Crystalline form of sofpironium bromide and preparation method thereof
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.
1. A stable co-crystal Form CO of sofpironium bromide, said co-crystal Form CO comprising in a 1:3 ratio:
a) a compound shown as formula I-a
and
b) a compound shown as formula I-b
wherein the purity of co-crystal Form CO is not less than 98% w/w based on the content of the compound (I), represented by the formula (I)
wherein said co-crystal Form CO is physicochemically stable and non-hygroscopic, exhibits a single sharp endothermic peak value of 150° C. using Differential Scanning Calorimetry thermal analysis method as described in Japanese Pharmacopoeia (17 th Edition), and is characterized as 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.
2. The co-crystal Form CO 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 compound (I), wherein the compound (I) is represented by the formula (I)
3. The co-crystal Form CO of claim 1 , wherein the total content of impurities is not more than 2.0% w/w based on a content of the compound (I), wherein the compound (I) is represented by the formula (I)
4. A stable topical pharmaceutical composition which is made by mixing:
a pharmaceutically effective amount of sofpironium bromide co-crystal Form CO according to claim 1 , and
a pharmaceutically acceptable carrier.
5. The topical composition of claim 4 wherein the active pharmaceutical agent co-crystal Form CO 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 of the active pharmaceutical agent.