CRYSTALLINE ANHYDRATE FORMS OF A PHARMACEUTICAL
The invention provides and describes solid state 17α-ethynyl-androst-5-ene-3β,7β,17β-triol including amorphous and crystalline forms and specific polymorphic forms thereof. Anhydrates and solvates of 17α-ethynyl-androst-5-ene-3β,7β,17β-triol include Form I anhydrate and Form IV and Form V solvates. The invention further relates to solid and suspension formulations containing 17α-ethynyl-androst-5-ene-3β,7β,17β-triol in a described solid state form and use of the formulations to treat hyperglycemic conditions, such as type 2 diabetes and metabolic syndrome, and autoimmune conditions, such as rheumatoid arthritis, ulcerative colitis and type 1 diabetes, among other inflammation related conditions in subjects or human patients. The invention also relates to methods to make liquid formulations from solid state forms of 17α-ethynyl-androst-5-ene-3β,7β,17β-triol and uses of such formulations in treating the described conditions.
1 . Crystalline anhydrate 17α-ethynylandrost-5-ene-3β,7β,17β-triol.
2 . The crystalline anhydrate 17α-ethynylandrost-5-ene-3β,7β,17β-triol of claim 1 substantially free of amorphous 17α-ethynylandrost-5-ene-3β,7β,17β-triol.
3 . A method to make a crystalline anhydrate 17α-ethynylandrost-5-ene-3β,7β,17β-triol of claim 1 wherein the crystalline anhydrate is Form II 17α-ethynyl-androst-5-ene-3β,7β,17β-triol comprising the steps of
a) slurrying crystalline anhydrate Form I 17α-ethynyl-androst-5-ene-3β,7β,17β-triol in ethyl acetate or methylethylketone;
b) separating the solid and liquid phases of the slurry obtained from step (a); and
c) evaporating the solvent from the liquid phase obtained from step (b),
whereby crystalline anhydrate Form II 17α-ethynyl-androst-5-ene-3β,7β,17β-triol is obtained.
4 . The method of claim 3 wherein the compound of 17α-ethynyl-androst-5-ene-3β,7β,17β-triol in Form I is substantially pure or has a purity of 99% or greater.
5 . The method of claim 3 wherein the crystalline anhydrate Form I 17α-ethynyl-androst-5-ene-3β,7β,17β-triol is micronized prior to the slurrying of step (a).
6 . The method of claim 5 wherein the micronized crystalline anhydrate Form I 17α-ethynyl-androst-5-ene-3β,7β,17β-triol has a particle size defined by (Dv, 90) between about 5 micron and about 30 micron.
7 . The method of claim 6 wherein the micronized crystalline anhydrate Form I 17α-ethynyl-androst-5-ene-3β,7β,17β-triol has a particle size defined by (Dv, 90) of about 7 micron.
8 . The method of claim 3 wherein the slurrying of step (a) is preformed at ambient temperature for 9 days.
9 . The method of claim 3 wherein the separation of step (b) is preformed by filtering the slurry obtained from step (a) through a 0.2 micron filter.
10 . The method of claim 3 wherein the evaporation of step (c) is preformed under ambient temperature and pressure.
11 . A method to make a crystalline anhydrate 17α-ethynylandrost-5-ene-3β,7β,17β-triol of claim 1 by desolvation of Form III or Form IV 17α-ethynylandrost-5-ene-3β,7β,17β-triol.