(452e) Pharmaceutical Processes Selection from Shear Cell Analysis and Compaction Simulation

The objective of this work is to develop guidelines for first intent manufacturing process selection for solid dose pharmaceuticals, based on systematic evaluation of powder flow utilizing shear cell and powder compressibility utilizing compaction simulation.    Continuous processing requires the powder to flow from one piece of equipment to another; therefore, powder flow is the first critical attribute to consider when determining if a powder is eligible for a particular pharmaceutical process route.  Powder compressibility, i.e.,the ability of the powder to irreversibly deform under mechanical stress and make robust compacts of sufficient tensile strength at optimum solid fractions, is the other key factor to consider when designing a robust formulation for an intended manufacturing process.  

  Dry processing routes are preferred as they offer lower cost, lower complexity, and have no need to dry the material, which reduces the risk of prolonged heat and moisture exposure.    If the drug product blend has good powder flow and good compressibility, then continuous blending and tablet compression can be utilized as the first intent manufacturing process.   For assessment of flow requirements for continuous processing, models using shear cell flow data for prediction of resulting tablet weight variation in compression are discussed.   In addition, based on compaction simulation analysis for a wide range of pharmaceutical materials, tablet robustness criteria for tensile strength, ejection stress and solid fraction have been developed.

  Drug product blends that do not flow well enough to enable direct compression require granulation prior to compression.  Roller compaction is the preferred process, followed by continuous twin screw granulation, then batch high shear granulation.   Both roller compaction and twin screw granulation utilize screw conveyed hoppers to feed powder, and the shear cell flow index can be utilized to predict the instantaneous discharge variation from these hoppers.   The impact of this instantaneous feed variation can have significant impacts on powder wetting and granule consistency during twin screw granulation, or can impact ribbon density variation during roller compaction.  Density of the granules, either made by dry or wet granulation, significantly impacts granule compressibility.  The impact of granule density on tablet compressibility has been additionally probed in this work using compaction simulation.     

  This work illustrates the value of utilizing fundamental mechanical properties of powders to enable a rapid and material-sparing selection of manufacturing process and formulation design of solid oral pharmaceuticals.