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Crystalline active pharmaceutical ingredients with comparable size and surface area can demonstrate surface anisotropy induced during crystallization or downstream unit operations such as milling. To the extent that varying surface properties impacts bulk powder properties, the final drug product performance such as stability, dissolution rates, flowability, and dispersibility can be predicted by understanding surface properties such as surface chemistry, energetics, and wettability. Here, we investigate the surface properties of different batches of Odanacatib prepared through either jet milling or fast precipitation from various solvent systems, all of which meet the particle size specification established to ensure equivalent biopharmaceutical performance. This work highlights the use of orthogonal surface techniques such as Inverse Gas Chromatography (IGC), Brunauer–Emmett–Teller (BET) surface area, contact angle, and X-ray Photoelectron Spectroscopy (XPS) to demonstrate the effect of processing history on particle surface properties to explain differences in bulk powder properties.

Micronized particles are commonly used to improve the content uniformity (CU), dissolution performance, and bioavailability of active pharmaceutical ingredients (API). Different particle engineering routes have been developed to prepare micron-sized API in a specific size range to deliver desirable biopharmaceutical performance. However, such API particles still risk varying bulk powder properties critical to successful manufacturing of quality drug products due to different particle shapes, size distribution, and surface energetics, arising from the anisotropy of API crystals. In this work, we systematically investigated key bulk properties of 10 different batches of Odanacatib prepared through either jet milling or fast precipitation, all of which meet the particle size specification established to ensure equivalent biopharmaceutical performance. However, they exhibited significantly different powder properties, solid-state properties, dissolution, and tablet CU. Among the 10 batches, a directly precipitated sample exhibited overall best performance, considering tabletability, dissolution, and CU. This work highlights the measurable impact of processing route on API properties and the importance of selecting a suitable processing route for preparing fine particles with optimal properties and performance.