Claims for Patent: 11,584,715

Summary for Patent: 11,584,715

Title:	Crystalline form of sofpironium bromide and preparation method thereof
Abstract:	A cocrystal containing the 1′R-diastereomer and the 1′S-diastereomer of sofpironium bromide at a ratio of 1:3 (Form CO), a crystal mixture (for example, Form B) containing Form CO and a crystalline form of the 1′R-diastereomer (Form MN), and a method for preparing sofpironium bromide, which is suitable for manufacture of the crystal mixture are provided. Form CO and a crystalline form of sofpironium bromide containing Form CO (for example, Form B) have superior stability without hygroscopic property, and accordingly they can be preferably used as a raw material of medicaments.
Inventor(s):	Kazuyoshi MARUBAYASHI, Masahito Watanabe, Herbert R. Brinkman
Assignee:	Kaken Pharmaceutical Co Ltd, Botanix Sb Inc
Application Number:	US17/364,445
Patent Claims:	1. Sofpironium bromide crystal Form B characterized by showing peaks at 5.9±0.2, 7.2±0.2, 7.7±0.2, 11.1±0.2, 22.3±0.2, and 24.6±0.2 as diffraction angles 2θ in a powder X-ray diffraction spectrum, wherein Form B is a mixture of a) sofpironium bromide cocrystal Form CO, and b) sofpironium bromide crystal Form MN, wherein said cocrystal Form CO comprises, in a 1:3 ratio: a compound shown as formula I-a and a compound shown as formula I-b wherein the cocrystal Form CO has a purity of not less than 98% w/w based on the content of the compound (I), represented by the formula (I) said cocrystal Form CO being characterized by showing peaks at 5.9±0.2, 7.6±0.2, 11.0±0.2, and 22.2±0.2 degrees as diffraction angles 2θ in a powder X-ray diffraction spectrum and has a single sharp endothermic peak value of 150° C. using a thermal analysis method as described in Japanese Pharmacopoeia (17th Edition); and wherein said sofpironium bromide crystal Form MN, which is a single crystal form of formula I-a, is characterized by showing peaks at 7.1±0.1, 21.4±0.1, 22.3±0.1, and 24.5±0.1 as diffraction angles 2θ in a powder X-ray diffraction spectrum. 2. The crystal Form B of claim 1, wherein the crystal Form B is not hygroscopic. 3. The crystal Form B of claim 1, wherein the crystal form is a physicochemically stable crystalline form. 4. The crystal Form B of claim 1, wherein the purity of the crystal form is not less than 98% w/w based on the content of the compound (I), wherein the compound (I) is represented by the formula (I) 5. The crystal Form B of claim 1, wherein a content of each compound represented by formulae III, IV and V is not more than 0.5% w/w based on a content of the crystal compound (I), wherein the compound (I) is represented by the formula (I) 6. The crystal Form B of claim 1, wherein the total content of impurities is not more than 2.0% w/w based on a content of compound (I), wherein the compound (I) is represented by the formula (I) 7. The crystal Form B of claim 1 not containing a crystal Form MJ, wherein crystal Form MJ is a crystal form of compound I-b represented by the formula: and characterized by showing peaks at 6.7±0.2, 9.6±0.2, 15.1±0.2, 19.2±0.2, 20.1±0.2, and 21.7±0.2 as diffraction angles 2θ in a powder X-ray diffraction spectrum. 8. The crystal Form B of claim 1, wherein the crystal Form B is prepared by the steps of: preparing a suspension of sofpironium bromide in a solvent comprising ethyl acetate and methyl t-butyl ether, and stirring the suspension for at least 1 hour, and filtering the suspension to obtain the crystalline Form B. 9. A stable topical pharmaceutical composition comprising: a pharmaceutically effective amount of sofpironium bromide Form B of claim 1, in a pharmaceutically acceptable carrier. 10. The topical composition of claim 9 wherein the composition comprising Form B is prepared by the steps of: preparing a suspension of sofpironium bromide in a solvent comprising ethyl acetate and methyl t-butyl ether, and stirring the suspension for at least 1 hour, and filtering the suspension to obtain the crystalline Form B of the active pharmaceutical agent; and adding the crystal Form B to a pharmaceutically acceptable carrier.