A Spironolactone−Saccharin 1:1 Cocrystal Hemihydrate

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Abstract

We investigated the structures of the hydrated and dehydrated states and the in vitro dissolution of a spironolactone−saccharin 1:1 cocrystal hemihydrate, the cocrystal hydrate of a nonionizable, poorly water-soluble drug with a pharmaceutically acceptable coformer. The cocrystal hydrate has linear channels in its crystal structure where the water molecules locate and shows nonstoichiometric hydration, suggesting that the cocrystal hydrate and anhydrate are isostructural. Single-crystal X-ray diffraction using the cocrystal anhydrate prepared from single-crystal to single-crystal dehydration confirmed the isostructural relationship and showed retention of the linear channels and subtle shrinkage of the unit cell volume (∼0.3%) after dehydration. The dissolution of the cocrystal hydrate was evaluated in simulated intestinal fluid and fasted-state simulated intestinal fluid. The cocrystal hydrate improved solubility at about 2-fold the maximum supersaturated concentration with respect to the saturated solubility of spironolactone form II (the most stable form) in both media. However, the concentration decreased after reaching the maximum and the cocrystal hydrate converted to a previously unreported spironolactone 1/3 hydrate which was ∼0.8 times less soluble than spironolactone form II.

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