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Claims for Patent: 6,124,363

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Claims for Patent: 6,124,363

Title: Dofetilide polymorphs
Abstract:The invention relates to the substantially pure dofetilide polymorphs P162, P162a and P143, and to processes for the preparation of, compositions containing and to the uses of, such polymorphs.
Inventor(s): Appleby; Ian Colin (Sandwich, GB), Newbury; Trevor Jack (Sandwich, GB), Nichols; Gary (Sandwich, GB)
Assignee: Pfizer Inc. (New York, NY)
Application Number:09/423,986
Patent Claims: 1. Substantially pure, crystalline, dofetilide polymorph P162 which is characterised by differential scanning calorimetry (DSC) in which it exhibits an endothermic thermal event at about 162.degree. C.

2. Dofetilide polymorph P162 as claimed in claim 1 which is further characterised by a powder X-ray diffraction (PXRD) pattern obtained by irradiation with copper K-alpha.sub.1 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.

3. Dofetilide polymorph P162 as claimed in claim 2 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.sup.-1.

4. A process for the preparation of dofetilide polymorph P162 as claimed in claim 1 which comprises crystallisation of any other form of dofetilide, including mixtures thereof, from aqueous acetonitrile.

5. A process as claimed in claim 4 wherein from 98.5:1.5 to 99.5:0.5, by volume, acetonitrile:water is used.

6. A process as claimed in claim 5 wherein about 99:1, by volume, acetonitrile:water is used.

7. A pharmaceutical composition comprising dofetilide polymorph P162 as claimed in claim 1 together with a pharmaceutically acceptable diluent or carrier.

8. A composition as claimed in claim 7 which is a suitable for administration in a capsule dosage form.

9. A method of treating cardiac arrhythmia which comprises administering an effective amount of dofetilide polymorph P162 as claimed in claim 1 or a pharmaceutically acceptable composition thereof to an animal in need of such treatment.

10. A method of treating heart failure, particularly congestive heart failure, which comprises administering an effective amount of dofetilide polymorph P162 as claimed in claim 1 or a pharmaceutically acceptable composition thereof, to an animal in need of such treatment.

11. Substantially pure, crystalline, dofetilide polymorph P162a which is characterised by DSC in which it exhibits an endothermic thermal event at about 160.degree. C.

12. Dofetilide polymorph P162a as claimed in claim 11 which is further characterised by a PXRD pattern obtained by irradiation with copper K-alpha.sub.1 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.

13. Dofetilide polymorph P162a is as claimed in claim 11 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.sup.-1.

14. A process for the preparation of dofetilide polymorph P162a as claimed in claim 11 which comprises 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.

15. A process as claimed in claim 14 wherein the base is sodium hydroxide.

16. A process as claimed in claim 14 wherein the acid is a mineral acid such as hydrochloric acid.

17. Substantially pure, crystalline, dofetilide polymorph P143 which is characterised by DSC in which it exhibits an endothermic thermal event at about 144.degree. C.

18. Dofetilide polymorph P143 as claimed in claim 17 which is further characterised by a PXRD pattern obtained by irradiation with copper K-alpha.sub.1 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.

19. Dofetilide polymorph P143 as claimed in claim 17 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.sup.-1.

20. A process for the preparation of dofetilide polymorph P143 as claimed in claim 17 which comprises 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.

21. A pharmaceutical composition comprising dofetilide polymorph P162a as claimed in claim 11 together with a pharmaceutical acceptable diluent or carrier.

22. A method of treating cardiac arrhythmia which comprises administering an effective amount of dofetilide polymorph P162a as claimed in claim 11 or a pharmaceutically acceptable composition thereof to an animal in need of such treatment.

23. A method of treating heart failure, particularly congestive heart failure, which comprises administering an effective amount of dofetilide polymorph P162a as claimed in claim 11 or a pharmaceutically acceptable composition thereof to an animal in need of such treatment.

24. A polymorph as claimed in claim 1 wherein substantially pure means at least 95% by weight pure.

25. A polymorph as claimed in claim 24 wherein substantially pure means at least 98% by weight pure.

26. A polymorph as claimed in claim 25 wherein substantially pure means at least 99% by weight pure.

27. A pharmaceutical composition comprising dofetilide polymorph P143 as claimed in claim 17 together with a pharmaceutical acceptable diluent or carrier.

28. A method of treating cardiac arrhythmia which comprises administering an effective amount of dofetilide polymorph P143 as claimed in claim 17 or a pharmaceutically acceptable composition thereof to an animal in need of such treatment.

29. A method of treating heart failure, particularly congestive heart failure, which comprises administering an effective amount of dofetilide polymorph P143 as claimed in claim 17 or a pharmaceutically acceptable composition thereof to an animal in need of such treatment.
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