Anomalous behavior of mannitol hemihydrate: Implications on sucrose crystallization in colyophilized systems.

When solutions containing mannitol and sucrose are freeze-dried, depending on the processing conditions and the formulation composition, mannitol can crystallize in the anhydrous form, as mannitol hemihydrate (MHH; CHO·0.5HO) or as a mixture of the two. The retention of MHH in the final lyophile, and its dehydration during product storage could lead to instability of the final drug product. Our aim was to determine the influence of water vapor pressure on the kinetics of MHH dehydration and the implications on the physical stability of sucrose. Therefore, the lyophiles were exposed to a range of relative humidities (RH) and the kinetics of MHH dehydration and sucrose crystallization were monitored by X-ray diffractometry. A second set of vials (rubber stoppers fitted with humidity/temperature sensor) were stored at 40 °C, the headspace RH was continually recorded and water content was determined by Karl Fischer titrimetry. The dehydration rate of MHH increased as a function of water vapor pressure, an anomalous behavior explained by the Smith-Topley effect. An increase in headspace RH and decrease in lyophile water content in sealed vials attributed to MHH dehydration, eventually triggered sucrose crystallization. There was also evidence of moisture transfer from the lyophile to the rubber stoppers.