Physicochemical properties of carbovir, a potential anti-HIV agent

Article abstract of DOI:10.1002/jps.2600790908

(±)-Carbovir [(±)-9-[4α-(hydroxymethyl)-cyclopent-2-ene-1α-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 pK(a), solubility versus pH and solvent composition, and octanol-water partition coefficient have been examined. Ultraviolet spectrophotometry indicated that carbovir has pK(a) values of 3.15 and 9.68, respectively, at 25°C and 0.01 ionic strength. The acqueous solubility of carbovir over the pH range 7-10.5 was consistent with that expected of a weak acid with a pK(a) 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-β-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-β-cyclodextrin was found to be more effective, with a K(1:1) of 105 M^-1 for the complexation. The pH profiles generated at 50, 70, and 90°C were accounted for by acid-catalyzed degradation at low pH leading to the formation of quanine 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.