Partition Behavior of Lipophilic Compounds Incorporated in Submicron Emulsion: Effects of Physicochemical Properties, Concentrations and Incorporation Methods

Abstract

The effects of physicochemical properties, concentration and method of incorporation of pharmaceutical substances on their partitions in various phases of submicron emulsion were studied. Series of alkyl-4-hydroxybenzoate comprising methylparaben, ethylparaben, propylparaben and butylparaben, and series of benzodiazepine drugs comprising alprazolam, clonazepam, diazepam and lorazepam, were used as model substances. Determination of aqueous solubility, oil solubility and oil-water partition coefficient indicated the relationship of these parameters with molecular structure of alkyl-4-hydroxybenzoate group whereas no correlation with chemical structure of benzodiazepine drugs was observed. Three methods of drug incorporation were investigated, dissolved model compound in oil phase prior to emulsification process (de novo emulsification), the model compound was dissolved in solubilizer and then mixed with submicron emulsion base (extemporaneous addition) and directly shaking of drug powder in submicron emulsion base (shaking method). The larger mean particle size and the lower in zeta potential including pH value of drug containing emulsion were observed as compared with submicron emulsion bases. After keeping at ambient temperature for a period of seven days, the mean particle size was larger while the higher zeta potential and lower pH were observed in drug containing submicron emulsions as well as submicron emulsion bases. Ultracentrifugation technique was used to separate emulsion into different phases namely oil phase, phospholipids rich phase, aqueous phase and mesophase, then drug content in each phase was determined. The higher lipophilic model substance was mostly deposited in oil phase. The moderate lipophilic drug likely partitioned to the phospholipids rich phase and mesophase. The lower lipophilic drug predominantly distributed to the aqueous phase. However, the concentration of incorporated drug apparently had less effect on the distribution through various phases of submicron emulsion. In addition, method of incorporation affected the distribution of model substance in submicron emulsion depending on which phase that was firstly contacted with the incorporated drug molecule. Drug incorporating in submicron emulsion by de novo emulsification mostly accumulated in oil phase, whereas was predominantly accumulated in aqueous phase and mesophase when incorporating by extemporaneous addition and shaking method, respectively.