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Related Experiment Videos

Combined effect of complexation and pH on solubilization.

P Li1, S E Tabibi, S H Yalkowsky

  • 1The Department of Pharmaceutical Sciences, College of Pharmacy, University of Arizona, Tucson 85721, USA.

Journal of Pharmaceutical Sciences
|April 3, 1999
PubMed
Summary

The combined use of pH control and complexation enhances drug solubility. This study explains the synergistic effect by showing how drug ionization and complexation constants influence total solubility, particularly for weakly basic drugs like flavopiridol.

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Area of Science:

  • Pharmaceutical Sciences
  • Drug Delivery
  • Physical Chemistry

Background:

  • pH control and complexation are common drug solubilization methods.
  • The synergistic effect of combining these techniques is not well-theoretically explained.
  • Understanding this synergy is crucial for optimizing drug formulations.

Purpose of the Study:

  • To develop a theoretical framework explaining the synergistic effect of combined pH control and complexation on drug solubility.
  • To elucidate the roles of pH-dependent ionization and complexation constants in this synergy.
  • To validate the theoretical model using flavopiridol as a model drug.

Main Methods:

  • Formulated a theoretical model for total drug solubility, considering free un-ionized drug [Du], free ionized drug [Di], un-ionized drug complex [DuL], and ionized drug complex [DiL].

Related Experiment Videos

  • Analyzed the contribution of complexation constants (Ku and Ki) and drug ionization pH to solubility.
  • Utilized flavopiridol, a weakly basic drug, to experimentally test the derived solubility equation.

    • Main Results:

    • The theoretical model demonstrates that both complexation constants and drug ionization pH critically influence solubility.
    • For flavopiridol, despite a lower complexation constant for the ionized form (Ki), the ionized drug complex [DiL] solubility was 6-fold higher than the un-ionized complex [DuL].
    • This enhanced solubility of [DiL] was attributed to the significantly higher solubility of the ionized drug [Di] at acidic pH compared to the un-ionized drug [Du] at basic pH.

    Conclusions:

    • The study provides a theoretical explanation for the synergistic solubilization effect of combined pH control and complexation.
    • The derived equation, 'If [Di]/[Du] > Ku/Ki, then [DiL] > [DuL]', predicts when ionized complex solubility will exceed un-ionized complex solubility.
    • The findings are applicable to various drugs and support the rational design of drug formulations utilizing combined solubilization strategies.