POLYMORPHIC MODIFICATIONS OF CRYSTALLINE (2-BENZHYDRYL-1-AZABICYCLO[2,2,2]OCT-3-YL)-(5-ISOPROPYL-2-METHOXYBENZYL)-AMMONIUMCHLORIDE AS NK-1 RECEPTOR ANTAGONISTS

摘要

1. The crystalline forms of (2-Benzhydryl-1-azo-bicyclo[2.2.2]oct-3-yl)-(5-isopropyl-2-methoxy-benzgi)-amine dihydrochloride having the formula wherein said crystalline form is selected from the group consisting of a) a hygroscopic dihydrochloride anhydrous form; b) a nonhygroscopic dihydrochloride dihydrate, Form I polymorph exhibiting the x-ray powder diffraction pattern Peak Distance d 1 17.2 2 9.5 3 8.4 4 6.9 5 4.9 6 4.4 7 3.9 8 3.5 and c) a nonhygroscopic dihydrochloride dihydrate, Form II polymorph exhibiting the x-ray powder diffraction pattern Peak Distance d 1 11.3 2 8.8 3 7.5 4 6.4 5 4.9 6 4.5 7 3.8 8 3.7 9 3.0 2. The anhydrous dihydrochloride according to claim 1 wherein the anhydrous dihydrochloride crystalline habits are rods. 3. The anhydrous dihydrochloride according to claim 2 wherein said rods have a particle size of about 5 to 30 mum. 4. The anhydrous dihydrochloride according to claim 1 wherein a differential scanning calorimetry thermogram gave a sharp endothern with an onset at about 224 degree C., temperature maximum at about 236 degree C. and a DeltaHf of about 32.8 cal/gram. 5. The nonhygroscopic dihydrochloride dihydrate polymorph according to claim 1 wherein Form I's crystalline habit are flakes. 6. The dihydrochloride dihydrate polymorph according to claim 5 wherein Form I's crystalline flake size is about 30 mum to 60 mum. 7. The dihydrochloride dihydrate polymorph according to claim 1, wherein Form I's solubility is about 640-1160 mg/ml. 8. The dihydrochloride dihydrate polymorph according to claim 1 wherein Form I has a differential scanning calorimetry thermogram with onsets at about 175 degree C. and 230 degree C. 9. The dihydrochloride dihydrate polymorph according to claim 1, wherein Form II has a solubility of about 390 to 400 mg/ml. 10. The dihydrochloride dihydrate polymorph according to claim 1 wherein Form II's crystalline habit are flakes. 11. Polymorph modification of the form II according to claim 10 wherein the crystalline flakes have a size range of about 15 to 25 mum. 12. A pharmaceutical composition having substance P antagonist activity comprising at least one of the polymorphic Forms I or II according to claim 1, in an amount effective in the treatment of emesis and a pharmaceutically acceptable carrier. 13. A method of treating emesis which comprises administering to a subject in need of treatment an antiemetic effective amount of the polymorphic Form I of the compound according to claim 1. 14. A method of treating emesis which comprises administering to a subject in need of treatment an antiemetic effective amount of the polymorphic Form II of the compound according to claim 1. 15. A pharmaceutical composition having substance P antagonist activity comprising the anhydrous dihydrochloride according to claim 1, in an amount effective in the treatment of emesis, and a pharmaceutically acceptable carrier. 16. A method of treating emesis which comprise administering to a subject in need of treatment an antiemetic effective amount of the anhydrous dihydrochloride of the compound according to claim 1. 17. A method of making crystalline dihydrochloride dihydrate polymorphic Form I of the anhydrous dihydrochloride of (2-Benzhydryl-1-azo-bicyclo 2,2,2 Oct-3-yl)-(5-isopropyl-2-methoxybenzyl)-amine comprising stirring at ambient temperature the anhydrous dihydrochloride in an organic solvent containing about 0.5 to 2.5% water for about 15-25 hours to effect crystallization. 18. A method of claim 17, wherein the organic solvents are selected from ethyl alcohol, isopropyl alcohol, ethyl acetate, acetonitrile, tetrahydrofuran and acetone. 19. A method of making crystalline dihydrochloride dihydrate polymorphic Form II of the anhydrous dihydrochloride of (2-Benzhydryl-1-azo-bicyclo 2,2,2-Oct-3-yl)-(5-isopropyl-2-methoxybenzyl)-amine comprising stirring at ambient temperature Form I of the dihydrochloride dihydrate or the anhydrous dichloride in an organic solvent containing about 3 to 5% water for about 15 to 25 hours to effect crystallization. 20. The method of claim 19, wherein the organic solvents are chosen from ethyl acetate with about 3.5% water, tetrahydrofuran with about 5% water, acetone with about 5% water and acetonitrile with about 5% water.