A MECHANISTIC STUDY OF GRISEOFULVIN DISSOLUTION INTO SURFACTANT SOLUTIONS UNDER LAMINAR-FLOW CONDITIONS

The in vivo dissolution of many poorly soluble drugs is enhanced by th e action of surfactants secreted into the upper gastrointestinal (GI) tract. These substances may act by solubilizing individual drug molecu les into two separate liquid phases: the free aqueous phase and a mice llar phase in which the drug is incorporated into a complex of two or more surfactant molecules. This complex process, micellar solubilizati on, was the subject of this in vitro study, wherein griseofulvin (gris ) dissolution was observed in flowing surfactant solutions. Aqueous so lutions of sodium dodecyl sulfate (SDS), an anionic surfactant, were p umped over a gris tablet embedded in a laminar flow device to simulate flow in the human upper GI tract. SDS solutions were well above the c ritical micellar concentration (cmc approximate to 6-7 mM), and flow r ates ranged from 4 to 7 mL/min. Gris solubility in premicellar (4 mM), near-micellar (6 mM), and micellar (>6 mM) SDS solutions was also det ermined. The measured solubility of gris increased linearly with SDS c oncentrations above the cmc. Drug solubility in SDS concentrations bel ow the cmc was also higher than that in water. Gris diffusion coeffici ents were measured using pulsed-field gradient NMR spectroscopy. To de termine the controlling mechanism for surfactant-enhanced dissolution, a mathematical model was developed. The model solution, an equation f or drug dissolution rate, was compared with experimental data to demon strate that drug transport away from the solid surface is the slow ste p in the process. Measured gris diffusion coefficients and solubility values were used as constants in the mathematical model solution and w ere combined to calculate an effective gris diffusion coefficient. Usi ng these experimentally determined properties, model-calculated dissol ution rates were within 7% of the measured values. As hypothesized, di ssolution rates were found to be directly proportional to the transpor t properties of the system (effective drug diffusion coefficient and f luid flow rate) as well as to the drug solubility. To further verify t ransport-limited dissolution, the measured dissolution rates were foun d to be proportional to the surrounding medium flow rate to the 1/3 po wer, as predicted by the model dissolution rate equation.