Combined effect of complexation and pH on solubilization.
Both pH control and complexation are widely used as solubilization techniques in drug formulation studies. Although these two techniques are often utilized in combination, few theoretical studies have shown why the combined approach would work better than either one alone. This study constructs a background in which both the pH effect and complexation constants are used to explain the synergism between these techniques. The total solubility is determined by the addition of the concentrations of the four components present in the solution: free un-ionized drug [Du], free ionized drug [Di], un-ionized drug complex [DuL], and ionized drug complex [DiL]. A detailed description of [Di] and [DiL] reveals that the complexation constants and the pH at which the drug may ionize are both critical. The weakly basic drug flavopiridol is used as a test compound to examine the validity of the equation. Although the complexation constant for ionized flavopiridol (Ki = 124 M(-1)) is less than one-third of that of the un-ionized species (Ku = 445 M(-1)), the solubility of the ionized drug complex [DiL] is 6-fold greater than that of the un-ionized drug complex [DuL]. This unexpected result is due to the 25-fold greater solubility of the ionized drug [Di] at pH 4.3 over that of the free un-ionized species [Du] at pH 8.4. The results of this and other complexation studies of several drugs taken from the literature lend the support to the following: If [Di]/[Du] >Ku/Ki, then [DiL] >[DuL].
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The Department of Pharmaceutical Sciences, College of Pharmacy, University of Arizona, Tucson 85721, USA.
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Yalkowsky
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D002626:Chemistry, Pharmaceutical; D005419:Flavonoids / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007477:Ions; D008956:Models, Chemical; D010880:Piperidines / Q000737:chemistry*; D012995:Solubility
D005419:Flavonoids; D007477:Ions; D010880:Piperidines; C077990:alvocidib