Emulsification diffusion method

C. Mora-Huertas, H. Fessi, and A. Elaissari, Influence of process and formulation parameters on the formation of submicron particles by solvent displacement and emulsification-diffusion methods Critical comparison, Adv. Colloid Interfac. Sci., 163,90-122, 2011. 

A similar technique, the so-called spontaneous emulsification solvent diffusion method, is derived from the solvent injection method to prepare liposomes [161]. Kawashima et al. [162] used a mixed-solvent system of methylene chloride and acetone to prepare PLGA nanoparticles. The addition of the water-miscible solvent acetone results in nanoparticles in the submicrometer range this is not possible with only the water-immiscible organic solvent. The addition of acetone decreases the interfacial tension between the organic and the aqueous phase and, in addition, results in the perturbation of the droplet interface because of the rapid diffusion of acetone into the aqueous phase. 

T Niwa, H Takeuchi, T Hino, N Kunou, Y Kawa-shima. Preparations of biodegradable nanospheres of water-soluble and insoluble drugs with d,l-lacti-de/glycolide copolymer by a novel spontaneous emulsification solvent diffusion method, and the drug release behavior. J Control Rel 25 89-98, 1993. 

Spontaneous emulsification and solvent diffusion method Solid lipid nanoparticles 20-80 nm Horn and Rieger, 2001 Cui et al., 2006 Ribeiro et al., 2008... 

There are various methods of production. The most important ones are i) nanoprecipitation with the evaporation of the solvent, ii) emulsification-diffusion, iii) emulsification-coacervation, iv) coating with pol)nner, and v) layer by layer method [55, 57] (Figure 18.11). 

Nanoparticle fabrication includes methods such as solvent evaporation, spontaneous emulsification, solvent diffusion, salting out/emulsification diffusion, and polymerization techniques [24]. The synthesis method can greatly impact the particle s physical, chemical, and biological properties and the dispersion and stability of the particles, which are important considerations in biomedical applications. The nanoparticle size and shape is of great importance because the internalization, circulation, distribution, and targeting aspects of the system can be affected by these characteristics [5]. 

T Niwa. H Takeuchi. T Hino. N Kunon, Y Kawashima. In-vitro drug release behaviour of D.L-laciide/glycolide copolymer (Plga) nanospheres with nafarelin acetate prepared by a novel spontaneous emulsification, solvent diffusion method. J. Pharm. Sci. 83 727-732. 1994. 

Emulsions are formed by mixing two liquids, a process which creates discrete droplets in a continuous phase. During emulsification,by mechanical agitation for example, both liquids tend to form droplets resulting in a complex mixture of 0/W and W/0 emulsions. Which of the components forms the continuous phase depends on the emulsifier used since one of the types of droplet is unstable and coalesces. Therefore, there is a need to identify the continuous phase in emulsion systems not only in the final emulsion system, but also at short times after emulsion formation or even dining the emulsification process. The NMR self-diffusion method may easily distinguish the continuous and... 

Murakami H, Kobayashi M, Takeuchi H et al (1999) Preparation of poly (d, L-lactide-co-glycolide) nanoparticles by modified spontaneous emulsification solvent diffusion method. IntJ Pharm 187 143-152... 

The salting-out procedure can be considered as a modification of the emulsification/solvent diffusion method. The technique is based on the salting out of water miscible solvents from aqueous solution containing electrolyte salts such as calcium chloride, magnesium acetate or sucrose. Pol)mier and drug are initially... 

S. Galindo-Rodriguez et ah. Physicochemical parameters associated with nanoparticle formation in the salting-out, emulsification-diffusion, and nanoprecipitation methods. Pharm. Res., 21(8), 1428-1439 (2004). 

J. You, ED. Cui, X. Han, Y.S. Wang, L. Yang, Y.W. Yu, O.P. Li, Study of the preparation of sustained release microspheres containing zedoary turmeric oil by the emulsion solvent diffusion method and evaluation of the self emulsification and bioavailabihty of the oil. Colloids SurfB Biointerfaces, 48 35-41,2006. 

With cetyl alcohol, there is the complication that the polarity of the molecule may cause it to reside at the surface of the droplet, imparting additional colloidal stability. Here, the surfactant and costabilizer form an ordered structure at the monomer-water interface, which acts as a barrier to coalescence and mass transfer. Support for this theory lies in the method of preparation of the emulsion as well as experimental interfacial tension measurements [79]. It is well known that preparation of a stable emulsion with fatty alcohol costabilizers requires pre-emulsification of the surfactants within the aqueous phase prior to monomer addition. By mixing the fatty alcohol costabilizer in the water prior to monomer addition, it is believed that an ordered structure forms from the two surfactants. Upon addition of the monomer (oil) phase, the monomer diffuses through the aqueous phase to swell these ordered structures. For long chain alkanes that are strictly oil-soluble, homogenization of the oil phase is required to produce a stable emulsion. Although both costabilizers produce re-... 

Ultrasound-assisted emulsification in aqueous samples is the basis for the so-called liquid membrane process (LMP). This has been used mostly for the concentration and separation of metallic elements or other species such as weak acids and bases, hydrocarbons, gas mixtures and biologically important compounds such as amino acids [61-64]. LMP has aroused much interest as an alternative to conventional LLE. An LMP involves the previous preparation of the emulsion and its addition to the aqueous liquid sample. In this way, the continuous phase acts as a membrane between both the aqueous phases viz. those constituting the droplets and the sample). The separation principle is the diffusion of the target analytes from the sample to the droplets of the dispersed phase through the continuous phase. In comparison to conventional LLE, the emulsion-based method always affords easier, faster extraction and separation of the extract — which is sometimes mandatory in order to remove interferences from the organic solvents prior to detection. The formation and destruction of o/w or w/o emulsions by sonication have proved an effective method for extracting target species. 

The solvent diffusion/spontaneous emulsification process can create much smaller droplet sizes than the solvent evaporation method. In this case, the dispersed phase is composed of a water-immiscible solvent and a water-miscible solvent, which is emulsified into an aqueous solution. The diffusion of the water-miscible solvent causes turbulence and further breakup of the droplets in the emulsion. The removal of solvent can be conducted similarly to the solvent evaporation method. 

Although water-immiscible solvents display low solubility in water, there is some amount of solubility. The solvent diffusion/emulsification method exploits this for the production of nanoparticles. In this technique, drug and polymer are dissolved in an organic, water-immiscible solvent that is emulsified into an aqueous solution containing emulsifiers and stabilizers. The emulsion is then diluted with water to increase the level of organic solvent, which can be dissolved in the... 

Finally, we present an interpretation of our observations in terms of diffusion paths. Basically, the diffusion equations are solved for the case of two semi-infinite phases brought into contact under conditions where there is no convection and no interfacial resistance to mass transfer. Other simplifying assumptions such as uniform density and diffusion coefficients in each phase are usually made to simplify the mathematics. The analysis shows that the set of compositions in the system is independent of time although the location of a particular composition is time-dependent. The composition set can be plotted on the equilibrium phase diagram, thus showing the existence of intermediate phases and, as explained below, providing a method for predicting the occurrence of spontaneous emulsification. 

The diffusion path method has been used to interpret nonequilibrium phenomena in metallurgical and ceramic systems (10-11) and to explain diffusion-related spontaneous emulsification in simple ternary fluid systems having no surfactants (12). It has recently been applied to surfactant systems such as those studied here including the necessary extension to incorporate initial mixtures which are stable dispersions instead of single thermodynamic phases (13). The details of these calculations will be reported elsewhere. Here we simply present a series of phase diagrams to show that the observed number and type of intermediate phases formed and the occurrence of spontaneous emulsification in these systems can be predicted by the use of diffusion paths. 

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