FTIR spectrum substantially as shown in FIG. 19.
- 83. A method of making risedronate sodium having at least one characteristic of form E comprising the step of refluxing a combination of risedronic acid, a sodium base, and a liquid comprising 80%, v/v water, the remainder being methanol.
- 84. The method of claim 83 further comprising the steps of:
cooling the combination to a temperature of about room temperature, isolating risedronate sodium having at least one characteristic of form E.
- 85. The method of claim 84 further comprising the step of, before isolating the risedronate sodium having at least one characteristic of form E, cooling the mixture to a temperature of about 5° C. or less.
- 86. The method of claim 83 wherein the sodium base is sodium hydroxide.
- 87. Risedronate sodium having at least one characteristic of form E made by the method of claim 83.
- 88. A method of making risedronate sodium comprising crystalline form E comprising the steps of:
a) refluxing a combination of risedronic acid, sodium hydroxide, and water, b) cooling the combination to a temperature of about room temperature, and c) isolating risedronate sodium comprising form E from the combination.
- 89. The method of claim 88 further comprising the step, before step c, of further cooling the combination to a temperature of about 5° C. or less.
- 90. Risedronate sodium in a crystalline form characterized by x-ray peaks at about 6.6, 8.4, 8.9, 12.2, and 18.6+/−0.2 degrees two-theta.
- 91. The risedronate sodium of claim 90 characterized by an x-ray diffraction diagram substantially as shown in FIG. 20.
- 92. Risedronate sodium in a crystalline form characterized by absorption bands at 971, 1133, and 1306 cm−1 in FTIR spectroscopy.
- 93. The risedronate sodium of claim 92 characterized by an FTIR spectrum substantially as shown in FIG. 22.
- 94. Risedronate sodium having at least one characteristic of form F stable against transformation to form A in an atmosphere having a relative humidity up to 60%.
- 95. A method of making risedronate sodium having at least one characteristic of form F comprising the step of heating risedronate sodium form A, form B, or a mixture of these at 160° C.
- 96. Risedronate sodium having at least one characteristic of form F made by the method of claim 95.
- 97. Risedronate sodium in a crystalline form characterized by x-ray peaks at about 8.0, 9.9, 12.2, 15.2, and 19.6+/−0.2 degrees two-theta.
- 98. The risedronate sodium of claim 97 characterized by an x-ray diffraction diagram substantially as shown in FIG. 23.
- 99. Risedronate sodium in a crystalline form characterized by absorption bands at 724, 871, 1174, and 1285 cm−1 in FTIR spectroscopy.
- 100. The risedronate sodium of claim 99 characterized by an FTIR spectrum substantially as shown in FIG. 25.
- 101. A method of making risedronate sodium having at least one characteristic of form G comprising the step of heating a mixture of risedronate sodium forms A and E at a temperature between about 120° and about 180° C.
- 102. Risedronate sodium having at least one characteristic of form G made by the method of claim 101.
- 103. Risedronate sodium in a crystalline form characterized by x-ray diffraction reflections at about 6.9, 9.8, 10.9, 13.7, 16.0, and 18.0+/−0.2 degrees two theta.
- 104. A method for making risedronate sodium having at least one characteristic of form H comprising the step of exposing risedronate sodium form C in an atmosphere having a relative humidity between about 60% and about 100%.
- 105. The method of claim 104 wherein the atmosphere has a relative humidity of at least about 80%.
- 106. Risedronate sodium having at least one characteristic of form H made by the method of claim 104.
- 107. A method of making risedronate sodium form B comprising the steps of:
a) combining a solution of sodium hydroxide in a mixture of water and ethanol, 60% v/v, with risedronic acid, wherein the amount of sodium hydroxide combined is about one equivalent based on risedronic acid, b) heating the combination at reflux for a reflux time, c) cooling the mixture to about room temperature, d) further cooling the mixture to a temperature of about 5° C. or less, and e) isolating risedronate sodium form B.
- 108. The method of claim 107 wherein the risedronate sodium form B is risedronate sodium pure form B.
- 109. The method of claim 107 wherein the risedronate sodium form B is risedronate sodium stable form B.
- 110. A method of making risedronate sodium having at least one characteristic of form A comprising the step of refluxing a mixture of risedronic acid, a sodium base, and a liquid comprising about 20%, v/v, iso-propanol and water.
- 111. The method of claim 110 further comprising the steps of:
cooling the mixture to a temperature of about room temperature, and isolating risedronate sodium having at least one characteristic form A.
- 112. The method of claim 110 further comprising the step of, before isolating risedronate sodium having at least one characteristic of form A, further cooling the mixture to a temperature of about 5° C. or less.
- 113. A method of making risedronate sodium having at least one characteristic of form A comprising the steps of:
a) refluxing a water solution of sodium risedronate, b) cooling the solution to obtain a suspension, and c) isolating risedronate sodium having at least one characteristic of form A from the suspension.
- 114. A method of making risedronate sodium form A comprising the step of exposing risedronate sodium form E, risedronate sodium form G, or a mixture of risedronate sodium forms E and G to an atmosphere having a relative humidity of at least about 80% for a period of about one week.
- 115. A method of making risedronate sodium form A comprising the step of incubating risedronate sodium form E at 60° C. for a period of at least about 5 hours.
- 116. A method of making risedronate sodium form A comprising the step of treating risedronate sodium form B or form D, or a mixture of these, with water at a temperature between about room temperature and about reflux temperature.
- 117. The method of claim 116 wherein the risedronate sodium is risedronate sodium form B.
- 118. The method of claim 116 wherein the risedronate sodium is risedronate sodium form D.
- 119. A method of making risedronate sodium having at least one characteristic form B comprising the step of treating risedronate sodium form A with 1:1, v/v, mixture of a lower alkanol and water at a temperature between about room temperature and about reflux temperature.
- 120. The method of claim 119 wherein the risedronate sodium having at least one characteristic of form B is risedronate sodium pure form B.
- 121. The method of claim 119 wherein the lower alkanol is ethanol.
- 122. A method of making risedronate sodium having at least one characteristic of form D comprising the step of treating risedronate sodium comprising form BB in ethanol at a temperature between about room temperature and about reflux temperature.
- 123. Risedronate sodium having at least one characteristic of form D made by the method of claim 122.
- 124. A pharmaceutical composition comprising pure risedroante sodium form B and at least one pharmaceutically acceptable excipient.
- 125 The pharmaceutical composition of claim 124 wherein at least about 60% by weight of the risedronate sodium form B remains untransformed to form A when the composition is stored for at least 3 months at 40° C. and 75% RH.
- 126. The pharmaceutical composition of claim 125 wherein at least about 60% by weight of the risedronate sodium form B remains untransformed to form A when the composition is stored for at least 6 months at 40° C. and 75% RH.
- 127. The pharmaceutical composition of claim 125 wherein at least about 60% by weight of the risedronate sodium form B remains untransformed to form A when the composition is stored for at least about 2 years at a temperature of about 25° C. and 75% RH. 6 months at 40° C. and 75% RH.
- 128. The pharmaceutical composition of claim 125 in the form of a tablet.
- 129. A pharmaceutical composition comprising stable risedronate sodium form B and at least one pharmaceutically acceptable excipient.
- 130. A pharmaceutical composition comprising risedronate sodium crystalline form C and at least one pharmaceutically acceptable excipient.
- 131. A pharmaceutical composition comprising risedronate sodium crystalline form B1 and at least on pharmaceutically acceptable excipient.
- 132. A pharmaceutical composition comprising risedronate sodium crystalline form D and at least one pharmaceutically acceptable excipient.
- 133. A pharmaceutical composition comprising risedronate sodium crystalline form BB and at least one pharmaceutically acceptable excipient.
- 134. A pharmaceutical composition comprising risedronate sodium crystalline form E and at least one pharmaceutically acceptable excipient.
- 135. A pharmaceutical composition comprising risedronate sodium crystalline form F and at least one pharmaceutically acceptable excipient.
- 136. A pharmaceutical composition comprising risedronate sodium crystalline form G and at least one pharmaceutically acceptable excipient.
- 137. A pharmaceutical composition comprising risedronate sodium crystalline form H and at least one pharmaceutically acceptable excipient.
- 138. A method of treating osteoporosis comprising the step of administering to a patient suffering from osteoporosis an osteoporosis treating effective amount of risedronate sodium pure form B.
- 139. A method of treating osteoporosis comprising the step of administering to a patient suffering from osteoporosis an osteoporosis treating effective amount of at least one of risedronate sodium crystal forms B, C, D, B1, BB, E, F, G, and H.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of provisional applications Serial No. 60/372,465, filed Apr. 11, 2002; Serial No. 60/404,174, filed Aug. 16, 2002, and Serial No. 60/405,668, filed Aug. 22, 2002.
Provisional Applications (3)
|
Number |
Date |
Country |
|
60372465 |
Apr 2002 |
US |
|
60404174 |
Aug 2002 |
US |
|
60405668 |
Aug 2002 |
US |