The solubilization of dimyristoylphosphatidylcholine (DMPC) liposomes by the weak electrolyte drug, cefotaxime (CFX), has been studied as a function of pH, DMPC, temperature, presence of cholesterol (CHOL), and method of liposome preparation. At 7.5 mM CFX the lag time for solubilization increased, the rate of solubilization decreased, and the minimum turbidity reached increased as a function of DMPC at pH 1.0 and 40 degrees C. Solubilization was most pronounced at pHs below the pK(a) but inhibited at least one pH unit above the pK(a). The critical mole ratio of unionized CFX:DMPC, R-e(c), for solubilization was estimated to be 0.12. Reducing the temperature slowed the rate of solubilization as did the addition of CHOL. Encapsulation of CFX in liposomes did not significantly reduce CFX degradation, k(1) = 0.048 h(-1) at 40 degrees C and a complex of DMPC and a degradation product of CFX precipitated as rectangular crystals. As a result, an increase in the turbidity of solubilized systems was observed from about 20 h to 48 h depending on the conditions. Liposomes in the gel state or with at least 20% CHOL did not undergo an apparent reversal of solubilization. It is concluded that the inclusion of weak electrolyte drugs existing predominantly as the unionized species in liquid crystalline state liposomes may undergo a slow solubilization process not necessarily recognized during characterization.