Continuous and reversible transformation of the polymorphs of an MGAT2 inhibitor (S-309309) from the anhydrate to the hydrate in response to relative humidity

Quality control is a strict requirement of pharmaceutical manufacture. The stability of a drug can be enhanced by crystallization owing to the relatively low energy of a crystal lattice. Herein, we investigated the hydrate and anhydrate polymorphs of a monoacylglycerol acyltransferase 2 inhibitor (S-309309) to elucidate their relationship with each other. Polymorphic screening by solvent evaporation and slurry conversion revealed two polymorphs: Form I (the hydrate) and Form II (the solvate). Form II transformed to Form I during thermogravimetry–differential thermal analysis. X-ray powder diffraction demonstrated that Form I transformed to the anhydrate via an intermediate state when heated. These crystal forms were confirmed under controlled humidity conditions; the presence of the anhydrate, the intermediate hydrate, or the hydrate depended on the relative humidity at 25°C. The stoichiometry of S-309309 to water in the hydrate form was 4:1. The hydrate and anhydrate had similar crystal structures. The water of hydration in the intermediate hydrate was 0.1–0.15 mol according to the dynamic vapor sorption profile. We discovered a mechanism of reversible crystal transformation between the anhydrate and pseudo-polymorphs of the hydrate at ambient humidity. We conclude that S-309309 should be treated carefully because the experimental conditions affect its crystal form.