Abstract:
:(+-)-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.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Anderson BD,Chiang CYdoi
10.1002/jps.2600790908subject
Has Abstractpub_date
1990-09-01 00:00:00pages
787-90issue
9eissn
0022-3549issn
1520-6017pii
S0022-3549(15)48343-1journal_volume
79pub_type
杂志文章abstract::Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate-release (IR) solid oral dosage forms containing efavirenz as the only active pharmaceutical ingredient (API) are reviewed. Because of lack of conclusive data about efavirenz's permeability and i...
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