Hydrophile-lipophile ratio

Another important factor which is not directly related to the hydrophilicity/lipophilicity ratio of various pluronics but which strongly influences the efflux pump inhibitoiy activity of pluronics is micelle formation. Above a certain concentration, the so called critical micelle concentration (CMC), amphiphilic block copolymers self assemble into micelles. It has been demonstrated, that the efflux pump inhibitory activity of pluronics increases with increasing pluronie concentrations, but only until the CMC is reached. Above the CMC, substrate accumulation in cancer cells could not be further increased or was found to even decrease [37]. Therefore, the occurrence of pluronie unimers can be regarded as the crucial prerequisite for the efflux pump inhibitory activity of pluronics [37]. As one mechanism for efflux pump inhibition has been identified to be ATP depletion, it seems necessary that the pluronie unimers are transported into the cells in order to exert this action. 

Knigliakov (95-97) proposed a concept called hydrophile-lipophile ratio (HLR). which i.s the ratio of the energy of adsorption of the surfactant molecule from the water phase to its energy of adsorption from the oil phase. The HLR is a good alternative, but it suffers from (he same drawback that Winsor R ratio... 

The property of interest to characterize a surfactant or a mixture of surfactants is its hydrophilic-lipophilic tendency, which has been expressed in many different ways through a variety of concepts such as the hydrophiUc-lipophilic balance (HLB), the phase inversion temperature (PIT), the cohesive energy ratio (CER), the surfactant affinity difference (SAD) or the hydrophilic-lipophilic deviation (HLD) [1], which were found to be more or less satisfactory depending on the case. In the next section, the quantification of the effects of the different compounds involved in the formulation of surfactant-oil-water systems will be discussed in details to extract the concept of characteristic parameter of the surfactant, as a way to quantify its hydrophilic-lipophilic property independently of the nature of the physicochemical environment. 

Different surfactants are usually characterised by the solubility behaviour of their hydrophilic and hydrophobic molecule fraction in polar solvents, expressed by the HLB-value (hydrophilic-lipophilic-balance) of the surfactant. The HLB-value of a specific surfactant is often listed by the producer or can be easily calculated from listed increments [67]. If the water in a microemulsion contains electrolytes, the solubility of the surfactant in the water changes. It can be increased or decreased, depending on the kind of electrolyte [68,69]. The effect of electrolytes is explained by the HSAB principle (hard-soft-acid-base). For example, salts of hard acids and hard bases reduce the solubility of the surfactant in water. The solubility is increased by salts of soft acids and hard bases or by salts of hard acids and soft bases. Correspondingly, the solubility of the surfactant in water is increased by sodium alkyl sulfonates and decreased by sodium chloride or sodium sulfate. In the meantime, the physical interactions of the surfactant molecules and other components in microemulsions is well understood and the HSAB-principle was verified. The salts in water mainly influence the curvature of the surfactant film in a microemulsion. The curvature of the surfactant film can be expressed, analogous to the HLB-value, by the packing parameter Sp. The packing parameter is the ratio between the hydrophilic and lipophilic surfactant molecule part [70] ... 

For abbreviation of analyte names see Sect. Abbreviations . ACN acetonitrile, CBA carboxylic acid, FA formic acid, HLB hydrophilic-lipophilic balance, hum human, IS internal standard, LRC large reservoir capacity, MCX mixed-mode cation exchange, metab. metabolites (biotransformation products produced in vivo), MeOH methanol, n.s. not specified, OAc acetate, PB phosphate buffer, PBS phosphate-buffered saline, SCX strong cation exchange Ratio given as v/v... 

The solubility of the surfactant of polyethyleneglycol type in different phases can be described by the HLB (hydrophilic-lipophilic-balance) concept [ 27]. This concept attributes to the molecule a HLB number that represents the geometric ratios of the hydrophilic and the hydrophobic moieties. It should, however, be emphasized that the HLB does not represent a fundamental property of the system but is based on experience. For fatty alcohol ethoxylates... 

The ratio of the hydrophilic and the hydrophobic groups of the surfactant molecules, that is, their hydrophile-lipophile balance (HLB), is also important in determining interfacial him curvature and consequently the structure of the ME. The HLB system has been used for the selection of surfactants to formulate MEs and accordingly the HLB of the candidate surfactant blend should match the required HLB of the oily component for a particular system furthermore a match in the lipophilic part of the surfactant used with the oily component is favorable [7],... 

The hydrophile-lipophile balance is related to the solubility of a surfactant. At high HLB the surfactant is very water soluble while at low HLB the surfactant is very lipid soluble. Because HLB is solubility related, it is in turn related to the partition coefficient (or ratio of the solubility of the surfactant in a lipid phase to its solubility in an aqueous phase). A high HLB value suggests a low oil/water partition coefficient, and conversely a low HLB shows a high partition coefficient. Hence, an optimum surfactant HLB for enhancing biological activity also implies an optimum partition coefficient for activity enhancement. 

The type of emulsion formed (normally water-in-oil or oil-in-water, commonly expressed as wlo or olw, w denoting the aqueous phase and o the organic phase) is determined by the volume ratio of the two liquids and also by the phase addition sequence and the nature of any additives used to promote emulsification [29] the affinity of emulsifiers for oil and water is measured on the hydrophile-lipophile balance (HLB) scale [30]. Oil-in-water emulsions are most common in all application fields. 

Hydrophilic-lipophilic balances (HLl HL2) are the ratio between the hydrophilic regions measured at -3 and -4 kcal moF and the hydrophobic regions measured at -0.6 and -0.8 kcal mol". These descriptors represent the balance between both interaction types. 

High soil-release performance, excellent softness and combinability with fluorocarbon finishes may be achieved by special silicone/polyalkylene oxide copolymers. The silicone segments contain hydrophobic dimethylsiloxane structures and hydrophilic silicone modifications with ethoxylated or amino group-containing side groups. The different hydrophilic-lipophilic balance (HLB) of the polyalkylene blocks is adjusted by the ratio of hydrophobic (polypropylene oxide) and hydrophilic (polyethylene oxide) components. 

For nonionic surfactants, an optimization of the process was achieved by using a similar approach to the so-called Cohesive Energy Ratio (CER) concept developed by Beerbower and Hill for the stability of classical emulsions (H). Its basic assumption is that the partial solubility parameters of oil and emulsifier lipophilic tail and of water and hydrophilic head are perfectly matched. Thus, the Vinsor cohesive energy ratio Ro, which determines the nature and the stability of an emulsion, is directly related to the emulsifier HliB (hydrophile-lipophile balance) by... 

An anionic mlcroemulslon system was based on blends of monoethanolamlne salts of bilinear dodecyl benzene sulfonic acid and branched pentadecyl o-xylene sulfonic acid. The bilinear structure results from the alkylation of benzene with a linear a-olefin. The former acts as a surfactant hydrophile (H) while the latter acts as a surfactant lipophile (L) at room temperature for the oil and water phases used in this study. The hydrophile tends to form water-continuous emulsions while the lipophile forms oil-continuous emulsions. The hydrophile-lipophile characteristics were varied by changing the weight ratio of H/L from 0.5 to 0.8. Decane was used as the oil phase and 2.0 wt. X NaCl In water as the aqueovis phase. The water-oil ratio was fixed at 95/5 and the total surfactant content was fixed at 2 g/dl. 

Four different emulsifier selection methods can be applied to the formulation of microemulsions (i) the hydrophilic-lipophilic-balance (HLB) system (ii) the phase-inversion temperature (PIT) method (iii) the cohesive energy ratio (CER) concept and (iv) partitioning of the cosurfactant between the oil and water phases. The first three methods are essentially the same as those used for the selection of emulsifiers for macroemulsions. However, with microemulsions attempts should be made to match the chemical type of the emulsifier with that of the oil. A summary of these various methods is given below. 

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. 

It was a century ago that researchers started to study the factors affecting the behaviour of water-oil-surfactant systems but it is only with the introduction of Winsor s R theory (1954) that the formulation effects could be interpreted. Winsor s R theory was the first qualitative description of the formulation, paving the way to an understanding of how intermolecular interactions among the different chemical species present in a system are related to its behaviour. Throughout the following decades, several empirical experimental correlations such as the phase inversion temperature (PIT), semiempirical ones such as the cohesive energy ratio (CER), and models based on thermodynamics such as the surfactant affinity difference (SAD) or the hydrophilic-lipophilic deviation (HLD) [15, 143, 144] led... 

Not all of the surfactants are capable of forming micelles. The appropriate ratio between the size of hydrophobic (hydrocarbon chains) and hydrophilic (polar group) parts of surfactant molecules, which determines their hydrophile-lipophile balance (HLB, see Chapter VIII, 3), is necessary for the formation of micelles to take place. Sodium and ammonium salts of C12 - C20 fatty acids, alkylsulfates, alkylbenzenesulfonates, and other synthetic ionic and nonionic surfactants are the examples of micelle-forming surface active substances. The true solubility, i.e. the concentration of dissolved substance in its molecular or ionic form, of such surfactants is rather low for ionic surfactants it is on the order of hundredths and thousandths of kmol m 3, while for nonionic ones it can be even lower by one or two orders of magnitude. 

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