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. A pharmaceutical composition, comprising crystalline Polymorph A of psilocybin and a pharmaceutically acceptable excipient, wherein the Polymorph A is 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 psilocybin has a chemical purity of greater than 97% and no single impurity of greater than 1% as determined by HPLC analysis.
2. The pharmaceutical composition of claim 1 , wherein the composition is a capsule.
3. The pharmaceutical composition of claim 1 , wherein the composition is a tablet.
4. The pharmaceutical composition of claim 1 , wherein the Polymorph A is further characterized by at least one peak selected from the group consisting of 20.4±0.1, 22.2±0.1, 24.3±0.1, and 25.7±0.1 °2θ.
5. The pharmaceutical composition of claim 1 , wherein the composition comprises about 5 mg of the crystalline Polymorph A of psilocybin.
6. The pharmaceutical composition of claim 1 , wherein the composition comprises about 10 mg of the crystalline Polymorph A of psilocybin.
7. The pharmaceutical composition of claim 1 , wherein the composition comprises about 25 mg of the crystalline Polymorph A of psilocybin.
8. Crystalline Polymorph A of psilocybin, wherein the Polymorph A is 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 psilocybin has a chemical purity of greater than 97% and no single impurity of greater than 1% as determined by HPLC analysis.
9. The crystalline psilocybin of claim 8 , wherein the Polymorph A is further characterized by at least one peak selected from the group consisting of 20.4±0.1, 22.2±0.1, 24.3±0.1, and 25.7±0.1 °2θ.
10. The crystalline psilocybin of claim 8 , wherein the Polymorph A is characterized by a XRPD diffraction pattern that is substantially the same as shown in FIG. 7 a.
11. The crystalline psilocybin of claim 8 , wherein the crystalline psilocybin is further characterized by a water content of <0.5% w/w.
12. The crystalline psilocybin of claim 8 , wherein the crystalline psilocybin is further characterized by a <0.5% w/w loss in the TGA thermogram between 25° C. and 200° C.
13. The crystalline psilocybin of claim 8 , wherein the crystalline psilocybin is further characterized by an endothermic event in a DSC thermogram having an onset temperature of between 205° C. and 220° C.
14. The crystalline psilocybin of claim 8 , wherein the crystalline psilocybin is further characterized by an endothermic event in a DSC thermogram having an onset temperature of between 145° C. and 155° C.
15. The crystalline psilocybin of claim 8 , wherein the crystalline psilocybin is 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 THF, and 890 ppm toluene, as measured by high resolution gas chromatography (HRGC);
e) phosphoric acid content of no more than 1% w/w as measured by 31 P NMR; and
f) Inductively Coupled Plasma Mass Spectrometry (ICP-MS) elemental analysis of:
i. no more than 1.5 ppm Cd;
ii. no more than 1.5 ppm Pb;
iii. no more than 4.5 ppm As;
iv. no more than 9.0 ppm Hg;
v. no more than 15 ppm Co;
vi. no more than 30 ppm V;
vii. no more than 60 ppm Ni;
viii. no more than 165 ppm Li; and
ix. no more than 30 ppm Pd.
16. A method of treating major depressive disorder, the method comprising: administering a therapeutically effective amount of crystalline Polymorph A of psilocybin to a patient in need thereof,
wherein the Polymorph A is 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, and
wherein the psilocybin has a chemical purity of greater than 97% and no single impurity of greater than 1% as determined by HPLC analysis.
17. The method of claim 16 , wherein about 5 mg of the crystalline Polymorph A of psilocybin is administered.
18. The method of claim 16 , wherein about 10 mg of the crystalline Polymorph A of psilocybin is administered.
19. The method of claim 16 , wherein about 25 mg of the crystalline Polymorph A of psilocybin is administered.
20. The method of claim 16 , wherein the crystalline Polymorph A of psilocybin is orally administered.
21. The method of claim 20 , wherein the crystalline Polymorph A of psilocybin is administered in a capsule.
22. The method of claim 20 , wherein the crystalline Polymorph A of psilocybin is administered in a tablet.
23. The method of claim 16 , wherein the Polymorph A is further characterized by at least one peak selected from the group consisting of 20.4±0.1, 22.2±0.1, 24.3±0.1, and 25.7±0.1 °2θ.