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Solubility Behavior of Narcotic Analgesics in Aqueous Media: Solubilities and Dissociation Constants of Morphine,Fentanyl, and Sufentanil
Authors:Roy  Samir D.  Flynn  Gordon L.
Affiliation:(1) College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109-1065;(2) Cygnus Research Corporation, 701 Galveston Drive, Redwood City, California, 94063
Abstract:The pH dependence of the aqueous solubility of morphine, fentanyl, and sufentanil was investigated at 35°C. Dissociation constants and corresponding pKaprime values of the drugs were obtained from measured free-base solubilities (determined at high pH's) and the concentrations of saturated solutions at intermediate pH's. Morphine, fentanyl, and sufentanil exhibited pKaprime values of 8.08, 8.99, and 8.51, respectively. Over the pH range of 5 to 12.5 the apparent solubilities are determined by the intrinsic solubility of the free base plus the concentration of ionized drug necessary to satisfy the dissociation equilibrium at a given pH. Consequently, the drug concentrations of saturated aqueous solutions fall off precipitously as the pH is raised and ionization is suppressed. Further, at low pH's the aqueous solubility of morphine increased in a linear fashion with increases in the molar strength of citric acid which was added to acidify the medium, suggesting the formation of a soluble morphine–citrate complex.
Keywords:narcotic analgesics  dissociation constants  pH–  solubility profiles  solubility  amines
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