The Influence of Water on the Stability of Lyophilized Formulations with Inositol and Mannitol as Excipients

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The stability of a moisture-sensitive drug in lyophilized products was investigated under conditions with varying water content and temperature using two model formulations: a formulation containing inositol (IF) as the excipient and a formulation containing mannitol (MF) as the excipient. IF showed better chemical stability (a lower hydrolysis rate) than MF when both formulations contained 2% water. However, in the case of formulations with 8% water, MF showed similar or better stability than IF. From the results of hygroscopicity and phase transition experiments for both formulations, it was assumed that this stability profile was exhibited because 1) more water was taken up into the amorphous inositol in IF than into the crystalline Form-III mannitol in MF at a low water content, so that drug hydrolysis in IF was suppressed compared with MF and 2) when the water content increased, the amorphous inositol crystallized to anhydrate in IF causing expulsion of absorbed water from the excipient, meaning that IF lost its superior chemical stability due to the highly mobile water generated by the crystallization. This assumption was supported by the results of the 2H-NMR measurement, which estimated water mobility from the signal shape and the spin–lattice relaxation time (T1) of deuterium oxide.

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