Physicochemical properties of carbovir, a potential anti-HIV agent

(+-)-Carbovir [(+-)-9-[4 alpha-(hydroxymethyl)-cyclopent-2-ene-1 alpha-yl]guanine; NSC 614846] is a novel carbocyclic nucleoside analogue which has been shown to be a potent and selective inhibitor of HIV in vitro. As part of an effort to develop a parenteral formulation for subsequent clinical and toxicological evaluation of this compound, the aqueous solution stability of carbovir as a function of pH and temperature and various physicochemical properties of carbovir including its pKa, solubility versus pH and solvent composition, and octanol-water partition coefficient have been examined. Ultraviolet spectrophotometry indicated that carbovir has pKa values of 3.15 and 9.68, respectively, at 25 degrees C and 0.01 ionic strength. The aqueous solubility of carbovir over the pH range 7-10.5 was consistent with that expected of a weak acid with a pKa of 9.65 and an intrinsic solubility of 1.24 mg/mL. Due to the limited solubility of carbovir at physiological pH, methods for solubilizing carbovir in aqueous solution were explored, including propylene glycol-water cosolvents and complexation with hydroxypropyl-beta-cyclodextrin. As expected for carbovir, a semipolar compound with an octanol-water partition coefficient of 0.29, propylene glycol:water cosolvents were not highly effective in enhancing solubility. Complex formation between carbovir and 2-hydroxypropyl-beta-cyclodextrin was found to be more effective, with a K1:1 of 105 M-1 for the complexation. The pH profiles generated at 50, 70, and 90 degrees C were accounted for by acid-catalyzed degradation at low pH leading to the formation of guanine and a neutral degradation pathway which dominates above pH 4. Prototype lyophilized formulations containing (after reconstitution) 10 mg/mL of carbovir at a pH of 10.6 were developed and evaluated.