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

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

Polycaprolactone multicore-matrix particle for the simultaneous encapsulation of hydrophilic and hydrophobic compounds produced by membrane emulsification and solvent diffusion processes

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

Sustainable Production of Drug-Loaded Particles by Membrane Emulsification

As the field of drug delivery is expanding into consumer products, it is essential to advance in the development of efficient synthesis technologies while preserving, at the same time, human health and the environment for future generations. Here, the sustainable development of polymeric particles for drug delivery is described. Poly­(ethylene glycol) methyl ether-<i>block</i>-poly­(lactide-<i>co</i>-glycolide) based particles containing dexamethasone were produced by membrane emulsification-solvent diffusion methods. The ability of the synthesis process to control particle-size distribution and morphology and its green impactful (energy consumption, simple (sEF) and complete (cEF) <i>E</i> factor) were evaluated. Particles with sufficiently narrow distribution in their droplet size and mean diameter similar to the membrane pore diameter were produced by increasing the dispersed phase flux to 12.84 L h^–1 m^–2, minimizing the maximum shear stress to 1.12 Pa and the energy consumption to 3.96 × 10⁵ J m^–3. The impact of the solvent used on size distribution, particles morphology and green performance scores was also studied. More uniform particles, with dense and slightly rough surface, high encapsulation efficiency and drug loading were obtained by replacing dichloromethane with ethyl acetate. The <i>E</i> factor was also decreased by 80%. Results demonstrated that membrane emulsification is an environmentally improved method for the production of drug delivery systems with enormous impact in terms of formulation quality, energy consumption reduction and waste minimization

Microencapsulation of oil droplets using cold water fish gelatine/gum arabic complex coacervation by membrane emulsification

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