Effect of pH and solubility on in vitro skin penetration of methotrexate from a 50% v/v propylene glycol-water vehicle

In vitro percutaneous absorption of methotrexate from a saturated solution in a 50% v/v propylene glycol-water vehicle was examined across suitably characterized human cadaver skin. A detailed study of solubility and pH parameters in the range of 2–6 pH units was conducted. A clear trend towards increasing steady-state penetration rate with increasing pH was evident. Relatively high lag times were observed even at optimal pH values emphasizing the importance of prolonged application of drug to achieve therapeutic concentrations. From a vehicle at pH 2, the steady-state rate of penetration was very low and the data suggested drug binding with stratum corneum. Although the drug solubility in the vehicle was considerably lower at pH 4 than at pH 2–3, the steady-state rate and extent of penetration were higher. Both drug solubility and steady-state penetration rate were significantly higher at pH 5.29 than at pH 4. Increasing the vehicle pH to 6.34 increased the drug solubility as well as steady-state rate of penetration but the percent amount penetrated declined. The lag times were also large at this pH. Relatively high drug solubility and gradually increasing contribution of shunt pathways probably account for this result. In view of the observed pH-solubility profile, for a 50% v/v propylene glycol-water vehicle, a pH between 4 and 5 would appear to provide the most favorable environment for passive diffusion since the concentration of unionized methotrexate would be optimal.