A novel microemulsion formulation capable of delivering rifampicin and isoniazid in combination was created to allow for their differences in solubility and potential for chemical reaction. The developed model allowed better understanding of the process of microemulsion formation and stability within pseudoternary colloidal systems.

The aim of this study is to develop and optimize a simple and reliable high-performance liquid chromatography (HPLC) method for the simultaneous determination of rifampicin (RIF), isoniazid (INH), and pyrazinamide (PZA) in a fixed-dose combination. The method is developed and optimized using an artificial neural network (ANN) for data modeling. Retention times under different experimental conditions (solvent, buffer type, and pH) and using four different column types (referred to as the input and testing data) are used to train, validate, and test the ANN model. The developed model is then used to maximize HPLC performance by optimizing separation. The sensitivity of the separation (retention time) to the changes in column type, concentration, and type of solvent and buffer in the mobile phase are investigated. Acetonitrile (ACN) as a solvent and tetrabutylammonium hydroxide (tBAH), used to adjust pH, have the greatest influence on the chromatographic separation of PZA and INH and are used for the final optimization. The best separation and reasonably short retention times are produced on the micro-bondapak C18, 4.6 x 250-mm column, 10 microm/125 A using ACN-tBAH (42.5:57.5, v/v) (0.0002M) as the mobile phase, and optimized at a final pH of 3.10.

The aim of this study to design a stable microemulsion formulation to deliver a combination of rifampicin, isoniazid and pyrazinamide in quantities suitable for administration to a paediatric population. The chemical stability of rifampicin, isoniazid and pyrazinamide alone and in various combinations was investigated in different solvents, solubilizing agents and surfactants. An artificial neural network was used to model data from the stability studies and a sensitivity analysis was applied to optimize the selection of the formulation components. Imwitor 308 and Crillet 3, exhibiting the highest overall positive sensitivity were selected to formulate the stable microemulsion. Due to drug dose specifications and solubility limitations, the final formulation contained only rifampicin and isoniazid, since the solubility of pyrazinamide in the lipid and aqueous components of the microemulsion did not achieve the required dose. The stability and solubility of rifampicin were improved in the formulation. Solubilization of the rifampicin in the lipid droplets of the internal phase and lipophilic chains of the surfactants increased the quantity of rifampicin that can be incorporated, while protecting it from oxidative degradation and also limited its contact with isoniazid, which has been shown to affect its stability. The results of this study indicate that the Artificial Neural Network can be successfully used to optimize the choice of solvents, solubilizing agents and surfactants prior to formulation of the microemulsion, limiting the amount of experiments, thus reducing the costs during the preformulation study.

Microemulsions, being thermodynamically stable systems, with low viscosity and elegant in appearance have attracted interest not only for the delivery of single drug substances with low water solubility but for the stabilization of drugs in combination due to their preferential solubility in either the water or oil phases. Microemulsion design involves the solubilisation of an optimum amount of the dispersed phase in the continuous phase, utilizing the minimum amount of surfactant/mixture of surfactants/cosurfactants. It is the choice of the surfactant/surfactant mixture and/or cosurfactants, which poses the greatest challenge in the design of a thermodynamically stable microemulsion formulation. This paper will present a strategy for choosing surfactants to achieve a stable, dilutable microemulsion formulation for oral administration. Ternary and pseudo-ternary phase diagrams were constructed by titrating a series of mixtures [lipid (miglyol 812): cosurfactant and/or surfactant (cremophor RH, imwitor 308/742, sorbitol, brij 97, crillet 3)] with water at room temperature, the phases formed visually assessed after each addition and classified as isotropic (ME), liquid crystalline (LC) or coarse emulsions (EM). Results indicate that the surfactant combination of imwitor 308 and crillet 3 proved most successful in incorporating 25 to 30% miglyol 812 into a microemulsion formulation utilizing an intermediate quantity of surfactant and maintaining homogeneity on dilution.