Effect of hydroxypropyl-β-cyclodextrin-complexation and pH on solubility of camptothecin

The influence of both pH and complexation by hydroxypropyl-beta-cyclodextrin (HP-beta-CD) on the overall solubility of camptothecin (CPT) was studied, with particular focus on the equilibrium between its lactone- and carboxylate-form. Phase solubility studies at therapeutically relevant pH values (pH 5.5-7.0) and physiologically acceptable HP-beta-CD-concentrations (0-25% (w/v)) were performed, and amounts of solubilized CPT quantified by HPLC. The solubility of CPT increased with both increasing pH and HP-beta-CD-concentration. The apparent complexation constant (K-C) decreased with increasing pH (245 M-1 at pH 5.5; 184 M-1 at pH 7.0). The lactone-carboxylate equivalence point shifted from a pH value of 6.8-7.0 and 7.1 with 0, 10 and 25% HP-beta-CD, respectively. The lactone-carboxylate-ratios from the equilibrium study were applied to the phase-solubility data, and the lactone- and carboxylate concentrations at 0, 10 and 25% HP-beta-CD calculated. Separate complexation constants (K-C) for the carboxylate-CPT and lactone-CPT could thus be derived, and found to be 113 +/- 7 and 260 +/- 18 M-1, respectively. This allows the prediction of amounts of both lactone- and carboxylate-CPT solubilized at any HP-beta-CD concentration and pH-combination. (C) 2004 Elsevier B.V. All rights reserved.