Control of Drug-Excipient Particle Attributes with Droplet Microfluidic-based Extractive Solidification Enables Improved Powder Rheology.

PURPOSE: Industrial implementation of continuous oral solid dosage form manufacturing has been impeded by the poor powder flow properties of many active pharmaceutical ingredients (APIs). Microfluidic droplet-based particle synthesis is an emerging particle engineering technique that enables the production of neat or composite microparticles with precise control over key attributes that affect powder flowability, such as particle size distribution, particle morphology, composition, and the API's polymorphic form. However, the powder properties of these microparticles have not been well-studied due to the limited mass throughputs of available platforms. In this work, we produce spherical API and API-composite microparticles at high mass throughputs, enabling characterization and comparison of the bulk powder flow properties of these materials and greater understanding of how particle-scale attributes correlate with powder rheology. METHODS: A multi-channel emulsification device and an extractive droplet-based method are harnessed to synthesize spherical API and API-excipient particles of artemether. As-received API and API crystallized in the absence of droplet confinement are used as control cases. Particle attributes are characterized for each material and correlated with a comprehensive series of powder rheology tests. RESULTS: The droplet-based processed artemether particles are observed to be more flowable, less cohesive, and less compressible than conventionally synthesized artemether powder. Co-processing the API with polycaprolactone to produce composite microparticles reduces the friction of the powder on stainless steel, a common equipment material. CONCLUSIONS: Droplet-based extractive solidification is an attractive particle engineering technique for improving powder processing and may aid in the implementation of continuous solid dosage form manufacturing.

Label-free direct visual analysis of hydrolytic enzyme activity using aqueous two-phase system droplet phase transitions.

Dextran hydrolysis-mediated conversion of polyethylene glycol (PEG)-dextran (DEX) aqueous two-phase system droplets to a single phase was used to directly visualize Dextranase activity. DEX droplets were formed either by manual micropipetting or within a continuous PEG phase by computer controlled actuation of an orifice connecting rounded channels formed by backside diffused light lithography. The time required for the two-phase to one-phase transition was dependent on the Dextranase concentration, pH of the medium, and temperature. The apparent Michaelis constants for Dextranase were estimated based on previously reported catalytic constants, the binodal polymer concentration curves for PEG-DEX phase transition for each temperature, and pH condition. The combination of a microfluidic droplet system and phase transition observation provides a new method for label-free direct measurement of enzyme activity.

Precisely targeted delivery of cells and biomolecules within microchannels using aqueous two-phase systems.

Laminar and pulsatile flow of aqueous solutions in microfluidic channels can be useful for controlled delivery of cells and molecules. Dispersion effects resulting from diffusion and convective disturbances, however, result in reagent delivery profiles becoming blurred over the length of the channels. This issue is addressed partially by using oil-in-water phase systems. However, there are limitations in terms of the biocompatibility of these systems for adherent cell culture. Here we present a fully biocompatible aqueous two-phase flow system that can be used to pattern cells within simple microfluidic channel designs, as well as to deliver biochemical treatments to cells according to discrete boundaries. We demonstrate that aqueous two-phase systems are capable of precisely delivering cells as laminar patterns, or as islands by way of forced droplet formation. We also demonstrate that these systems can be used to precisely control chemical delivery to preformed monolayers of cells growing within channels. Treatments containing trypsin were localized more reliably using aqueous two-phase delivery than using conventional delivery in aqueous medium.

Dacron Skirt Reconstruction of the Left Ventricular Outflow Tract: Extending the Capabilities of a Valved Conduit.

Aortic root reconstruction in the setting of redo aortic valve procedures or infective endocarditis may be technically challenging, particularly because of variable destruction or distortion of the left ventricular outflow tract. Homograft aortic root replacement is an excellent option for aortic root abscesses but is limited by homograft availability. We describe a simple technique of a bioprosthetic valved conduit constructed on the table using a Dacron (DuPont, Wilmington, DE) skirt below the valve. The use of the Dacron skirt facilitates easy reconstruction of the left ventricular outflow tract.