(124d) Optimization and Scale up of High Shear Wet Granulation Process

High shear wet granulation is traditionally defined as a unit operation which produces bigger granules from fine powder under the influence of a binder. The bigger granules have better flow and compressibility ensuring better mixing and content uniformity while retaining the same effective surface area for dissolution and minimizing solvent resistance and inhalational hazards. Despite widespread use in pharmaceutical, chemical, agriculture, food, detergent and mineral industries; this process is often characterized by a lack of well-defined end point due to limited process understanding. Different parameters that affect how well the product is mixed include:  liquid addition rate, impeller speed, chopper speed, fill volume, binder volume, viscosity and surface tension of the liquid binder. Current study focusses on optimization and scale up of this process in a standard granulator (KG5, Key International Inc.) in lab scale.  The performance of granulation is quantified by recording the granule size distribution and dynamic strength of granules as a function of time. Particle size distributions were measured through Mastersizer 2000E.  Parametric studies on 1L and 5L  vessels were conducted with a 3 level factorial design using spray dried lactose (d₅₀ = 107 µm) and microcrystalline cellulose (MCC, d₅₀= 54 µm) particles with water, hydroxypropyl cellulose (HPC) and sodium lauryl sulfate (SLS) as binders. Fixed liquid volume percentage and maximum power consumption were used to determine end point. Scale up studies on vessels of defined sizes were done using Buckingham pi theorem.

Torque curves gathered during high shear wet granulation experiments are found to allow reasonable end point control of the process. Statistical analysis showing the significance of individual parameters and interaction between two parameters were done using MINITAB 16.0 using Principal Component analysis (PCA) Methodology. The influence of chopper speed had relatively little influence on both dynamic power and granule size especially in the smaller vessel for both lactose and MCC systems. Impeller speed was found to have a relatively greater impact for distribution of viscous binders. However, increasing impeller speed shortens granulation time but increases adhesion producing large lumps. Adhesion to the walls was much greater for lactose compared to MCC. In general, order of wall adhesion was water> HPC>SLS. This was also correlated with the maximum impeller power consumption being less reproducible in smaller vessel with material sticking to the walls. Increased content of liquid binder corresponded to increased size and strength but also increased wall adhesion. Decreased surfaces tension led to more granule collisions leading to quicker granulations but relatively weak granules were formed. A 3D Discrete Element Method (DEM) based model comprising microscopic particle interactions in agglomeration behavior within a shearing granular bed is validated in smaller scale.