PH-METRIC LOGP .7. OCTANOL-GLYCOL, CHLOROFORM-GLYCOL, AND PROPYLENE-GLYCOL DIPELARGONAT-WATER PARTITIONING OF MORPHINE-6-GLUCORONIDE AND OTHER RELATED OPIATES

The pK(a) and log P values of morphine-6-beta-D-glucuronide (M6G) and morphine-3-beta-D-glucuronide (M3G) and a range of structurally-relate d opiates (morphine, normorphine, codeine, norcodeine, 6-acetylmorphin e, diacetylmorphine, and buprenorphine) were accurately measured using a potentiometric approach. The measured lipophilicity profiles (pH 2- 11, 0.15 M KCl matrix) of M3G and M6G were compared using a proton don or solvent (chloroform) and a proton acceptor solvent (propylene glyco l dipelargonate, PGDP), in addition to octanol. The log P values and l ipophilicity profiles of M6G and M3G determined in octanol-water have confirmed the unexpectedly high lipophilicity of the two glucuronides. These results show the importance of measuring the effect of pH on li pophilicity, since log D (pH 7.4) values gave a notably different orde r of lipophilicity for the opiates compared with log P. M6G, but not M 3G, showed significant differences in log P between different types of partitioning solvents. The observed order of lipophilicities (log D, pH 7.4) was buprenorphine (3.93), diacetylmorphine (0.85), 6-acetylmor phine (0.61), codeine (0.22), morphine (-0.07), M6G (-0.79), M3G (-1.1 2), norcodeine (-1.26), and normorphine (-1.56).