Highly Polymorphic Materials and Dissolution Behaviour: The Peculiar Case of Rifaximin

Rifaximin is a locally acting antibiotic practically insoluble in water. It presents several crystal phases characterized by different degrees of hydration. The aim of this work is to investigate the dissolution behaviour of rifaximin alpha, beta, and amorphous forms in relation to their relative thermodynamic stability to contribute to clarifying possible solvent- or humidity-mediated conversion patterns. Kinetic and intrinsic solubility were investigated along with particle size distribution, specific surface area, and external morphology. The solution and moisture mediated conversion from metastable alpha and amorphous forms to stable beta form were elucidated by coupling intrinsic dissolution test with chemometric analysis as well as by dynamic vapour sorption measurements. The dissolution behaviour of the alpha form stems mainly from the transition to beta form that occurs upon exposition to relative humidity higher than 40%. The alpha form converted more rapidly than the amorphous form due to the smaller supersaturation ratio. It can be concluded that, due to its marked tendency to transform into beta form, the dissolution test for the alpha form, even if conducted according to compendial procedures, needs to be accompanied by a panel of further tests that allow to uniquely identify the solid phase under investigation.

Automated summary

The aim of this study is to investigate the dissolution behavior of rifaximin alpha, beta, and amorphous forms in relation to their relative thermodynamic stability. The conversion from metastable alpha and amorphous forms to stable beta form mediated by solution and moisture was elucidated. The alpha form dissolves mainly by transitioning to the beta form at relative humidity higher than 40%.