Quantifying and reducing powder shear sensitivity when manufacturing capsules with lubricants.

The purpose of this work was to develop a methodology that quantifies the extent of shear induced during an encapsulation process and show how formulation composition and manufacturing process designs can be changed to reduce the negative impact on drug product quality attributes. The powder feed system used in a dosing disc type pharmaceutical capsule filling machine induced additional shear of the powder prior to slug formation. The shear occurred both in the hopper portion, via the rotation of the feed auger and impeller, and in the powder bowl via the tamping pin agitation and/or shear against the stationary surfaces such as the powder level scraper. The extent of shear was quantified to assess the impact of further dispersing the hydrophobic lubricant, magnesium stearate, in both active and placebo formulations. Stratified samples over the course of the encapsulation run showed suppression in the drug dissolution profiles and decrease in the interparticulate tensile strength of the encapsulated product. The amount of shear (duration and rate) induced during the encapsulation unit operation can be much greater than that from typical bin blending operations and therefore requires consideration during product design and scale-up to ensure product robustness.

Understanding the role of magnesium stearate in lowering punch sticking propensity of drugs during compression.

The sticking of active pharmaceutical ingredient (API) to the surfaces of compaction tooling, frequently referred to as punch sticking, causes costly downtime or product failures in commercial tablet manufacturing. Magnesium stearate (MgSt) is a common tablet lubricant known to ameliorate the sticking problem, even though there exist exceptions. The mechanism by which MgSt lowers punch sticking propensity (PSP) by covering API surface is sensible but not yet experimentally proven. This work was aimed at elucidating the link between PSP and surface area coverage (SAC) of tablets by MgSt, in relation to some key formulation properties and process parameters, namely MgSt concentration, API loading, API particle size, and mixing conditions. The study was conducted using two model APIs with known high PSPs, tafamidis (TAF) and ertugliflozin-pyroglutamic acid (ERT). Results showed that PSP decreases exponentially with increasing SAC by MgSt. The composition of material stuck to punch face was also explored to better understand the onset of punch sticking and the impact of possible MgSt-effected punch conditioning event.