Polycaprolactone multicore-matrix particle for the simultaneous encapsulation of hydrophilic and hydrophobic compounds produced by membrane emulsification
ABSTRACT: Co-encapsulation of drugs in the same carrier, as well as the development of microencapsulation processes for biomolecules using mild operating conditions, and the production of particles with tailored size and uniformity are major challenges for encapsulation technologies. In the present work, a suitable method consisting of the combination of membrane emulsification with solvent diffusion is reported for the production of multi-core matrix particles with tailored size and potential application in multi-therapies. In the emulsification step, the production of a W/O/W emulsion was carried out using a batch Dispersion Cell for formulation testing and subsequently a continuous azimuthally oscillating membrane emulsification system for the scaling-up of the process to higher capacities. In both cases precise and gentle control of droplet size and uniformity of the W/O/W emulsion was achieved, preserving the encapsulation of the drug model within the droplet. Multi-core matrix particles were produced in a post emulsification step using solvent diffusion. The compartmentalized structure of the multicore-matrix particle combined with the different chemical properties of polycaprolactone (matrix material) and fish gelatin (core material) was tested for the simultaneous encapsulation of hydrophilic (copper ions) and hydrophobic (α-tocopherol) test components. The best operating conditions for the solidification of the particles to achieve the highest encapsulation efficiency of copper ions and α-tocopherol of 99 (±4)% and 93(±6)% respectively were found. The multi-core matrix particle produced in this work demonstrates good potential as a co-loaded delivery system.
Imbrogno, A, Dragosavac, MM, Piacentini, E, Vladisavljevic, GT, Holdich, RG, Giorno, L (2015) Polycaprolactone multicore-matrix particle for the simultaneous encapsulation of hydrophilic and hydrophobic compounds produced by membrane emulsification
COLLOIDS AND SURFACES B-BIOINTERFACES, 135, pp.116-125, DOI: 10.1016/j.colsurfb.2015.06.071.
Azimuthally Oscillating Membrane Emulsification for Controlled Droplet Production
ABSTRACT: A novel membrane emulsification (ME) system is reported consisting of a tubular metal membrane, periodically azimuthally (tangentially) oscillated with frequencies up to 50 Hz and 7 mm displacement in a gently cross flowing continuous phase. A computational fluid dynamics (CFD) analysis showed consistent axial shear at the membrane surface, which became negligible at distances from the membrane surface greater than 0.5 mm. For comparison, CFD analysis of a fully rotating ME system showed local vortices in the continuous phase leading to a variable shear along the axis of the membrane. Using an azimuthally oscillating membrane, oil-in-water emulsions were experimentally produced with a median diameter of 20–120 μm, and a coefficient of variation of droplet size of 8%. The drop size was correlated with shear stress at the membrane surface using a force balance. In a single pass of continuous phase, it was possible to achieve high dispersed phase concentrations of 40% v/v. © 2015 American Institute of Chemical Engineers AIChE J, 61: 3607–3615, 2015
Silva, PS, Dragosavac, MM, Vladisavljevic, GT, Bandulasena, HCH, Holdich, RG, Stillwell, M, Williams, B (2015) Azimuthally Oscillating Membrane Emulsification for Controlled Droplet Production AICHE JOURNAL, 61(11), pp.3607-3615, DOI: 10.1002/aic.14894.
Controlled production of eco-friendly emulsions using direct and premix membrane emulsification
ABSTRACT: Eco-friendly O/W emulsions were produced by membrane emulsification using nickel membrane consisting of hexagonal arrays of cylindrical pores of 10 or 20 μm diameter and 200 μm spacing. The dispersed phase was a mixture of N,N-dimethyldecanamide (AMD-10TM) and d-limonene containing 0–35 wt% AMD-10TM in the dispersed phase and the continuous aqueous phase was 3 wt% polyoxyethylene glycerol fatty acid ester (Levenol® C-201). In direct membrane emulsification, the droplet-to-pore size ratio was 1.5–4.6 and the most uniform droplets were obtained with pure d-limonene at a stirrer speed of 620 rpm, corresponding to the peak shear stress on the membrane surface of 7 Pa. In premix membrane emulsification, the median droplet diameter decreased with increasing the transmembrane flux and was smaller than the pore size at the flux above 2000 L m−2 h−1. The droplet size was 6 μm after two passes through the membrane with a pore diameter of either 10 or 20 μm. The viscosity of emulsions with 30 wt% was not influenced by the shear rate but an emulsion with a dispersed phase content of 40 wt% showed shear thinning behaviour and viscoelastic properties. The produced emulsions can be used as environmentally friendly matrices for incorporation of agrochemical actives.
Santos, J, Vladisavljevic, GT, Holdich, RG, Dragosavac, MM, Munoz, J (2015) Controlled production of eco-friendly emulsions using direct and premix membrane emulsification, CHEMICAL ENGINEERING RESEARCH & DESIGN, 98, pp.59-69, ISSN: 0263-8762. DOI: 10.1016/j.cherd.2015.04.009.
Production of food-grade multiple emulsions with high encapsulation yield using oscillating membrane emulsification
ABSTRACT: Food-grade water-in-oil-in-water (W/O/W) multiple emulsions with a volume median diameter of outer droplets of 50–210 μm were produced by injecting a water-in-oil (W/O) emulsion at the flux of 30 L m−2 h−1 through a 10-μm pore electroplated nickel membrane oscillating at 10–90 Hz frequency and 0.1–5 mm amplitude in 2 wt% aqueous Tween® 20 (polyoxyethylene sorbitan monolaurate) solution. The oil phase in the primary W/O emulsion was 5 wt% PGPR (polyglycerol polyricinoleate) dissolved in sunflower oil and the content of water phase in the W/O emulsion was 30 vol%. The size of outer droplets was precisely controlled by the amplitude and frequency of membrane oscillation. Only 3–5% of the inner droplets with a mean diameter of 0.54 μm were released into the outer aqueous phase during membrane emulsification. A sustained release of 200 ppm copper (II) loaded in the inner aqueous phase was investigated over 7 days. 95% of Cu(II) initially present in the inner water phase was released in the first 2 days from 56-μm diameter multiple emulsion droplets and less than 15% of Cu(II) was released over the same interval from 122 μm droplets. The release rate of Cu(II) decreased with increasing the size of outer droplets and followed non-zero-order kinetics with a release exponent of 0.3–0.5. The prepared multiple emulsions can be used for controlled release of hydrophilic actives in the pharmaceutical, food, and cosmetic industry.
Vladisavljevic, GT, Wang, B, Dragosavac, MM, Holdich, RG (2014) Production of food-grade multiple emulsions with high encapsulation yield using oscillating membrane emulsification, COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS, 458, pp.78-84, DOI: 10.1016/j.colsurfa.2014.05.011.
Production of liposomes using microengineered membrane and co-flow microfluidic device
ABSTRACT: Two modified ethanol injection methods have been used to produce Lipoid® E80 and POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) liposomes: (i) injection of the organic phase through a microengineered nickel membrane kept under controlled shear conditions and (ii) injection of the organic phase through a tapered-end glass capillary into co-flowing aqueous stream using coaxial assemblies of glass capillaries. The organic phase was composed of 20 mg ml−1 of phospholipids and 5 mg ml−1 of cholesterol dissolved in ethanol and the aqueous phase was ultra-pure water. Self-assembly of phospholipid molecules into multiple concentric bilayers via phospolipid bilayered fragments was initiated by interpenetration of the two miscible solvents. The mean vesicle size in the membrane method was 80 ± 3 nm and consistent across all of the devices (stirred cell, cross-flow module and oscillating membrane system), indicating that local or temporal variations of the shear stress on the membrane surface had no effect on the vesicle size, on the condition that a maximum shear stress was kept constant. The mean vesicle size in co-flow microfludic device decreased from 131 to 73 nm when the orifice diameter in the injection capillary was reduced from 209 to 42 μm at the aqueous and organic phase flow rate of 25 and 5.55 ml h−1, respectively. The vesicle size was significantly affected by the mixing efficiency, which was controlled by the orifice size and liquid flow rates. The smallest vesicle size was obtained under conditions that promote the highest mixing rate. Computational Fluid Dynamics (CFD) simulations were performed to study the mixing process in the vicinity of the orifice.
Vladisavljević, GT, Laouini, A, Charcosset, C, Fessi, H, Bandulasena, HCH, Holdich, RG (2014) Production of liposomes using microengineered membrane and co-flow microfluidic device, Colloids and Surfaces A: Physicochemical and Engineering Aspects, 458(1), pp.168-177, ISSN: 0927-7757. DOI: 10.1016/j.colsurfa.2014.03.016.
Membrane emulsification for the production of uniform poly-N-isopropylacrylamide-coated alginate particles using internal gelation
ABSTRACT: Alginate particles, crosslinked by calcium ions, have a number of potential biopharmaceutical industry applications due to the biocompatibility of the materials used and formed. One such use is as microcarriers for cell attachment, growth and then detachment without the use of proteolytic enzymes. A straightforward and reproducible method for producing uniform calcium alginate particles with controllable median diameters which employs membrane emulsification and internal gelation (solid particles contained in the dispersed phase) is demonstrated, as well as functionalisation of the resulting beads with amine terminated poly N-isopropylacrylamide (pNIPAM) to form temperature responsive particles, by taking advantage of the electrostatic interaction between the carboxyl groups of the alginate and amino groups of the modified pNIPAM. Cell attachment, growth and detachment capabilities of these core–shell structures were assessed and successfully demonstrated by using phase contrast microscopy and fluorescent staining with calcein-AM and ethidium homodimer-1.
The formulation used for the alginate particles avoided non-GRAS chemicals by only using food grade and pharmaceutical grade reagents. The median particle size was controllable within the range between 55 μm and 690 μm and the size distributions produced were very narrow: ‘span’ values as low as 0.2. When using a membrane pore size of 20 μm no membrane blockage by the suspended calcium carbonate necessary for internal gelation of the alginate particles was observed. Membrane pore openings with diameters of 5 and 10 μm were also tested, but blocked with the 2.3 μm median diameter calcium carbonate solids.
Hanga, MP and Holdich, RG (2014) Membrane emulsification for the production of uniform poly-N-isopropylacrylamide-coated alginate particles using internal gelation, Chemical Engineering Research and Design, 92(9), pp.1664-1673, DOI: 10.1016/j.cherd.2013.12.010.
Preparation of liposomes: a novel application of microengineered membranes: From laboratory scale to large scale
ABSTRACT: 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 73 ml of the liposomal suspension and the product volume was then increased by a factor of 8 at the same transmembrane flux (140 l m−2 h−1), volume ratio of the aqueous to organic phase (4.5) and peak shear stress on the membrane surface (2.7 Pa). 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 (∼40 Hz) in a direction normal to the flow of the injected organic phase. Using the same membrane with a pore size of 5 μm and pore spacing of 200 μm in all devices, the size of the POPC liposomes produced in all three membrane systems was highly consistent (80–86 nm) 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.
Laouini, A, Charcosset, C, Fessi, H, Holdich, RG, Vladisavljevic, GT (2013) Preparation of liposomes: a novel application of microengineered membranes: From laboratory scale to large scale, Colloids and Surfaces B: Biointerfaces, 112, pp.272-278, DOI: 10.1016/j.colsurfb.2013.07.066.
pH-Sensitive micelles for targeted drug delivery prepared using a novel membrane contactor method
ABSTRACT: 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.
Laouini, A, Koutroumanis, KP, Charcosset, C, Georgiadou, S, Fessi, H, Holdich, RG, Vladisavljevic, GT (2013) pH-Sensitive micelles for targeted drug delivery prepared using a novel membrane contactor method, ACS Applied Materials and Interfaces, 5(18), pp.8939-8947, DOI: 10.1021/am4018237.
Microencapsulation of oil droplets using cold water fish gelatine/gum arabic complex coacervation by membrane emulsification
ABSTRACT: Food grade sunflower oil was microencapsulated using cold water fish gelatine (FG)–gum arabic (GA) complex coacervation in combination with a batch stirred cell or continuous pulsed flow membrane emulsification system. Oil droplets with a controllable median size of 40–240 μm and a particle span as low as 0.46 were generated using a microengineered membrane with a pore size of 10 μm and a pore spacing of 200 μm at the shear stress of 1.3–24 Pa. A biopolymer shell around the oil droplets was formed under room temperature conditions at pH 2.7–4.5 and a total biopolymer concentration lower than 4% w/w using weight ratios of FG to GA from 40:60 to 80:20. The maximum coacervate yield was achieved at pH 3.5 and a weight ratio of FG to GA of 50:50. The liquid biopolymer coating around the droplets was crosslinked with glutaraldehyde (GTA) to form a solid shell. A minimum concentration of GTA of 1.4 M was necessary to promote the crosslinking reaction between FG and GTA and the optimal GTA concentration was 24 M. The developed method allows a continuous production of complex coacervate microcapsules of controlled size, under mild shear stress conditions, using considerably less energy when compared to alternative gelatine types and production methods.
Piacentin, E, Giorno, L, Dragosavac, MM, Vladisavljevic, GT, Holdich, RG (2013) Microencapsulation of oil droplets using cold water fish gelatine/gum arabic complex coacervation by membrane emulsification, Food Research International, 53(1), pp.362-372, DOI: 10.1016/j.foodres.2013.04.012.
Continuous membrane emulsification with pulsed (oscillatory) flow
ABSTRACT: Tubular micrometer pore sized sieve type membranes with internal diameter of 14 mm and length of 60 mm containing uniform pores of diameter 10 and 20 μm were used to generate emulsions of sunflower oil dispersed in water and stabilized by Tween 20 using oscillatory flow of the continuous phase. Drop diameters between 30 and 300 μm could be produced, in a controllable way and with span values of down to 0.4. By using pulsed flow it was possible to provide dispersed phase concentrations of up to 45% v/v in a single pass over the membrane, that is, without the need to recirculate the continuous phase through the membrane tube. It was possible to correlate the drop size produced with the shear conditions at the membrane surface using the wave shear stress equation. The oscillatory Reynolds number indicated flow varying from laminar to substantially turbulent, but the change in flow conditions did not show a notable influence on the drop diameters produced, over what is predicted by the varying wall shear stress applied to the wave equation. However, the 20 μm pore sized sieve type membrane appeared to allow the passage of the pressure pulse through the membrane pores, under certain operating conditions, which did lead to finer drop sizes produced than would be predicted. These through-membrane pulsations could be suppressed by changes in operating conditions: a higher dispersed phase injection rate or more viscous continuous phase, and they did not occur under similar operating conditions used with the 10 μm pore sized sieve type of membrane. Generating emulsions of this size using pulsed continuous phase flow provides opportunities for combining drop generation at high dispersed phase concentration, by membrane emulsification, with downstream processing such as reaction in plug flow reactors.
Holdich, RG, Dragosavac, MM, Vladisavljević, GT, Piacentini, E (2013) Continuous membrane emulsification with pulsed (oscillatory) flow, Industrial and Engineering Chemistry Research, 52(1), pp.507-515, ISSN: 0888-5885. DOI: 10.1021/ie3020457.
Preparation of liposomes: a novel application of microengineered membranes - Investigation of the process parameters and application to the encapsulation of vitamin E
Laouini, A, Charcosset, C, Fessi, H, Holdich, RG, Vladisavljevic, GT (2013) Preparation of liposomes: a novel application of microengineered membranes, RSC Advances, 3(15), pp.4985-4994, ISSN: 2046-2069. DOI: 10.1039/C3RA23411H.
Production and evaluation of floating photocatalytic composite part
Holdich, RG, Lazrigh, M, Shama, G, Ipek, IY (2012) Production and evaluation of floating photocatalytic composite particles formed using pickering emulsions and membrane emulsification, Industrial and Engineering Chemistry Research, 51(38), pp.12509-12516, ISSN: 0888-5885. DOI: 10.1021/ie3001748.
Stirred cell membrane emulsification for multiple emulsions containing unrefined
Dragosavac, MM, Holdich, RG, Vladisavljevic, G, Sovilj, M (2012) Stirred cell membrane emulsification for multiple emulsions containing unrefined pumpkin seed oil with uniform droplet size, Journal of Membrane Science, 392-393, pp.122-129, ISSN: 0376-7388. DOI: 10.1016/j.memsci.2011.12.009.
Production of porous silica microparticles by membrane emulsification
Dragosavac, MM, Vladisavljević, GT, Holdich, RG, Stillwell, MT (2012) Production of porous silica microparticles by membrane emulsification, Langmuir: the ACS journal of surfaces and colloids, 28(1), pp.134-143, ISSN: 0743-7463. DOI: 10.1021/la202974b.
Novel membrane emulsification method of producing highly uniform silica particles using inexpensive silica sources
Dragosavac, MM, Vladisavljevic, G, Holdich, RG, Stillwell, MT (2012) Novel membrane emulsification method of producing highly uniform silica particles using inexpensive silica sources, Progress in Colloid and Polymer Science, 139, pp.7-11, ISSN: 0340-255X.
Membrane Emulsification with Oscillating and Stationary Membranes
Holdich, RG, Dragosavac, MM, Vladisavljević, GT, Kosvintsev, SR (2010) Membrane Emulsification with Oscillating and Stationary Membranes, Industrial and Engineering Chemistry Research, 49(8), pp.3810-3817, DOI: 10.1021/ie900531n.
PLGA particle production for water-soluble drug encapsulation: Degradation and release behaviour
Gasparini, G, Holdich, RG, Kosvintsev, SR (2010) PLGA particle production for water-soluble drug encapsulation: Degradation and release behaviour, Colloids and Surfaces B: Biointerfaces, 75, pp.557-564, DOI: 10.1016/j.colsurfb.2009.09.035.
Synthesis and characterization of size-selective nanoporous polymeric adsorbents for blood purification
Malik, DJ, Webb, C, Holdich, RG, Ramsden, JJ, Warwick, GL, Roche, I, Williams, DJ, Trochimczuk, AW, Dale, JA, Hoenich, NA (2009) Synthesis and characterization of size-selective nanoporous polymeric adsorbents for blood purification, Separation and Purification Technology, 66(3), pp.578-585, DOI: 10.1016/j.seppur.2009.01.016.
Controlled production of oil-in-water emulsions containing unrefined pumpkin seed oil using stirred cell membrane emulsification
Dragosavac, MM, Sovilj, MN, Kosvintsev, SR, Holdich, RG, Vladisavljević, GT (2008) Controlled production of oil-in-water emulsions containing unrefined pumpkin seed oil using stirred cell membrane emulsification, Journal of Membrane Science, 322(1), pp.178-188, ISSN: 0376-7388. DOI: 10.1016/j.memsci.2008.05.026.
Membrane emulsification using membranes of regular pore spacing: Droplet size and uniformity in the presence of surface shear
Egidi, E, Gasparini, G, Holdich, RG, Vladisavljević, GT, Kosvintsev, SR (2008) Membrane emulsification using membranes of regular pore spacing: Droplet size and uniformity in the presence of surface shear, Journal of Membrane Science, 323(2), pp.414-420, DOI: 10.1016/j.memsci.2008.06.047.
Membrane emulsification: Droplet size and uniformity in the absence of surface shear
Kosvintsev, SR, Gasparini, G, Holdich, RG (2008) Membrane emulsification: Droplet size and uniformity in the absence of surface shear, Journal of Membrane Science, 313, pp.182-189, DOI: 10.1016/j.memsci.2008.01.009.
Preparation and characterization of PLGS particles for subcutaneous controlled drug release by membrane emulsification
Gasparini, G, Kosvintsev, SR, Stillwell, MT, Holdich, RG (2008) Preparation and characterization of PLGA particles for subcutaneous controlled drug release by membrane emulsification, Colloids and Surfaces B: Biointerfaces, 61, 199¿207, ISSN: 0927-7765. DOI: 10.1016/j.colsurfb.2007.08.011.
Stirred cell membrane emulsification and factors influencing dispersion drop size and uniformity
Stillwell, MT, Holdich, RG, Kosvintsev, SR, Gasparini, G, Cumming, IW (2007) Stirred cell membrane emulsification and factors influencing dispersion drop size and uniformity, Industrial and Engineering Chemistry Research, 46, pp.965-972, DOI: 10.1021/ie0611094.
Pore design and engineering for filters and membranes
Holdich, RG, Kosvintsev, SR, Cumming, IW, Zhdanov, S (2006) Pore design and engineering for filters and membranes, Philosophical Transactions of The Royal Society A: Mathematical, Physical and Engineering Sciences, 364(1838), pp.161-174, ISSN: 1471-2962. DOI: 10.1098/rsta.2005.1690.
Liquid-liquid membrane dispersion in a stirred cell with and without controlled shear
Kosvintsev, SR, Gasparini, G, Holdich, RG, Cumming, IW, Stillwell, MT (2005) Liquid-liquid membrane dispersion in a stirred cell with and without controlled shear, Ind. Eng. Chem. Res, 44(24), pp.9323-9330, ISSN: 1520-5045. DOI: 10.1021/ie0504699.
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