Novel crystal forms, methods for their preparation and method for preparation of olanzapine

Abstract

The invention is directed to a series of novel crystalline olanzapine forms, in particular hydrated and solvated crystalline forms of olanzapine, methods of use in pharmaceutical compositions, and method of treating psychiatric disorders using the crystalline forms. One series of the crystalline forms are hydrates, i.e. water containing crystals, wherein water may be present in a ratio of about 2:1.5 to a ratio of about 1:3 olanzapine:water, while another includes solvates such as an isobutanol solvate. The olanzapine crystalline forms include Forms H, G, Y, X, K, S, Q, Z, and J.

1 . Crystalline olanzapine isobutanol solvate.  
   
   
       2 . A crystalline form of olanzapine characterized by a powder X-ray diffraction pattern having peaks at about 8.7, 18.4, 19.2, 20.0, 21.1, 21.6, 22.4, 23.1, 23.6 and 24.0, ±0.2 degrees two-theta.  
   
   
       3 . The crystalline form according to  claim 2 , having additional peaks in the powder X-ray diffraction pattern at about 10.4, 12.5, 14.1, 14.7, 17.2, 17.9, 24.9 and 25.4±0.2 degrees two-theta.  
   
   
       4 . The crystalline form of olanzapine according to  claim 3 , having a powder X-ray diffraction pattern substantially as depicted in  FIG. 1 .  
   
   
       5 . The crystalline form of olanzapine according to  claim 2 , which is an isobutanol solvate.  
   
   
       6 . A process for preparing the crystalline form of olanzapine of  claim 2  comprising the steps of dissolving olanzapine in isobutanol, cooling the mixture, and isolating the crystals.  
   
   
       7 . A crystalline form of olanzapine characterized by a powder X-ray diffraction pattern having peaks at about 6.6, 9.0, 16.4, 17.9, 18.6, 18.8, 19.6, 22.8 and 25.2, ±0.2 degrees two-theta.  
   
   
       8 . The crystalline form according to  claim 7 , having additional peaks in the powder X-ray diffraction pattern at about 14.3, 14.8, 20.5, 23.2, 23.8, 24.2±0.2 degrees two-theta.  
   
   
       9 . The crystalline form of olanzapine according to  claim 8 , having a powder X-ray diffraction pattern substantially as depicted in  FIG. 2 .  
   
   
       10 . The crystalline form of olanzapine according to  claim 7 , which is a dihydrate.  
   
   
       11 . A process for preparing the crystalline form of olanzapine of  claim 7  comprising the steps of creating a slurry of olanzapine dihydrate in methyl tertiary-butyl ether, stirring the mixture, and isolating the crystals.  
   
   
       12 . A crystalline form of olanzapine characterized by a powder X-ray diffraction pattern having peaks at about 8.4, 8.8, 9.3, 16.9, 18.4, 19.4, 20.1, 22.2, 23.1, 23.8 and 25.2, ±0.2 degrees two-theta.  
   
   
       13 . The crystalline form according to  claim 12 , having additional peaks in the powder X-ray diffraction pattern at about 14.2, 14.5 and 18.9±0.2 degrees two-theta.  
   
   
       14 . The crystalline form of olanzapine according to  claim 13 , having a powder X-ray diffraction pattern substantially as depicted in  FIG. 3 .  
   
   
       15 . The crystalline form of olanzapine according to  claim 12 , which is a hydrate.  
   
   
       16 . A process for preparing the crystalline form according to  claim 12  comprising the steps of: 
 a) dissolving olanzapine in methylene chloride to form a solution;    b) adding cyclohexane to the solution;    c) cooling the solution; and    d) isolating the crystals.    
   
   
       17 . The process of  claim 16 , wherein the solution is formed by heating.  
   
   
       18 - 26 . (canceled)  
   
   
       27 . Crystalline olanzapine trihydrate.  
   
   
       28 . A crystalline form of olanzapine characterized by a powder X-ray diffraction pattern having peaks at about 8.8, 13.7, 16.3, 18.4, 19.6, 20.2 and 22.4±0.2 degrees two-theta.  
   
   
       29 . The crystalline form according to  claim 28 , having additional peaks in the powder X-ray diffraction pattern at about 15.1, 15.3, 23.0, 24.0, 24.4, 25.1 and 29.7±0.2 degrees two-theta.  
   
   
       30 . The crystalline form of olanzapine according to  claim 29 , having a powder X-ray diffraction pattern substantially as depicted in  FIG. 5 .  
   
   
       31 . The crystalline form of olanzapine according to  claim 28 , which is a trihydrate.  
   
   
       32 . A process for preparing the crystalline form according to  claim 28  comprising the steps of: 
 a) dissolving olanzapine in a solution of acetic acid and water;    b) filtering the solution;    c) stirring the solution;    d) precipitating the crystalline form by adding a base; and    e) isolating the crystals.    
   
   
       33 . The process of  claim 32 , wherein step (c) is carried out at a temperature of about 20° C.  
   
   
       34 . The process of  claim 32 , wherein the base is ammonium hydroxide.  
   
   
       35 . The process of  claim 32 , wherein the base is added to reach a pH prior to step (e) of about 9.8.  
   
   
       36 . A crystalline form of olanzapine characterized by a powder X-ray diffraction pattern having peaks at about 8.6, 10.3, 11.4, 14.6, 19.8, 21.0, 21.5, 22.3, 23.9 and 29.7, ±0.2 degrees two-theta.  
   
   
       37 . The crystalline form according to  claim 36 , having additional peaks in the powder X-ray diffraction pattern at about 12.5, 17.0, 17.8, 19.0 and 25.2±0.2 degrees two-theta.  
   
   
       38 . The crystalline form of olanzapine according to  claim 37 , having a powder X-ray diffraction pattern substantially as depicted in  FIG. 9 .  
   
   
       39 . The crystalline form of olanzapine according to  claim 36 , which is a dihydrate.  
   
   
       40 . A process for preparing the crystalline form according to  claim 36  comprising the steps of heating Form X olanzapine at a temperature of at least about 100° C.  
   
   
       41 . The process of  claim 40 , wherein the temperature is about 160° C.  
   
   
       42 - 50 . (canceled)  
   
   
       51 . A crystalline form of olanzapine characterized by a powder X-ray diffraction pattern having peaks at about 8.8, 18.1, 18.8, 19.3, 22.9, 23.3 and 24.8±0.2 degrees two-theta.  
   
   
       52 . The crystalline form according to  claim 51 , having additional peaks in the powder X-ray diffraction pattern at about 8.2, 12.8, 13.8, 14.3, 14.9, 24.3 and 25.7±0.2 degrees two-theta.  
   
   
       53 . The crystalline form of olanzapine according to  claim 52 , having a powder X-ray diffraction pattern substantially as depicted in  FIG. 6 .  
   
   
       54 . The crystalline form of olanzapine according to  claim 51 , which is a dihydrate.  
   
   
       55 . A process for preparing the crystalline form according to  claim 51  comprising the steps of: 
 a) dissolving olanzapine in an organic solvent;    b) adding water;    c) cooling the solution; and    d) isolating the crystals.    
   
   
       56 . The process of  claim 55 , wherein the organic solvent is at least one of DMSO, dioxane, or acetone.  
   
   
       57 . The process of  claim 55 , wherein the organic solvent in step (a) is heated to about 80° C.  
   
   
       58 . A crystalline form of olanzapine characterized by a powder X-ray diffraction pattern having peaks at about 9.0, 16.3, 18.5, 19.6, 20.0, 20.4, 22.8, 24.2, and 25.6±0.2 degrees two-theta.  
   
   
       59 . The crystalline form according to  claim 58 , having additional peaks in the powder X-ray diffraction pattern at about 17.1, 17.5, 21.2, 23.4, 23.7 and 27.6±0.2 degrees two-theta.  
   
   
       60 . The crystalline form of olanzapine according to  claim 59 , having a powder X-ray diffraction pattern substantially as depicted in  FIG. 7 .  
   
   
       61 . The crystalline form of olanzapine according to  claim 58 , which is a dihydrate.  
   
   
       62 . A process for preparing the crystalline form according to  claim 58  comprising the steps of: 
 a) dissolving olanzapine in a mixture of ethylacetate and toluene;    b) heating the mixture;    c) cooling the mixture;    d) adding water to the mixture;    e) cooling the mixture; and    f) isolating the crystals.    
   
   
       63 . The process of  claim 62 , wherein the mixture is heated to about 80° C.  
   
   
       64 . The process of  claim 62 , wherein the mixture in step (c) is cooled to about 60° C.  
   
   
       65 . The process of  claim 62 , wherein the mixture in step (e) is cooled to room temperature.  
   
   
       66 . A process for preparing olanzapine crystalline Form II comprising drying the form of  claim 2 ,  claim 7 , or  claim 51 .  
   
   
       67 . A process for preparing olanzapine crystalline Form V comprising drying the form of  claim 12 .  
   
   
       68 . A pharmaceutical composition comprising the forms selected from the group consisting of Forms H, G, X, K, Q and J and a pharmaceutically acceptable excipient.