Monodisperse Polymeric Ionic Liquid Microgel Beads with Multiple Chemically Switchable Functionalities

We present simple, inexpensive microfluidics-based fabrication of highly monodisperse poly­(ionic liquid) microgel beads with a multitude of functionalities that can be chemically switched in facile fashion by anion exchange and further enhanced by molecular inclusion. Specifically, we show how the exquisite control over bead size and shape enables extremely precise, quantitative measurements of anion- and solvent-induced volume transitions in these materials, a crucial feature driving several important applications. Next, by exchanging diverse anions into the synthesized microgel beads, we demonstrate stimuli responsiveness and a multitude of novel functionalities including redox response, controlled release of chemical payloads, magnetization, toxic metal removal from water, and robust, <i>reversible</i> pH sensing. These chemically switchable stimulus-responsive beads are envisioned to open up a vast array of potential applications in portable and preparative chemical analysis, separations and spatially addressed sensing

Monodisperse Polymeric Ionic Liquid Microgel Beads with Multiple Chemically Switchable Functionalities

We present simple, inexpensive microfluidics-based fabrication of highly monodisperse poly­(ionic liquid) microgel beads with a multitude of functionalities that can be chemically switched in facile fashion by anion exchange and further enhanced by molecular inclusion. Specifically, we show how the exquisite control over bead size and shape enables extremely precise, quantitative measurements of anion- and solvent-induced volume transitions in these materials, a crucial feature driving several important applications. Next, by exchanging diverse anions into the synthesized microgel beads, we demonstrate stimuli responsiveness and a multitude of novel functionalities including redox response, controlled release of chemical payloads, magnetization, toxic metal removal from water, and robust, <i>reversible</i> pH sensing. These chemically switchable stimulus-responsive beads are envisioned to open up a vast array of potential applications in portable and preparative chemical analysis, separations and spatially addressed sensing

Simultaneous Spherical Crystallization and Co-Formulation of Drug(s) and Excipient from Microfluidic Double Emulsions

We demonstrate the fabrication of engineered pharmaceutical formulations of drug(s) and excipient as monodisperse spherical microparticles. Specifically, we fabricate monodisperse microparticles of ∼200 μm size containing crystals of a hydrophobic model drug (ROY) embedded within a hydrophilic matrix (sucrose) (DE formulation), which in turn may also contain a hydrophilic model drug (glycine) (D²E formulation). To do this, we dispense the components of the formulation into monodisperse oil-in-water-in-oil (O₁/W/O₂) double emulsions using capillary microfluidics, to subsequently enable simultaneous crystallization and co-formulation via solvent evaporation. We provide detailed morphological and polymorphic characterization of the particles obtained and highlight how (a) microfluidic methods enable formulations that are nearly impossible to achieve using conventional crystallization methods, and (b) these ‘bottom-up’ methods could potentially circumvent several energy intensive ‘top-down’ processes in traditional manufacturing, thereby offering the potential of continuous, sustainable pharmaceutical crystallization coupled with advanced formulations

Highly selective, kinetically driven polymorphic selection in microfluidic emulsion-based crystallization and formulation

Crystal Growth and Design151212-21

Spherical Crystallization of Glycine from Monodisperse Microfluidic Emulsions

Emulsion-based crystallization to produce spherical crystalline agglomerates (SAs) is an attractive route to control crystal size during downstream processing of active pharmaceutical ingredients (APIs). However, conventional methods of emulsification in stirred vessels pose several problems that limit the utility of emulsion-based crystallization. In this paper, we use capillary microfluidics to generate monodisperse water-in-oil emulsions. Capillary microfluidics, in conjunction with evaporative crystallization on a flat heated surface, enables controllable production of uniformly sized SAs of glycine in the 35–150 μm size range. We report detailed characterization of particle size, size distribution, structure, and polymorphic form. Further, online high-speed stereomicroscopic observations reveal several clearly demarcated stages in the dynamics of glycine crystallization from emulsion droplets. Rapid droplet shrinkage is followed by crystal nucleation within individual droplets. Once a nucleus is formed within a droplet, crystal growth is very rapid (<0.1 s) and occurs linearly along radially advancing fronts at speeds of up to 1 mm/s, similar to spherulitic crystal growth from impure melts. The spherulitic aggregate thus formed ages to yield the final SA morphology. Overall crystallization times are on the order of minutes, as compared to hours in conventional batch processes. We discuss these phenomena and their implications for the development of more generalized processes applicable to a variety of drug molecules. This work paves the way for microfluidics-enabled continuous spherical crystallization processes

Highly Selective, Kinetically Driven Polymorphic Selection in Microfluidic Emulsion-Based Crystallization and Formulation

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 <i>specific</i> and <i>different</i> 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

Simultaneous spherical crystallization and Co-formulation of drug(s) and excipient from microfluidic double emulsions

10.1021/cg4012982Crystal Growth and Design141140-146CGDE