Estimating the dissolution and absorption of water-insoluble drugs in the small intestine.

Abstract

The intrinsic dissolution rate and solubility of carbamazepine, a water insoluble drug by working definition, were determined in water, sodium lauryl sulfate solutions, and a 20% soybean oil in water emulsion. Micelle facilitated dissolution of carbamazepine in 2% w/v sodium lauryl sulfate was over sixfold higher than in water. Two models, the reaction plane and film equilibrium model, were used to describe the flux enhancement and both models expressed the flux enhancement as a linear function of the surfactant concentration. No significant difference in dissolution was observed for different degrees of surfactant purity, but the solubility of carbamazepine in 99% sodium lauryl sulfate was significantly higher than in the 95% pure surfactant and 95% pure surfactant in 0.15M NaCl. This was attributed to the incorporation of lauryl alcohol impurities to form mixed micelles. Dissolution of carbamazepine in the emulsion system was approximately twofold higher than in water. Computer simulations were performed to determine the effect of particle size distribution and small intestinal transit time on the fraction of ordinary doses of carbamazepine and griseofulvin absorbed using a Macroscopic Mass Balance Approach (MMBA) model. At a constant mean particle diameter of 150 microns, varying the geometric standard deviation of the particle size distribution from 1.0 to 2.0 decreased the estimated fraction dose absorbed from 1.0 to 0.6 for carbamazepine and 0.28 to 0.02 for griseofulvin. Varying the small intestinal transit time $\pm$ two standard deviations from the mean (182.5 minutes) resulted in fraction dose absorbed values between 1.0 and 0.19 for carbamazepine (particle diameter range 50-200 microns) and 0.5 and 0.04 for griseofulvin (particle diameter range 40-100 microns). The results of the in vitro dissolution experiments and computer simulations are useful in interpreting the variability in absorption of slightly water soluble drugs observed in clinical usage. The MMBA model described can help identify the source of variability in oral drug absorption of these compounds. This information can be used to optimize formulations to increase bioavailability either by physical (particle size reduction, size distribution limitations) or chemical (increased solubility, prodrug approach) modification.