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Horn, Jacqueline; Tolardo, Eleonora; Fissore, Davide; Friess, Wolfgang (2018): Crystallizing amino acids as bulking agents in freeze-drying. In: European Journal of Pharmaceutics and Biopharmaceutics, Vol. 132: pp. 70-82
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Abstract

Bulking agents as mannitol (Man) and glycine (Gly) require high bulking agent to stabilizer ratios to ensure their crystallization during the freeze-drying process. The aim of this study was to investigate several amino acids (AA) as potential alternative bulking agents in low AA to sucrose (Suc) ratios. A fast freeze-drying process was performed above the collapse temperature (Tc) of the amorphous phase challenging the crystalline AA scaffold. Lyophilizates and liquid formulations were characterized by differential scanning calorimetry. Karl-Fischer titration and X-ray powder diffraction as well as macroscopic cake appearance and reconstitution times were evaluated. Stability of a monoclonal antibody was investigated by UV-Vis spectroscopy, light obscuration and size exclusion chromatography. Phenylalanine (Phe), leucine (Leu) and isoleucine (Ile) crystallized upon freeze-drying at 5/45 and 10/40 AA/Suc ratios. 2.5/47.5 AA/Suc ratio showed less pronounced crystallization. Crystallization peaks were not suppressed by 2 or 50 mg/mL antibody in Leu and Ile lyophilizates. Reconstitution times could be improved by addition of surfactant. No signs of protein aggregation were detected after freeze-drying. Man and Gly yielded inacceptable cake appearance when dried with the fast freeze-drying cycle in such low bulking agent to Suc ratios. Leu, Ile and Phe can be used as alternate bulking agents at lower bulking agent to Suc ratios compared to Man or Gly. The selected AAs provided promising cake characteristics and good protein process stability.