Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
This invention relates to the large-scale production of psilocybin for use in medicine. More particularly, it relates to a method of obtaining high purity crystalline psilocybin, particularly, in the form of Polymorph A. It further relates to a method for the manufacture of psilocybin and intermediates in the production thereof and formulations containing psilocybin.
1. Crystalline psilocybin characterized by X-ray powder diffraction (XRPD) peaks at 11.5±0.1, 12.0±0.1, 14.5±0.1, 17.5±0.1, and 19.7±0.1 °2θ, wherein the crystalline psilocybin has a chemical purity of greater than 98% and no single impurity of greater than 1% as determined by high-performance liquid chromatography (HPLC) analysis.
2. The crystalline psilocybin of claim 1 , further characterized by XRPD peaks at least one of 20.4±0.1, 22.2±0.1, 24.3±0.1, or 25.7±0.1 °2θ.
3. The crystalline psilocybin of claim 1 , further characterized by a XRPD diffraction pattern that is substantially the same as shown in FIG. 7 a.
4. The crystalline psilocybin of claim 1 , having a chemical purity of greater than 99%.
5. The crystalline psilocybin of claim 1 , further characterized by a water content of <0.5% w/w as determined by Karl Fisher Titration.
6. The crystalline psilocybin of claim 1 , having less than 1% psilocin as determined by HPLC analysis.
7. The crystalline psilocybin of claim 1 , having less than 0.5% psilocin as determined by HPLC analysis.
8. The crystalline psilocybin of claim 1 , having less than 1% phosphoric acid as determined by 31 P nuclear magnetic resonance ( 31 P NMR).
9. The crystalline psilocybin of claim 1 , having less than 0.5% phosphoric acid as determined by 31 P NMR.
10. The crystalline psilocybin of claim 1 , further characterized by a <0.5% w/w loss in the thermogravimetric analysis (TGA) thermogram between 25° C. and 200° C.
11. The crystalline psilocybin of claim 1 , further characterized by an endothermic event in a differential scanning calorimetry (DSC) thermogram having an onset temperature of between 205° C. and 220° C.
12. The crystalline psilocybin of claim 1 , further characterized by an endothermic event in a DSC thermogram having an onset temperature of between 145° C. and 155° C.
13. The crystalline psilocybin of claim 1 , further characterized by one or more of the following:
a) a loss on drying of no more than 2% w/w;
b) residue on ignition of no more than 0.5% w/w;
c) assay (on a dry basis) of 95-103% by weight as measured by HPLC;
d) residual solvent content of no more than 3000 ppm methanol, 5000 ppm ethanol, 720 ppm tetrahydrofuran (THF), and 890 ppm toluene, as measured by high resolution gas chromatography (HRGC);
e) Inductively Coupled Plasma Mass Spectrometry (ICP-MS) elemental analysis of:
i. no more than 1.5 ppm cadmium (Cd);
ii. no more than 1.5 ppm lead (Pb);
iii. no more than 4.5 ppm arsenic (As);
iv. no more than 9.0 ppm mercury (Hg);
v. no more than 15 ppm cobalt (Co);
vi. no more than 30 ppm vanadium (V);
vii. no more than 60 ppm nickel (Ni);
viii. no more than 165 ppm lithium (Li); and
ix. no more than 30 ppm lead (Pd).
14. The crystalline psilocybin of claim 1 , comprising crystals with a size ranging from 50 to 200 microns.
15. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline psilocybin of claim 1 and a pharmaceutically acceptable excipient.
16. The pharmaceutical composition of claim 15 , wherein the pharmaceutical composition is a capsule.
17. The pharmaceutical composition of claim 15 , wherein the pharmaceutical composition is a tablet.
18. The pharmaceutical composition of claim 15 , comprising about 1 mg to about 40 mg of the crystalline psilocybin.
19. The pharmaceutical composition of claim 15 , comprising about 1 mg of the crystalline psilocybin.
20. The pharmaceutical composition of claim 15 , comprising about 25 mg of the crystalline psilocybin.
21. The pharmaceutical composition of claim 15 , wherein the crystalline psilocybin has a chemical purity of greater than 99%.
22. The pharmaceutical composition of claim 15 , wherein the crystalline psilocybin has content of <0.5% w/w as determined by Karl Fisher Titration.
23. The pharmaceutical composition of claim 15 , having less than 1% psilocin as determined by HPLC analysis.
24. The pharmaceutical composition of claim 15 , having less than 1% phosphoric acid as determined by 31 P NMR.
25. The pharmaceutical composition of claim 19 , wherein the crystalline psilocybin has a chemical purity of greater than 99%.
26. The pharmaceutical composition of claim 19 , having less than 1% psilocin as determined by HPLC analysis.
27. The pharmaceutical composition of claim 19 , having less than 1% phosphoric acid as determined by 31 P NMR.
28. The pharmaceutical composition of claim 20 , wherein the crystalline psilocybin has a chemical purity of greater than 99%.
29. The pharmaceutical composition of claim 20 , having less than 1% psilocin as determined by HPLC analysis.
30. The pharmaceutical composition of claim 20 , having less than 1% phosphoric acid as determined by 31 P NMR.