The Effect of In-Situ-Generated Moisture on Disproportionation of Pharmaceutical Salt.

Pharmaceutical salts are ubiquitously present in the market given their benefits in optimizing the critical properties of an active pharmaceutical ingredient (API). Achieving these benefits requires careful selection and understanding of the salt form of choice. Stability is especially critical here, as salts are susceptible to disproportionation. Several studies have shown the impact of moisture on disproportionation, with more focus on external humidity (moisture coming from outside the system). This work, on the other hand, is systematically designed to study the impact of moisture generated in situ (moisture produced within the system). To that end, an in-house developed compound 1 was selected as our salt API, and its disproportionation was studied in blends (binary and prototype) with hydrated model excipient─trisodium phosphate dodecahydrate (TSPD). TSPD possesses 12 water molecules, which could get released when triggered with enough energy (confirmed by thermogravimetric analysis and humidity studies). As a control for this study, similar blends were prepared with anhydrous trisodium phosphate (TSP), which has comparable properties to TSPD but lacks water. Overall, significant disproportionation was observed in TSPD blends exposed to 40 °C or 70 °C in a closed system; while no disproportionation was observed when the system was left open due to the escape of the moisture generated in situ. The API also remained intact for the blends with anhydrous TSP, as expected. Meanwhile, stressing at 40 °C/75%RH condition resulted in significant disproportionation for both TSPD and TSP blends due to the exposure to external humidity. Hydrated excipients are normally used in drug development, and this work stresses the need for probing the impact from within the system when such excipients are utilized with salt API. This will help fully unravel the overall effect of moisture on the drug, which is relevant downstream when selecting processing conditions, packaging, and so forth.