Psilocybin: Characterization of the Metastable Zone Width (MSZW), Control of Anhydrous Polymorphs, and Particle Size Distribution (PSD)
ACS Omega – February 07, 2022
Source: OpenAlex
Summary
Optimizing psilocybin production for psychedelics and drug studies reveals critical insights into crystallization. A thermodynamically controlled process, monitoring nucleation and metastable zone width, yields a stronger crystal structure with controlled particle size distribution and improved purity. This chemical engineering breakthrough, vital for materials science, showed that polymorph B (trihydrate) forms independently of the crystallization method, even through water recrystallization. Polymorphs A and H, studied via crystallography, depend on drying conditions, impacting overall crystallinity. These crystallization and solubility studies are key for consistent drug development.
Abstract
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.