Predicting the crystallization propensity of carboxylic acid buffers in frozen systems-relevance to freeze-drying

Prakash Sundaramurthi, Raj Suryanarayanan

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Selective crystallization of buffer components in frozen solutions is known to cause pronounced pH shifts. Our objective was to study the crystallization behavior and the consequent pH shift in frozen aqueous carboxylic acid buffers. Aqueous carboxylic acid buffers were cooled to -25°C and the pH of the solution was measured as a function of temperature. The thermal behavior of solutions during freezing and thawing was investigated by differential scanning calorimetry. The crystallized phases in frozen solution were identified by X-ray diffractometry. The malate buffer system was robust with no evidence of buffer component crystallization and hence negligible pH shift. In the citrate and tartarate systems, at initial pH <pKa2, only the most acidic buffer component (neutral form) crystallized on cooling, causing an increase in the freeze-concentrate pH. Carboxylic acid buffers were rank ordered based on their propensity to crystallize in frozen solutions. From the aqueous solubility values of these carboxylic acids, which have been reported over a range of temperatures, it was also possible to estimate the degree of supersaturation at the subambient temperature of interest. This enabled us to predict their crystallization propensity in frozen systems. The experimental and the predicted rank orderings were in excellent agreement.

Original languageEnglish (US)
Pages (from-to)1288-1293
Number of pages6
JournalJournal of Pharmaceutical Sciences
Issue number4
StatePublished - Apr 2011

Bibliographical note

Funding Information:
Part of the work was conducted at the I.T. Characterization Facility which receives partial support from National Science Foundation.


  • Buffer crystallization
  • Crystallization
  • Freeze drying
  • Freeze-concentrate
  • Frozen solution
  • Injectables
  • Material science
  • PH change
  • Physical characterization
  • Solubility


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