Impact of freeze-drying on ionization of sulfonephthalein probe molecules in trehalose - citrate systems

Ramprakash Govindarajan, Koustuv Chatterjee, Larry Gatlin, Raj Suryanarayanan, Evgenyi Y. Shalaev

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"pH memory," i.e., correlation between pH of solution before freeze-drying and chemical reactivity in the freeze-dried state, has been reported in many systems. In this study, the "pH memory" is explored by comparing the extent of protonation of sulfonephthalein probe molecules, bromophenol blue, bromocresol green, and chlorophenol red, in aqueous solution in the pH range of 3.4-6.0 and in the resulting freeze-dried amorphous matrix (lyophile) containing trehalose and sodium citrate buffer. The protonation of the probe molecules was measured in the lyophiles by diffuse reflectance visible spectroscopy, and compared with that in the solution before drying. The protonation of the indicators in the amorphous matrix correlated with solution pH, that is, an increase in solution pH resulted in a progressive decrease in the indicator protonation in the corresponding lyophile. However, the protonation was consistently higher in the lyophile than in the corresponding solution. The Hammett acidity function of lyophiles was calculated based on the extent of protonation of the probe molecules. Protonation of the probe molecules and the Hammett acidity function depended not only on prelyophilization solution pH, but also on the residual water content and the presence of amorphous sugar in the lyophile.

Original languageEnglish (US)
Pages (from-to)1498-1510
Number of pages13
JournalJournal of Pharmaceutical Sciences
Issue number7
StatePublished - Jul 2006

Bibliographical note

Funding Information:
Dr. Ramprakash Govindarajan was supported by a grant from Pfizer, Inc. We also thank anonymous reviewers for useful comments and suggestions which allowed us to improve the study.

Copyright 2017 Elsevier B.V., All rights reserved.


  • Amorphous
  • Carbohydrates
  • Diffuse reflectance
  • Freeze-drying
  • Hammett acidity function
  • Ionization
  • Lyophilization
  • Solid state
  • Sulfonephthalein pH indicators
  • UV-VIS spectroscopy


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