The development and characterisation of a novel reverse-phase wet granulation process

摘要

Conventional wet granulation processes involve controlled coalescence of moist particles through the addition of binder liquid to dry powder particles such that the process proceeds in the direction of increasing liquid saturation. The process is terminated immediately prior to an undesirable state of uncontrolled granule growth and batch loss. The ideal conventional wet granulation process is stated to require tight control over granule nucleation conditions which are often not possible to execute commercially. Consequently, a novel reverse-phase granulation process was developed and studied involving immersion of dry powder into the binder liquid, thus eliminating the traditional granule nucleation process. The reverse-phase process proceeds in the direction of reduced liquid saturation, thus decreasing the risk of uncontrolled growth and batch loss.The effects of binder liquid quantity, binder liquid viscosity and impeller speed on the granules produced using the reverse-phase and conventional processes were compared. The conventional process exhibited induction growth behaviour and uncontrolled granule growth at elevated liquid saturation. In contrast the reverse-phase process demonstrated steady granule growth behaviour at all liquid saturations indicating greater robustness to process failure. The primary mechanism of the reverse-phase granulation process was breakage of large moist agglomerates and mechanical dispersion of the binder liquid throughout the powder formulation. The size and porosity of reverse-phase granules were controlled by the liquid saturation and impeller speed, with these physical properties being best described by the dimensionless Stokes deformation number and the growth regime map.Two potentially negative consequences associated with the reverse-phase granulation approach were evaluated. First, the compaction properties of reverse-phase granules were shown to be similar to those of conventional granules. Second, the rate and extent of hydration of the model drug anhydrous theophylline was shown to be similar for both the reverse-phase and conventional granulation processes. Based upon these findings it was concluded that the reverse-phase process may represent a feasible alternative to the conventional process, particularly should scale-up to the industrial scale prove applicable.