TY - JOUR
T1 - Anomalous behavior of mannitol hemihydrate
T2 - Implications on sucrose crystallization in colyophilized systems
AU - Thakral, Seema
AU - Sonje, Jayesh
AU - Suryanarayanan, Raj
N1 - Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/9/25
Y1 - 2020/9/25
N2 - 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; C6H14O6·0.5H2O) 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.
AB - 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; C6H14O6·0.5H2O) 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.
KW - Dehydration
KW - Freeze-drying
KW - Mannitol
KW - Mannitol hemihydrate
KW - Moisture content
KW - Rubber stopper
KW - Smith-Topley effect
KW - Sucrose
KW - X-ray diffractometry
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U2 - 10.1016/j.ijpharm.2020.119629
DO - 10.1016/j.ijpharm.2020.119629
M3 - Article
C2 - 32653598
AN - SCOPUS:85088023564
SN - 0378-5173
VL - 587
JO - International journal of pharmaceutics
JF - International journal of pharmaceutics
M1 - 119629
ER -