The effect of surfactants on the microencapsulation and release of phenobarbitone from gelatin-acacia complex coacervate microcapsules

Abstract

The effects of sodium lauryl sulphate (SLS), cetrimide and polysorbate 20 surfactants at concentrations below, at and above their critical micelle concentration (CMC) on the microencapsulation and release of phenobarbitone have been described. Bimodal particle size distributions were produced both in the absence and presence of each of the three surfactants. The presence of surfactant had little or no effect on the particle size distribution at any given stirring speed. A large variation was noted in the amount of phenobarbitone microencapsulated dependent upon the type of surfactant and its concentration. The amount of phenobarbitone encapsulated decreased with increasing concentration of polysorbate 20 and with SLS. Cetrimide (0025 per cent w/v) enhanced encapsulation with 2 per cent w/w colloids but higher concentrations at the CMC and above decreased encapsulation. The results are explained in terms of decreased interfacial tension by the surfactant and by steric and electrostatic effects caused by surfactant adsorption onto the coacervate droplets and phenobarbitone particles.     

The effect of sodium lauryl sulphate, cetrimide and polysorbate 20 surfactants on complex coacervate volume and droplet size

The effects of sodium lauryl sulphate (SLS), cetrimide and polysorbate 20 surfactants at concentrations below, at and above their critical micelle concentration (CMC) on the complex coacervation of varying concentrations of gelatin and acacia have been described. The overall effect of increasing concentration of SLS was to reduce the weight of coacervate formed. The addition of increasing concentrations of cetrimide produced an increase in the weight of coacervate. The two lowest concentrations of polysorbate 20 produced an increase in coacervate weight while the highest concentration, above the CMC, reduced the coacervate weight. These effects have been explained in terms of shielding of electrostatic attractions between gelatin and acacia polyions by adsorption of ionic and non-ionic surfactant molecules onto the polyions. The addition of surfactants influenced the size distribution of the coacervate droplets that were produced. It is believed that the reduction in interfacial tension by the aggregation of surfactant molecules at the coacervate-equilibrium liquid interface permitted the formation of smaller coacervate droplets.     

Effect of polysorbate 80 on the apparent partition coefficient of drugs and on their intestinal absorption in the rat II. Phenobarbital

The effect of polysorbate 80 on the apparent partition coefficient of phenobarbital between chloroform and a 0.05 M Tris buffer of pH 5.9 were investigated. Three different concentrations of the surfactant were studied; namely 0.001, 0.01 and 1.0% (w/v). The effect of the surfactant in the same medium and at the same concentrations on the absorption of phenobarbital from the rat intestine in situ was also investigated.The apparent partition coefficient of phenobarbital decreased in the presence of polysorbate 80, reaching a minimum at the CMC, then increased markedly at higher concentration.Polysorbate 80 at or below the CMC did not produce a significant effect on the per cent phenobarbital absorbed from the rat intestine in 30 min. Higher concentration of polysorbate 80 produced a significant increase in the per cent absorbed. The mechanisms involved in the effect on apparent partition coefficient as well as on the per cent absorbed are discussed.     

Modifying the Release Properties of Liposomes Toward Personalized Medicine

Surfactant-liposome interactions have historically been investigated as a simplified model of solubilization and breakdown of biological membranes by surfactants. In contrast, our goal was to utilize surfactants to modify the encapsulation and release properties of liposomes. The ability to manufacture one liposomal formulation, which could be modified by the addition of a surfactant to support a wide range of release profiles, would provide greater flexibility than manufacturing multiple batches of liposomes, each differing in composition and with its own specific release profile. A liposomal ciprofloxacin formulation was modified by the addition of various surfactants. These formulations were characterized in terms of liposome structure by cryo-TEM imaging, vesicle size by dynamic light scattering, drug encapsulation by centrifugation-filtration, and in vitro release (IVR) performance. The addition of polysorbate 20 or polysorbate 80 to liposomal ciprofloxacin, in a hypotonic environment, resulted in a concentration-dependent loss of encapsulated drug, and above 0.4% polysorbate 20, or 0.2% polysorbate 80, a modified IVR profile as well. This study demonstrates that the encapsulation and release properties of a liposomal formulation can be modified postmanufacture by the addition of judiciously chosen surfactants in combination with osmotic swelling of the liposomes and may support a personalized approach to treating patients. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1851-1862,2014     

The enhancement effect of surfactants on the penetration of lorazepam through rat skin

Lorazepam is an anxiolytic, antidepressant agent, having suitable feature for transdermal delivery. The percutaneous permeation of lorazepam was investigated in rat skin after application of a water:propylene glycol (50:50%v/v). The enhancing effects of various surfactants (sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), benzalkonium chloride or Tween 80) with different concentrations on the permeation of lorazepam were evaluated using Franz diffusion cells fitted with rat skins. Flux, K_p, lag time and enhancement ratios (ERs) of lorazepam were measured over 24 h and compared with control sample. Furthermore, lorazepam solubility in presence of surfactants was determined. The in vitro permeation experiments with rat skin revealed that the surfactant enhancers varied in their ability to enhance the flux of lorazepam. The permeation profile of lorazepam in presence of the cationic surfactant, CTAB, reveals that an increase in the concentration of CTAB results in an increase in the flux of lorazepam in comparison with the control. But an increase in concentration of CTAB or benzalkounium chloride from 0.5 to 1% w/w or from 1 to 2.5% w/w resulted in a reduction in ER, respectively. Benzalkonium chloride which possessed the highest lipophilicity (log P=1.9) among cationic surfactants provided the greatest enhancement for lorazepam flux (7.66-fold over control) at 1% w/w of the surfactant. CTAB (log P<1) and sodium lauryl sulphate at a concentration of 5% w/w (the highest concentration) exhibited the greatest increase in flux of lorazepam compared with control (9.82 and 11.30-fold, respectively, over control). This is attributed to the damaging effect of the cationic and anionic surfactants on the skin at higher concentration. The results also showed that the highest ER was obtained in presence of 1% w/w surfactant with the exception of SLS and CTAB. The increase in flux at low enhancer concentrations is normally attributed to the ability of the surfactant molecules to penetrate the skin and increase its permeability. Reduction in the rate of transport of the drug present in enhancer systems beyond 1% w/w is attributed to the ability of the surfactant molecules to form micelles and is normally observed only if interaction between micelle and the drug occurs.     

Effect of surfactants on the solubility and intrinsic dissolution rate of sparfloxacin

The effect of surfactants on the solubility and intrinsic dissolution rate of sparfloxacin was investigated at room temperature. The surfactants used in the study were anionic sodium lauryl sulfate (SLS) and nonionic polysorbate 80 (Tween 80). Sodium lauryl sulfate showed very significant increase in solubility Tween 80 at the highest concentration studied. The intrinsic dissolution rates were determined compared to at the same surfactant concentrations used in the solubility study by rotating disk method. Diffusion coefficient (D) of sparfloxacin was evaluated to be 7.19 x 10(-6) cm2S(-1) and the apparent mean diffusion coefficient for sparfloxacin-loaded micelle was estimated to 3.98 x 10(-6) and 2.21 x 10(-6) cm2S(-1) in Tween 80 and SLS respectively.     

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.     

The effect of surfactants on the skin penetration of diazepam

The percutaneous permeation of diazepam was investigated in rat skin after application of a water-propylene glycol (50:50% v/v) using a diffusion cell technique. The effect of various surfactants (sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), benzalkonium chloride or Tween 80) with different concentrations on skin permeability were evaluated. Flux, K(p), lag time and enhancement ratios (ERs) of diazepam were measured over 10 h and compared with control sample (containing no surfactant). Furthermore, diazepam solubility in presence of surfactants was determined. The in vitro permeation experiments with rat skin revealed that the surfactant enhancers varied in their ability to enhance the flux of diazepam. Benzalkonium chloride which possessed the highest lipophilicity (logP=1.9) among cationic surfactants provided the greatest enhancement for diazepam flux (7.98-fold over control). CTAB (logP<1) at a concentration of 1% w/w exhibited no significant increase in flux of diazepam compared to control (1.16-fold over control). The results also showed that the highest ER was obtained in presence of 1% w/w surfactant with the exception of SLS and CTAB. The increase in flux at low enhancer concentrations is normally attributed to the ability of the surfactant molecules to penetrate the skin and increase its permeability. Reduction in the rate of transport of the drug present in enhancer systems beyond 1% w/w is attributed to the ability of the surfactant to form micelles and is normally observed only if interaction between micelle and the drug occurs. The results showed that the nature of enhancer greatly influences cutaneous barrier impairment.     

The effect of various surfactants on the release rate of propranolol hydrochloride from hydroxypropylmethylcellulose (HPMC)-Eudragit matrices.

Hydrophilic and lipophilic polymers are widely used excipients to control the release rate of drugs from matrices. Researchers found that surfactants are able to control the release rate of drugs. The aim of the present investigation is to determine the effects of surfactant type, its concentration and the different ratios of surfactants on the release rate of highly soluble drug (propranolol HCl). In this study, sodium lauryl sulphate (SLS) as an anionic surfactant, cetyl trimethyl ammonium bromide (CTAB) as a cationic surfactant, Tween 65 and Arlacel 60 as non-ionic surfactants were selected. The different concentrations of surfactants were incorporated into hydroxypropylmethylcellulose-Eudragit matrices and then dissolution rate of the drug from the matrices were evaluated at pH 1.2 or 6.8. The results showed that the release rate of propranolol decreased as the concentration of SLS increased. This is due to that SLS is able to form complex with propranolol. In contrast Tween 65 caused an increase in the release rate of the drug. Cationic surfactant (CTAB) had little effect on the release rate of the drug. It was shown that as the ratio of CTAB:SLS increased the release rate of propranolol increased from matrices. This indicated that as CTAB is able to interact with SLS molecules, therefore number of the interacting anionic molecules with the cationic drug was decreased. It can be concluded that, the type and ionization of surfactant, hydrophilicity and lipophilicity of surface active agent and various ratios of surfactants are important factors in controlling the release rate of propranolol.     

Effects of some non-ionic surfactants on transepithelial permeability in Caco-2 cells

The effects of the non-ionic surfactants polysorbate 20, polysorbate 60, polysorbate 85, cholesteryl poly (24) oxyethylene ether (Solulan C24) and the lanolin-based poly (16) oxyethylene ether (Solulan 16) on the epithelial integrity of monolayers of human intestinal epithelial (Caco-2) cells has been studied using metformin as a model drug. The aim was to identify the surfactants and their optimal concentrations capable of enhancing drug transport while causing no, or only minor, cellular damage. Effects on cell permeability were assessed by measurements of the transport of metformin, a hydrophilic drug, by monitoring transepithelial electrical resistance. Cell viability was determined by the diphenyltetrazolium bromide test (the MTT test). All the surfactants studied demonstrated concentration-dependent effects on cell permeability and cell viability. The effects on transepithelial electrical resistance correlated with cell viability, i.e. increased transepithelial electrical resistance and increased cell-monolayer permeability for metformin corresponded to decreased cell viability. The results indicate that the Solulan and polysorbate surfactants were active as absorption enhancers, Solulan C24 and 16 being more effective than polysorbates 20, 60 or 85, causing an increase in metformin transport at lower concentrations than the polysorbates. Polysorbate 20 exerted its greatest effect at a concentration of 5%-increasing the flux of metformin after 3 h by a factor of around 20 over the control. Large increases in the transport of metformin, especially at surfactant levels of 0.05%, 0.1% and 0.5%, were related to the effect of Solulan C24 and Solulan 16 on the cell permeability. The Caco-2 cell monolayer experiments confirmed the ability, especially of polysorbate 20, Solulan C24 and Solulan 16, to increase the absorption of metformin. The polysorbates increased permeability as a result of solubilisation of membrane components, while Solulans did so by penetrating and solubilising the membrane. Correlation between increase in membrane permeability and the toxicity of the surfactants towards the cell membrane has been established.     

Surface Activity of a Monoclonal Antibody

The development of high concentration antibody formulations presents a major challenge for the formulation scientist, as physical characteristics and stability behavior change compared to low concentration protein formulations. The aim of this study was to investigate the potential correlation between surface activity and shaking stress stability of a model antibody-polysorbate 20 formulation. The surface activities of pure antibody and polysorbate 20 were compared, followed by a study on the influence of a model antibody on the apparent critical micelle concentration (CMC) of polysorbate 20 over a protein concentration range from 10 to 150 mg/mL. In a shaking stress experiment, the stability of 10, 75, and 150 mg/mL antibody formulations was investigated containing different concentrations of polysorbate 20, both below and above the CMC. The antibody increased significantly the apparent CMC of antibody-polysorbate 20 mixtures in comparison to the protein-free buffer. However, the concentration of polysorbate required for stabilization of the model antibody in a shaking stress experiment did not show dependence on the CMC. A polysorbate 20 level of 0.005% was found sufficient to stabilize both at low and high antibody concentration against antibody aggregation and precipitation. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4525–4533, 2009     

Physical and biophysical effects of polysorbate 20 and 80 on darbepoetin alfa

We studied the physical and biophysical affects of the nonionic surfactants polysorbate 20 and 80 and their mechanism of interaction using darbepoetin alfa, a 4-helix bundle protein, as the exemplary protein. Differences were observed between the abilities of the polysorbates to prevent surface loss/aggregation and correlated with each polysorbates initiation of micelle formation prior to the critical micelle concentration (CMC). The biophysical properties monitored by far-UV circular dichroism (CD) and tryptophan (Trp) fluorescence showed effects due to polysorbates, but were not correlated with their CMC. At a constant protein concentration PS-80 induced α-helix in the protein with a maximal effect at 15:1 molar ratio of PS-80/protein. PS-20 initially induced α-helix with a maximal effect at 1.5:1 ratio followed by a decrease in the α-helix content. PS-80 had no effect on near-UV CD but increased Trp fluorescence only at the 150:1 polysorbate/protein ratio. PS-20 decreased the near-UV CD and Trp fluorescence. Thermodynamic studies by isothermal titration calorimetry (ITC) demonstrated that the protein interacts with monomeric polysorbate, but not with polysorbate micelles. The data suggest that the polysorbates differentially interact with the protein and that the biophysical effects are dependent on the structure of the polysorbate and the polysorbate to protein ratio. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3200–3217, 2009     

Effect of combined use of nonionic surfactant on formation of oil-in-water microemulsions

PURPOSE: This study evaluated the effects of combined use of two nonionic surfactants on the characteristics (i.e., appearance, emulsification time, and particle size) of oil-in-water microemulsions generated from flurbiprofen-loaded preconcentrates. METHODS: Three phase diagrams were constructed using Capmul PG8 (propylene glycol monocaprylate) as the oil, Tween 20 (polysorbate 20) and/or Cremophor EL (polyoxyl 35 castor oil) as surfactants. A number of preconcentrates were selected based on phase diagrams: O20T80 (20% Capmul PG8, 80% Tween 20), O20C80 (20% Capmul PG8, 80% Cremophor EL), O20T40C40 (20% Capmul PG8, 40% Tween 20, 40% Cremophor EL). Flurbiprofen loading in preconcentrates was tested at 0%, 1%, 2.5%, and 5% (w/w). The resulting mixtures of these preconcentrates upon dilution 100-fold with aqueous medium were characterized by visual and microscopic observation, HPLC and photon correlation spectroscopy. RESULTS: (a) For preconcentrates using single surfactant, either O20T80 or O20C80, the dilution generated emulsions with visible cloudiness. The particle size increased as the drug loading increased; (b) for preconcentrates using two surfactants O20T40C40, the dilution generated clear microemulsions with small particle sizes (10-11nm), and the increased drug loading seemed to have little effect on the particle size. The microemulsions from preconcentrate O20T40C40 was also found to be stable at ambient temperature over 20 days without significant change in particle size at different drug loadings. Dilution with different aqueous medium, either water, or simulated gastric fluid or simulated intestinal fluid, also did not change the particle sizes of the microemulsions. CONCLUSIONS: The combined use of surfactants in preconcentrate showed the promise in generating desired self-emulsifying microemulsions with small particle size, increased drug loading, and improved physical stability. This will have significant implications in future dosage development for poorly water-soluble drugs in using self-emulsifying microemulsions drug delivery system (SMEDDS).     

Interaction of epirubicin HCl with surfactants: effect of NaCl and glucose

The interaction of an antitumoural drug, Epirubicin HCl, with anionic (sodiumdodecylsulfate; SDS), cationic (cetyltrimethylammonium bromide; CTAB), and nonionic (t-octylphenoxypolyethoxyethanol; TX-100, polyoxyethylenesorbitanmonolaurate; Tween 20) surfactants has been studied by absorption spectra as a function of surfactant concentration ranging from the premicellar to postmicellar region. At the concentrations below the critical micelle concentration (CMC), the equilibrium complex formation constant between Epirubicin cations and SDS anions has been determined by Job's method. Above the CMC, binding constant (K(b)) of Epirubicin to various types of micelles has been calculated by means of the Benesi-Hildebrand Equation. The nonionic surfactant micelles showed stronger interaction than the ionic SDS micelles, and the binding tendency of Epirubicin followed the order: Tween 20 > TX-100 > SDS. Binding of Epirubicin also has been studied in the presence of NaCl and glucose because it is administered to patients intravenously in 0.9% NaCl or 5% glucose solution. The additives have been observed to affect the CMC of the surfactants and the Epirubicin-micelle binding constant appreciably. The presence of NaCl and glucose lowered the CMC of all the surfactants studied. The binding constant of Epirubicin decreased in the presence of NaCl but increased in the presence of glucose. The equilibrium complex formation constant between Epirubicin and SDS decreased in the presence of NaCl compared with purely aqueous media.     

Increased dissolution and physical stability of micronized nifedipine particles encapsulated with a biocompatible polymer and surfactants in a wet ball milling process

Suspensions of nifedipine, a practically water-insoluble drug, were prepared in the presence of a biocompatible polymer, polyvinylpyrrolidone (PVP, K value 17), and three surfactants, sodium lauryl sulfate (SLS, anionic), cetyltrimethylammonium bromide (CETAB, cationic), polysorbate 80 (Tween 80, nonionic), by wet milling in ceramic ball mills. Nifedipine powders encapsulated with PVP and the surfactants were recovered from the suspensions after milling and evaluated for changes in particle size, morphology, sedimentation rate in aqueous suspensions, crystal form, and dissolution. Particle size analysis indicated that milling of suspensions in solutions of PVP and surfactants is an efficient method for reducing the particle size of nifedipine to below 10 microm. Furthermore, DSC and XPS analysis indicated that during milling the nifedipine crystals were coated with the PVP or surfactants and that milling with PVP stabilized the nifedipine crystal form during milling while nifedipine was gradually amorphisized when milled in a quaternary nifedipine/PVP/SLS/CETAB system. The decrease in particle size caused a significant decrease in sedimentation rate and increased the dissolution rate of nifedipine in simulated gastric fluid when compared to milled nifedipine and powder mixtures of the drug and the excipients.     

Multivariate design for the evaluation of lipid and surfactant composition effect for optimisation of lipid nanoparticles

Physicochemical properties of lipid nanoparticles (LN), such as size, size distribution and surface charge, have a major influence both, on in vitro stability and delivery of the incorporated drug in vivo. With the purpose of understanding how these properties are influenced by variations of LN composition (e.g. lipid and surfactant type and concentration) 2(2) factorial designs with centre point were applied for several types of lipids and surfactants in the present study. Tested factors and levels were the type and concentration of lipid (cetyl palmitate, Dynasan 114 and Witepsol E85) at the concentrations of 5%, 10% and 15%, in combination with type and concentration of surfactant (polysorbate 20, 40, 60 and 80 and poloxamer 188 and 407) at concentrations of 0.8%, 1.2% and 2.0%. Responses measured within the design space were the mean size and polydispersity index (photon correlation spectroscopy), content of microparticles (optical single particle sizing), macroscopic appearance, pH and zeta potential on the day of production, 1 and 2 years after production. Multivariate evaluation and modelling were performed starting with a principal component analysis (PCA) and followed by partial least square regression analysis (PLS) to assess both qualitative and quantitative influence of the investigated factors in the LN. Our study showed that both, lipid and surfactant concentration and the type of surfactant are crucial parameters for the particle size of the LN prepared by high pressure homogenisation (HPH). For LN stability during 2 years both, lipid and surfactant types and concentrations were identified as the most relevant parameters. Among the surfactants most suitable for producing LN with small sizes were the polysorbates and the lipid yielding best storage stability was cetyl palmitate. Furthermore, the models allowed the prediction of the mean size of LN that could be achieved with a certain lipid/surfactant combination and concentration. The obtained results are considered useful for future design of stable LN formulations without the need of extensive empirical testing of formulation parameters within the given HPH technology.     

Behaviour of polysorbate 20 during dialysis, concentration and filtration using membrane separation techniques

During formulation development of a therapeutic protein, combinations of buffers, pH and excipients need to be tested. As the protein bulk solution used for formulation development usually contains a buffer component at a defined pH and potentially one or more excipients already, this bulk requires to be processed. In case low concentrations of non-ionic surfactants, for example polysorbate 20, are already present in the bulk, the surfactant needs to be removed in lab-scale for further development use. The scope of the work was to study the behaviour of low concentrations of polysorbate 20 during membrane separation processes. The first part focuses on evaluating the behaviour of polysorbate 20 during a dialysis process, whereas the second part analyses concentration changes of polysorbate during a membrane concentration process using a stirred cell. The third part analyses potential membrane absorption of polysorbate at sterilizing-grade filters. In conclusion, it was found that polysorbate could not be significantly reduced during a dialysis process and accumulated during a membrane concentration process in unreproducable manner. During sterile filtration, no significant influence on the concentration of polysorbate was measurable. In any case, it is recommendable to quantify the concentration of polysorbate during critical membrane process steps in pharmaceutical industry.     

In-vitro studies of enteric coated diclofenac sodium-carboxymethylcellulose microspheres

Abstract

Microspheres containing diclofenac sodium (DS) were prepared using carboxy-methylcellulose (CMC) as the main support material (1·0, 2·0, 3·0% (w/v)) and aluminium chloride as the crosslinker. Drug to polymer ratios of 1:1, 1:2 and 1:4 were used to obtain a range of microspheres. The microspheres were then coated with an enteric coating material, Eudragit®S-100, with aqueous solution concentrations of 10 and 20% (w/v). Encapsulation efficiency, % yield value, particle sizes and in-vitro dissolution behaviour were investigated. The surface of the enteric coated microspheres seemed to be all covered with Eudragit®S-100 from scanning electron microscopy observation. It was also observed that increasing the CMC concentration led to an increase in the encapsulation efficiency, % yield value and particle size and decreased the release rate. Eudragit®S-100 coating did not significantly alter the size but the release rate was significantly lower even when the lower concentration solution was used.     

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.     

Non-aqueous emulsions: hydrocarbon-formamide systems

There are few reports in the literature on formulation of non-aqueous emulsions. This study was designed to evaluate some design criteria for such systems. Formamide is the closest polar solvent that has the ability to replace water in emulsification when employing established non-ionic surfactants as stabilisers. For the majority of studies, linear alkanes (C6-C16) were dispersed in formamide as the continuous phase were stabilised with polysorbate 20. Initial studies involved gentle emulsification and observing mean globule size. The mean globule size varied in a non-linear fashion with alkyl chain length, the minimum being between C10 and C12. Sonication for 30 s led to smaller differences in the mean globule size. The effect of various parameters such as surfactant concentration and solvophilicity of the surfactant was observed. The surface activities of polysorbate 20, 40, 60 and 80 in formamide and critical micellar concentrations were determined. The latter were several orders of magnitude higher in formamide than in water, and the areas per molecule larger. The addition of water to the dodecane formamide systems did not destabilise the emulsion. Release of the model drug dehydroepiandrosterone from dodecane in formamide emulsions was studied in distilled water, the rate of release being dependent on the volume fraction of dodecane.