Polymorphic forms of nateglinide

Abstract

Provides are crystalline forms of nateglinide, labeled Forms A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, U, V, Y, α, β, γ, δ, ε, σ, θ and Ω, processes for their preparation and processes for preparation of other crystalline forms of nateglinide. Also provided are their pharmaceutical formulations and methods of administration.

1 . A crystalline form of nateglinide (Form L) characterized by data selected from the group consisting of: an XRPD pattern with peaks at 17.6, 17.9 and 19.6±0.2 degrees 2θ, a DSC thermogram with endotherms at about 131 and 138° C. and an FTIR spectrum with peaks at about 1741, 1726, 1621, 1600, 1538, 1211, 1191 cm −1 . 
   
   
       2 . The crystalline form of  claim 1 , wherein the crystalline form is characterized by an XRPD pattern with peaks at 17.6, 17.9 and 19.6±0.2 degrees 2θ. 
   
   
       3 . The crystalline form of  claim 2 , wherein the crystalline form has an XRPD pattern as substantially depicted in  FIG. 10 . 
   
   
       4 . The crystalline form of  claim 1 , wherein the crystalline form is stable when heated at a temperature of about 100° C. for at least about 8 hours. 
   
   
       5 . A process for preparing nateglinide of  claim 1  comprising the step of heating a nateglinide selected from the group consisting of Form D, M and N for a sufficient amount of time to obtain the nateglinide of  claim 1 . 
   
   
       6 . A process for preparing nateglinide of  claim 1  comprising the step of storing nateglinide Form I at a suitable temperature for a sufficient time to obtain the nateglinide of  claim 1 . 
   
   
       7 . A crystalline form of nateglinide (Form P) characterized by data selected from the group consisting of: an XRPD pattern with peaks at 4.0, 4.6, 13.4, 13.9 and 19.1±0.2 degrees 2θ; an FTIR spectrum with peaks at about 3309, 1748, 1589 cm −1 ; and a DSC thermogram with endotherms at about 106 and 128° C. and an exotherm at about 113° C. 
   
   
       8 . The crystalline form of  claim 7 , wherein the crystalline form is characterized by an XRPD pattern with peaks at 4.0, 4.6, 13.4, 13.9 and 19.1±0.2 degrees 2θ. 
   
   
       9 . The crystalline form of  claim 8 , wherein the crystalline form has an XRPD pattern as substantially depicted in  FIG. 14 . 
   
   
       10 . A process for preparing the crystalline nateglinide of  claim 7  comprising the steps of:
 a) triturating nateglinide in a solvent selected from the group consisting of acetone, nitromethane and acetonitrile to obtain the crystalline form of  claim 7 , with the proviso that the nateglinide triturated in nitromethane is not Form H; and   b) recovering the crystalline form of nateglinide.   
   
   
       11 . The process of  claim 10 , wherein the nateglinide triturated is Form H and the solvent is acetonitrile. 
   
   
       12 . The process of  claim 10 , wherein the nateglinide triturated is Form U and the solvent is acetone or nitromethane. 
   
   
       13 . A process for preparing nateglinide of  claim 7  comprising the step of heating nateglinide Form epsilon for a sufficient amount of time at a suitable temperature. 
   
   
       14 . A crystalline form of nateglinide (Form α) characterized by data selected from the group consisting of: an XRPD pattern with peaks at 4.8, 5.1, 19.0, 19.4, 27.2, 28.9 and 31.2±0.2 degrees 2θ; a DSC thermogram with an endotherm at about 129° C.; and an FTIR spectrum with peaks at about 3283, 1711, 1646, 1420, 1238 cm −1 . 
   
   
       15 . The crystalline form of nateglinide of  claim 14 , wherein the crystalline form is characterized by an XRPD pattern with peaks at 4.8, 5.1, 19.0, 19.4, 27.2, 28.9 and 31.2±0.2 degrees 2θ. 
   
   
       16 . The crystalline form of  claim 15 , wherein the crystalline form has an XRPD pattern as substantially depicted in  FIG. 21 . 
   
   
       17 . The crystalline form of  claim 14 , wherein the crystalline form is stable when heated to a temperature of about 60° C. for about 8 hours. 
   
   
       18 . A process for preparing crystalline nateglinide of  claim 14  comprising the steps of:
 a) triturating nateglinide in a solvent selected from the group consisting of methanol, n-butanol and ethanol to obtain the crystalline form of  claim 14 , with the proviso that the nateglinide triturated is not Form H; and   b) recovering the nateglinide Form α.   
   
   
       19 . The process of  claim 18 , wherein the nateglinide triturated is Form U. 
   
   
       20 . A process for preparing crystalline form of nateglinide of  claim 14  comprising the steps of:
 a) preparing a solution of nateglinide in a solvent selected from the group consisting of n-propanol, n-butanol, isopropyl alcohol and acetonitrile;   b) crystallizing the crystalline form from the solution; and   c) recovering the crystalline form of  claim 14 .   
   
   
       21 . A process for preparing crystalline nateglinide of  claim 14  comprising the step of heating a form of nateglinide selected from the group consisting of Form K and Form C for a sufficient time to obtain the crystalline form. 
   
   
       22 . A process for preparing a mixture of crystalline nateglinide Form α and Form H comprising the step of triturating a nateglinide in a solvent selected from the group consisting of methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone and dimethyl ethane. 
   
   
       23 . The process of  claim 22 , wherein the nateglinide triturated is crystalline Form U. 
   
   
       24 . A pharmaceutical formulation comprising a crystalline form selected from the group consisting of nateglinide Form L, P, alpha, and a pharmaceutically acceptable excipient. 
   
   
       25 . A method for lowering blood sugar level in a mammal comprising administering the pharmaceutical formulation of  claim 24  to the mammal.