Crystal and Particle Engineering – An Indispensable Tool for Developing and Manufacturing Quality Pharmaceutical Products

Abstract

Design and manufacture of high-quality pharmaceutical products remains challenging due to the inherent complexities arising, in part, from multitudes of components in particulate forms, each having different functionality and potential for unwanted interactions during processing, storage, handling, or administration. Hence, it follows that particles and crystals play an essential role in pharmaceutical manufacturing. Successful manufacturing and quality of finished pharmaceutical products, even if the final dosage form may not be a solid, critically depend on powder properties, such as flowability, tabletability, wettability, and solubility. These powder properties, in turn, are controlled by the properties of constituting particles or crystals of active pharmaceutical ingredients (API) and excipients, such as size, size distribution, shape, porosity, mechanical properties, surface energy, and surface roughness [1,2]. Hence, appropriate engineering of crystals or particles through various processes, such as crystallization, granulation (dry, wet, fluid bed), hot-melt extrusion, spray-drying, and dry coating, is necessary for the purpose of overcoming problems in pharmaceutical manufacturing. Thus, engineering pharmaceutical materials at particle level is an important step in solving many problems in pharmaceutical manufacturing. In summary, the interrelationships among structure, property, performance, and processing, succinctly captured through materials science tetrahedron (MST) [1], could guide research in

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

“…27−31 In addition, crystal engineering strategies such as coprecipitation have been proposed for selecting solid materials exhibiting isotropic crystal growths. 10,32,33 An immediate CMC strategy would be to resort to a different DP technology with less demanding requirements, in terms of particle properties. This would allow relaxing the particle constraints, set in the GSA, and as a consequence expand the design space toward a less demanding region of seeding conditions.…”

“…Therefore, more pragmatic solutions are required for precisely controlling the particle properties instead of increasing seed load to 10%, as required here. To this end, nucleation platforms for the in situ preparation of considerably fine seeds have been developed. − In addition, crystal engineering strategies such as coprecipitation have been proposed for selecting solid materials exhibiting isotropic crystal growths. ,, An immediate CMC strategy would be to resort to a different DP technology with less demanding requirements, in terms of particle properties. This would allow relaxing the particle constraints, set in the GSA, and as a consequence expand the design space toward a less demanding region of seeding conditions.…”

“…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. − …”