Detecting and Quantifying Microscale Chemical Reactions in Pharmaceutical Tablets by Stimulated Raman Scattering Microscopy.

It has been estimated that approximately 50% of all marketed drug molecules are manufactured and administered in the form of salts, often with the goal of improving solubility, dissolution rate, and efficacy of the drug. However, salt disproportionation during processing or storage is a common adverse effect in these formulations. Due to the heterogeneous nature of solid drug formulations, it is essential to characterize the drug substances noninvasively at micrometer resolution to understand the molecular mechanism of salt disproportionation. However, there is a lack of such capability with current characterization methods. In this study, we demonstrate that stimulated Raman scattering (SRS) microscopy can be used to provide sensitive and quantitative chemical imaging of the salt disproportionation reaction of pioglitazone hydrochloride (PIO-HCl) at a very low drug loading (1% w/w). Our findings illuminate a water mediated pathway of drug disproportionation and highlight the importance of noninvasive chemical imaging in a mechanistic study of solid-state chemical reactions.