Dissolution of ionizable water-insoluble drugs: The combined effect of pH and surfactant

This study reports the results of the combined effect of pH and surfactant on the dissolution of piroxicam (PX), an ionizable water-insoluble drug in physiological pH. The intrinsic dissolution rate (J(total)) of PX was measu red in the pH range from 4.0 to 7.8 with 0%, 0.5%, and 2.0% sodium lauryl s ulfate (SLS) using the rotating disk apparatus. Solubility (c(total)) was a lso measured in the same pH and SLS concentration ranges. A simple additive model including an ionization (PX <-> H+ + PX-) and two micellar solubiliz ation equilibria (PX + micelle <-> [PX](micelle), PXL + micelle <-> [PX-](m icelle)) were considered in the convective diffusion reaction model. J(tota l) and c(total) of PX increased with increasing pH and SLS concentration in an approximately additive manner. Nonlinear regression analysis showed tha t observed experimental data were well described with the proposed model (r (2) = 0.86, P < 0.001 for J(total) and r(2) = 0.98, P < 0.001 for c(total)) . The pK(a) value of 5.63 +/- 0.02 estimated from c(total) agreed well with the reported value. The micellar solubilization equilibrium coefficient fo r the unionized drug was estimated to be 348 +/- 77 L/mol, while the value for the ionized drug was nearly equal to zero. The diffusion coefficients o f the species PX, PX-, and [PX](micelle) were estimated from the experiment al results as (0.93 +/- 0.35) x 10(-5), (1.4 +/- 0.30) x 10(-5), and (0.59 +/- 0.21) x 10(-5) cm(2)/s, respectively. The total flux enhancement is les s than the total solubility enhancement due to the smaller diffusion coeffi cients of the micellar species. This model may be useful in predicting the dissolution of an ionizable water insoluble drug as a function of pH and su rfactant and for establishing in vitro-in vivo correlations, IVIVC, for mai ntaining bioequivalence of drug products. (C) 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association.