Interaction of model aryl- and alkyl-boronic acids and 1,2-diols in aqueous solution

William A Marinaro, Richard Prankerd, Kaisa Kinnari, Valentino J Stella

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Abstract

The goal of this work was to quantitate ester formation between alkyl and aryl boronic acids and vicinal-diols or 1,2-diols in aqueous solution. As used here, 1,2-diols includes polyols with one or more 1,2-diol pairs. Multiple techniques were used including apparent pKa shifts of the boronic acids using UV spectrophotometry (for aryl acids) and titration (for aryl and alkyl acids). Isothermal microcalorimetry was also used, with all reactions being enthalpically favored. For all the acids and 1,2-diols and the conditions studied, evidence only supported 1:1 ester formation. All the esters formed were found to be significantly more acidic, as Lewis acids, by 3-3.5 pKa units than the corresponding nonesterified boronic acid. The equilibrium constants for ester formation increased with increasing number of 1,2-diol pairs but stereochemistry may also play a role as sorbitol with five possible 1,2-diol pairs and five isomers (taking into account the stereochemistry of the alcohol groups) was twice as efficient at ester formation compared with mannitol, also with five possible 1,2-diol pairs but only three isomers. Alkyl boronic acids formed esters to a greater extent than aryl acids. Although some quantitative differences were seen between the various techniques used, rank ordering of the structure/reactivity was consistent. Formulation implications of ester formation between boronic acids and 1,2-diols are discussed.
Original languageEnglish
Pages (from-to)1399-1408
Number of pages10
JournalJournal of Pharmaceutical Sciences
Volume104
Issue number4
DOIs
Publication statusPublished - 2015

Keywords

  • 1,2-diols,<preformulation>
  • acid base equilibria
  • boronic acid
  • esters
  • isothermal calorimetry
  • mannitol
  • stability
  • structure-property relationship (SPR)

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