The Amorphous Form of Salicylsalicylic Acid: Experimental Characterization and Computational Predictability

Abstract

Amorphous solids challenge our understanding of phase behavior. For small organic molecules, particularly pharmaceuticals, they offer improved solubility and bioavailability. A computational approach to understanding of amorphous stability and ease of formation would be valuable. An apparently ideal test case is salicylsalicylic acid (salsalate), which has been reported to form an amorphous phase that is long-term stable below and above its glass temperature. In this study we report the application of computational crystal structure prediction (CSP) techniques to salsalate, supported by an experimental investigation of the amorphous phase by solid form screening and X-ray derived pair distribution functions (PDFs). CSP reveals a pair of hydrogen bonding motifs that appear to be severely detrimental to the molecule’s ability to pack efficiently and stably, indicating an explanation for salsalate’s formation of a stable amorphous phase. However, experimental data caution against overstating this stability. The amorphous phase is found to crystallize under a wider variety of conditions than has previously been reported. Furthermore the molecule is prone to thermal degradation, giving rise to impurities that may play a role in frustrating crystallization.