Effect of Oil, Surfactant and Co-Surfactant Concentrations on the Phase Behavior, Physicochemical Properties and Drug Release from Self-Emulsifying Drug Delivery Systems

Research Article

J Drug Discov Develop and Deliv. 2014;1(1): 7.

Effect of Oil, Surfactant and Co-Surfactant Concentrations on the Phase Behavior, Physicochemical Properties and Drug Release from Self-Emulsifying Drug Delivery Systems

Chukwuma O Agubata*1, Ifeanyi T Nzekwe2, Nicholas C Obitte1, Calister E Ugwu1, Anthony A Attama3 and Godswill C Onunkwo1

1Department of Pharmaceutical Technology and Industrial Pharmacy, University of Nigeria, Nigeria

2Department of Pharmaceutics and Pharmaceutical Technology, Nnamdi Azikiwe University, Nigeria

3Department of Pharmaceutics, University of Nigeria, Nigeria

*Corresponding author: Chukwuma O Agubata, Department of Pharmaceutical Technology and Industrial Pharmacy, University of Nigeria, Nsukka, Enugu State, Nigeria

Received: July 17, 2014; Accepted: Aug 07, 2014; Published: Aug 11, 2014


Microemulsions are isotropic, thermodynamically stable systems. The aim of this study was to evaluate the effect of oil, surfactant and co-surfactant concentrations on the phase behavior, physico-chemical properties and drug release of Self-Emulsifying Drug Delivery Systems (SEDDS). Solubility of artemether in Peceol® (oil), Labrasol® (surfactant), Transcutol® (co-surfactant) and their mixtures was studied while pseudoternary phase diagrams were constructed using water titration method as surfactant efficiency and water solubilization capacity were examined. Artemether SEDDS were prepared by dissolving artemether in the oil prior to further mixtures with surfactant, cosurfactants and characterized by evaluation of phase stability, self-emulsification, pH, viscosity, drug precipitation, refrigeration thaw cycle, centrifugation, drug release and dispersion. SEDDS prepared with surfactant-co-surfactant mixture (Smix) at 3:1 ratio had the largest zone of microemulsion in the pseudoternary phase diagrams and highest surfactant efficiency. Formulations with higher Labrasol® content showed faster self-emulsification, while artemether release and dispersion from capsule-filled SEDDS was optimum and fastest using Peceol®/ Smix ratio of 1:2 and a Labrasol®/Transcutol® ratio of 3:1. Combinations of oil, surfactant and co-surfactants at varied ratios produced self-emulsifying systems with different emulsification, drug release and dispersion qualities.

Keywords: Microemulsion; Pseudoternary phase diagram; Selfemulsification; Artemether


Self-emulsifying formulations are isotropic mixtures of oil, surfactant, co-solvent and solubilized drug [1]. These formulations can rapidly form oil in water (o/w) fine emulsions when dispersed in aqueous phase under mild agitation and are commonly called Self-Emulsifying Drug Delivery Systems (SEDDS). The rapid emulsification of these formulations in the gastrointestinal tract can provide both improved oral bioavailability and a reproducible plasma concentration of drug. Furthermore, the droplet size of the emulsion would influence the extent of absorption of the orally administered drug. SEDDS would require a relatively high intrinsic lipophilicity of the drug substance since the active ingredient should be dissolved in a limited amount of oil. Self-emulsification occurs when the entropy change that favors dispersion is greater than the energy required to increase the surface area of the dispersion [2]. The free energy of the conventional emulsion is a direct function of the energy required to create a new surface between the oil and water phases. The two phases of emulsion tend to separate with time to reduce the interfacial area and subsequently the emulsion is stabilized by emulsifying agents, which form a monolayer over emulsion droplets, which reduces the interfacial energy and provides a barrier to prevent coalescence [3]. Emulsification process may be associated with the ease with which water penetrates the oil-water interface with formation of liquid crystalline phase resulting in swelling at the interface, thereby causing greater ease of emulsification [4]. Large interfacial surface area provided by fine droplet size of the formulation promotes rapid release of the drug substance and/or formation of mixed micelles containing the drug [5]. Lipids (e.g. triglycerides) affect the oral bioavailability of drugs by changing biopharmaceutical properties such as increasing dissolution rate and solubility in the intestinal fluid, protecting the drug from chemical as well as enzymatic degradation in the oil droplets and the formation of lipoproteins promoting lymphatic transport of highly lipophilic drugs [6]. Many drugs degrade in the physiological system through enzymatic or hydrolytic cleavages under acidic pH of stomach [7]. Such drugs when presented in form of SEDDS can be well protected against these degradation processes as liquid crystalline phase in SEDDS act as barrier between degrading environment and the drug. The most widely recommended surfactants for SEDDS are non-ionic surfactants with relatively high Hydrophile-Lipophile- Balance (HLB) values. The hydrophilicity of the surfactants assists the immediate formation of oil-in-water droplets and rapid spreading of the formulation in aqueous media. SEDDS are often referred to as Self-Microemulsifying Drug Delivery Systems (SMEDDS) if they form transparent microemulsions. The flexibility of the surfactant film is important and enables the existence of several different structures including droplet-like shapes, aggregates and bicontinuous structures [8]. The interface of microemulsions is stabilized by an appropriate combination of surfactant and/or co-surfactant. The lipid mixtures with higher surfactant and co-surfactant/oil ratios lead to the formation of self-microemulsifying formulation [9].

It is important to note that compositional variables (oil, presence of other amphiphiles, hydrophilic molecules or electrolytes) as well as temperature may have an influence on hydrophilic and hydrophobic properties, the geometry of the surfactant molecule and the efficiency of a surfactant to generate microemulsion [10]. In most cases, single chain surfactants alone are unable to reduce the oil/water interfacial tension sufficiently to enable a microemulsion to form [11]. The efficiency of a surfactant usually represents the amount of an amphiphile required to completely homogenize equal quantities of oil and water [12]. Oils, surfactants and co-surfactants have different physico-chemical properties and their interactions modify the characteristics of the resultant self-emulsifying drug delivery systems.

Artemether is an antimalarial drug used for the treatment of multidrug resistant strains of Plasmodium falciparum malaria. Artemether is a relatively lipophilic and unstable drug [13]. Studies indicate that the bioavailability of artemether increases with the administration of fatty meals [14]. Hence, the objective of this study was to investigate the effect of oil, surfactant and co-surfactant concentrations on the phase behavior, physicochemical properties and drug release from self-emulsifying drug delivery systems containing artemether.

Materials and Methods


The following materials were used as procured without further purification: artemether (Hangzhou Dayang Chemical, China), Peceol®- glycerol monooleate, Labrasol® - caprylocaproyl macrogol-8- glyceride, Transcutol® - diethylene glycol monoethyl ether (Gattefosse, St. Priest, France). All other reagents and solvents were analytical grade.

Solubility of drug in oil, surfactant and co-surfactant for SEDDS

Solubility studies of artemether in Peceol® (oil), Labrasol® (surfactant), Transcutol® (co-surfactant) and different oil-surfactant/ co-surfactant mixtures were performed visually and confirmed with shake flask method. The solubility was observed visually by first saturating the vehicle with a known weight of the drug and then adding an increasing drop-wise amount of the vehicle and allowing for equilibration for 24 h before further addition until the drug completely dissolved. The solubility study was then performed using the shake flask method. An excess of each drug was separately added to 5 ml of oil, surfactants and oil/surfactant mix in a screwcapped tube and mixed. The tubes were then kept at 37 ± 1°C in an isothermal water bath shaker for 24 h after which each sample was centrifuged. The resulting supernatant was filtered, diluted appropriately with 1 M methanolic HCl, heated at 60 ± 2°C for 3 h for artemether derivatization and analysed using UV spectrophotometer (Spectrumlab 752s, UK) at wavelength of 254 nm.

Construction of pseudoternary phase diagrams

The pseudoternary phase diagrams were constructed using the water titration method. A series of SEDDS was prepared by varying mass ratio of oil to surfactant (or surfactant mixture, Smix) from 9:1 to 1:9. The ratio of surfactant to co-surfactant was optimized by varying their mass ratio from 1:0, 1:1, 2:1, 3:1, to 4:1 (Labrasol®/Transcutol®). Each pre-concentrate mixture was titrated drop-wise with distilled water at room temperature and agitated after each drop. For the purpose of conversions, 35 drops of water was equivalent to 0.5 ml. The end point of the titration was taken as the point when the solution became cloudy and turbid, and the quantity of water required was recorded. The pseudoternary phase diagram was established to delineate the area of microemulsion and boundary of phases. The pseudoternary phase diagrams were plotted using SigmaPlot® 12.3 software.

Surfactant efficiency (Smin) and water solubilization capacity (Wmax)

The efficiency of a surfactant usually represents the amount of an amphiphile required to completely homogenize equal quantities of oil and water. It was determined at equal oil to water weight fractions in order to avoid effects of domain curvature on the surfactant efficiency measurement [15]. The surfactant efficiency of the surfactants or Smix was determined at experimental temperature of 25 ± 1°C and was expressed as the minimum concentration of the surfactant required to obtain a single phase microemulsion (Smin, %w/w). The result was compared with values extrapolated from a graph.

The water solubilization capacity (Wmax) of the surfactant-oil pre-concentrate at constant surfactant to oil mass ratio 1:1, was determined by titrating the mixtures with distilled water (drop wise) to the water solubilization limit which was detected visually as the transition from transparent to turbid/cloudy system upon addition of excess water. The transparent samples containing Smin and Wmax were allowed to equilibrate for a minimum of 72 h and then examined visually for transparency. Clear isotropic one phase systems were designated as microemulsions.

Formulation of unloaded self-microemulsifying drug delivery systems

Based on microemulsion area in the pseudoternary phase diagram and safety requirement, appropriate quantities of Peceol®, Labrasol® and Transcutol® were mixed together in different selected ratios to obtain homogenous self- microemulsifying systems as presented in Table 1. A 3 x 2 factorial design was adopted for the SEDDS formulation using 2 independent variables (oil/surfactant ratio, and surfactant/ co-surfactant ratio (Kmin)) with 3 and 2 use levels respectively. A formulation without co-surfactant was used as control.