PHYSICOCHEMICAL PROPERTIES OF CARBOVIR, A POTENTIAL ANTI-HIV AGENT

(±)‐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 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 °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‐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 K1:1 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 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. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company