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Application of pharmacokinetics and biopharmaceutics in the design of toxicological studies

1980; Elsevier BV; Volume: 53; Issue: 2 Linguagem: Inglês

10.1016/0041-008x(80)90418-4

1096-0333

Robert D. Smyth, G. H. Hottendorf,

Innovative Microfluidic and Catalytic Techniques Innovation

The effect of pH on the intrinsic dissolution rate and solubility of josamycin, a macrolide antibiotic, has been investigated to determine the possible effects of the gastro-intestinal pH on absorption. The intrinsic dissolution rate (G) was determined in various dissolution media over a pH range of 1.2–7.5 using a disc rotated at 50, 100, 200 and 300 rpm at each pH. The intrinsic dissolution rate at infinite rotation speed (G∞) was determined using an extrapolation procedure described previously (Nicklasson and Brodin, Acta Pharm. Suec., 19 (1982) 109–118). A plot of log G∞ vs time was linear (linear regression equation y = 1.4288 − 0.6007x, correlation coeffiecient = 0.9904) with values of G∞ ranging by a factor of > 8500 from a maximum of 5.16 mg cm−2 s−1 at pH 1.2 to 5.81 × 10−4 mg cm−2 s−1 at pH 7.5. Furthermore, comparison of G∞ values with limits suggested by Kaplan (Drug Metab. Rev., 1 (1972) 15–34) indicates that the absorption of josamycin could be dissolution rate-limited from an environment of pH 5.4 to 7.0, and is highly likely to be dissolution rate-limited from intestinal fluid at pH values above 7.0. The solubility of josamycin was equally dependent on pH and ranged from 212 mg ml−1 (21%) at pH 5.45 to 0.18 mg ml−1 (0.018%) at pH 9.0. Josamycin has a solubility of approx. 1% at pH 6.0 and decreases with increasing pH to approx. 0.019% at pH 8.5. This suggests that the absorption of josamycin may also be solubility rate-limited particularly from an intestinal environment of pH 6.0 and above.