Pharmaceutical solid state forms
View Patent ↗The invention provides and describes solid state 17α-ethynyl-5α-androstane-3α,17β-diol including amorphous and crystalline forms and specific polymorphic forms thereof. Anhydrates and solvates of 17α-ethynyl-5α-androstane-3α,17β-diol include Form III anhydrate and Form I solvate. The invention further relates to solid and suspension formulations containing 17α-ethynyl-5α-androstane-3α,17β-diol in a described solid state form and use of the formulations to treat cancers or precancers such as prostate cancer or breast cancer in subjects or human patients. The invention also relates to methods to make liquid formulations from solid state forms of 17α-ethynyl-5α-androstane-3α,17β-diol and uses of such formulations in treating the described conditions.
1. Crystalline anhydrate 17α-ethynyl-5α-androstane-3α,17β-diol.
2. The crystalline anhydrate 17α-ethynyl-5α-androstane-3α,17β-diol of claim 1 wherein the crystalline anhydrate contains 10% 10% w/w or less of amorphous 17α-ethynyl-5α-androstane-3α,17β-diol and other crystalline forms of 17α-ethynyl-5α-androstane-3α,17β-diol.
3. The crystalline anhydrate 17α-ethynyl-5α-androstane-3α,17β-diol of claim 2 wherein crystalline anhydrate form of 17α-ethynyl-5α-androstane-3α,17β-diol is Form III wherein Form III comprises at least 90% by weight of all crystalline 17α-ethynyl-5α-androstane-3α,17β-diol that is present, wherein Form III is characterized by or has:
an X-ray powder diffraction pattern with peak positions of 9.85, 11.33, 15.96, 16.48 and 18.95±0.10 degrees 2-theta or peak positions of 15.96, 16.48 and 18.95±0.10 degrees 2-theta and one two or three peak positions at 9.30, 11.33, 13.45, 16.16 or 17.42±0.10 degrees 2-theta, or
an IR-Raman spectroscopy spectrum with peak positions at 1236, 1190 and 490 cm −1 , optionally with one, two or three peak positions at 1458, 1435, 619, 604, 526, 237 or 206 cm −1 or is represented by FIG. 5A or FIG. 5B .
4. The crystalline anhydrate 17α-ethynyl-5α-androstane-3α,17β-diol of claim 3 wherein the crystalline anhydrate form of 17α-ethynyl-5α-androstane-3α,17β-diol is Form III, wherein Form III is further characterized by or has:
a differential scanning calorimetry thermogram with a prominent endotherm at 164° C. obtained using a temperature ramp of 10° C./min and has a thermogravimetric analysis weight loss of 0.5% or less when heated between 4° C. to 105° C. using a temperature ramp of 10° C./min.
5. The crystalline anhydrate 17α-ethynyl-5α-androstane-3α,17β-diol of claim 2 wherein the crystalline anhydrate form of 17α-ethynyl-5α-androstane-3α,17β-diol is Form V, wherein Form V is characterized by or has:
(i) X-ray powder diffraction pattern with peak positions of 5.82, 9.48, 11.49, 13.50, 15.21, 17.28 and 18.93±0.10 degrees 2θ, or
(i) and (ii) a TGA thermogram with negligible weight loss, 2% or less weight loss, or 0.3% or less weight loss on heating to the melting point and a DTA or DSC thermogram having an endotherm at about 164° C.
6. The crystalline anhydrate 17α-ethynyl-5α-androstane-3α,17β-diol of claim 2 wherein the crystalline anhydrate form of 17α-ethynyl-5α-androstane-3α,17β-diol is Form VII, wherein Form VII is characterized by or has:
(i) an XRPD pattern with prominent peaks at about 5.91, 9.78, 13.47, 14.16, 15.78, 17.85, 19.50 and 21.45±0.10 degrees 2θ, or
(i) and (ii) a TGA thermogram with negligible weight loss, 2% or less weight loss, or 0.3% or less weight loss on heating to the melting point and a DTA or DSC thermogram having an endotherm at about 164° C.
7. The crystalline anhydrate 17α-ethynyl-5α-androstane-3α,17β-diol of claim 2 wherein the crystalline anhydrate form of 17α-ethynyl-5α-androstane-3α,17β-diol is Form VIII, wherein Form VIII is characterized by or has:
(i) an XRPD pattern with prominent peaks at about 11.13, 15.96, 16.62, 17.76 and 18.75±0.10 degrees 2θ, or
(i) and (ii) a TGA thermogram with negligible weight loss, 2% or less weight loss, or 0.3% or less weight loss on heating to the melting point and a DTA or DSC thermogram having an endotherm at about 164° C.
8. A pharmaceutical formulation comprising one or more pharmaceutically acceptable excipients and crystalline anhydrate 17α-ethynyl-5α-androstane-3α,17β-diol.
9. The pharmaceutically acceptable formulation of claim 8 wherein the pharmaceutically acceptable formulation is a solid.
10. The pharmaceutically acceptable formulation of claim 9 wherein the solid formulation is present in tablets, capsules or another unit dosage form suitable for oral administration to humans.
11. A method of preparing a pharmaceutically acceptable formulation comprising the step of contacting, mixing and/or blending crystalline anhydrate 17α-ethynyl-5α-androstane-3α,17β-triol with one, two, three, four or more pharmaceutically acceptable excipients to obtain a mixture and processing the mixture to obtain a pharmaceutically acceptable formulation.
12. The method of claim 11 wherein the pharmaceutically acceptable formulation is present in tablets, capsules or another unit dosage form suitable for oral administration to humans.
13. The method of claim 11 wherein the crystalline anhydrate form of 17α-ethynyl-5α-androstane-3α,17β-diol is Form III.
14. The method of claim 11 wherein at least one of the excipients is a surface active agent.
15. The method of claim 14 wherein the surface active agent is sodium lauryl sulfate or Polysorbate-80.