Intrinsic dissolution rate modeling for the pharmacopoeia apparatus rotating disk compared to flow channel method.

For a solid understanding of drug characteristics, in vitro measurement of the intrinsic dissolution rate is important. Hydrodynamics are often emphasized as the decisive parameter influencing the dissolution. In this study, experiments and computational fluid dynamic (CFD) simulations showed that the mixing behavior in the rotating disc apparatus causes an inhomogeneous flow field and a systematic error in the calculation of the intrinsic dissolution rate. This error is affected by both the experimental time and the velocity. Due to the rotational movement around the tablet center, commonly utilized in pharmacopeia methods, a broad variance is present with regard to the impact of fluid velocity on individual particles of the specimen surface. As this is significantly reduced in the case of uniform overflow, the flow channel is recommended for investigating the dissolution behavior. It is shown that rotating disc measurements can be compared with flow channel measurements after adjusting the measured data for the rotating disc based on a proposed, representative Reynolds number and a suggested apparatus-dependent correction factor. Additionally, modeling the apparatus-independent intrinsic dissolution rate for different temperatures in the rotating disc apparatus is possible using the adapted Levich's equation.

Determination of Inherent Dissolution Performance of Drug Substances.

The dissolution behavior of novel active pharmaceutical ingredients (API) is a crucial parameter in drug formulation since it frequently affects the drug release. Generally, a distinction is made between surface-reaction- and diffusion-controlled drug release. Therefore, dissolution studies such as the intrinsic dissolution test defined in the pharmacopeia have been performed for many years. In order to overcome the disadvantages of the common intrinsic dissolution test, a new experimental setup was developed within this study. Specifically, a flow channel was designed and tested for measuring the mass transfer from a flat, solid surface dissolving into a fluid flowing over the surface with well-defined flow conditions. A mathematical model was developed that distinguishes between surface-reaction- and diffusion-limited drug release based on experimental data. Three different drugs-benzocaine, theophylline and griseofulvin-were used to investigate the mass flux during dissolution due to surface reaction, diffusion and convection kinetics. This new technique shows potential to be a valuable tool for the identification of formulation strategies.

Elucidation of mass transfer mechanisms in pellet formation by spheronization.

Previously published mechanisms of pellet formation during extrusion-spheronization include a transfer of material between different granules. This research aimed to specify the origin of this transfered mass, enabling further insight into the extrusion-spheronization process. Granules of various diameters were rounded simultaniously in a spheronizer to ascertain if mass transfer between smaller and larger granules is truly in balance, or if mass transfer from smaller to larger granules is preferred. Granules were also marked with a fluorescent tracer to enable quantification of mass transfer. By using differently sized and shaped granules as starting material, different modes of mass transfer were investigated. Samples were taken after various process durations to investigate the kinetics of the tranfer mechanism. It was found that both small and large granules dispense and receive mass during spheronization. In general, small granules increase their size, while large granules maintain their size or show a slight size decrease, resulting in the particularly narrow monomodal size distribution.

The interplay of dissolution, solution crystallization and solid-state transformation of amorphous indomethacin in aqueous solution.

Supersaturation profiles of amorphous indomethacin in aqueous solution containing 0.4 wt% and 4 wt% of isopropanol were predicted by combining separately-determined kinetics for dissolution, solution crystallization, and solid-state transformation. The kinetics of solid-state transformation were measured and compared to various data from the literature. The proposed kinetic model accounts for dissolution, solution crystallization and amorphous-to-crystalline solid-state transformation. It was validated for different initial amounts of amorphous and crystalline material and systems with different isopropanol contents. Furthermore, the influence of polyethylene glycol on the supersaturation behavior was investigated. The results clearly show the robustness of the model and give insight into the interplay of dissolution, solution crystallization, and solid-state transformation of. In particular, the influence of solid-state transformation on the overall supersaturation profile was elucidated in a quantitative manner. An amorphicity function φ(t) is proposed to account for the kinetics of the solid-state transformation. Its general form could be derived consistently from different sets of experimental data and seems to be independent of the particle size of the amorphous material and hydrodynamic conditions. This work is among the first of its kind to successfully integrate dissolution, crystallization from solution and solid-state transformation in a model that shows good predictability.