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

Abstract

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.

Using Morphological Population Balance to Develop a Model-Driven Quality-by-Design Approach for Crystallization Processes

“…At present, the reconciliation of crystallization, which involves dual purification and particle engineering, with downstream drug-product manufacturing has become increasingly important in the biopharmaceutical industry. The increasing business and scientific demands have fueled the continuous manufacturing of dry drug products (DPs). − For the continuous dry manufacturing of DPs, active pharmaceutical ingredients (APIs) with appropriate particle size and morphology are crucial. − The interplay between these characteristics determines, to a considerable extent, the feasibility of dry-DP processes, such as continuous direct compression. − …”

Controlling Microparticle Morphology in Melt-Jet Printing of Active Pharmaceutical Ingredients through Surface Phenomena

“…One crucial aspect is the crystallization of the API in reactors to obtain a crystal slurry through cooling, evaporation, seeding, or antisolvent addition. This is followed by solid–liquid separation, washing, and drying field [ 1 , 2 ]. Each solid form of the API has unique properties that affect its solubility, bioavailability, hygroscopicity, melting point, stability, flowability, compressibility, and other performance characteristics [ 3 ].…”

“…Each solid form of the API has unique properties that affect its solubility, bioavailability, hygroscopicity, melting point, stability, flowability, compressibility, and other performance characteristics [ 3 ]. Controlling these processes and understanding their impact on the resulting drug properties is crucial in the pharmaceutical industry as API particles’ physicochemical properties and solid-state morphology directly affect their performance [ 2 , 3 ].…”

Comparative Pharmacokinetic Profiles of a Novel Low‐Dose Micronized Formulation of Raloxifene 45 mg (AD‐101) and the Conventional Raloxifene 60 mg in Healthy Subjects

“…12 The larger surface area following active pharmaceutical ingredient particle size reduction through micronization might yield higher solubility, faster dissolution rate, and enhanced bioavailability of the poorly water-soluble drugs. 13 A novel formulation of micronized raloxifene 45 mg has been developed by adopting the air-jet fluid energy milling. 14 It was designed to reduce the dosage by 75% with the pharmacokinetic (PK) parameters and, thus, efficacy equivalent to those of conventional formulation and to decrease the tablet size by 80%.…”

“…The various approaches, such as micronized active pharmaceutical ingredients and nanoparticle technology, have been attempted to improve the bioavailability of various hydrophobic drugs 12 . The larger surface area following active pharmaceutical ingredient particle size reduction through micronization might yield higher solubility, faster dissolution rate, and enhanced bioavailability of the poorly water‐soluble drugs 13 . A novel formulation of micronized raloxifene 45 mg has been developed by adopting the air‐jet fluid energy milling 14 .…”