(503d) API Particle Engineering for Drug Substance: Crystallization & Wet Milling to Control API Powder Properties
In the pharmaceutical industry, target drug substance powder properties, such as particle size and flow are defined for a given formulation to ensure robust drug product processing. Batch crystallizations are primarily designed to maximize the active pharmaceutical ingredient (API) yield and product purity and frequently produce API’s with non-ideal size and morphology. In this investigation, the effect of seeding, supersaturation, and post crystallization wet milling were used to produce API batches with a range of particle sizes and flow properties to define the initial design space of acceptable content uniformity and powder flow. For laboratory and pilot plant scale-up experiments, the particle size was measured real-time during crystallization and wet milling using focused beam reflectance measurement (FBRM) and correlated to spot slurry samples analyzed by laser light scattering as well as image based particle characterization. These results were compared with empirical correlations to account for initial particle size, mill generator configuration, rotor or tip speed, milling residence time, and rotor/stator gap or tooth dimensions to aid successful crystallization and wet milling scale-up.