Purpose: Dissolution testing is an important formulation development tool and often a surrogate for in vivo analysis. However, with the increase in complex formulation strategies due to the prevalence of poorly soluble drug compounds, new approaches are warranted as the simple well-stirred conventional dissolution apparatus fails to predict performance of such formulations. An improved approach is combined dissolution-absorption testing. The presence of an absorptive compartment in dissolution studies not only provides information about solution thermodynamics, but also influences the dissolution kinetics of any undissolved material, as well as crystallization kinetics. The currently available mass transport apparatuses, however, offer small membrane surface area with slow mass transfer rates which impacts their usefulness. In this work, a novel high surface area, flow-through apparatus for concurrent dissolution and absorption testing has been developed. The central component of the apparatus is a hollow fiber membrane used to simulate the absorption process. It offers a large surface area per unit volume allowing formulation testing in a biorelevant time frame. The dissolution-absorption studies of different crystallizing and non-crystallizing formulations have also been performed and the results compared with closed-compartment dissolution.
Methods: Absorptive dissolution testing setup:
The apparatus consists of a donor container with drug dissolved or suspended in the aqueous medium, hollow fiber membrane module, a buffer reservoir containing absorption medium, a receiver container to collect drug following absorption across the membrane and a peristaltic pump, to pump fluids in the apparatus. The solute in the donor solution flowing through the hollow fibers is absorbed across the membrane surface into the buffer reservoir flowing on the shell-side of the module. The donor fluid is recycled to allow transfer of total drug. The fluid flow was co-current with flow rate of 2 mL/min. The concentration of drug absorbed was measured non-cumulatively, using an in-line flow-through UV probe, while donor concentration was measured cumulatively. Studies were carried out using nevirapine as a model weakly basic drug compound with a pKa of 2.8 and in pH 6.5 50mM phosphate buffer. The apparatus was maintained at 37 C.
Dissolution-absorption studies of formulations:
Three formulations were evaluated namely, crystalline suspension, powder and tablet. Crystalline suspension was prepared by adding excess of drug in pH 6.5 buffer. Powder and tablet were first dissolved for 30 min in 0.1 N HCl and then the pH was changed to pH 6.5 by addition of 0.17M Na2HPO4, generating supersaturation. Absorption measurements were commenced at pH 6.5, for 4 h. For studies carried out to understand the influence of polymer on supersaturation and crystallization propensities, polymer was pre-dissolved in the buffer. Closed-compartment dissolution in the absence of absorptive compartment was also evaluated.
Results: Preliminary studies of the new apparatus showed 30 times higher mass transfer due to 16-fold increase in the surface area as compared to a conventional side-by-side diffusion cell. The non-cumulative receiver concentration profile first showed a maximum in concentration (Cmax) indicating membrane saturation, with a value dependent on the initial donor concentration. Following this, the receiver concentration declined reflecting a decrease in the donor concentration due to absorption. A linear relation was obtained between the donor concentration and amount of drug transferred, confirming its utility for mass transport studies. In dissolution-absorption studies, the excess crystalline drug in suspension showed a constant receiver profile indicating that a reservoir was provided by the undissolved solids. The absorption profiles for supersaturated solutions generated from powder and tablet dissolution showed a higher Cmax than the crystalline suspension, however, the concentration profile declined rapidly due to crystallization. In the presence of a polymer, the concentration profiles showed higher Cmax and a gradual decline in the concentration due to absorption. Thus, the results provided a real-time analysis and quantitative measure for supersaturation and crystallization. In contrast, the closed-compartment dissolution profiles simply revealed information about crystallization tendencies of formulations. Moreover, the study of a labile system revealed that the system crystallized during closed-compartment dissolution whereas no crystallization was observed in combined dissolution-absorption testing, further highlighting the importance of an absorptive compartment in dissolution testing of supersaturating formulations. A mathematical model was also developed for the mass transfer in the apparatus which provided good predictions of the donor and receiver concentration profiles.
Conclusion: This study introduces a novel approach to in vitro analysis of formulation performance. Preliminary results highlight several advantages of the hollow fiber membrane, particularly greatly enhanced rates of mass transfer. Dissolution-absorption studies of crystallizing and non-crystallizing systems clearly showed that the apparatus was sensitive to subtle differences in the formulations. Hence, the apparatus provides additional information about formulation performance, typically not realized in conventional dissolution testing. It is anticipated that this robust apparatus could be a promising tool to rank order pharmaceutical formulations and identify systems that may perform optimally in vivo.
Susan Reutzel-Edens– Senior Research Advisor, Small Molecule Design & Development, Eli Lilly and Company, Indianapolis, Indiana
Lynne Taylor– Professor, Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana