T-Butanol Enables Dual Functionality of Mannitol: A Cryoprotectant in Frozen Systems and Bulking Agent in Freeze-Dried Formulations

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Abstract

The effect of tertiary butyl alcohol (TBA) as a cosolvent on the phase behavior of mannitol in frozen and freeze-dried systems was characterized using differential scanning calorimetry (DSC) and X-ray diffractometry (XRD; laboratory and synchrotron sources). Solutions of mannitol (2 and 5% w/w) in TBA-water systems of different compositions (5 to 30% w/w TBA) were characterized, both during cooling and warming using DSC and XRD. At and below the TBA-water eutectic composition (22.5% w/w TBA), mannitol crystallization was completely inhibited in the frozen state, while it crystallized as anhydrous δ-mannitol in the final lyophile. The presence of mannitol did not affect the phase behavior of TBA. The ability of mannitol to serve as a cryoprotectant in frozen solutions, and as a bulking agent in final lyophile was evaluated using human serum albumin (HSA) as a model protein. When HSA in a TBA (5% w/w)-water solution containing mannitol (2% w/w) was freeze-thawed or freeze-dried, there was no evidence of HSA aggregation. Thus, when TBA was used as a cosolvent, mannitol exhibited dual functionality, serving as a cryoprotectant in frozen solutions and as a bulking agent in the final lyophile.

Original languageEnglish (US)
Pages (from-to)3075-3086
Number of pages12
JournalMolecular pharmaceutics
Volume17
Issue number8
DOIs
StatePublished - Aug 3 2020

Bibliographical note

Funding Information:
Parts of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program. The Advanced Photon Source (17-BM; Dr. Wenqian Xu and Dr. Andrey Yakovenko) was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Science, under contract no. DE-AC02-06CH11357. We acknowledge funding from the Dane O. Kildsig Center for Pharmaceutical Processing Research and the William and Mildred Peters Endowment Fund. We thank Dr. Bakul Bhatnagar for his help with various stimulating discussions regarding TBA–water systems. Portions of this work were conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nano Coordinated Infrastructure Network (NNCI) under award number ECCS-1542202.

Publisher Copyright:
© 2020 American Chemical Society.

Keywords

  • DSC
  • amorphous mannitol
  • cryoprotection
  • eutectic melting
  • freeze-drying
  • freeze-thawing
  • low-temperature XRD
  • synchrotron XRD
  • t-butyl alcohol

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