Methods of Manufacturing Crystalline Forms of Rapamycin Analogs

Abstract

A process for preparing a crystalline rapamycin analog includes: combining the rapamycin analog with an organic medium to form a mixture; incubating the mixture until the rapamycin analog crystallizes; and recovering the crystalline rapamycin analog. The organic medium can be a solvent, and the process can include causing the rapamycin analog to dissolve into the solvent, and incubating the solvent until the rapamycin analog crystallizes. The following can also be performed: forming a slurry of crystalline rapamycin analog; stirring the rapamycin analog mixture until the rapamycin analog crystallizes; saturating the rapamycin analog solution; forming a supersaturated rapamycin analog solution; combining an antisolvent with the rapamycin analog and the solvent to form a biphasic mixture, and incubating the biphasic mixture to cause a liquid-liquid phase split.

1 . A pharmaceutical composition comprising:
 a pharmaceutically acceptable carrier; and   a therapeutically effective amount of a crystalline form of a compound, or a pharmaceutically acceptable salt thereof, having a structure of Formula 4:   
       
         
           
           
               
               
           
         
       
     
     
         2 . The composition of  claim 1 , wherein the crystalline compound or salt thereof is a solvate or a desolvate thereof. 
     
     
         3 . The composition of  claim 2 , wherein the solvate comprises a solvent selected from the group consisting of acetone, ethyl acetate, methanol, ethanol, n-propanol, isopropanol, isobutanol, tertbutanol, 2-butanol, acetronitrile, tetrahydrofuran, isobutyl acetate, n-butyl acetate, ethyl formate, n-propyl acetate, isopropyl acetate, methylethyl ketone, toluene, N,N dimethyl formamide, anisole, methyl isopropyl ketone, nitromethane, propionitrile, 2-butanone, 1,2-dimethoxyethane, and combinations thereof. 
     
     
         4 . The composition of  claim 2 , wherein the crystalline form of the compound or salt thereof is a solvate having a form according to the X-ray diffraction pattern substantially as shown in one of the following:
   FIG. 2A ;     FIG. 2B ;     FIG. 4A ;     FIG. 4B ;     FIG. 5A ;     FIG. 5B ;     FIG. 7A ;     FIG. 7B ;     FIG. 9A ;     FIG. 9B ;     FIG. 10A ;     FIG. 10B ;     FIG. 11A ;     FIG. 11B ;     FIG. 13A ;     FIG. 14A ;     FIG. 16 ;     FIG. 15A ;     FIG. 12A ;     FIG. 17A ;     FIG. 18A ;     FIG. 19A ;     FIG. 20A ; or     FIG. 21A .   
     
     
         5 . The composition of  claim 2 , wherein the crystalline form of the compound or salt thereof is a desolvate having a form according to the X-ray diffraction pattern substantially as shown in one of the following:
   FIG. 3A ;     FIG. 3B ;     FIG. 6A ;     FIG. 6B ;     FIG. 4E ;     FIG. 13B ;     FIG. 14B ;     FIG. 15B ;     FIG. 8 ;     FIG. 12B ;     FIG. 17B ;     FIG. 18B ;     FIG. 19B ;     FIG. 20B ; or     FIG. 21B .   
     
     
         6 . The composition of  claim 5 , wherein the crystalline form or salt thereof is an acetonitrile solvate or a desolvate thereof, an acetone solvate or a desolvate thereof, a toluene solvate, an ethyl formate solvate, a hydrate, an isopropyl solvate, an isobutyl solvate, an ethanol solvate, a N,N-dimethyl formamide solvate, or an anisole solvate. 
     
     
         7 . The composition of  claim 1 , further comprising a second pharmacological agent. 
     
     
         8 . The composition of  claim 7 , wherein the second pharmacological agent is selected from the group consisting of anti-proliferative agents, anti-platelet agents, anti-inflammatory agent, anti-thrombotic agents, and thrombolytic agents. 
     
     
         9 . The composition of  claim 8 , wherein the anti-proliferative agent is an anti-mitotic agent. 
     
     
         10 . The composition of  claim 9 , wherein the anti-mitotic agent is a vinca alkaloid or an alkylating agent. 
     
     
         11 . The composition of  claim 8 , wherein the anti-proliferative agent is selected from the group consisting of vincristine, paclitaxel, etoposide, nocodazole, indirubin, anthracycline derivatives, tauromustine, bofumustine, and fotemustine, and anti-mitotic metabolites. 
     
     
         12 . The composition of  claim 8 , wherein the anti-platelet agent is selected from the group consisting of eptifibatide, tirofiban, RGD-base peptides, disagregin, and cilostazol. 
     
     
         13 . The composition of  claim 8 , wherein the anti-inflammatory agent is selected from the group consisting of prednisone, dexamethasone, hydrocortisone, estradiol, fluticasone, clobetasol, acetaminophen, ibuprofen, naproxen, and sulindac. 
     
     
         14 . A method of treating intimal smooth muscle cell hyperplasia, restenosis, or vascular occlusion in mammals, comprising administering the pharmaceutical composition of  claim 1  to a subject in need thereof. 
     
     
         15 . A method of treating intimal smooth muscle cell hyperplasia, restenosis, or vascular occlusion in mammals, comprising administering the pharmaceutical composition of  claim 8  to a subject in need thereof. 
     
     
         16 . A process for preparing a crystalline form of a compound of Formula 4: 
       
         
           
           
               
               
           
         
       
       the process comprising:
 combining the compound with at least one organic solvent to form a mixture; and 
 incubating the mixture until the compound crystallizes. 
 
     
     
         17 . The process of  claim 16 , further comprising causing the compound to dissolve into the organic solvent. 
     
     
         18 . The process of  claim 16 , further comprising recovering the crystalline compound from the organic solvent. 
     
     
         19 . The process of  claim 1 , further comprising:
 combining at least one antisolvent with the compound and the solvent to form a biphasic mixture; and   incubating the biphasic mixture to cause a liquid-liquid phase split with a majority of the compound being in the solvent and a minority of the compound being in the antisolvent.   
     
     
         20 . The process of  claim 4 , further comprising separating the organic solvent from the antisolvent.