Effect of buffer media composition on the solubility and effective permeability coefficient of ibuprofen


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Abstract

The effect of perfusion medium composition on the two important biopharmaceutical parameters drug solubility and permeability was determined for ibuprofen. Eight commonly used buffers were examined. Equilibrium solubility, buffer capacity profiles and permeability coefficients, using the in situ rat gut perfusion model, were determined for each medium at 37 °C. The solubility of ibuprofen differed sixfold over the range of buffer systems studied. The differences in solubility were associated with different pHs of the buffers when saturated with drug and also the presence of micelles and divalent ions. The solubility of ibuprofen in FeSSIF was significantly higher than predicted from the pH due to micellisation, while that in Krebs was significantly lower due to ibuprofen-calcium salt formation. Buffer capacities varied over a 40-fold range. The pKa values of the buffer components were determined from the buffer capacity versus pH profiles and were in good agreement with the thermodynamic values when corrected for temperature and ionic strength. Smaller, but statistically significant differences in Papp values for ibuprofen were also observed between some of the buffers. During perfusion, pHs of the perfusate samples gradually changed over time towards a median value of approximately 6.5. HBSS gave a Papp ∼50% greater than that observed in PBS 7.4. Physicochemical factors such as medium pH, buffer capacity and osmolarity should be considered when determining the Papp values of ionisable compounds. Care needs to be exercised when comparing Papp values from different laboratories as buffer composition can have a significant effect on both solubility and permeability of a drug, whose ionisation is substantially changed over the pH range of the buffers. Despite the high amount ionised, ibuprofen appears to be well absorbed and it can be classified as a highly permeable drug.

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