Continuous wet granulation using fluidized-bed techniques. I. Examination of powder mixing kinetics and preliminary granulation experiments.

The movement of powder/granules within the reaction chambers of two continuously-operating granulators (Niro/Aeromatic-Fielder Contipharm and the Glatt Continuous Fluidized-Bed Granulator) was examined by adding dyestuffs to the powder-inlet. Comparison of the dye mass-fraction in the product with the appropriate transport equation indicated random mixing and transport within the product-chamber. Photographs of powder movement on the gill-plate of the Contipharm showed, however, air-driven transport of powder from inlet to outlet, which evidently does not prevent overall random mixing. The output half-life is > 20 min, showing substantial residence time within each machine. A simplex granule was also prepared using the two machines. With the Niro it was shown that an increase in binder solution spraying rate during the continuous process produced an increase in particle size distribution and moisture content. Reduction of air volumetric flow rate on the Glatt machine during continuous operation produced higher moisture content of the product. It was thus demonstrated that changes in process conditions during continuous operation produce predictable alterations in product properties,

Particulate contamination from siliconized rubber closures for freeze drying.

It can be shown that siliconized closures for freeze drying may cause the opalescence and turbidity observed in freeze-dried products after reconstitution. Closures of different rubber composition show different intensities of turbidity when treated identically with the same quantity and type of silicone oil. Clear solutions are obtained after reconstitution if ETFE-coated closures are used instead of siliconized closures. Samples stored at 4 degrees C for up to 6 months show no change in the intensity of turbidity, while the turbidity of samples manufactured with siliconized closures and stored at higher temperatures increase with time. Samples with ETFE-coated closures show clear solutions when stored at 25 degrees C and 37 degrees C for up to 6 months and at 45 degrees C for 3 months. After 6 months only a very weak opalescence could be observed in these samples.

Modeling and numerical computation of drug transport in laminates: model case evaluation of transdermal delivery system.

This study reports on the modeling and numerical computation of drug transport from a laminated system into the skin. The model is based on the diffusion equation, on partitioning of the drug between individual layers of the device, and on continuity conditions for diffusive flux across the material interfaces of the system. Numerical computation of concentration profiles across the system was performed using a sophisticated software package designed for a general class of kinetics-diffusion problems, including time variable diffusion coefficients and interface conditions in case of nonhomogeneous media. This program is demonstrated by a model case evaluation of a transdermal delivery system for nitroglycerin and applies previous data on drug diffusion and partitioning in this system. The layers involved in drug transport are: a polymer film to carry the drug depot; a microporous membrane, the pores of which are filled with nonpolar liquids and solids; an adhesive layer; and a final layer representing the skin. Transport kinetics in the delivery system and the skin are being followed by plots of concentration profiles as a function of application time. Major concentration gradients indicate sites of release control. For practical purposes, the package is intended to serve for preformulation studies of laminated drug delivery systems.