Uncovering Hidden Risks in Solid-State API Properties

Abstract

Locating and understanding hydrated forms of an API As discussed, facile hydrate formation can drastically alter the processability, stability, and aqueous solubility of a given API; this example shows how an API was fully characterized to allow the development of a reliable method for synthesis, avoiding an undesirable hemi-hydrated form that was uncovered during a polymorph screening project. [...]thermal gravimetric analysis (TGA) confirmed the anhydrous, non-solvated nature of the form, while analysis by dynamic vapor sorption (DVS) at 25 °C, showed minor hysteresis with a maximum mass uptake of 0.95 wt.% at 90% relative humidity (RH), confirming its status as a developable form (Figure 1). Using the non-random two-liquid (NRTL) equation and measured water activity, a detailed hydration map was investigated across multiple organic solvents; it was found that the morphology of Form 1 was greatly improved using small volume aliquots of water in ICH class 3 solvents (e.g., 0.5 Aw = 95 % isopropanol : 5 % water, % v/v) to minimize the risk of hemi-hydrate formation.