Addition of Monovalent Electrolytes to Improve Storage Stability of Freeze-Dried Protein Formulations

作者：Goshima Hiroshika; Forney Stevens Kelly M; Liu Ming; Qian Ken K; Tyagi Madhusudan; Cicerone Marcus T; Pikal Michael J^*

来源：Journal of Pharmaceutical Sciences, 2016, 105(2): 530-541.

DOI：10.1016/j.xphs.2015.10.004

• protein formulation
• stability
• freeze drying
• lyophilization
• glass dynamics
• mobility
• free volume
• PALS
• mean square displacement
• neutron scattering

This study investigates the effect of low levels of electrolytes on storage stability in freeze-dried sucrose-based protein formulations. Both bovine serum albumin and recombinant human serum albumin were freeze dried with sucrose and alkali halides (LiCl, NaCl, KCl, RbCl, and CsCl) at selected low levels. All formulations were stored at 50 degrees C and 65 degrees C up to 2 months and then assayed for protein aggregation. The data demonstrate that low levels of LiCl and NaCl enhance stability. No obvious correlations with either protein secondary structure or global dynamics (structural relaxation time) were found. However, good correlations were found between stability and both free-volume hole size via positron annihilation lifetime spectroscopy (PALS) and fast dynamics by neutron scattering. Volume changes on mixing and the partial molal volume of salt were also studied in an effort to detect decreases in free volume. These data did not support the hypothesis that reduction in free volume was the primary mechanism for salt-induced stabilization. Finally, a positive effect of postlyophilization annealing on stability was demonstrated. In summary, we find that small amounts of LiCl and NaCl significantly stabilize these proteins, which is a result at variance with conventional formulation wisdom.

• 出版日期2016-2