Effect of structural variations of non-ionic surfactants on surface properties: surfactants with semi-polar hydrophobes

The surface properties of a series of non-ionic surfactants in which a polar group (either an ether or a keto group) has been introduced into a hydrocarbon chain of octadecylpolyoxyethylene glycol monoether (C18E17-19) have been investigated. Surface tension measurements indicated that the critical micelle concentrations for these semi-polar surfactants in aqueous solution were all significantly higher than those of C18E22, the corresponding unsubstituted octadecylpolyoxyethylene glycol monoether. The minimum areas per molecule of the semi-polar surfactants in the surface monolayer were all larger than the area obtained for C18E22, from which it was concluded that the hydrophobe, and not the polyoxyethylene chain was the main determinant of surface area.     

Solubilisation capacity of Brij surfactants

The aim of this study was to investigate the potential of selected Brij non-ionic surfactants for enhancing the solubility of poorly water-soluble drugs. Griseofulvin was selected as a model drug candidate enabling comparisons to be made with the solubilisation capacities of other poly(ethylene oxide)-based copolymers. UV/Vis and (1)H NMR spectroscopies were used to quantify the enhancement of solubility of griseofulvin in 1wt% aqueous micellar solutions of Brij 78 (C(18)H(37)E(20)), Brij 98 (C(18)H(35)E(20)) and Brij 700 (C(18)H(37)E(100)) (where E represents the OCH(2)CH(2) unit of the poly(ethylene oxide) chain) at 25, 37 and 40°C. Solubilisation capacities (S(cp) expressed as mg griseofulvin per g Brij) were similar for Brij 78 and 98 (range 6-11mgg(-1)) but lower for Brij 700 (3-4mgg(-1)) as would be expected for the surfactant with the higher ethylene oxide content. The drug loading capacity of micelles of Brij 78 was higher than many di- and triblock copolymers with hydrophilic E-blocks specifically designed for enhancement of drug solubility.     

Toxicological evaluation of mixtures of nonionic surfactants,alone and in combination with oil

The toxicity to human bronchial (16-HBE14o-) epithelium cells of nonionic surfactants, polyoxyethylene-10-oleyl ether (C(18:1)E(10)), polyoxyethylene-10-dodecyl ether (C(12)E(10)), and N,N-dimethyl-dodecylamine-N-oxide (C(12)AO) alone or in combination with a range of pharmaceutically acceptable oils (namely, ethyl esters and triglyceride oils), was determined with the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Regardless of the presence of oil, all C(12)E(10)- and C(12)AO-containing systems were toxic at concentrations around or below their critical aggregation concentrations (as determined by surface tension measurements), suggesting that surfactant toxicity was due to the disruption caused by the partitioning of monomeric surfactant into the cell membrane. Systems prepared from C(18:1)E(10) alone or in combination with a low-molecular-weight oil, such as ethyl butyrate or tributyrin, were toxic above their critical aggregation concentration. In contrast, systems prepared from C(18:1)E(10) in combination with a high-molecular-volume oil (e.g., ethyl oleate, Miglyol 812, or soybean oil) were toxic only at concentrations significantly greater than their critical aggregation concentration, suggesting that in these cases surfactant toxicity was mediated by the aggregated form of the surfactant solubilizing components of the cell membrane. In the C(18:1)E(10)-stabilized system, it is proposed that toxicity was significantly reduced on incorporation of high-molecular-volume oils because these oils cause formation of a distinct oil core in the aggregates that leads to a reduction in the ability of the system to solubilize components of the cell membrane.     

Demonstration of maximum solubilization in a polyoxyethylene alkyl ether series of non-ionic surfactants

The solubilization of azobenzene, menaphthone, cortisone acetate, and griseofulvin was measured in a series of non-ionic surfactants of structure CH3[CH2](m-1) [OCH2CH2]1.25m OH, where m varied from 8 to 18. Maximum solubilization occurs when m = 16 (the hexadecyl alkyl ether). This is explained in terms of changes in the oxyethylene mantle close to the micelle core/mantle interface, which appears to be the main locus of solubilization. Micellar properties of CH3[CH2]17[OCH2CH2]22OH are also reported and discussed.     

Investigating the stability of the nonionic surfactants tocopheryl polyethylene glycol succinate and sucrose laurate by HPLC-MS, DAD, and CAD

High-performance liquid chromatography (HPLC) methods using a charged aerosol detector (CAD), a mass selective detector (MSD), and a diode array detector (DAD) were developed to characterize the nonionic surfactants d-α-tocopheryl polyethylene glycol (1000) succinate (TPGS) and Surfhope sugar ester D-1216 (sucrose laurate). The molecular structure and the heterogeneous composition resulting from different isomers and various lengths of polyethylene glycol (PEG) chains make it difficult to develop sensitive and specific analytical methods for both surfactants. Hence, there is lack of knowledge about the stability and grade of impurity of these compounds. Sucrose laurate does not possess any chromophore, thus UV detection is not applicable. Therefore, CAD and MSD have been used for determination. The aim of the study was to characterize these nonionic surfactants and to examine chemical stability at pH 1.0 and 37 °C, simulating harsh gastric conditions. It was shown that both compounds are liable to degradation under these conditions. Sucrose monolaurate exhibited a massive degradation within 8 h incubation due to cleavage of the glycosidic bondage. About 50% of sucrose monolaurate broke down, whereas a marginal amount of 3.4% (± 0.4%) of TPGS degraded into d-α-tocopheryl succinate and the associated PEG chain.     

Phagocytic uptake by mouse peritoneal macrophages of microspheres coated with phosphocholine or polyethylene glycol phosphate-derived perfluoroalkylated surfactants

A series of perfluoroalkylated amphiphiles derived from phosphocholine (PC) and polyethylene glycol (PEG) phosphates has been studied and compared to hydrocarbon analogs with respect to their ability to modify the in vitro protein adsorption, and phagocytic uptake by mouse peritoneal macrophages of polystyrene microspheres coated with these surfactants. A significant correlation between protein adsorption and phagocytosis was seen. Within the PC-derived amphiphiles investigated, those with the shorter C2 and C5 spacers between the fluorinated tail and the phosphocholine group, F8C2PC and F8C5PC, caused significantly lower protein adsorption and a decrease of phagocytic uptake of the microspheres in serum vs a buffer. Phagocytic uptake is then comparable to that observed when pegylated surfactants are used as the coating material. These effects were no longer seen when the spacer was longer, as in F8C11PC, with the non-fluorinated analogues C10PC and C15PC, or when one methyl group was replaced by an ethyl group in the phosphocholine polar head. The beneficial impact of the fluorinated tail thus appear to be related to its distance from the surfactant film's external surface and/or to the lipophobic character of the surfactant. Without serum present phagocytic uptake was lower for the fluorinated surfactants with hydrophilic PEG phosphate head-groups, F8C5PPEG 2000 and F8C5P[PEG 750]2, than for the PC derivatives, although it was significantly greater than with Pluronic F-68 or DSPE-PEG5000. Phagocytosis was, however, not reduced in the presence of serum and the difference between these surfactants and the fluorinated PC derivatives was no longer appreciable.     

Cationic surfactants derived from lysine: effects of their structure and charge type on antimicrobial and hemolytic activities

Three different sets of cationic surfactants from lysine have been synthesized. The first group consists of three monocatenary surfactants with one lysine as the cationic polar head with one cationic charge. The second consists of three monocatenary surfactants with two amino acids as cationic polar head with two positive charges. Finally, four gemini surfactants were synthesized in which the spacer chain and the number and type of cationic charges have been regulated. The micellization process, antimicrobial activity, and hemolytic activity were evaluated. The critical micelle concentration was dependent only on the hydrophobic character of the molecules. Nevertheless, the antimicrobial and hemolytic activities were related to the structure of the compounds as well as the type of cationic charges. The most active surfactants against the bacteria were those with a cationic charge on the trimethylated amino group, whereas all of these surfactants showed low hemolytic character.     

Non-ionic surfactants and the membrane transport of barbiturates in goldfish

The effect of a series of polyoxyethylene non-ionic surfactants on the membrane transport of barbiturates in goldfish has been assessed using the overturn time technique. The surfactants, ranging in polyoxyethylene chain length from 2 to 60 and alkyl chain length from 4 to 18, were used at concentrations ranging from 0.001 to 0.1% w/v. Presence of the surfactants in the bathing medium caused a concentration-dependent alteration in the absorption of secobarbitone and thiopentone. The greatest enhancement of absorption for each barbiturate occurred with surfactants with 10 to 20 ethylene oxide moieties, alkyi chain lengths of C₁₂-C₁₆ and molecular areas of between 1.00 and 1.60 nm². The results are comparable with data obtained with the same surfactants using other epithelial membranes.     

Structure elucidation,synthesis, and contact allergenic activity of a major hydroperoxide formed at autoxidation of the ethoxylated surfactant C12E5

Ethoxylated alcohols, widely used as surfactants, are known to be susceptible to oxidation when exposed to air. At autoxidation, a complex mixture is formed, in which alkyl poly(ethylene glycol) aldehydes, alkyl poly(ethylene glycol) formates, hydroxyaldehydes, and formaldehyde have previously been identified. These compounds are all secondary oxidation products, some of which have been shown to be skin sensitizers and irritants. The primary oxidation products from ethoxylated alcohols are described in the literature as peroxides and hydroperoxides, but their structures have not been elucidated more closely. Peroxides and hydroperoxides are usually reactive species and can be suspected to be biologically active as skin sensitizers and irritants. In the present investigation, we studied the autoxidation of the pure ethoxylated alcohol pentaethylene glycol mono-n-dodecyl ether (C(12)E(5)), using NMR and HPLC-MS. On the basis of experience from previous studies on a small model compound, diethyleneglycol monoethyl ether (C(2)E(2)), the hydroperoxide expected to be found in the highest amount in autoxidized C(12)E(5) was synthesized and used as a reference substance in the analyses. This same hydroperoxide, 16-hydroperoxy-3,6,9,12,15-pentaoxaheptacosan-1-ol, was identified in the autoxidation mixture of C(12)E(5), and its sensitizing capacity was determined. It was found to be a moderate allergen in experimental sensitization studies in guinea pigs. Our data further indicate the presence of at least three additional hydroperoxides in the autoxidation mixture of C(12)E(5), one of which was identified as 1-hydroperoxy-3,6,9,12,15-pentaoxaheptacosan-1-ol. The results accentuate the importance of controlling the storage, transportation, and handling conditions of ethoxylated surfactants, to avoid the formation of allergenic and skin irritant oxidation products.     

Effects of non-ionic surfactants that modify experimental tuberculosis on lipase activity of macrophages

1. Six series of non-ionic surface active polyethylene glycol ethers, whose effects on experimental tuberculosis have previously been correlated with their polyoxyethylene chain lengths, were examined for their influence on the activity of a lipase present in homogenates of normal mouse peritoneal macrophages. The surfactants are concentrated in the lysosomes of macrophages-a cell type in which the host-parasite confrontation takes place. A preparation of soy bean oil was used as triglyceride substrate; and hydrolysis at pH 4.5 was compared in the presence and absence of surfactant, the products of hydrolysis being assayed by photodensitometry of thin-layer chromatograms.2. The compounds with short polyoxyethylene chains inhibited the release of fatty acid, compared with surfactant-free standard, more than did those with long chains; and some of the latter showed actual enhancement of release. Accumulation of monoglyceride was observed in the presence of six of the seven long-chained compounds, but with none of the seven short-chained compounds.3. The similarity between this correlation of chain length of the surfactants with their effect on macrophage lipase activity, and the known correlation of their chain length with their effect on experimental tuberculosis, suggests a possible connection. How this connection might relate to the mechanism of the varying effects on tuberculosis is briefly discussed.     

Correlation between epithelial toxicity and surfactant structure as derived from the effects of polyethyleneoxide surfactants on caco-2 cell monolayers and pig nasal mucosa

The cell toxic effects of nonionic surfactants were investigated by means of two in vitro models, namely pig nasal mucosa mounted in horizontal Ussing chambers, and Caco-2 cell monolayers. A series of homologous polyethyleneoxide (PEO) surfactants with a wide span in hydrophilic head-group size and hydrophobic chain lengths were screened for concentration-dependent effects on the transepithelial electrical resistance (TEER) and mannitol permeability across Caco-2 cell monolayers. Trends in effects on permeability in the presence of increasing surfactant concentration coincided with the effects seen on TEER. Correlation of surfactant molecular structure with cell toxicity showed the size of the PEO group to be a more critical parameter than the size of the hydrocarbon chain. More specifically, the presence of very long PEO groups (>30 EO units) were found to lead to a decrease in cell toxicity. Similar trends were observed in the studies of the effects of PEO surfactants on pig nasal mucosa mounted in horizontal Ussing chambers. However, the nasal mucosa was somewhat more tolerant towards high surfactant concentrations than the Caco-2 cells. The relation between surfactant molecular structure and cell toxic effects is discussed in terms of micellar surface adsorption and micellar solubilization. The effect of the surfactants on the solubility of budesonide was investigated at two different surfactant concentrations (0.01 and 1 mg/mL). At the lower concentration, the solubilizing capacity of all of the surfactants was marginal, and there was no correlation between solubilizing capacity and cmc. At the higher concentration, on the other hand, all surfactants substantially increased the solubility of budesonide. The C18 PEO-ester with 40 EO units in the head group was found to be an efficient micellar solubilizer for budesonide, without causing adverse effects on the Caco-2 cell monolayers.     

Drug solubilization and in vitro toxicity evaluation of lipoamino acid surfactants

To improve solubilization of a water insoluble anticancer drug, novel surfactants were synthesized. All surfactants derived from lysine, with a so-called nitrilo triacetic acid (NTA) polar head, and differed from the length and saturation degree of their hydrophobic moieties: C19:0-NTA, C20:4-NTA, C25:0-NTA and C25:4-NTA. Self-assembling properties and critical micellar concentration (CMC) values were determined using pyrene fluorescence and cytotoxicity using MTT and LDH assays on endothelial cells. Surfactant haemolytic activity and drug solubilization capacity were also evaluated. All surfactants self-assemble with low CMC values from 0.012 to 0.430 mg/mL. Cytotoxicity assays showed that C20:4-NTA and C25:0-NTA were less cytotoxic than polysorbate 80. Unsaturations and alkane chain length have a marked influence on toxicity. Saturated surfactants had a similar haemolytic activity, explained by their low CMC values and the linear configuration of their hydrophobic tail. C20:4-NTA and C25:4-NTA were less haemolytic than polysorbate 80. Furthermore, C19:0-NTA, C25:0-NTA and C25:4-NTA increased drug solubility from <0.15 μg/mL up to 7 mg/mL, with 46% (w/w) drug loading, due to their linear and flexible hydrophobic chain configuration, as evidenced by molecular modelling. Although these solubilizers are promising, a compromise between drug solubilization and toxicity remains to be found.     

Comparison of impact of the different hydrophilic carriers on the properties of piperazine-containing drug.

The objective of this study was to determine the impact of a series of nonionic surfactants on the solubility of piperazine-containing drug (meclizine, MZ) in comparison to that of natural cyclodextrins (alpha-CD and beta-CD) and dimethyl-beta-cyclodextrin (DM-beta-CD). The solubility of the drug was studied in either CDs solutions or nonionic surfactant solutions. Three classes of nonionic surfactants were used namely; polyoxyethylene (POE) sorbitan fatty acid esters (polysorbates), POE fatty acid esters (Myrjs) and polyethylene oxide (PEO) fatty alcohol ethers (Brijs and Eumulgins). The solubility of MZ was increased linearly with the increasing surfactant concentration, indicating that micellar solubilization follows the partition model. It was found that the longer the hydrocarbon chain in a homologous series, the more efficient is the solubilizing power of surfactant. For example, polysorbate 80 (Tween-80) is a more efficient solubilizer than polysorbate 20 (Tween-20), indicating that the drug was incorporated in the core of micelle more than the capsular region of the micelle. On the other hand, in case of POE fatty acid esters, the solubilizing power increased with decreasing polyoxyethylene chain as Myrj 53 was more efficient than Myrj 59. In class of PEO fatty alcohol ethers, the shorter the hydrophilic chain and longer lipophilic chain, the more efficient was the solubilizing capacity. Thus, Brij 58 was more efficient solubilizer than Brij 35 and Eumulgin C1000 was more active than Eumulgin C1500. Comparatively, Eumulgin C1000 had the highest solubilizing power for MZ among the studied PEO fatty alcohol ethers and other groups of surfactants. The solubility action of surfactants toward MZ was increased by raising the temperature of the surfactant solutions from 30 to 45 degrees C. Hydrophilic macromolecules (PEG 1000 and PEG 6000) or cosolvents (glycerol and propylene glycol) have a very slight effect on the solubility of MZ and confirm the predominance of hydrophobic interaction between the drug and nonionic surfactants. A(L)-type phase solubility diagrams were obtained for the drug with alpha-, beta- and DM-beta-CDs showing that the solubility of MZ was enhanced through inclusion complexation. Comparatively, DM-beta-CD had the highest solubilizing efficiency for the drug among the investigated CDs, which could be attributed to its larger hydrophobic cavity size.     

A combination of nonionic surfactants and iontophoresis to enhance the transdermal drug delivery of ondansetron HCl and diltiazem HCl

The present work reports the evaluation of three nonionic ether-monohydroxyl surfactants (C(12)E(1), C(12)E(5,) and C(12)E(8)) as skin permeation enhancers in the transdermal drug delivery of two drugs: ondansetron hydrochloride and diltiazem hydrochloride, formulated as hydrogels. The enhancers are used alone, or in combination with iontophoresis (0.3 mA - 8h). After 1h of pre-treatment with 0.16 M enhancer solutions in propylene glycol (PG), passive and iontophoretic 24 h in vitro studies across dermatomed porcine skin were performed using vertical Franz diffusion cells. Data obtained showed that the nonionic surfactant C(12)E(5) was the most effective permeation enhancer, both for the passive process as well as for samples subjected to iontophoresis, resulting in cumulative amounts of ondansetron HCl after 24h of approximately 93 μg/cm(2) and 336 μg/cm(2), respectively. Data obtained using diltiazem HCl showed a similar trend. The use of the nonionic surfactant C(12)E(5) resulted in higher enhancement ratios (ER) in passive studies, but C(12)E(8) yielded slightly higher values of drug permeated (2678 μg/cm(2)) than C(12)E(5) (2530 μg/cm(2)) when iontophoresis was also employed. Skin integrity studies were performed to assess potential harmful effects on the tissues resulting from the compounds applied and/or from the methodology employed. Skin samples used in permeation studies visualized by light microscopy and Scanning Electron Microscopy (SEM) at different levels of magnification did not show significant morphological and structural changes, when compared to untreated samples. Complementary studies were performed to gain information regarding the relative cytotoxicity of the penetration enhancers on skin cells. MTS assay data using human epidermal keratinocytes (HEK) and human dermal fibroblasts (HDF) indicated that HEK are more sensitive to the presence of the enhancers than HDF and that the toxicity of these compounds is enhancer molecular weight dependent.     

Determination of optimal combination of surfactants in creams using rheology measurements

The effect of surfactant on the rheological properties of some cream formulations was studied. Two surfactants from two different series were combined to determine the combination which yielded the most viscoelastic structure for creams. The surfactants were the soybean derivatives soya sterol, polyethylene glycol 10 soya sterol and polyethylene glycol 25 soya sterol and the sorbitol derivatives sorbitan monooleate and sorbitan trioleate. The rheological properties of the creams were studied using oscillation stress sweep, oscillation frequency sweep and viscosity tests. Droplet size distribution and conductivity of the creams were also determined. The combination polyethylene glycol 10 soya sterol and sorbitan trioleate yielded the most viscoelastic structure with linearly viscoelastic behaviour.     

Synergistic effect of low-frequency ultrasound and surfactants on skin permeability.

Low-frequency ultrasound (20 kHz) and surfactants have been individually shown to enhance transdermal drug transport. In this study, we investigated the synergistic effect of ultrasound and surfactants on transdermal drug delivery. Surfactants with different head group chemistries including anionic, cationic, and nonionic with varying tail lengths (8-16-carbon atoms) were studied. We found that surfactants possessing anionic and cationic head groups were more potent than those possessing nonionic head groups in increasing skin conductivity in the presence of ultrasound. Furthermore, for surfactants possessing the same head group, those with a 14-carbon tail length were found to be most effective in enhancing skin permeability. The data presented in this report show that ultrasound and surfactants synergistically enhance skin permeability. Two mechanisms are shown to play a role in this synergistic effect. First, ultrasound enhances surfactant delivery (enhanced delivery) into the skin and, second, ultrasound disperses surfactant (enhanced dispersion) within the skin. In general, surfactants that are potent enhancers by themselves are potent enhancers in the presence of ultrasound as well. We performed imaging experiments to assess the effect of ultrasound on delivery of a model permeant, sulforhodamine B, into the skin. These experiments show that ultrasound enhances surfactant delivery and dispersion in the skin.     

The effect of some non-ionic surfactants and a polyoxyethylene glycol on the dissolution rate of griseofulvin

Measurements of the dissolution rate of griseofulvin in water, four non-ionic surfactants, and a polyoxyethylene glycol have been made. These results are analysed in terms of a zero order rate constant (k₁) for transfer of the drug from the crystal to the bulk of the solution, and a first order constant (k₂) for the reverse process. Surfactants greatly increase the dissolution rate, increasing k₁ and decreasing k₂. Polyoxyethylene glycol is not so effective as the surfactants at increasing dissolution rates. In an attempt to interpret k₁ and k₂, it appears that both chemical and transport processes are involved in the dissolution, the presence of surfactant decreasing the energy change for transferring griseofulvin molecules from the crystal to the solution.     

Non-ionic surfactants and membrane transport of thioridazine in goldfish.

Polysorbate 80, which has been widely used in studies of the effects of surfactants on drug absorption, increases the rate of absorption of some drugs at concentrations near its critical micelle concentration (cmc). To determine whether all non-ionic surfactants were capable of inducing this effect, the effects of six commercial non-ionic surfactants on thioridazine absorption in goldfish have been compared with the effect of polysorbate 80. The reciprocal death time (T-1) determined when the fish were immersed in the solution under study was the index of absoprtion rate used. Not all surfactants tested increased T-1. Cremophor EL (polyoxyethylated castor oil), Atlas G1295 (a polyoxyethylene fatty glyceride), Atlas G1300 (a polyoxyethylene glyceride ester) had no effect below their cmc's. Those surfactants that did increase T-1 [polysorbate 80 (a polyoxyethylene lanolin derivative), G2162 (a polyoxyethylene oxypropylene monosterate) and Renex 650 (a polyoxyethylene alkyl aryl ether)] display the concentration-dependent behaviour reported previously - a decrease in absorption rate when the surfactant concentration is increased above its cmc. The factor determining whether or not the surfactant will increas absorption rate appears to be the configuration of the surfactant molecule rather than its hydrophile-lipophile balance or its surface activity.     

Comparative evaluation of cytotoxicity and phototoxicity of mono and diacylglycerol amino acid-based surfactants

Extensive efforts have been made, recently, to find surfactants with lower irritancy potential than those presently commercially employed in pharmaceutical and cosmetic preparations. Cytotoxic and phototoxic effects of novel mono and diacylglycerol amino acid-based surfactants (glutamic acid, or arginine) were evaluated.All tested surfactants showed a clear concentration–response relationship to two immortalized cell lines, murine fibroblast cell line, 3T3, and one human keratinocyte cell line, HaCaT, demonstrated by and decrease of NR uptake. Concentrations resulting in 50% inhibition of NR uptake (IC₅₀) range from 30 to 300 μg mL⁻¹.The potential phototoxicity which could result in irritant products, was determined by modulated cytotoxicity via the resazurin reduction to resorufin and neutral red uptake (NRU) endpoints. Surfactants with two chains showed, in general, less cytotoxic but higher phototoxic effect than surfactants with only one chain.     

Evaluation of penetration enhancement of lidocaine by nonionic surfactants through hairless mouse skin in vitro

The effect of two nonionic surfactants (polyoxyethylene sorbitan monoesters) on percutaneous absorption of lidocaine in the presence of various concentrations of propylene glycol is reported. Comparisons were made in vitro using excised hairless mouse skin as the barrier membrane. Under infinite dose conditions, steady-state flux was enhanced by surfactants at high propylene glycol concentrations. The same trend was observed following application of a thin layer of formulation to the skin (finite-dose conditions). However, penetration behavior was complex due to: (a) changes in vehicle composition following application, (b) temperature changes resulting from evaporation or moisture uptake, and (c) depletion of lidocaine as a result of penetration with compositions that lost water by evaporation. Two peaks in the flux versus time curve were observed. Surfactant monomer concentration in the vehicles was increased in the presence of propylene glycol.