Microemulsions formulation considerations

In addition to their usefulness in the enhancement of oral bioavailability of lipophilic drugs, microemulsion formulations have found considerable application as potential delivery systems for peptides whose delivery is often limited by poor GI permeability. W/O microemulsions provide a convenient means of delivery of both permeability-enhancing lipids and water-soluble peptides. The GI permeability-enhancing effects of lipids and their use in the delivery of highly water-soluble compounds are reviewed elsewhere [18, 56, 59],... 

The method developed originally for microemulsion formulation (Section II above) has been adapted (Salager, 1983, 2000) to macroemulsion formation. In this method, the value of the left-hand side of equation 8.10 or 8.11 is called the hydrophilic-lipophilic deviation (HLD). When the value equals zero, as in Section II, a microemulsion is formed when the value is positive, a W/O macroemulsion is preferentially formed when it is negative, an O/W macroemulsion is preferentially formed. The HLD is similar in nature to the Winsor R ratio (equation 5.2) in that when the HLD is larger than, smaller than, or equal to 0, R is larger than, smaller than, or equal to 1. The value of the HLD method is that, on a qualitative basis, it takes into consideration the other components of the system (salinity, cosurfactant, alkane chain length, temperature, and hydrophilic and hydrophobic groups of the surfactant). On the other hand, on a quantitative basis, it requires the experimental evaluation of a number of empirical constants. 

The phenomenon of microemulsification is mainly governed by factors such as (1) nature and concentration of the oil, surfactant, co-surfactant and aqueous phase, (2) oil/surfactant and surfactant/co-surfactant ratio, (3) temperature, (4) pH of the environment and (5) physicochemical properties of the API such as hydrophilicity/lipophilicity, plformulating microemulsions. From a pharmaceutical perspective, one of the most important factors to be considered is acceptability of the oil, surfactant and co-surfactant for the desired route of administration. This factor is very important while developing micro emulsions for parenteral and ocular delivery as there is only limited number of excipients which are approved for the parenteral and ocular route. In Chapter 3 of this book a more general overview of formulating microemulsions is given and formulation considerations with respect to the components of microemulsions used in pharmaceutical applications are discussed below. 

This chapter focuses on silica synthesis via the microemulsion-mediated alkoxide sol-gel process. The discussion begins with a brief introduction to the general principles underlying microemulsion-mediated silica synthesis. This is followed by a consideration of the main microemulsion characteristics believed to control particle formation. Included here is the influence of reactants and reaction products on the stability of the single-phase water-in-oil microemulsion region. This is an important issue since microemulsion-mediated synthesis relies on the availability of surfactant/ oil/water formulations that give stable microemulsions. Next is presented a survey of the available experimental results, with emphasis on synthesis protocols and particle characteristics. The kinetics of alkoxide hydrolysis in the microemulsion environment is then examined and its relationship to silica-particle formation mechanisms is discussed. Finally, some brief comments are offered concerning future directions of the microemulsion-based alkoxide sol-gel process for silica. 

The effect of surfactant charge on the reaction rate was investigated for a related reaction, ring opening of 1,2-epoxyoctane with sodium hydrogen sulfite (Scheme 2 of Fig. 2). The reaction, which was performed in a Winsor III microemulsion, was fast when a nonionic surfactant was used as the sole surfactant and considerably more sluggish when a small amount of SDS was added to the formulation [9]. 

Equation 8.10 takes into consideration the formulation ingredients that may be necessary to produce a microemulsion with the ultralow interfacial tension (Chapter 5, Section III A) required for enhancing the recovery of petroleum from the reservoir rock. 

True micellar systems have low capacity for dissolving non-polar reactants, however. They are therefore of limited preparative value. Microemulsions, which contain not only surfactant and water but also an oil component, can dissolve appreciable amounts of both a polar and a non-polar reactant and are therefore much more practically useful as media for organic synthesis. There has been considerable interest in the use of microemulsions as media for organic reactions in recent years [7—11]. Not only can such a formulation be a way to overcome compatibility problems, the capability of microemulsions to compartmentalise and concentrate reactants can also lead to considerable rate enhancement compared to one-phase systems. A third aspect of interest for preparative organic synthesis is that the large oil-water interface of the system can be used as a template to induce regioselectivity. These aspects will be dealt with in this chapter. 

At higher surfactant concentration liquid crystalline phases may be formed. Surfactant liquid crystals can also solubilise appreciable amounts of oil into the non-polar regions made up of the surfactant tails. Thus, both binary surfactant-water systems and ternary systems with oil included can be formulated into liquid crystals. Such systems can also be used as media for organic synthesis. In fact, a reaction in a surfactant liquid crystal often runs very rapidly, considerably faster than in a microemulsion based on the same surfactant [19]. Figure 5.1 shows the reaction profiles of a typical substitution reaction of... 

In addition to the traditional dermal delivery formulations discussed above, several other pharmaceutical semi-solid and liquid formulation types have been the subject of a considerable amount of R D. These include sprays, foams, multiple emulsions, microemulsions, liposomal formulations, niosomes, cyclodextrins, glycospheres, dermal membrane structures and microsponges. Although some of these formulations form part of the pharmaceutical armamentarium, they are yet to achieve widespread application and are not within the scope of this chapter. The interested reader is referred to the excellent coverage by Osborne and Amann (1990), Kreuter (1994) and Liu and Wisniewski (1997). 

Microemulsion research has since its inception been stimulated by the great potential for practical applications. In particular, considerable research interest has been invested in the possibility of using microemulsions for enhanced oil recovery (EOR). It was observed that surfactant formulations forming three-phase microemulsion systems, often termed Winsor III systems [29], in the oil well could increase the oil yield considerably. Important contributions to the understanding of the mechanisms involved were made by Shah and Hamlin [30] and the Austin group led by Schechter and Wade (see Bourrel et al. [31]). 

Mixtures of anionic and nonionic surfactants were proposed to provide temperature-insensitive systems [37], a suggestion that has considerable practical interest not only for microemulsion systems but also in emulsion polymerization and enhanced oil recovery It was recently shown that since both the anionic and nonionic surfactants can be selected, this double degree of freedom can be used to attain both temperature insensitivity and mixture composition insensitivity so that the formulation is a particularly robust one as far as the applications are concerned [39]. 

Figure 18 [99] shows the optimum formulation for three-phase behavior (as the optimum salinity) as a function of the composition of a mixture of anionic (sodium dodec)4 sulfate) and cationic (tetradecyltrimethylammonium bromide) species loaded with a considerable amount of alcohol to avoid the formation of liquid crystals. The surfactant pair was selected so that both individual surfactants produced a three-phase microemulsion-oil-water behavior at about the same salinity, i.e., 5-10% NaCl. As some cationic surfactant is added to the anionic one, the shaded region that indicates the three-phase behavior goes down (from left to right). This downward displacement and the fact that three-phase behavior is still exhibited means that the addition of a small amount of the cationic surfactant to the anionic one results in a less hydrophilic surfactant mixture. 

In order for microemulsion-based materials synthesis to be feasible, surfactant/oil/water formulations that give stable microemulsions must be identified. Phase diagrams already available in the literature [122-124] provide a useful starting point. Frequently, however, these published diagrams do not extend to conditions directly relevant to materials synthesis, e.g., in terms of the specific metal salt, base, acid, and temperature. Of important consideration, therefore, are investigations into the effects of the reactants... 

A number of comparative researches exist in literatures, some of which have evaluated the utility of microemulsion and emulsion formulations against alternative delivery systems for antitumor agents. Furthermore, it has proven possible to formulate preparations suitable for most routes of administration. There is still, however, a considerable amount of fundamental work in order to figure out the physicochemical behavior of microemulsions that needs to be performed before they can live up to their potential as multipurpose drug delivery vehicles. 

This book contains significant contributions regarding the applications of microemulsions for pharmaceutical formulations, as well as for other applications, and will no doubt help considerably to provide an excellent basis for applications into new fields. 

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