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Pharmacokinetics of Morphine and its Surrogates VI: Bioanalysis, Solvolysis kinetics, Solubility, pKa′ Values, and Protein Binding of Buprenorphine

1985; Elsevier BV; Volume: 74; Issue: 5 Linguagem: Inglês

10.1002/jps.2600740505

1520-6017

Edward R. Garrett, V. Ravi Chandran,

Tryptophan and brain disorders

Abstract The 10-fold greater sensitivity of buprenorphine to fluorescence compared with morphine provides excellent detection for HPLC assay of buprenorphine in biological fluids with a 5-ng/mL sensitivity. Buprenorphine yields a stoichiometric final acid degradation product, a fluorescent-detectable, rearranged demethoxy analogue of buprenorphine, which serves as an excellent bioassay internal standard. Buprenorphine solvolysis is specific-acid and specific-base catalyzed. Alkaline hydrolysis produces no fluorescent products. Acid hydrolysis also produces a fluorescent-detectable, transient dehydro intermediate that is also completely transformed to the demethoxy analogue. The rate constants and Arrhenius parameters for these transformations have been determined. Estimated buprenorphine p K a ′ values are 8.24 and 10 for the ammonium and phenol groups, respectively. The intrinsic aqueous solubility of neutral buprenorphine is 12.7 ± 1.2 μg/mL at 23°C. The red blood cell-plasma water partition coefficients of buprenorphine ranged between 6 and 15. Ultracentrifugation and the red blood cell partition methods led to an estimated 95–98% plasma protein binding. Ultrafiltration and equilibrium dialysis methods were inappropriate because of the high membrane binding of neutral buprenorphine.