Stability of lyophilized albumin formulations: Role of excipient crystallinity and molecular mobility

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In freeze-dried protein formulations, the composition governs the physical forms of the excipients and hence their functionality. It is also necessary to understand the effect of composition on the molecular relaxation behavior, a key factor influencing protein stability. Mannitol (bulking agent) – trehalose (lyoprotectant) – bovine serum albumin (BSA) lyophiles with varying trehalose to BSA mass ratios were investigated. The crystalline phases were characterized by X-ray diffractometry. The secondary structure of albumin in lyophiles and reconstituted solutions was evaluated by IR spectroscopy and circular dichroism, respectively. Dielectric spectroscopy was used to obtain the relaxation time of freeze-dried samples. When trehalose to BSA ratio was 0.2, while mannitol crystallized predominantly as the δ-anhydrous polymorph, trehalose remained amorphous. At lower concentrations of BSA, mannitol crystallized in both hemihydrate and anhydrous forms, and trehalose as dihydrate. The extent of dehydration during subsequent drying was dictated by the trehalose to BSA ratio in the formulation. A gradual increase in the Johari-Goldstein relaxation time was observed as the concentration of trehalose increased in the formulation. BSA was more susceptible to stresses from thawing than drying.

Original languageEnglish (US)
Article number118568
JournalInternational journal of pharmaceutics
StatePublished - Oct 5 2019



  • Crystallization
  • Freeze-drying
  • Mannitol
  • Relaxation
  • Stability
  • Trehalose

PubMed: MeSH publication types

  • Journal Article

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