Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 624, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2022.121974
Keywords
Mannitol hemihydrate dehydration; Mannitol; Sucrose; Protein aggregation; Freeze-drying; Moisture content; Phase transitions
Categories
Funding
- NSF through the MRSEC [DMR-2011401]
- NNCI [ECCS-2025124]
- U.S. Department of Energy, Office of Science, Office of Basic Energy Science [DE-AC02-06CH11357]
- William and Mildred Peters Endowment Fund
Ask authors/readers for more resources
Mannitol has a high propensity to crystallize in frozen solutions, making it a good bulking agent. Adding sucrose to protein formulations is crucial for retaining the protein in its native state. This study aims to evaluate the dehydration kinetics of mannitol hemihydrate (MHH) on storage and its impact on sucrose crystallization and protein stability.
The high propensity of mannitol to crystallize in frozen solutions along with its high eutectic temperature enabling higher primary drying temperatures makes it a good bulking agent. In protein formulations, addition of a sugar (sucrose) that has the ability to remain amorphous throughout processing as well as storage is imperative to retain the protein in its native state. It is well known that in the presence of amorphous excipients and protein, mannitol can crystallize as a mixture of anhydrous polymorphs - alpha-, beta- and delta-forms and a hemihydrate form [mannitol hemihydrate (MHH); C6H14O6.0.5H(2)O]. The conditions of formation of MHH due to processing and formulation variables are well established in the literature. However, MHH's dehydration kinetics on storage and its impact on the stability of a protein has not been systematically evaluated. The overall objective was to identify conditions (temperature and humidity) at which MHH can dehydrate on storage and the consequences of the release of associated water on sucrose phase behavior and protein stability. In a mannitol-sucrose-protein lyophile, the purpose of this study was (i) to investigate the dehydration behavior of MHH (ii) to determine the influence of dehydration on sucrose crystallization and (iii) the effect of moisture released due to MHH dehydration on model protein (Bovine serum albumin, BSA or Human serum albumin, HSA) aggregation. MHH dehydration and sucrose crystallization was observed in cases where the relative humidity was >= 55% (open vials). A relative humidity of <= 33% RH prevented MHH dehydration while retaining sucrose amorphous. No protein aggregation was observed irrespective of presence of MHH or its dehydration.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available