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Beyond pH: Acid/Base Relationships in Frozen and Freeze-Dried Pharmaceuticals

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Principles and Practices of Lyophilization in Product Development and Manufacturing

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 59))

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Abstract

Stability of the majority of pharmaceuticals and biopharmaceuticals depends on acidity/basicity of the environment. In aqueous solutions, acidity/basicity is commonly expressed using proton activity scale, pH, while definition and experimental measurements of acid-base relationships in frozen and freeze-dried materials are less straightforward. The chapter starts with a brief summary of the current understanding of several critical aspects of pH and apparent acidity/basicity as related to freezing and freeze-drying, whereas the main part of the chapter is focused on areas which are underrepresented in the pharmaceutical literature, with both overview of the literature and previously unpublished data presented. In particular, the following topics are covered: (i) Hammett acidity function and pH-equivalent (pHeq); (ii) Factors which impact apparent solid-state acidity in lyophiles; (iii) Solid-state acidity and chemical instability of lyophiles; (iv) Freezing fundamentals: quasi-liquid layer, polarity of the freeze-concentrated solution, and the Workman-Reynolds potential. Potential directions for future studies in this field are also outlined.

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Acknowledgements

We thank Dr. Mark Berry for his expert help in statistical analysis of the data reported in Sect. 4. Dominik Heger is thankful for the support by Czech Science Foundation via project GA 19-08239S.

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Authors and Affiliations

  1. Masaryk University, Brno, Czech Republic

    Dominik Heger & Lukáš Veselý

  2. Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA

    Ramprakash Govindarajan, Enxian Lu & Raj Suryanarayanan

  3. College of Pharmacy, The University of Iowa, Iowa City, IA, USA

    Ramprakash Govindarajan

  4. Auson Pharmaceuticals Inc., Bridgewater, NJ, USA

    Enxian Lu

  5. Pharmaceutical R & D, Pfizer Inc, Groton, CT, USA

    Susan Ewing, Larry Gatlin & Bruno Hancock

  6. College of Pharmacy, University of Kentucky, Lexington, KY, USA

    Ashley Lay-Fortenbery

  7. Pharmaceutical Sciences R & D, Abbvie, Irvine, CA, USA

    Xiaoda Yuan & Evgenyi Shalaev

  8. College of Pharmacy, Purdue University, West Lafayette, IN, USA

    Eric Munson

  9. Merck & Co, Inc, Kenilworth, NJ, USA

    Ashley Lay-Fortenbery

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  1. Dominik Heger
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Corresponding author

Correspondence to Evgenyi Shalaev .

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  1. Nimble BioSolutions, Gurnee, IL, USA

    Feroz Jameel

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Heger, D. et al. (2023). Beyond pH: Acid/Base Relationships in Frozen and Freeze-Dried Pharmaceuticals. In: Jameel, F. (eds) Principles and Practices of Lyophilization in Product Development and Manufacturing . AAPS Advances in the Pharmaceutical Sciences Series, vol 59. Springer, Cham. https://doi.org/10.1007/978-3-031-12634-5_3

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