Crystalline forms of the tri-mesylate salt of perphenazine-gaba and process of producing the same

Abstract

Novel crystalline form of perphenazine 4-aminobutyrate trimesylate and a process of producing the same are disclosed. The novel crystalline form is characterized by a unique XRPD pattern and a DSC that exhibits an endothermic peak at a relatively high temperature (e.g., higher than 209° C.). Also disclosed are a process of preparing perphenazine 4-aminobutyrate trimesylate by in situ deprotection and salification, in a single-step synthesis, and a highly pure perphenazine 4-aminobutyrate trimesylate obtained thereby. Uses of any of the described perphenazine 4-aminobutyrate trimesylate are also disclosed.

What is claimed is: 
     
         1 . A crystalline form of perphenazine 4-aminobutyrate trimesylate, having at least one of:
 (a) an X-Ray Powder Diffraction (XRPD) pattern exhibiting at least five of the peaks shown in  FIG. 2 ; and   (b) a Differential Scanning Calorimetry (DSC) exhibiting an endothermic peak at or higher than about 209° C.   
     
     
         2 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 1 , wherein said endothermic peak is at about 214° C. 
     
     
         3 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 1 , having an X-Ray Powder Diffraction (XRPD) pattern exhibiting at least six of the peaks shown in  FIG. 2 . 
     
     
         4 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 1 , having an X-Ray Powder Diffraction (XRPD) pattern exhibiting at least seven of the peaks shown in  FIG. 2 . 
     
     
         5 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 1 , having an X-Ray Powder Diffraction (XRPD) pattern substantially identical to one or more of the XRPD patterns shown in  FIG. 2 . 
     
     
         6 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 1 , having an X-Ray Powder Diffraction (XRPD) pattern substantially identical to one or more of the XRPD patterns shown in  FIGS. 3A-3I . 
     
     
         7 . A crystalline form of perphenazine 4-aminobutyrate trimesylate having an X-Ray Powder Diffraction (XRPD) pattern exhibiting at least five of the peaks shown in  FIG. 2 . 
     
     
         8 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 7 , having an X-Ray Powder Diffraction (XRPD) pattern exhibiting at least six of the peaks shown in  FIG. 2 . 
     
     
         9 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 7 , having an X-Ray Powder Diffraction (XRPD) pattern exhibiting at least seven of the peaks shown in  FIG. 2 . 
     
     
         10 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 7 , having an X-Ray Powder Diffraction (XRPD) pattern substantially identical to one or more of the XRPD patterns shown in  FIG. 2 . 
     
     
         11 . A crystalline form of perphenazine 4-aminobutyrate trimesylate having an X-Ray Powder Diffraction (XRPD) pattern exhibiting at least five of the peaks selected from the group consisting of 2Θ values (in units of degrees) of about 4.7, 5.4, 6.4, 7.8, 12.8, 14.0, 15.3, 15.7, 16.0, 16.1, 16.9, 17.7, 18.0, 19.7, 20.0, 20.6, 21.0, and 21.2. 
     
     
         12 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 11 , having an X-Ray Powder Diffraction (XRPD) pattern exhibiting at least six of the peaks selected from the group consisting of 2Θ values (in units of degrees) of about 4.7, 5.4, 6.4, 7.8, 12.8, 14.0, 15.3, 15.7, 16.0, 16.1, 16.9, 17.7, 18.0, 19.7, 20.0, 20.6, 21.0, and 21.2. 
     
     
         13 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 11 , having an X-Ray Powder Diffraction (XRPD) pattern exhibiting at least seven of the peaks selected from the group consisting of 2Θ values (in units of degrees) of about 4.7, 5.4, 6.4, 7.8, 12.8, 14.0, 15.3, 15.7, 16.0, 16.1, 16.9, 17.7, 18.0, 19.7, 20.0, 20.6, 21.0, and 21.2. 
     
     
         14 . A crystalline form of perphenazine 4-aminobutyrate trimesylate, having an X-Ray Powder Diffraction (XRPD) pattern substantially identical to one or more of the XRPD patterns shown in  FIGS. 3A-3I . 
     
     
         15 . A crystalline form of perphenazine 4-aminobutyrate trimesylate having a Differential Scanning Calorimetry (DSC) exhibiting an endothermic peak at or higher than about 209° C. 
     
     
         16 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 15 , wherein said endothermic peak is at about 214° C. 
     
     
         17 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 1 , having a purity greater than 99%, as determined by HPLC area percentage measurements. 
     
     
         18 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 1 , having an average particle size smaller than 100 microns. 
     
     
         19 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 18 , wherein said average particle size is smaller than 10 microns. 
     
     
         20 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 1 , being generally shaped as needles and spherulite fragments exhibiting birefringence with extinction. 
     
     
         21 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 1 , being generally shaped as needles. 
     
     
         22 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 1 , having a surface area higher than 2.5 m 2 /g. 
     
     
         23 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 22 , having a surface area that ranges from 4.5 m 2 /g to 5 m 2 /g. 
     
     
         24 . The crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 1 , prepared by reacting N-protected perphenazine 4-aminobutyrate and methanesulfonic acid, in the presence of a mixture of acetonitrile and butyl acetate as a solvent. 
     
     
         25 . A process for preparing the crystalline form of  claim 1 , the process comprising reacting an N-protected perphenazine 4-aminobutyrate and methanesulfonic acid, in the presence of a mixture of acetonitrile and butyl acetate, thereby producing the crystalline form of perphenazine 4-aminobutyrate trimesylate. 
     
     
         26 . The process of  claim 25 , wherein said N-protected perphenazine 4-aminobutyrate comprises t-butoxycarbonyl as an N-protecting group. 
     
     
         27 . The process of  claim 25 , wherein said reacting comprises:
 (i) dissolving said N-protected perphenazine 4-aminobutyrate in said mixture of acetonitrile and butyl acetate; and   (ii) adding a solution of methanesulfonic acid in acetonitrile to the solution of said N-protected perphenazine 4-aminobutyrate in said mixture of acetonitrile and butyl acetate.   
     
     
         28 . The process of  claim 27 , wherein the solution of said N-protected perphenazine 4-aminobutyrate in said mixture of acetonitrile and butyl acetate is heated to about 40° C. 
     
     
         29 . The process of  claim 25 , further comprising isolating the crystalline form of perphenazine 4-aminobutyrate trimesylate from the reaction mixture. 
     
     
         30 . The process of  claim 25 , further comprising purifying the perphenazine 4-aminobutyrate trimesylate salt. 
     
     
         31 . A process for preparing perphenazine 4-aminobutyrate trimesylate, the process comprising reacting an N-protected perphenazine 4-aminobutyrate and methanesulfonic acid, in the presence of a mixture of acetonitrile and butyl acetate, thereby producing perphenazine 4-aminobutyrate trimesylate. 
     
     
         32 . The process of  claim 31 , wherein said N-protected perphenazine 4-aminobutyrate comprises t-butoxycarbonyl as an N-protecting group. 
     
     
         33 . The process of  claim 31 , wherein said reacting comprises:
 (i) dissolving said N-protected perphenazine 4-aminobutyrate in said mixture of acetonitrile and butyl acetate; and   (ii) adding a solution of methanesulfonic acid in acetonitrile to the solution of said N-protected perphenazine 4-aminobutyrate in said mixture of acetonitrile and butyl acetate.   
     
     
         34 . The process of  claim 33 , wherein the solution of said N-protected perphenazine 4-aminobutyrate in said mixture of acetonitrile and butyl acetate is heated to about 40° C. 
     
     
         35 . The process of  claim 31 , further comprising isolating the perphenazine 4-aminobutyrate trimesylate from the reaction mixture. 
     
     
         36 . The process of  claim 31 , further comprising purifying the perphenazine 4-aminobutyrate trimesylate. 
     
     
         37 . The process of  claim 31 , wherein the perphenazine 4-aminobutyrate trimesylate has a purity higher than 99%, as determined by area percentage in HPLC measurements. 
     
     
         38 . The process of  claim 31 , wherein the perphenazine 4-aminobutyrate trimesylate is in a crystalline form, and when said crystalline form is characterized by Differential Scanning Calorimetry (DSC), said crystalline form exhibits an endothermic peak at or higher than 209° C. 
     
     
         39 . A perphenazine 4-aminobutyrate trimesylate having a purity higher than 99%, as determined by area percentage in HPLC measurements, prepared by the process of  claim 31 . 
     
     
         40 . A pharmaceutical composition comprising the crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 1  and at least one pharmaceutically acceptable carrier. 
     
     
         41 . The pharmaceutical composition of  claim 40 , packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment of a CNS disease or disorder. 
     
     
         42 . A method of treating a CNS disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 1 , thereby treating the CNS disease or disorder. 
     
     
         43 . The method of  claim 42 , wherein said CNS disease or disorder is Schizophrenia. 
     
     
         44 . A method of improving cognitive function, the method comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form of perphenazine 4-aminobutyrate trimesylate of  claim 1 , thereby improving cognitive function. 
     
     
         45 . A method of treating a CNS disease or disorder, the method comprising administering to a subject in need thereof the pharmaceutical composition of  claim 40 , thereby treating the CNS disease or disorder. 
     
     
         46 . A method of improving cognitive function, the method comprising administering to a subject in need thereof the pharmaceutical composition of  claim 40 , thereby improving cognitive function.