Goran T. Vladisavljevic

Preparation and analysis of oil-in-water emulsions with a narrow droplet size distribution using Shirasu-porous-glass (SPG) membranes

Abstract Shirasu-porous-glass (SPG) membranes with a mean pore size from 0.4–6.6 μm were used to produce O/W emulsions consisting of vegetable (rape seed) oil as the dispersed phase and Span 80 dissolved in demineralized water as the continuous phase. The emulsion droplets with a mean droplet size 3.5 times larger than the mean pore size and the span of the droplet size distribution between 0.26 and 0.45 were produced using 2% emulsifier at a transmembrane pressure slightly exceeding the capillary pressure. Under these conditions the dispersed phase flux through the membrane was in the range of 0.7–7 1·m−2·h−1 and only about 2% of the pores were active. However, if the transmembrane pressure was considerably higher than the capillary pressure, the dispersed phase flux strongly increased and droplets with a broad droplet size distribution were produced. The hydraulic resistance of the SPG membrane was inversely proportional to the square of the mean pore size, which is in agreement with the Hagen-Poiseuille law. The membrane porosity is independent on the pore size and ranged from 53–60%.

Industrial lab-on-a-chip: Design, applications and scale-up for drug discovery and delivery

Microfluidics is an emerging and promising interdisciplinary technology which offers powerful platforms for precise production of novel functional materials (e.g., emulsion droplets, microcapsules, and nanoparticles as drug delivery vehicles- and drug molecules) as well as high-throughput analyses (e.g., bioassays, detection, and diagnostics). In particular, multiphase microfluidics is a rapidly growing technology and has beneficial applications in various fields including biomedicals, chemicals, and foods. In this review, we first describe the fundamentals and latest developments in multiphase microfluidics for producing biocompatible materials that are precisely controlled in size, shape, internal morphology and composition. We next describe some microfluidic applications that synthesize drug molecules, handle biological substances and biological units, and imitate biological organs. We also highlight and discuss design, applications and scale up of droplet- and flow-based microfluidic devices used for drug discovery and delivery.

Influence of process parameters on droplet size distribution in SPG membrane emulsification and stability of prepared emulsion droplets

SPG membranes were used to prepare monodispersed O/W and W/O/W emulsions over a wide range of membrane wall shear stress (0.37–40 Pa), dispersed phase content (1–20 vol.%) and transmembrane pressure. Although the most uniform droplets were prepared at the membrane wall shear stress of 30 Pa, a monodispersed O/W emulsion can be even obtained at the wall shear stress of 0.37 Pa, corresponding to laminar flow regime of continuous phase inside the membrane tube. The minimum droplet size somewhat decreased with time, probably due to gradual activation of smaller pores. There was no significant difference in the size distribution curve of pure oil droplets of O/W emulsions and W/O drops of W/O/W emulsions, if they were both prepared under the same conditions. No significant change in droplet size distribution of prepared O/W emulsions was observed during the storage time of up to 159 days.

Permeate flux and fouling resistance in ultrafiltration of depectinized apple juice using ceramic membranes

Raw depectinized apple juice was clarified in a laboratory scale ultrafiltration system using ceramic tubular membranes (Tech-Sep Carbosep) with a molecular weight cut-off of 300,000, 50,000, and 30,000 Da. The experiments have been carried out over a wide range of transmembrane pressures (100–400 kPa), temperatures (20–55 °C), and feed flow rates (100–900 ml/min). Permeate flux significantly decreased with time until a steady-state was established. The steady-state permeate flux reached a maximum at a transmembrane pressure of about 200 kPa. Higher permeate flux was obtained at higher temperatures due to lower permeate viscosity. The steady-state permeate flux was proportional to the feed flow rate raised to powers ranging between 0.22 and 0.31. All the membranes studied produced the clarified juice with a satisfactory clarity and color intensity value.

Preparation of water-in-oil emulsions using microporous polypropylene hollow fibers: influence of some operating parameters on droplet size distribution

Abstract Emulsification is usually performed using high-pressure homogenizers and rotor/stator systems. In the dispersing zone of these machines high shear stresses are applied to deform and disrupt large droplets of a premix. Membrane emulsification is a new emulsification technology based on the use of a microporous membrane. In this process, the disperse phase is pressed through the pores into the continuous phase where the droplets are formed. The droplets reaching a critical diameter detach from the membrane surface under the influence of shear forces caused by the flow of the continuous phase. In this investigation, polypropylene hollow fibers with 0.4 μm pores and 1.7 mm inside diameter were used to produce water-in-oil (W/O) emulsions consisting of demineralized water as the dispersed phase, mineral oil Velocite no. 3 as the continuous phase, and polyglycerol polyricinoleate (PGPR 90) as the emulsifier. The size of water droplets in the prepared emulsions and the droplet size distribution strongly depended on the membrane pretreatment procedure, the transmembrane pressure, the dispersed phase content and the emulsifier concentration. The emulsion droplets with a mean Sauter diameter of about 0.3 μm and a span value between 1.1 and 1.6 were produced using 10 wt.% emulsifier at a transmembrane pressure below 50 kPa. Droplet sizes smaller than pore size were obtained; this effect is explained by existing of an oil film inside the pores reducing the effective pore size. This effect could provide a new possibility for producing small droplets of uniform distribution.

Preparation of Emulsions with a Narrow Particle Size Distribution Using Microporous α‐Alumina Membranes

Abstract O/W emulsions with the smallest spans of particle size distribution (PSD) [span = (d 90 − d 10)/d 50] reported until now for ceramic α‐alumina membranes (0.42–0.56) were prepared using a 1.4‐µm membrane cleaned thoroughly after use in an ultrasonic bath. The smallest span values of 0.42–0.48 were achieved at transmembrane pressures 2.6–3.5 times greater than the capillary pressure. A narrow particle size distribution with a span of 0.48–0.49 was obtained at a wall shear stress of 0.55 Pa, provided that the dispersed phase flux was not above 4.6 L m2 h−1. The span and mean droplet size were remarkably constant over the 1–10 vol.% range of dispersed phase content. Membrane cleaning by ultrasonication was one of the critical conditions for successful operation. If the membrane was cleaned only by the cleaning in place (CIP) method, emulsions with a span value in the range of 0.7–1.4 were obtained.

Glass capillary microfluidics for production of monodispersed poly (dl-lactic acid) and polycaprolactone microparticles: Experiments and numerical simulations

HYPOTHESIS Droplet size in microfluidic devices is affected by wettability of the microfluidic channels. Three-dimensional countercurrent flow focusing using assemblies of chemically inert glass capillaries is expected to minimize wetting of the channel walls by the organic solvent. EXPERIMENTS Monodispersed polycaprolactone and poly(lactic acid) particles with a diameter of 18-150 μm were produced by evaporation of solvent (dichloromethane or 1:2 mixture of chloroform and toluene) from oil-in-water or water-in-oil-in-water emulsions produced in three-dimensional flow focusing glass capillary devices. The drop generation behaviour was simulated numerically using the volume of fluid method. FINDINGS The numerical results showed good agreement with high-speed video recordings. Monodispersed droplets were produced in the dripping regime when the ratio of the continuous phase flow rate to dispersed phase flow rate was 5-20 and the Weber number of the dispersed phase was less than 0.01. The porosity of polycaprolactone particles increased from 8 to 62% when 30 wt% of the water phase was incorporated in the organic phase prior to emulsification. The inner water phase was loaded with 0.156 wt% lidocaine hydrochloride to achieve a sustained drug release. 26% of lidocaine was released after 1 h and more than 93% of the drug was released after 130 h.

Preparation of liposomes: A novel application of microengineered membranes-From laboratory scale to large scale

A novel ethanol injection method using microengineered nickel membrane was employed to produce POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and Lipoid(®) E80 liposomes at different production scales. A stirred cell device was used to produce 73ml of the liposomal suspension and the product volume was then increased by a factor of 8 at the same transmembrane flux (140lm(-2)h(-1)), volume ratio of the aqueous to organic phase (4.5) and peak shear stress on the membrane surface (2.7Pa). Two different strategies for shear control on the membrane surface have been used in the scaled-up versions of the process: a cross flow recirculation of the aqueous phase across the membrane surface and low frequency oscillation of the membrane surface (∼40Hz) in a direction normal to the flow of the injected organic phase. Using the same membrane with a pore size of 5μm and pore spacing of 200μm in all devices, the size of the POPC liposomes produced in all three membrane systems was highly consistent (80-86nm) and the coefficient of variation ranged between 26 and 36%. The smallest and most uniform liposomal nanoparticles were produced in a novel oscillating membrane system. The mean vesicle size increased with increasing the pore size of the membrane and the injection time. An increase in the vesicle size over time was caused by deposition of newly formed phospholipid fragments onto the surface of the vesicles already formed in the suspension and this increase was most pronounced for the cross flow system, due to long recirculation time. The final vesicle size in all membrane systems was suitable for their use as drug carriers in pharmaceutical formulations.

Emulsion templating of poly(lactic acid) particles: droplet formation behavior.

Monodisperse poly(DL-lactic acid) (PLA) particles of diameters between 11 and 121 μm were fabricated in flow focusing glass microcapillary devices by evaporation of dichloromethane (DCM) from emulsion droplets at room temperature. The dispersed phase was 5% (w/w) PLA in DCM containing 0.1-2 mM Nile Red and the continuous phase was 5% (w/w) poly(vinyl alcohol) in reverse osmosis water. Particle diameter was 2.7 times smaller than the diameter of the emulsion droplet template, indicating very low particle porosity. Monodisperse droplets have only been produced under dripping regime using a wide range of dispersed phase flow rates (0.002-7.2 cm(3)·h(-1)), continuous phase flow rates (0.3-30 cm(3)·h(-1)), and orifice diameters (50-237 μm). In the dripping regime, the ratio of droplet diameter to orifice diameter was inversely proportional to the 0.39 power of the ratio of the continuous phase flow rate to dispersed phase flow rate. Highly uniform droplets with a coefficient of variation (CV) below 2% and a ratio of the droplet diameter to orifice diameter of 0.5-1 were obtained at flow rate ratios of 4-25. Under jetting regime, polydisperse droplets (CV > 6%) were formed by detachment from relatively long jets (between 4 and 10 times longer than droplet diameter) and a ratio of the droplet size to orifice size of 2-5.

pH-sensitive micelles for targeted drug delivery prepared using a novel membrane contactor method

A novel membrane contactor method was used to produce size-controlled poly(ethylene glycol)-b-polycaprolactone (PEG-PCL) copolymer micelles composed of diblock copolymers with different average molecular weights, Mn (9200 or 10,400 Da) and hydrophilic fractions, f (0.67 or 0.59). By injecting 570 L m(-2) h(-1) of the organic phase (a 1 mg mL(-1) solution of PEG-PCL in tetrahydrofuran) through a microengineered nickel membrane with a hexagonal pore array and 200 μm pore spacing into deionized water agitated at 700 rpm, the micelle size linearly increased from 92 nm for a 5-μm pore size to 165 nm for a 40-μm pore size. The micelle size was finely tuned by the agitation rate, transmembrane flux and aqueous to organic phase ratio. An encapsulation efficiency of 89% and a drug loading of ~75% (w/w) were achieved when a hydrophobic drug (vitamin E) was entrapped within the micelles, as determined by ultracentrifugation method. The drug-loaded micelles had a mean size of 146 ± 7 nm, a polydispersity index of 0.09 ± 0.01, and a ζ potential of -19.5 ± 0.2 mV. When drug-loaded micelles where stored for 50 h, a pH sensitive drug release was achieved and a maximum amount of vitamin E (23%) was released at the pH of 1.9. When a pH-sensitive hydrazone bond was incorporated between PEG and PCL blocks, no significant change in micelle size was observed at the same micellization conditions.