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

Abstract: Two crystalline polymorphic forms of (2-Benzhydryl-1-azo-bicyclo[2,2,2]Octyl-3-yl)-(5-iso-propyl-2-methoxybenzyl)amine dihydrochloride dihydrate are Form I and Form II. The pharmaceutical composition containing at least one of these polymorphs has advantageous stability for formulation to treat emesis in patients receiving chemotherapy. The administration of this pharmaceutical composition is conventional oral by preferably tablet or capsule or intravenous. A method of making Forms I and II is also disclosed.

Description: POLYMORPHS OF CRYSTALLINE (2-BENZHYDRYL-l-AZABICYCLO[2,2,23QCT-3-YL)-(5-ISO- PROPYL-2-METHOXYBENZYL)-AMMONIUMCHLORIDE AS NK-1 RECEPTOR ANTAGONISTS This invention is directed to certain polymorphs and forms of crystalline (2- Benshydryl-1-azo-bιcyclo 2,2,2 oct-3yl)-(5-ιsopropyl-2-methoxybenzyl)-amιne dihydrochloride (hereafter the dihydrochloride salt) and their pharmaceutical compositions The dihydrochloride salt is a CNS active NK-1 receptor antagonist and this invention is directed to methods of treating conditions effected or facilitated by a decrease in substance P mediated neuro-transmission This invention is also directed to a substance P antagonist which is evaluated for acute and delayed anti-emetic efficacy in a mammal including humans receiving chemotherapy Treating is defined here as preventing and treating United States Patent Number 5,393,762 and United States Serial Number 08/816,016 both incorporated by reference, describe pharmaceutical compositions and treatment of emesis using NK-1 receptor antagonists The crystalline anhydrous dihydrochloride is hygroscopic at humidities of about 52 % or greater and forms dihydrates The dihydrates do not readily dehydrate when exposed to low relative humidity of about 33% or less Summary of the Invention The present invention relates to the anhydrous dihydrochloride of (2-Benzhydryl-1- azo-bicyclo 2,2,2oct-3-yl)-(5-ιsoproyl-2-methoxybenzyl)-amιne, the dihydrochloride dihydrate and its two polymorphs In one embodiment of the invention, the anhydrous dihydrochloride is a crystalline hygroscopic single form The morphology of the anhydrous dihydrochloride is rods with particle size of about 5 to 30μm yielding birefringence A differential scanning caloπmetry (DSC) thermogram gave a sharp endotherm with an onset at 224°C, Tmax at 236°C and a ΔHf of 32 8 cal/gram In two other embodiments, the dihydrochloride dihydrate is in Form I or Form II Form I is characterized by the X-ray diffraction pattern below. Dihydrochloride Dihydrate Form I Peak No 1 2 3 4 5 6 7 8 d space 17 2 9.5 8 4 6 9 4 9 4 4 3 9 3.5 Form I of the dihydrochloride dihydrate is a nonhydroscopic single form and discloses a Differential Scanning Calorimetry thermogram with onsets at about 150°C and 230°C Form I has a solubility of about 110 to 120 milligrams per milliliter The crystalline habit of Form I is flakes with a size range of about 30μm to 60μm Form II is characterized by the X-ray diffraction pattern below Dihydrochloride Dihydrate Form II Peak No 1 2 3 4 5 6 7 8 9 d space 11.3 8.8 7 5 6.4 4.9 4.5 3.8 3 7 3 0 Form II is a lower energy, more stable form than Form I Form II has a solubility of about 390-400 milligrams per milliliter. Form ll's crystalline habit is flakes of about 15 to 25 μm. The method of making the polymorphic Form I of the dihydrochloride dihydrate comprises stirring at ambient temperature the anhydrous dihydrochloride in an organic solvent containing about 0.5 to 2 5% water for about 15 to 25 hours to effect crystallization The organic solvents are selected from ethyl or isopropyl alcohol, ethyl acetate, acetonitrile, tetrahydrofuran and acetone all containing about 0.5% to 2.5% water. The method of making the polymorphic Form II of the dihydrochloride dihydrate comprises stirring Form I or the anhydrous dihydrochloride at ambient temperature in an organic solvent containing about 3 to 5% water for about 15 to 25 hours to effect crystallization The solvents are chosen from ethyl acetate with about 5% water, tetrahydrofuran with about 5% water, acetone with about 5% water and acetonitrile with about 5% water Another aspect of the invention relates to a pharmaceutical composition having pharmaceutical activity which comprises at least one of polymorphic Forms I and II of the dihydrochloride dihydrate and the anhydrous dihydrochloride in the treatment of emesis A method of treating emesis comprises administering to a subject in need of treatment, an antiemetic effective amount of Form I or II or the anhydrous dichloπde Detailed Description of the Invention Polymorphic Form I of the dihydrochloride dihydrate may be formed by stirring the anhydrous form of the compound in an appropriate organic solvent containing 0 5% to 2 5% water for a suitable time to effect the crystallization Appropriate solvents may include the following ethyl or isopropyl alcohol, ethyl acetate, acetonitrile, tetrahydrofuran, and acetone, all containing between 0 5% to 2 5 % water Polymorphic Form II may be formed by stirring either Form I or the anhydrous form of the dihydrochloride in an appropriate organic solvent containing 3% to 5% water for a suitable time to effect the crystallization Appropriate solvents may include the following, Ethyl acetate containing 3 5% water, tetrahydrofuran (THF) containing 5% water, acetone containing 5% water and water The "wet" THF bridge resulted in complete conversion to Form II When Form I is slurπed in THF with less than 2% H 2 0 there is no conversion to Form II When Form I is slurned in THF with about 3% to 5% H 2 0, the conversion is to Form II When Form I is slurπed in THF with >5% H 2 0, solubility increases dramatically due to the high aqueous solubility Table I below shows an ambient polymorph screen with wet solvents Table I Table II below gives a polymorph characterization of Form I and Form II Table EXAMPLE 1 Preparation of crystalline anhydrous dihydrochloride A mixture of Benshydryl-1-azo-bιcyclo 2,2,2 oct-3yl)-(5-ιsopropyl-2-methoxybenzyl)- amine dihydrochloride dihydrate (10 Og) in ethylacetate (100ml) was heated at reflux in a Dean and Start apparatus for 23 hours The reaction was cooled to room temperature and stirred for 1 hour The solid was removed by filtration, washed with ethylacetate (20 ml) and dried in vacuo at 55°C with a nitrogen bleed for 24 hours to give the anhydrate as a white solid EXAMPLE 2 Preparation of the crystalline dihydrate Form I A 53 2 Kg portion of the 1-R-(-)-camphorsulfonate salt is dissolved in a mixture of 266 L of water and 266 L of methylene chloride The pH is adjusted to a range of 10-14 with 5 08 L of 50% sodium hydroxide The product rich methylene chloride layer is separated and back washed with 53 2 L of water The methylene chloride is concentrated atmospherically and is displaced by tetrahydrofran (668 4L) A 13 9 L portion of 12 N hydrochloric acid is added to the tetrahydrofuran and the mixture is heated to reflux for 3 hours The resulting slurry is cooled to 25°C to 30°C, granulated for 1 hour and the Form 1 crystal is collected by filtration EXAMPLE 3 Preparation of the crystalline dihydrate Form II A 25 Kg portion of Form I dihydrate is slurπed in THF/3%-5% water (3001 L THF+ 101 L water) at reflux (-64°C) for 48 hours The slurry is cooled to 25°C to 30°C, granulated for 1 hour and the Form II collected by filtration

Claims: WE CLAIM 1. The crystalline forms of (2-Benzhydryl-1-azo-bicyclo[2.2.2]oct-3-yl)-(5- isopropyl-2-methoxy-benzyl)-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 No. 1 2 3 4 5 6 7 8 d space 17.2 9.5 8.4 6.9 4.9 4.4 3.9 3.5 and c) a nonhygroscopic dihydrochloride dihydrate, Form II polymorph exhibiting the x-ray powder diffraction pattern Peak No. 1 2 3 4 5 6 7 8 9 d space 11.3 8.8 7.5 6.4 4.9 4.5 3.8 3.7 3.0 2 The anhydrous dihydrochlonde according to claim 1 wherein the anhydrous dihydrochlonde crystalline habits are rods 3 The anhydrous dihydrochloride according to Claim 2 wherein said rods have a particle size of about 5 to 30 μm 4 The anhydrous dihydrochloride according to Claim 1 wherein a differential scanning caloπmetry thermogram gave a sharp endothern with an onset at about 224°C temperature maximum at about 236°C and a ΔHf of about 32 8 cal/gram 5 The nonhygroscopic dihydrochlonde dihydrate polymorph according to Claim I wherein Form I's crystalline habit are flakes 6 The dihydrochlonde dihydrate polymorph according to Claim 5 wherein Form I's crystalline flake size is about 30 μm to 60 μm 7 The dihydrochloride dihydrate polymorph according to Claim 1 , wherein Form I's solubility is about 640 - 1 160 mg/ml 8 The dihydrochlonde dihydrate polymorph according to Claim 1 wherein Form I has a differential scanning caloπmetry thermogram with onsets at about 175°C and 230°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 dihydrochlonde dihydrate polymorph according to Claim 1 wherein Form ll's crystalline habit are flakes 11 The Form II polymorph according to Claim 10 wherein the crystalline flakes have a size range of about 15 to 25 μm 12 The dihydrochlonde dihydrate polymorph according to Claim 1 wherein Form II has a solubility of about 390 to 400 mg/ml 13 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 14 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 15 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 13 16 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 17 A method of treating emesis which comprise administering to a subject in need of treatment an antiemetic effective amount of the anhydrous dihydrochlonde of the compound according to Claim 16 18 A method of making crystalline dihydrochlonde dihydrate polymorphic Form I of the anhydrous dihydrochloride of (2-Benzhydryl-1-azo-bιcyclo 2,2,2 Oct-3-yl)-(5-ιsopropyl- 2-methoxybenzyl)-amιne comprising stirring at ambient temperature the anhydrous dihydrochlonde in an organic solvent containing about 0 5 to 2.5% water for about 15 25 hours to effect crystallization 19 A method of Claim 18 wherein the organic solvents are selected from ethyl alcohol, isopropyl alcohol, ethyl acetate, acetonitrile, tetrahydrofuran and acetone 20 A method of making crystalline dihydrochlonde dihydrate polymorphic Form II of the anhydrous dihydrochloride of (2-Benzhydryl-1-azo-bιcyclo 2,2,20ct-3-yl)-(5-ιsopropyl-2- methoxybenzyl)-amιne comprising stirring at ambient temperature Form I of the dihydrochloride dihydrate or the anhydrous dichlo de in an organic solvent containing about 3 to 5% water for about 15 to 25 hours to effect crystallization. 21. The method of Claim 20 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

Inventors: ALLEN DOUGLAS JOHN MELDRUM, APPLETON TROY ANTHONY, GUMKOWSKI MICHAEL JON, MUEHLBAUER DAVID JOSEPH, NORRIS TIMOTHY, ALLEN, DOUGLAS, JOHN, MELDRUM, APPLETON, TROY, ANTHONY, GUMKOWSKI, MICHAEL, JON, MUEHLBAUER, DAVID, JOSEPH, NORRIS, TIMOTHY
Applicants: ALLEN DOUGLAS JOHN MELDRUM, APPLETON TROY ANTHONY, GUMKOWSKI MICHAEL JON, MUEHLBAUER DAVID JOSEPH, NORRIS TIMOTHY, PFIZER PROD INC, ALLEN, DOUGLAS, JOHN, MELDRUM, APPLETON, TROY, ANTHONY, GUMKOWSKI, MICHAEL, JON, MUEHLBAUER, DAVID, JOSEPH, NORRIS, TIMOTHY, PFIZER PRODUCTS INC.
Application year: 2000
Main classification: C07D453
IPC codes: A61K31, A61P1, A61P25, A61P43, C07C9, C07C11, C07D453