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.
Anderson
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Department of Pharmaceutics, College of Pharmacy, University of Utah, Salt Lake City 84112.
Chiang
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CY
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000998:Antiviral Agents / Q000737:chemistry*; D003505:Cyclodextrins / Q000032:analysis; D015224:Dideoxynucleosides / Q000737:chemistry* / Q000494:pharmacology; D006678:HIV / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D007263:Infusions, Parenteral; D000442:Octanols; D011409:Propylene Glycols; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013696:Temperature; D047391:alpha-Cyclodextrins; D047392:beta-Cyclodextrins
D000998:Antiviral Agents; D003505:Cyclodextrins; D015224:Dideoxynucleosides; D007202:Indicators and Reagents; D000442:Octanols; D011409:Propylene Glycols; D047391:alpha-Cyclodextrins; D047392:beta-Cyclodextrins; C479658:hydroxypropyl-alpha-cyclodextrin; C057503:carbovir; D000073738:2-Hydroxypropyl-beta-cyclodextrin