(674d) Drug Polymer Constructs for Improved Powder Flow: Building Parametric Understanding and Manufacturability

Drug substance solids often exhibit poor powder flow properties, which can pose handling or processing issues during pharmaceutical manufacturing.  These issues are often approached by adding complexity in the form of additional excipients to modify flow or unit operations such as granulation or milling.  A novel technique has been introduced for manufacturing constructs of active pharmaceutical ingredient (API) with low levels of polymer material to improve flow properties of drug substance solids.  GSK APIs were selected for the study based on existing poor flow properties and opportunities to simplify complex formulation processes.  Commercially-available polymer materials were selected based on similar crystallization solubility profiles to the API and potential for improving flow properties.

Initial studies at GSK had previously demonstrated the improved powder flow properties of drug polymer constructs and the viability of an antisolvent precipitation method of manufacture.  In a reactor vessel typically used to prepare API, the final particle forming step was modified:  low levels (less than 10% w/w) of polymer solution were added to the crystallization slurry; polymer precipitated onto the surface of the API; and small agglomerates of drug substance were formed.  This change to the API crystallization has been demonstrated to deliver a drug substance which exhibits superior flow properties.

The investigation discussed extends earlier proof-of-concept work by building process knowledge, optimizing process parameters, and demonstrating scale independence.  Parameters such as polymer addition rate, slurry agitation rate, and mixing during drying were studied.  An analytical suite was developed to characterize and assess drug substance powders based on evidence of agglomeration, flow improvement, and changes in surface properties.  Polarized light microscopy and in-situ crystallization techniques indicated agglomeration of the API upon addition of polymer.  Flow analysis showed that API treated with polymer had increased density and flow properties.  Surface characterization data further supported polymer deposition on API surface.  Improved process understanding allowed for scale-up to a larger laboratory facility, demonstrating process robustness and manufacturability.  Batches of drug-polymer construct have been successfully carried through to dosage form using a simplified manufacturing process.