We present a simple, potentially generalizable method to create highly monodisperse spherical microparticles (SMs) of ∼200 μm size containing active pharmaceutical ingredient (API) crystals and a macromolecular excipient, with unprecedented, highly specific, and selective control over the morphology and polymorphic outcome. The basic idea and novelty of our method is to control polymorphic selection within evaporating emulsion drops containing API−excipient mixtures via the kinetics of two simultaneously occurring processes: liquid−liquid phase separation and supersaturation generation, both governed by solvent evaporation. We demonstrate our method using two model hydrophobic APIs: 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) and carbamazepine (CBZ), formulated with ethyl cellulose (EC) as excipient. We dispense monodisperse oil-in-water (O/W) emulsions containing the API−excipient mixture on a flat substrate with a predispensed film of the continuous phase, which are subsequently subjected to evaporative crystallization. We are able to control the polymorphic selection by varying solvent evaporation rate, which can be simply tuned by the film thickness; thin (∼0.5 mm) and thick (∼2 mm) films lead to completely specif ic and dif ferent polymorphic outcomes for both model APIs: yellow (YT04) and orange (OP) for ROY, and form II and form III for CBZ respectively. Our method paves the way for simultaneous, bottom-up crystallization and formulation processes coupled with unprecedented polymorphic selection through process driven kinetics.

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.

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.

We present the first study of a novel, generalizable method that uses a water-in-oil nanoemulsion as the continuous phase to generate uniform aqueous micro-droplets in a capillary-based microfluidic system. We first study the droplet generation mechanism in this system and compare it to the more conventional case where a simple oil/solvent (with surfactant) is used as the continuous phase. Next, we present two versatile methods - adding demulsifying chemicals and heat treatment - to allow active online chemical interaction between the continuous and dispersed phases. These methods allow each generated micro-droplet to act as a well-mixed micro-reactor with walls that are 'permeable' to the nanoemulsion droplets and their contents. Finally, we demonstrate an application of this system in the fabrication of uniform hydrogel (alginate) micro-beads with control over particle properties such as size and swelling. Our work expands the toolbox of droplet-based microfluidics, enabling new opportunities and applications involving active colloidal continuous phases carrying chemical payloads, both in advanced materials synthesis and droplet-based screening and diagnostic methods.

In this paper, we demonstrate a continuous flow evaporative crystallization platform for producing monodisperse microparticles containing crystalline API with tunable particle sizes and compositions, which are suitable for direct compounding. Monodisperse drugladen emulsions are first generated via microfluidics and undergo continuous solvent extraction within a tubular crystallizer to emerge as microparticles. We demonstrate this platform on four different types of hydrophobic drug and drug-excipient formulations to show the generality of this method and discuss the solvent extraction performance of the platform using a mathematical model. Our approach combines four conventional manufacturing steps in the conventional secondary drug manufacturing cycle− crystallization, blending, milling, and granulation, into a single step which directly produces monodisperse and spherical microparticles of tailored size and composition. This system paves the way for innovative continuous bottom-up formulation of microparticles and is aligned with the expanding suite of advanced continuous pharmaceutical manufacturing technologies.

This study presents a novel droplet-templated antisolvent spherical crystallization method applicable to both hydrophilic and hydrophobic drugs. In both cases, an alginate hydrogel binder forms in situ, concurrently with the crystallization process, effectively binding the drug crystals into monodisperse spheres. This study presents a detailed process description with mass transfer modeling, and with characterization of the obtained alginate/drug spheres in terms of morphology, composition, and drug loading. Although glycine and carbamazepine are used as model hydrophilic and hydrophobic drugs, this method is easily generalized to other drugs, and offers several benefits such as minimal thermal impact, fast crystallization rates, high drug-binder loading ratios, and high selectivity toward metastable polymorphs.

The crystallization of molecular solids is ubiquitous in various contexts, and forms the basis of pharmaceutical drug product design and manufacture. As drug molecules get more complex, their crystallization into well-controlled crystal forms becomes more challenging yet unquestionably important, from a process and product perspective. Here, we demonstrate the fabrication of molecular solids with exquisitely tunable crystalline microstructure by co-confinement of a highly supersaturated drug–colloidal dispersion within submillimeter droplets. Specifically, we show the evaporative solidification of an anti-retroviral drug molecule (Lamivudine, 4-amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2­(1H)-pyrimidinone) into spherical crystalline particles in the presence of colloidal silica or polystyrene, where we are able to tune the crystalline microstructure of the drug at the submicron level by using various colloid sizes. Confinement of the drug within droplets generated in a microfluidic device enables access to high degrees of supersaturation before the onset of crystal nucleation while allowing precise control over the amount of dispensed colloidal particles. The tunability of the microstructural length scale with colloid size and the surface-agnostic nature of the microstructure control are unprecedented observations that are not captured by currently available theories. Furthermore, differences in the polymorphic outcome of the crystallization conducted in the presence or absence of colloids were also observed. Our findings pave the way for the design and manufacturing of novel crystalline composites by colloid-induced microstructure control.

The recent progress of machine learning and microfluidics in the chemical and biological sciences has motivated the development of new online techniques to interrogate the (bio)chemical contents within moving droplets. To accelerate the optical characterization of new materials and chemical reactions, we combine a line-scan hyperspectral imaging system with a droplet-based microfluidic reactor. We demonstrate the performance of this platform on a model chemistry -silver nanoparticle synthesis. The platform can image the spectral signature of ~400 individual droplets in only 15 s, with droplet flow speeds exceeding 4 cm/s in the reaction tube. After correction of the keystone and smile effects on the hyper-spectral images, the absorbance spectra are extracted from the droplets with an accuracy comparable to industrial spectrophotometers. The time evolution of the UV/Vis absorbance spectra during the reactive synthesis can be tracked either by scanning all the droplets present in the reaction tube or by following a subset of the droplet ensemble at frame rates up to 92 fps. This high-throughput and high-speed platform is particularly interesting for screening large parameter spaces and imaging fast reactions with a high resolution, for eventual coupling with advanced machine learning techniques to infer kinetic models and obtain detailed mechanistic insights.