Functionalized Silica Nanoparticles as Additives for Polymorphic Control in Emulsion-Based Crystallization of Glycine

Emulsion-based crystallization to produce spherical crystalline agglomerates is an attractive route to control the size and morphology of active pharmaceutical ingredient (API) crystals, which in turn improves downstream processability. Here, we demonstrate the use of silica nanoparticles modified with different surface functional groups (hydroxyl, amino, carboxylic, imidazolim chloride, and chloride) as additives in water-in-oil emulsion-based crystallization of glycine, a model API molecule. Spherical agglomerates of glycine obtained under different experimental conditions are characterized by powder X-ray diffraction (XRD) and scanning electron microscopy. Our observations reveal the strong influence of particle functionalization on polymorphic outcome at near-neutral (pH ∼6) conditions, where we are able to selectively crystallize the least stable β-polymorph of glycine or tune the relative ratio of α- and β-polymorphs by selecting appropriate experimental conditions. Mixtures of α- and γ-glycine are typically obtained under acidic solutions (pH ∼3), irrespective of the functional groups used. We examine the influence of charge and immobilization density of surface functional groups and nanoparticle concentration on the polymorphic outcome and rationalize our results by analyzing molecular and functional group speciation

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