Granulation is a common manufacturing step for pharmaceutical drug products, which improves powder flowability, compactibility, and ensures tablet content uniformity. Granules of uniform content can conventionally be challenging to obtain due to powder segregation and mixing issues prior to granulation. Spherical crystallizationa method where drug crystals are directly formed into spherical granulesis a promising way to overcome issues with mixing and form granules with uniform content. However, a common challenge of existing quasi emulsion solvent diffusion or solvent extraction methods for spherical crystallization involving miscible solvents in stirred batch vessels is the coarse control over particles sizes, as they are sensitive to multiple scale-up factors (mixing efficiency, impeller and vessel geometry, inlet configuration). This limits the method in terms of content uniformity, which in turn limits the extent to which granules with tunable dissolution profiles can be created. Here, we propose a method for the formation of monodisperse drug-excipient microparticles with tunable release profiles via microfluidic spherical extractive crystallization using drug and excipient-loaded ethyl acetate-in-water emulsions. Monodisperse droplets are generated using microfluidics, and droplet saturation via solvent extraction leads to eventual and direct monodisperse spherical particle formation within minutes. We demonstrate this method using ethyl acetate droplets loaded with naproxen or naproxen and ethyl cellulose, as a hydrophobic drug and drug-excipient model system, respectively, and obtained monodisperse spherical microparticles in both cases. Lastly, preliminary investigations of in vitro drug release from a range of microparticles made from droplets containing different naproxen–ethyl cellulose ratios displayed clear differences in the release profiles. When coupled with microfluidic droplet generators that operate at high volumetric throughputs, this method has the potential to be applied in continuous manufacturing platforms for the production of monodisperse spherical drug particles or drug-excipient composites with excellent content uniformity and tunable release profiles at a kilogram per day scale throughput.

The processes of dissolution and fragmentation have high relevance in pharmaceutical research, medicine, digestive physiology, and engineering design. Experimentally, dissolution and fragmentation are observed to occur simultaneously, yet little is known about the relative importance of each of these processes and their impact on the dissolution process as a whole. Thus, in order to better explain these phenomena and the manner in which they interact, we have developed a novel mathematical model of dissolution, based on partial differential equations, taking into consideration the two constituent processes of surface area-dependent diffusive mass removal and physical fragmentation of the solid particles, and the basic physical laws governing these processes. With this model, we have been able to quantify the effects of the interplay between these two processes and determine the optimal conditions for rapid solid dissolution in liquid solvents. We were able to reproduce experimentally observed phenomena and simulate dissolution under a wide range of experimentally occurring conditions to give new perspectives into the kinetics of this common, yet complex process. Finally, we demonstrated the utility of this model to aid in experiment and device design as an optimisation tool.

We present a simple, bottom up method for the structural design of solid microparticles containing crystalline drug and excipient using microfluidic droplet-based processing. In a model system comprising 5-methyl-2-[(2-nitrophenyl)­amino]-3-thiophenecarbonitrile (ROY) as the drug and ethyl cellulose (EC) as the excipient, we demonstrate a diversity of particle structures, with exquisite control over the structural outcome at the single-particle level. Within microfluidic droplets containing drug and excipient, tuning droplet composition and solvent removal rates allows us to controllably access structural diversity via an interplay of three physical processes (liquid–liquid phase separation, drug crystallization, and polymer vitrification) occurring during solvent removal. Specifically, we demonstrate two levels of structural controla coarse “macro” particle structure and a finer “micro” structure. Further, we elucidate the key mechanistic elements responsible for the observed structural diversity using a combination of systematic experiments, thermodynamic arguments based on a three-component phase diagram, and dissipative particle dynamics simulations. We validate our method with two different excipient and drug combinationsROY and poly­(lactic-co-glycolic acid), and EC and carbamazepine (CBZ). Finally, we present preliminary investigations of in vitro drug release from two different types of CBZ–EC particles, highlighting how structural control allows the design of drug release profiles.

Ultrasound delivered via a microprobe horn allows for tunable and repeatable screening of drug release behavior in small volumes.

Biomedical and clinical scientists play a major role in translating observations into interventions – therapeutics, diagnostics, and medical devices including screening instruments – that improve the health of individuals and...