Role of arginine salts in preventing freezing-induced increase in subvisible particles in protein formulations

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Abstract

While arginine hydrochloride (ArgHCl) has emerged as a potential stabilizer of protein drugs in liquid formulations, the purpose of this manuscript was to evaluate its stabilization potential in frozen solutions. The phase behavior of frozen ArgHCl solutions was investigated by differential scanning calorimetry and low temperature powder X-ray diffractometry. The aggregation of β-galactosidase was evaluated following freeze–thaw cycling in ArgHCl solutions with and without mannitol. ArgHCl (5% w/v) was retained amorphous in frozen aqueous solutions and effectively inhibited protein aggregation even after 5 freeze–thaw cycles. Annealing frozen arginine solution (5% w/v) containing mannitol (10% w/v) induced mannitol crystallization which in turn facilitated crystallization of ArgHCl. The stabilizing effect of ArgHCl was completely lost in the presence of mannitol. Use of alternate arginine salts (aspartate, glutamate, and acetate) allowed selective crystallization of mannitol while arginine was retained amorphous and stabilized the protein.

Original languageEnglish (US)
Article number121694
JournalInternational journal of pharmaceutics
Volume619
DOIs
StatePublished - May 10 2022

Bibliographical note

Funding Information:
We thank Pfanstiehl for providing ArgHCl. This project was funded by the Dane O. Kildsig Center for Pharmaceutical Processing Research (CPPR) and the William and Mildred Peters Endowment fund. Parts of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program. Special thanks to Bio-Techne for providing access to their MFI 5200.

Publisher Copyright:
© 2022 Elsevier B.V.

Keywords

  • Arginine hydrochloride
  • Arginine salts
  • Counterions
  • Crystallization
  • Mannitol
  • Protein aggregation

PubMed: MeSH publication types

  • Journal Article

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