Psilocybin: Characterization of the Metastable Zone Width (MSZW), Control of Anhydrous Polymorphs, and Particle Size Distribution (PSD)

• Published in: ACS omega Vol. 7; no. 6; pp. 5429 - 5436
• Main Authors: Kargbo, Robert B, Sherwood, Alexander M, Meisenheimer, Poncho, Lenoch, Kelsey, Abebe, Solomon
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 15.02.2022
• ISSN: 2470-1343; 2470-1343
• DOI: 10.1021/acsomega.1c06708

Psilocybin, a serotonergic agonist, was granted a “breakthrough therapy” status by the Food and Drug Administration for clinical trials involving major depressive disorder and treatment-resistant depression. The direct phosphorylation of psilocin to psilocybin that uses a fast crystallization associated with a kinetically controlled process resulted in a smaller particle size distribution. Herein, the measurement of the metastable zone width (MSZW) and nucleation induction enabled a thermodynamically controlled crystallization process, which leads to the formation of a crystal structure with stronger interactions, controlled particle size distribution (PSD), and improved impurity profile. Employing a high-resolution inline microscopy viewer allowed the real-time monitoring of the crystallization process and the measurement of the particle size. We also present a comprehensive study of the formation of polymorph B (trihydrate), polymorph A (anhydrate), and polymorph H (anhydrate) using water recrystallization, which indicates that the formation of polymorph B (trihydrate) is independent of the crystallization method. However, polymorphs A and H are dependent on the mode of drying: drying at room temperature under vacuum gives rise to mainly polymorph A, and when heated even at relatively low temperatures, a mixture of polymorphs A and H beings to form.