Is Mannitol Hemihydrate Detrimental To Protein Stability?

Maintaining an amorphous excipient matrix is crucial for protein stability in freeze-dried pharmaceuticals. The high propensity to crystallize during freezing and its high eutectic temperature make mannitol an attractive bulking agent in lyophilized pharmaceuticals. However, mannitol, a widely used excipient, can form a metastable polymorph called mannitol hemihydrate (MHH) during freeze-drying, potentially impacting protein stability.

This study investigates the effects of MHH dehydration and subsequent sucrose crystallization on protein stability. Formulations of either bovine serum albumin (BSA) or human serum albumin (HSA), as model proteins, with mannitol:sucrose or mannitol alone or sucrose alone were prepared and filled into 10 mL vials using a fill volume of 7 mL. The formulations were freeze-dried to obtain solids with varying extents of MHH formation. Specific aims of the investigation were to study: (a) the effect of formulation variables on MHH (formation and dehydration), (b) the effect of process variables on MHH (formation and dehydration), and (c) the role of vial headspace relative humidity (RH) on MHH stability.

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