Patent EA-004206-B1 (EA)
Title: Polymorphs of crystalline (2-benzhydryl-1-azabicyclo[2.2.2]oct-3-yl)-(5-isopropyl-2-methoxybenzyl)-amine citrate as nk-1 receptor antagonists
Inventor: MASSETT STEPHEN SARGENT
IPC: C07D453/02
Filed: 2000-05-17
Abstract: 1. The crystalline forms of (2-Benzhydryl-1-azo-bicyclo (2,2,2) oct-3-yl)-(5-isopropyl-2-methoxybenzyl)-amine citrate having the formula wherein said crystalline form is selected from the group consisting of (a) a stable nonhygroscopic citrate anhydrous form exhibiting the X-ray powder diffraction pattern Peak No Space D 1 17.61 2 10.95 3 8.78 4 7.96 5 7.37 6 6.80 7 6.57 8 5.87 9 5.46 (b) a citrate monohydrate, Form A polymorph exhibiting the X-ray powder diffraction pattern Peak No Space D 1 17.74 2 10.93 3 9.65 4 8.25 5 6.71 6 5.98 7 5.67 8 5.45 9 4.83 and (c) A citrate monohydrate, Form B polymorph exhibiting the X-ray powder diffraction pattern. Peak No Space D 1 12.3 2 11.3 3 6.5 4 6.9 5 5.9 6 4.3 7 4.1 8 3.5 9 3.2 2. The monohydrate polymorph according to claim 1 wherein Form A's crystalline habits are either acicular needles or plates. 3. The monohydrate polymorph Form B according to Claim 1 wherein Form B's crystalline habits are crystalline plates. 4. The monohydrate polymorph Form B according to Claim 1 obtained by concentrating a solution of the citrate monohydrate in methanol. 5. The anhydrous citrate salt according to Claim 1 having a melt onset at about 159.9 degree C. 6. The anhydrous citrate according to Claim 1 wherein hygroscopicity measurements demonstrated that about 1.11% wt/wt water was absorbed at about 90% relative humidity. 7. The anhydrous citrate according to Claim 1 wherein it's crystalline habits are microcrystalline flakes. 8. The monohydrate polymorph form A according to Claim 1 which is characterized by a melt onset at about 162.6 degree C. 9. The monohydrate polymorph form B according to Claim 1 which is characterized by a melt onset at about 149 degree C with degradation. 10. A pharmaceutical composition having substance P antagonist activity comprising at least one of the polymorphic Forms A or B according to Claim 1, in an amount effective in the treatment of emesis and a pharmaceutically acceptable carrier. 11. A method of treating emesis which comprises administering to a subject in need of treatment an antiemetic effective amount of the polymorphic A Form of the compound according to Claim 1. 12. A method of treating emesis which comprises administering to a subject in need of treatment an antiemetic effective amount of the polymorphic B Form of the compound according to Claim 1. 13. A pharmaceutical composition having substance P antagonist activity comprising the anhydrous citrate according to Claim 1, in an amount effective in the treatment of emesis, and a pharmaceutically acceptable carrier. 14. A method of treating emesis which comprises administering to a subject in need of treatment an antiemetic effective amount of the anhydrous citrate of the compound according to Claim 1. 15. A method of making crystalline polymorphic Form A of (2-Benzhydryl-1-azo-bicyclo (2,2,2) oct-3-yl)-(5-isopropyl-2-methoxybenzyl)-amine citrate monohydrate comprising: dissolving anhydrous citrate in isopropyl alcohol and water; stirring the mixture overnight at room temperature; crystallizing the citrate monohydrate salt and collecting Form A by filtration; and drying at about 20 to 80 degree C under vacuum. 16. The method of claim 15 wherein the synthesis is carried out under ambient conditions for about 1.5 to 72 hours. 17. The method of clam 15, wherein large crystals of Form A with a plate like habit are grown from an isopropanol/water solution and are grown with needle-like habit in acetone/diisopropyl ether/water. 18. A method of making crystalline polymorphic Form B of (2-Benzhydryl-1-azo-bicyclo (2,2,2) oct-3-yl)-(5-isopropyl-2-methoxybenzyl)-amine citrate monohydrate comprising: concentrating a solution of the citrate monohydrate in methanol at room temperature for about 48 to 72 hours.