Cocrystallization of Niclosamide to Improve Its Hygroscopic Stability and Dissolution

초록

Niclosamide, a sparingly soluble drug compound, is moisture-sensitive and readily transforms into an even less soluble monohydrate. To enhance its hygroscopic stability and dissolution, cocrystallization with isomers of pyridinecarboxylic acids was attempted. Niclosamide successfully formed cocrystals with nicotinic acid and picolinic acid. While all cocrystals with the highly soluble coformers exhibited improved dissolution behavior, the niclosamide/nicotinic acid cocrystal demonstrated distinctly superior hygroscopic stability. Crystal structure analysis reveals its disjointed and reduced void structure, which appears closely related to the uniform parallel-displaced pi-pi stacking that does not exist in other crystals. Furthermore, niclosamide molecules are arranged in a manner that the solid-state transformation to the monohydrate is improbable without removing the hydrogen-bonded nicotinic acid. This transformation occurs rapidly for the neat niclosamide with its interconnected voids. This study suggests crystal packing features that could be utilized for other drugs facing similar hydrate formation challenges.

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