Preparation and Characterization of Novel Crystalline Solvates and Polymorphs of Psilocybin and Identification of Solid Forms Suitable for Clinical Development

Psilocybin is a psychedelic tryptamine currently being evaluated clinically for its ability to improve the symptoms of major depressive disorder (MDD). As part of a program to fully characterize psilocybin active pharmaceutical ingredient (API) that will be used for clinical development activities, a polymorph screen involving over 150 solvent and non-solvent based screening experiments was performed. The studies generated ten unique crystalline solid forms of psilocybin: three anhydrates, six solvates, and one hydrate, as well as X-ray amorphous material. Solids were generated using various crystallization techniques and then analyzed by x-ray powder diffraction (XRPD). Further analysis of the novel crystal forms by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and nuclear magnetic resonance (NMR) was conducted to characterize the polymorphs as solvates, hydrates, or anhydrates. These data were compared to all previously published literature on solid forms of psilocybin. Interconversion studies were performed which identified Form A anhydrate and Pattern B trihydrate as being preferable for drug development as stable crystalline forms that can be readily prepared. Suitable single crystals of Pattern B hydrate were grown and the resulting crystal structure confirmed as a trihydrate. Finally, psilocybin Form A was subjected to accelerated stability testing conditions to indicate that the selected form remained unchanged under representative pharmaceutical storage conditions supporting its suitability for clinical development.