Psilocybin: Crystal Structure Solutions Enable Phase Analysis of Prior Art and Recently Patented Examples

Presented During:

07/31/2022: 5:30 PM - 7:30 PM
Portland Marriott Downtown Waterfront  

Conference:

2022: 72nd ACA Annual Meeting

Session Type:

Poster 

Presenting Author :

James Kaduk  
Chemistry, Illinois Inst of Technology

Additional Author(s):

Alexander Sherwood  
Usona Institute
Robert Kargbo  
Usona Institute
Kristi Kaylo  
Usona Institute
Poncho Meisenheimer  
Usona Institute
Nicholas Cozzi  
University of Wisconsin School of Medicine and Public Health

Abstract Body:

Psilocybin (systematic name: 3-[2-(dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate) is a zwitterionic tryptamine natural product found in numerous species of fungi known for their psychoactive properties. Following its structural elucidation and chemical synthesis in 1959, purified synthetic psilocybin has been evaluated in clinical trials, and has shown promise in its utility for the alleviation of suffering associated with various mental health disorders. In a recent process-scale crystallization investigation, three crystalline forms of psilocybin were repeatedly observed: Hydrate A, Polymorph A, and Polymorph B. The crystal structure for Hydrate A was previously solved by single crystal X-ray diffraction. This report presents new crystal structure solutions for the two anhydrates, Polymorph A and Polymorph B, based on Rietveld refinement using laboratory and synchrotron X-ray diffraction data and density functional theory (DFT) optimizations. Utilizing the three solved structures, investigation was conducted via Rietveld method (RM) based quantitative phase analysis (QPA) to estimate the contribution of the three different forms in powder X-ray diffraction (PXRD) patterns of different sources of bulk psilocybin produced between 1963 and 2021. Over the last 57 years, each of these samples quantitatively reflect one or more of the hydrate and anhydrate polymorphs. In addition to quantitatively evaluating the composition of each sample, this paper evaluates correlations between the crystal forms present, corresponding process methods, sample age, and storage conditions. Further, revision is recommended on characterizations in recently granted patents that include descriptions of crystalline psilocybin inappropriately reported as a single phase "isostructural variant". Rietveld refinement demonstrated that the claimed material was composed of approximately 81% Polymorph A and 19% Polymorph B, both of which have been identified in historical samples. We show conclusively that all published data can be explained in terms of three well defined forms of psilocybin and that no additional forms are needed to explain the diffraction patterns.

Additional Information - Poster (2022)

Are you registered for the ACA meeting?

Yes

For scheduling purposes please select a session that most matches your poster topic. If your poster theme does not align with the topics of the sessions, please select a general category.

2.2.5 General Interest 2

If submitted for a poster would you like to be considered for a poster prize?

No