Varied Bulk Powder Properties of Micro Sized API within Size Specifications as A Result of Particle Engineering Methods

Abstract

Micronized particles of an active pharmaceutical ingredient (API) are commonly used to improve the content uniformity (CU), dissolution performance, and bioavailability of pharmaceutical products. Many techniques have been developed to prepare micronized API using different routes of particle engineering. However, API particles in a specific size range prepared from different routes present a risk for varied bulk powder properties critical to manufacturing and unknown impact to quality of finished drug products due to different surface energetics, particle shape, and size distribution arising from the anisotropy of molecular crystals. This aspect is usually less emphasized than biopharmaceutical performance in early development phase. In this work, we have systematically investigated the variability in key bulk properties of 10 different batches of Odanacatib prepared by jet milling or fast precipitation. All batches met the particle size specification of Mv <6 µm, which ensured that the target biopharmaceutical performance, based on models and supported by in vivo clinical data. This work revealed meaningful differences among all batches of Odanacatib. Thus, the processing route does have a measurable impact on the properties of API, including crystallinity, flowability, tabletability, wettability, dissolution, and content uniformity. For Odanacatib, the directly precipitated sample exhibited the overall best performance, in terms of tabletability, dissolution, and CU, than other API batches. The insights attained in this work help guide the selection of processing routes for preparing fine Odanacatib particles with optimal performance.