Crystalline anhydrate forms of a pharmaceutical
Inventors
White, Steven K • Ivanisevic, Igor • Stephens, Kyle • Andres, Mark • Wolfe, Brenton Skylar
Assignees
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Publication Number
US-9555046-B2
Publication Date
2017-01-31
Expiration Date
Abstract
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.
Core Innovation
The invention relates to solid-state forms of 17α-ethynyl-androst-5-ene-3β,7β,17β-triol, including amorphous form, crystalline polymorphs, anhydrates, and solvates/hydrates. The disclosed crystalline anhydrate forms include crystalline Form I, Form II, Form III, and Form IV, and the solid-state description further includes Form IV/V solvates. These forms are distinguished and characterized as discrete physical forms of Compound 1.
The document provides analytical approaches to distinguish the solid-state forms of Compound 1, including X-ray powder diffraction (XRPD), DSC/DTA/TGA, Raman spectroscopy, and SS-NMR. The disclosure references drawing-based analytical fingerprints for the forms, including XRPD peak lists, DSC/TGA transitions, and Raman absorptions. Characterization is used to identify the specific solid-state form among the amorphous and crystalline variants.
The disclosed utility of the solid-state forms includes treating hyperglycemia and metabolic syndrome, including type 2 diabetes, and treating autoimmune and inflammatory conditions, including rheumatoid arthritis, ulcerative colitis, Crohn’s disease, and type 1 diabetes. The document further describes process/method summaries for preparing and obtaining specific forms, including obtaining Form I and Form II via solvent slurry, phase separation/filtration, and solvent evaporation.
Claims Coverage
The independent claim is directed to a crystalline anhydrate form of Compound 1. The dependent claims refine the polymorphic conversion and processing of a specific crystalline anhydrate form (Form II), including conversion from a related form (Form I) and additional constraints.
Crystalline anhydrate compound 1
Crystalline anhydrate 17α-ethynylandrost-5-ene-3β,7β,17β-triol.
Solvent slurry conversion to crystalline anhydrate form ii
A method for making crystalline anhydrate Form II of 17α-ethynyl-androst-5-ene-3β,7β,17β-triol by slurrying the Form I crystalline anhydrate in ethyl acetate or methylethylketone, separating solid and liquid phases, and evaporating the solvent to obtain the Form II crystalline anhydrate.
Purity constraint for form i starting material
The method further specifies that the Form I 17α-ethynyl-androst-5-ene-3β,7β,17β-triol has a purity of 99% or greater.
Filtration through a 0.2 micron filter for separation
Separating step (b) by filtering a slurry from step (a) through a 0.2 micron filter.
Heating other forms to obtain crystalline anhydrate
Producing a crystalline anhydrate form by heating Form III or Form IV of the compound.
Claim coverage centers on a crystalline anhydrate form of 17α-ethynylandrost-5-ene-3β,7β,17β-triol, with dependent claims focusing on preparation of crystalline anhydrate Form II via solvent slurry conversion from Form I, including a Form I purity constraint and a specified filtration separation, and an alternative route by heating other forms (Form III or Form IV).
Stated Advantages
Treats hyperglycemia and metabolic syndrome, including type 2 diabetes.
Treats autoimmune and inflammatory conditions, including rheumatoid arthritis, ulcerative colitis, Crohn’s disease, and type 1 diabetes.
Documented Applications
Treating hyperglycemia and metabolic syndrome (e.g., type 2 diabetes) using the disclosed solid-state forms of Compound 1.
Treating autoimmune and inflammatory conditions, including rheumatoid arthritis, ulcerative colitis, Crohn’s disease, and type 1 diabetes, using the disclosed solid-state forms of Compound 1.
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