Bottom-up Structural Design of Crystalline Drug-Excipient Composite Microparticles via Microfluidic Droplet-based Processing

Abstract

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.

Microfluidic Extractive Crystallization for Spherical Drug/Drug-Excipient Microparticle Production

“…The drug-release profiles obtained with neat naproxen and naproxen–ethyl cellulose microparticles of drug–polymer ratios 2.5, 1.25, 0.75, and 0.625 are provided in Figure . The wide range and variety of dissolution profiles obtained crucially highlights the applicability of the method to formulate functional drug-containing microparticles by tuning particle composition; we note that similar drug-release trends have been seen from in vitro release studies of MK-8591 and carbamazepine drug release from nonerodible poly­(ethylene vinyl acetate) matrix implants and ethyl cellulose microparticles at varying drug–polymer loads, respectively. These studies have demonstrated that drug release from insoluble matrices is diffusion-controlled.…”

“…Kawashima et al introduced the concept of spherical crystallization nearly three decades ago; this is a particularly facile process of granulation, in which spherical crystal agglomerates are directly formed during crystallization via the introduction of a bridging liquid or by conducting antisolvent crystallization within transient droplets (quasi emulsions) formed from miscible solvent pairs using high shear and agitation. , The main challenge of the aforementioned methods when conducted in agitated vessels is the coarse control over particle sizes, as the operation is sensitive to multiple scale-up factors such as mixing efficiency, impeller and vessel geometry, and inlet configuration. Some recent studies that have addressed this challenge couple microfluidics with drug crystallization, allowing for facile production of neat drug and also drug-excipient microparticles with tunable sizes and structures using microfluidic evaporative crystallization. − In these demonstrations, monodisperse drug or drug-excipient mixture loaded droplets are generated in immiscible continuous fluids and subjected to solvent removal via evaporation to induce drug supersaturation for direct particle formation. Besides evaporative crystallization, recent demonstrations by Watanabe et al .…”

Spherical Cellulose Micro and Nanoparticles: A Review of Recent Developments and Applications

“…The production of sphere-shaped cellulose-based microparticles can be performed by emulsification processes [ 93 , 112 , 113 , 114 , 115 ], and microfluidics technology [ 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 ], as well as other less common techniques, namely spray-assisted techniques [ 126 , 127 , 128 , 129 , 130 ], and the LbL assembly [ 131 , 132 ]. Concerning the cellulosic substrate, the majority of the studies reported the utilization of cellulose derivatives, such as CMC [ 120 , 131 ], CA [ 114 , 119 ] and EC [ 123 , 124 , 133 , 134 ], but also pristine vegetable cellulose [ 112 , 135 , 136 , 137 ], bacterial nanocellulose [ 116 , 117 , 118 ] and microcrystalline cellulose (MCC) [ 93 , 115 , 138 , 139 ]. The preference for cellulose derivatives to generate microparticles was anticipated given their solubility in water or in most common organic solvents, which translates into simpler processability.…”

“…The microfluidic technology is another methodology that is being used to fabricate sphere-shaped cellulose-based microparticles. Table 2 summarizes some of the most recent examples of micro-sized particles based on pure cellulose [ 116 , 117 , 118 , 125 ], and cellulose derivatives, such as CA [ 119 ], CMC [ 120 ], EC [ 123 , 124 ] and TEMPO-oxidized CNFs [ 155 ], produced by microfluidics.…”

Cellulose through the Lens of Microfluidics: A Review

“…In all these applications, cellulose as a solid phase provides a large surface area that may separate chemicals from flowing liquids due to cellulose active functional groups. In chromatography [14], protein purification [15], and drug delivery [16][17][18][19], cellulose beads can be utilized as the stationary phase. Papermaking and the synthesis of micro fibrillated cellulose have both employed partially or considerably fibrillated cellulose.…”