Pharmaceutical particles design by membrane emulsification: preparation methods and applications in drug delivery

© 2017 Bentham Science Publishers.Nowadays, the rational design of particles is an important issue in the development of pharmaceutical medicaments. Advances in manufacturing methods are required to design new pharmaceutical particles with target properties in terms of particle size, particle size distribution, structure and functional activity. Membrane emulsification is emerging as a promising tool for the production of emulsions and solidified particles with tailored properties in many fields. In this review, the current use of membrane emulsification in the production of pharmaceutical particles is highlighted. Membrane emulsification devices designed for small-scale testing as well as membrane-based methods suitable for large-scale production are discussed. A special emphasis is put on the important factors that contribute to the encapsulation efficiency and drug loading. The most recent studies about the utilization of the membrane emulsification for preparing particles as drug delivery systems for anticancer, proteins/peptide, lipophilic and hydrophilic bioactive drugs are reviewed

Microparticles for cell encapsulation and colonic delivery produced by membrane emulsification

Membrane Emulsification was used to encapsulate yeast cells and form microparticles. W/O emulsions were produced using a Dispersion Cell; the aqueous phase consisted of gelatin/chitosan, or pure gelatin solution, containing yeast cells, the continuous phase was 2 wt% of SPAN 80 in kerosene. Varying the dispersed phase flux (from 70 to 350 L h- m-2) and the shear stress (from 17 to 1 Pa) applied on the membrane surface droplet sizes of between 60 and 340 µm were produced, with a coefficient of variation of 17% under the best operating conditions. The liquid drops were loaded with increasing amount of yeast (3.14×107 to 3.14×108 cells/mL). The stability and uniformity of the emulsions was independent of the cell concentration. PTFE coated hydrophobic membrane produced smaller W/O drops compared to FAS coated membranes. The liquid polymeric droplets were solidified in solid particles using thermal gelation and/or ionic crosslinking, obtaining yeast encapsulated particles sized ~100 µm. The pH sensitive polymer, Eudragit S100, was used as a coating to create gastro resistant particles suitable for intestinal-colonic targeted release. Viability of the released yeast cells was demonstrated using fluorescence probes and checking cell glucose metabolism with time

Production of food-grade multiple emulsions with high encapsulation yield using oscillating membrane emulsification

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

Novel membrane emulsification method of producing highly uniform silica particles using inexpensive silica sources

A membrane emulsification method for production of monodispersed silica-based ion exchange particles through water-in-oil emulsion route is developed. A hydrophobic microsieve membrane with 15 :m pore size and 200 :m pore spacing was used to produce droplets, with a mean size between 65 and 240 :m containing acidified sodium silicate solution (with 4 and 6% wt. SiO2) in kerosene. After drying, the final silica particles had a mean size in the range between 30 and 70 :m. Coefficient of variation for both the droplets and particles did not exceed 35%. The most uniform particles had a mean diameter of 40 :m and coefficient of variation of 17%. The particles were functionalised with 3-aminopropyltrimethoxysilane and used for chemisorption of Cu(II) from an aqueous solution of CuSO4 in a continuous flow stirred cell with slotted pore microfiltration membrane. Functionalised silica particles showed a higher binding affinity toward Cu(II) than non-treated silica particles

Continuous membrane emulsification with pulsed (oscillatory) flow

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

Production of porous silica microparticles by membrane emulsification

A method for the production of near-monodispersed spherical silica particles with controllable porosity based on the formation of uniform emulsion droplets using membrane emulsification is described. A hydrophobic metal membrane with a 15 μm pore size and 200 μm pore spacing was used to produce near-monodispersed droplets, with a mean size that could be controlled between 65 and 240 μm containing acidified sodium silicate solution (with 4 and 6 wt % SiO2) in kerosene. After drying and shrinking, the final silica particles had a mean size in the range between 30 and 70 μm. The coefficient of variation for both the droplets and the particles did not exceed 35%. The most uniform particles had a mean diameter of 40 μm and coefficient of variation of 17%. By altering the pH of the sodium silicate solution and aging the gel particles in water or acetone, the internal structure of the silica particles was successfully modified, and both micro- and mesoporous near-monodispersed spherical particles were produced with an average internal pore size between 1 and 6 nm and an average surface area between 360 and 750 m2 g–1. A material balance and particle size analysis provided identical values for the internal voidage of the particles, when compared to the voidage as determined by BET analysis

A comparison of azimuthal and axial oscillation microfiltration using surface and matrix types of microfilters with a cake-slurry shear plane exhibiting non-Newtonian behaviour

The mode of application of oscillation, axial or azimuthal, did not influence filtration performance, when filtering a calcite mineral with a d32 value of 2.7 µm. The equilibrium flux and deposit thickness correlated with shear stress, regardless of: filter type (metal slotted surface filter or homogeneous sintered filter); and mode of oscillation. Shear stress values up to 240 Pa were used and the particle compact believed to be at, or near, the deposited solids showed non-Newtonian flow behaviour described by the Herschel-Bulkley equation. The shear was computed using Comsol® to model the shear at, and near, the oscillating surface. The peak shear (maximum value) was used in the correlation for flux, which appeared to fit the data well and provide a realistic prediction for sustainable flux using a force balance model. The existence of a yield stress in the compact appeared to limit the internal fouling of the matrix (homogeneous) type of filter, which had a membrane thickness of 8 mm, but did not demonstrate significant internal fouling over time, nor between filtrations. Thus, the results were similar to those obtained for the surface filters, and the resistance to filtration was dominated by the deposit formed

Controlled production of oil-in-water emulsions containing unrefined pumpkin seed oil using stirred cell membrane emulsification

Membrane emulsification of unrefined pumpkin seed oil was performed using microengineered flat disc membranes on top of which a paddle blade stirrer was operated to induce surface shear. The membranes used were fabricated by galvanic deposition of nickel onto a photolithographic template and contained hexagonal arrays of uniform cylindrical pores with a diameter of 19 or 40 mu m and a pore spacing of 140 mu m. The uniformly sized pumpkin seed oil drops with span values less than 0.4 were obtained at oil fluxes up to 640 L m(-2) h(-1) using 2 wt.% Tween 20 (polyoxyethylene sorbitan monolaurate) or 2-10 wt.% Pluronic F-68 (polyoxyethylene-polyoxypropylen copolymer) as an aqueous surfactant solution. Pumpkin seed oil is rich in surface active ingredients that can be adsorbed on the membrane surface, such as free fatty acids, phospholipids, and chlorophyll. The adsorption of these components on the membrane surface gradually led to membrane wetting by the oil phase and the formation of uniform drops was achieved only for dispersed phase contents less than 10 vol.% At high oil fluxes, Pluronic F-68 molecules present at a concentration of 2 wt.% could not adsorb fast enough, on the newly formed oil drops, to stabilise the expanding inter-face. (c) 2008 Elsevier B.V. All rights reserved

Water in oil emulsions from hydrophobized metal membranes and characterization of dynamic interfacial tension in membrane emulsification

Hydrophobization of metal surfaces is reported based on silanization reactions. The aim was its application to metal porous membranes for the production of water in oil emulsions using a process known as membrane emulsification. A vertical oscillating membrane system was used to carry out drop formation experiments. It is shown that drop size can be tuned between 35 and 85. μm by changing just the surfactant concentration in the continuous phase. In addition, a method to determine the percentage of active pores during the membrane emulsification process is demonstrated. This method links knowledge acquired in the surfactant adsorption dynamics and drop expansion rate. Using this approach, pore velocity can be determined, which will help in determining the boundary between dripping and jetting from a pore. This study reinforces the importance of dynamic interfacial tension which must be considered in process design, and modelling purposes, particularly in two liquid phase systems using membranes such as membrane emulsification

Comparative investigation of membrane systems for crystallization and spherical agglomeration

In this study, two novel spherical agglomeration processes based on membrane systems were successfully implemented to produce spherical agglomerates of benzoic acid crystals obtained by antisolvent crystallization. Two membrane configurations were implemented; a flat disc mounted in a dispersion cell equipped with a mixing impeller, and a second one which uses a cylindrical membrane equipped with a vibrating module which created shear with upward-downward vibration. To optimize the performance of the spherical agglomeration process, the impact of the bridging liquid flowrate, membrane pore size and pore arrangement, as well as agitation rate were investigated. Both systems were successfully used to generate spherical agglomerates with enhanced quality and size distribution at comparable flux conditions. In near future, the membrane systems will be scaled-up to investigate the scalability of the proposed spherical agglomeration system under the optimized operating conditions identified from the current study