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. An oral dosage form comprising:
a therapeutically effective amount of crystalline psilocybin in the form Polymorph A characterized by peaks in an XRPD diffractogram at 11.5, 12.0, 14.5, 17.5, and 19.7°2θ±0.1°2θ, wherein the crystalline psilocybin has a chemical purity of greater than 97% by HPLC, and no single impurity of greater than 1%; and
silicified microcrystalline cellulose.
2. The oral dosage form of claim 1 comprising about 1 mg to 40 mg of crystalline psilocybin in the form Polymorph A.
3. The oral dosage form of claim 2 comprising about 5 mg of crystalline psilocybin in the form Polymorph A.
4. The oral dosage form of claim 2 comprising about 10 mg of crystalline psilocybin in the form Polymorph A.
5. The oral dosage form of claim 2 comprising about 25 mg of crystalline psilocybin in the form Polymorph A.
6. The oral dosage form of claim 1 , wherein the crystalline psilocybin is further characterized by having either:
i. a water content of <0.5% w/w; or
ii. <0.5% w/w loss in the TGA thermogram between 25° C. and 200° C.
7. The oral dosage form of claim 1 , wherein the crystalline psilocybin is further characterized by an endothermic event in a DSC thermogram having a first onset temperature of between 145° C. and 155° C. and a second onset temperature of between 205 and 220° C.
8. The oral dosage form of claim 1 , 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.
9. The oral dosage form of claim 1 , wherein the crystalline psilocybin has no single impurity of greater than 0.5%.
10. The oral dosage form of claim 1 , further comprising silicified microcrystalline cellulose with a particle size range from about 45 to 150 microns.
11. The oral dosage form of claim 10 , further comprising a mixture of two silicified microcrystalline cellulose variants wherein the first variant has a particle size from about 45 to 80 microns and the second variant has a particle size of about 90 to 150 microns.
12. The oral dosage form of claim 11 , wherein about 30% or less of the microcrystalline cellulose is the first variant having a particle size from about 45 to 80 microns and about 70% or more of the microcrystalline cellulose is the second variant having a particle size of about 90 to 150 microns.
13. The oral dosage form of claim 11 , wherein about 20% or less of the microcrystalline cellulose is the first variant having a particle size from about 45 to 80 microns and about 80% or more of the microcrystalline cellulose is the second variant having a particle size of about 90 to 150 microns.
14. The oral dosage form of claim 11 , wherein about 15% or less of the microcrystalline cellulose is the first variant having a particle size from about 45 to 80 microns and about 85% or more of the microcrystalline cellulose is the second variant having a particle size of about 90 to 150 microns.
15. The oral dosage form of claim 1 , wherein the dosage form is a capsule.
16. The oral dosage form of claim 1 , wherein the dosage form is a tablet.
17. The oral dosage form of claim 11 , wherein the dosage form is a capsule.
18. The oral dosage form of claim 11 , wherein the dosage form is a tablet.
19. The oral dosage form of claim 12 , wherein the dosage form is a capsule.
20. The oral dosage form of claim 12 , wherein the dosage form is a tablet.
21. A method of treating major depressive disorder comprising orally administering to a subject in need thereof the oral dosage form of claim 1 .
22. A method of treating major depressive disorder comprising orally administering to a subject in need thereof the oral dosage form of claim 11 .
23. A method of treating major depressive disorder comprising orally administering to a subject in need thereof the oral dosage form of claim 12 .