(700a) Polymorphic Stability Shifts, Co-Crystals and Crystalline Solid Solutions: The T-X Phase Diagram of Salicylic Acid and Salicylamide

Crystalline solid solutions (CSS) have been known for centuries in metallurgy and mineralogy, but have attracted little attention in organic systems, especially in pharmaceuticals. This growing interest has been amplified by a recent study that found the dominant mechanism in which impurities incorporate in binary systems containing an active pharmaceutical ingredient (API) and an impurity with unacceptable levels was when the impurity is miscible in the API and forms a CSS. From these findings, our group has sought to dive deeper into this mechanism and has published subsequent studies reporting that solid solutions can considerably enhance the solubility and dissolution rate for several compounds. CSS formation can also be selective for different polymorphic forms of a compound and may impact their thermodynamic stability, resulting in either the appearance of a previously unobtainable form or the loss of a form due to stability changes. The capability of this selectivity is particularly problematic as the amount of impurity retained in the product and crystallizing solution will vary as the process is scaled up and optimized.

In this work, a phase diagram was constructed for a binary system consisting of salicylic acid (SA) and salicylamide (SM) for the purpose of elucidating the solid phases present among a range of compositions by suspending mixtures of the solids until reaching equilibrium, followed by drying and annealing. Differential Scanning Calorimetry (DSC) was utilized to analyze the thermal events present during heating and melting of each mixed solid composition, while X-ray powder diffraction (XRPD) was done to analyze polymorphic form transformation. The results of the DSC and XRPD illustrate that there are three solid solution phases, two cocrystals, and a stability shift in the SM from the stable Form I to the metastable Form III, and in turn, a switch from the βI to the βIII CSS of SM and SA. This system provides an example of a complex T-X phase diagram that shows a polymorph form transformation induced by CSS at elevated temperatures. Both the polymorphic coexistence domain and the stability shift demonstrate how CSS can alter the thermodynamic stabilities in polymorphic systems in the presence of a second component (i.e. impurities).