Patent EA-002656-B1 (EA)
Title: Polymorphous dofetilide modifications
Inventor: APPLEBY IAN COLIN
IPC: C07C311/08
Filed: 1998-10-09
Abstract: 1. A process for the preparation of crystalline polymorphous form of dofetilide, which comprises preparing a polymorphous modification of said substance by crystallisation of any other form of dofetilide, including mixtures thereof, from aqueous acetonitrile or by dissolving any other form of dofetilide, including mixtures thereof, in an aqueous solution of a base, adjusting the solution to about pH 8.5 using an acid and collecting the product or by dissolving any other form of dofetilide, including mixtures thereof, in methanol, applying the solution obtained to a silica column, eluting the column with methanol and concentrating the eluted solution to dryness to provide the product. 2. The process as claimed in claim 1 wherein when preparing a polymorphous modification of said substance by crystallisation of any other form of dofetilide, including mixtures thereof, from aqueous acetonitrile from 98.5:1.5 to 99.5:0.5, by volume, acetonitrile: water is used. 3. The process as claimed in claim 2 wherein about 99:1, by volume, acetonitrile: water is used. 4. The process as claimed in claim 1 wherein when dissolving any other form of dofetilide, including mixtures thereof, in an aqueous solution of a base, adjusting the solution to about pH 8.5 using an acid and collecting the product, the base is sodium hydroxide. 5. The process as claimed in claim 1 or 4 wherein when dissolving any other form of dofetilide, including mixtures thereof, in an aqueous solution of a base, adjusting the solution to about pH 8.5 using an acid and collecting the product, the acid is a mineral acid such as hydrochloric acid. 6. Substantially pure, crystalline, dofetilide polymorph P162 which is characterised by an endothermic thermal event at about 162 degree C. 7. Dofetilide polymorph P162 as claimed in claim 6 which is further characterised by a powder X-ray diffraction (PXRD) pattern obtained by irradiation with copper K-alpha1 X-rays (wavelength = 1.5406 Angstroms) which shows main peaks with interplanar spacings at d.ANG. 21.303, 10.597, 7.053, 5.288, 5.088, 4.856, 4.793, 4.569, 4.504, 4.430, 4.256, 4.230, 4.133, 3.956, 3.911, 3.866, 3.674, 3.606, 3.524, 3.424, 3.384, 3.309, 3.255, 3.171, 3.083, 3.038, 3.021, 2.893, 2.842, 2.776, 2.679, 2.598, 2.557, 2.503, 2.482, 2.436, 2.419, 2.399, 2.345 and 2.323. 8. Dofetilide polymorph P162 as claimed in claim 6 or 7 which is further characterised by an infrared (IR) spectrum as a mull in nujol which shows absorption bands at 3246, 3013, 2807, 2776, 1907, 1611, 1593, 1510, 1398, 1366, 1357, 1321, 1300, 1277, 1251, 1220, 1171, 1146, 1106, 1091, 1051, 1031, 1023, 994, 966, 934, 925, 903, 851, 825, 808, 774, 723, 657, 603, 586, 559, 538, 528, 509, 499, 461 and 431 cm<-1>. 9. A pharmaceutical composition comprising dofetilide polymorph P162 as claimed in claim 6, 7 or 8, together with a pharmaceutically acceptable diluent or carrier. 10. A composition as claimed in claim 9 which is a suitable for administration in a capsule dosage form. 11. Dofetilide polymorph P162 as claimed in claim 6, 7 or 8, or a pharmaceutically acceptable composition thereof as claimed in claim 9 or 10, for use as a medicament. 12. The use of dofetilide polymorph P162 as claimed in claim 6, 7 or 8, or of a pharmaceutically acceptable composition thereof as claimed in claim 9 or 10, for the manufacture of an antiarrhythmic agent. 13. The use of dofetilide polymorph P162 as claimed in claim 6, 7 or 8, or of a pharmaceutically acceptable composition thereof as claimed in claim 9 or 10, for the manufacture of a medicament for treating heart failure, particularly congestive heart failure. 14. A method of treating cardiac arrhythmia which comprises administering an effective amount of dofetilide polymorph P162 as claimed in claim 6, 7 or 8, or a pharmaceutically acceptable composition thereof as claimed in claim 9 or 10, to an animal, including a human being, in need of such treatment. 15. A method of treating heart failure, particularly congestive heart failure, which comprises administering an effective amount of dofetilide polymorph P162 as claimed in claim 6, 7 or 8, or a pharmaceutically acceptable composition thereof as claimed in claim 9 or 10, to an animal, including a human being, in need of such treatment. 16. Substantially pure, crystalline, dofetilide polymorph P162a which is characterised by DSC in which it exhibits an endothermic thermal event at about 160 degree C. 17. Dofetilide polymorph P162a as claimed in claim 16 which is further characterised by a PXRD pattern obtained by irradiation with copper K-alpha1 X-rays (wavelength = 1.5406 Angstroms) which shows main peaks with interplanar spacings at d.ANG. 21.306, 10.603, 7.054, 5.289, 5.114, 5.094, 4.860, 4.572, 4.431, 4.260, 4.247, 4.228, 4.153, 4.136, 3.955, 3.870, 3.676, 3.607, 3.524, 3.435, 3.421, 3.384, 3.176, 3.038, 2.895, 2.778, 2.684, 2.559, 2.501, 2.486, 2.433, 2.326, 2.283, 2.248, 2.216, 2.171, 2.119, 2.051, 1.989 and 1.948. 18. Dofetilide polymorph P162a is as claimed in claim 16 or 17 which is further characterised by an IR spectrum as a mull in nujol which shows . absorption bands at 3246, 3013, 2807, 2776, 1907, 1611, 1593, 1510, 1397, 1366, 1357, 1321, 1300, 1277, 1251, 1220, 1171, 1146, 1106, 1091, 1051, 1031, 1023, 994, 966, 934, 926, 903, 851, 825, 807, 774, 726, 657, 602, 586, 559, 538, 528, 509, 499, 461 and 430 cm<-1>. 19. Substantially pure, crystalline, dofetilide polymorph P143 which is characterised by DSC in which it exhibits an endothermic thermal event at about 144 degree C. 20. Dofetilide polymorph P143 as claimed in claim 19 which is further characterised by a PXRD pattern obtained by irradiation with copper K-alpha1 X-rays (wavelength = 1.5406 Angstroms) which shows main peaks with interplanar spacings at d.ANG. 10.993, 9.006, 8.243, 6.769, 5.807, 5.530, 5.375, 5.104, 4.998, 4.735, 4.575, 4.539, 4.237, 4.179, 4.159, 4.019, 3.854, 3.705, 3.682, 3.601, 3.562, 3.482, 3.392, 3.343, 3.331, 3.263, 3.227, 3.173, 3.135, 3.082, 3.009, 2.946, 2.905, 2.859, 2.830, 2.803, 2.769, 2.672, 2.608 and 2.567. 21. Dofetilide polymorph P143 as claimed in claim 19 or 20 which is yet further characterised by an IR spectrum as a mull in nujol which shows absorption bands at 3266, 3123, 3107, 3041, 3027, 3013, 2766, 2723, 2610, 1895, 1614, 1607, 1587, 1511, 1414, 1395, 1337, 1319, 1301, 1287, 1248, 1230, 1215, 1202, 1187, 1157, 1148, 1130, 1110, 1060, 1042, 1018, 1005, 980, 975, 959, 940, 917, 853, 844, 831, 803, 785, 766, 752, 743, 718, 640, 613, 553, 536, 526, 509, 499, 455 and 429 cm<-1>. 22. A pharmaceutical composition comprising dofetilide polymorph P162a or P143, as claimed in any one of claims 16 to 18 and 19 to 21, respectively, together with a pharmaceutical acceptable diluent or carrier. 23. Dofetilide polymorph P162a or P143, as claimed in any one of claims 16 to 18 and 19 to 21, respectively, or a pharmaceutically acceptable composition thereof as claimed in claim 22, for use as a medicament. 24. The use of dofetilide polymorph P162a or P143, as claimed in any one of claims 16 to 18 and 19 to 2114 to 16 and 20 to 22, respectively, or of a pharmaceutically acceptable composition thereof as claimed in claim 22, for the manufacture of an antiarrhythmic agent. 25. The use of dofetilide polymorph P162a or P143, as claimed in any one of claims 16 to 18 and 19 to 21, respectively, or of a pharmaceutically acceptable composition thereof as claimed in claim 22, for the manufacture of a medicament for treating heart failure, particularly congestive heart failure. 26. A method of treating cardiac arrhythmia which comprises administering an effective amount of dofetilide polymorph P162a or P143, as claimed in any one of claims 16 to 18 and 19 to 21, respectively, or a pharmaceutically acceptable composition thereof as claimed in claim 22, to an animal, including a human being, in need of such treatment. 27. A method of treating heart failure, particularly congestive heart failure, which comprises administering an effective amount of dofetilide polymorph P162a or P143, as claimed in any one of claims 16 to 18 and 19 to 21, respectively, or a pharmaceutically acceptable composition thereof as claimed in claim 22, to an animal, including a human being, in need of such treatment. 28. A polymorph as claimed in claim 6, 7, 8, 16, 17, 18, 19, 20 or 21 wherein substantially pure means at least 95% by weight pure. 29. A polymorph as claimed in claim 28 wherein substantially pure means at least 98% by weight pure. 30. A polymorph as claimed in claim 29 wherein substantially pure means at least 99% by weight pure.