Polymorphic form of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4h-pyrido[1,2-alpha]pyrimidin-4-one and formulations thereof

#1. Field of the Invention

#The present invention relates to compositions and methods of preparing novel forms of the free base of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-α]pyrimidin-4-one (hereinafter referred to by its common name “risperidone”).

#2. Description of Related Art

#FIG. 1 shows an ORTEP drawing of the contents of the asymmetric unit of Form A risperidone;

#FIG. 2 shows an ORTEP drawing of the contents of the asymmetric unit of Form B risperidone;

#FIG. 3 shows an ORTEP drawing comparison of two unique molecules in the single crystal structure of Form A risperidone to Form B risperidone viewed along the C12-C8-C9 plane;

#It has been discovered that risperidone drug substance, generally used to prepare RISPERDAL and potential generic drugs thereto (risperidone API), has not been fully investigated and characterized as only one particular crystalline form of risperidone (Form B) has previously been reported. It has been unexpectedly discovered that risperidone API drug substance may be prepared so that novel Form A is present by itself or in combination with other forms of risperidone. The two identified polymorphs, novel Form A and previously identified Form B, are correlated to the relative melting point of each polymorph in risperidone, from lowest to highest. Novel Form A also may be combined with other forms of risperidone, such as amorphous risperidone (i.e., risperidone without any particular crystalline form).

#Preparation of risperidone, 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-α]pyrimidin-4-one, is described in U.S. Pat. No. 4,804,663. The compositions of the present invention are preferably prepared by using such risperidone API as the starting material in the processes used to prepare the API compositions of the present invention. The recrystallization and heating methods set forth below can be used as the final steps in many crystallization processes for the preparation of risperidone. Preferred methods for the preparation of Form A are set forth below, but are not intended to limit the scope of the present invention. The present invention is directed to polymorphic Form A of risperidone, and combinations thereof with other polymorphic forms, and mixtures therewith, the preparation thereof, pharmaceutical formulations thereof, and the use of such polymorphs, preferably in pharmaceutical formulations, for the therapeutic treatment of subjects in need of treatment. The polymorphic forms of the present invention were characterized using single crystal X-ray crystallography (XRC), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) and High Performance Liquid Chromatography (HPLC) analysis as discussed below. Characterization with some of these methods reveals distinctive features for each particular polymorphic form. For example, pure Form A provides a distinct range of significant peaks when analyzed by XRD. These significant peaks will be present with XRD analysis for pure Form A as well as for samples containing Form A in combination with other polymorphic forms of risperidone.

#It has further been discovered that Form A can be prepared in pure or substantially pure polymorphic form in robust, controllable, synthetic processes. Substantially pure Form A is defined by an amount of Form A wherein the amount of risperidone polymorphs other than Form A does not exceed an amount greater than about ten percent (w/w) and, preferably, does not exceed an amount greater than about five percent (w/w).