Formulation Optimization of an Improved Traditional Medicine from the Stem Bark Extract of Mangifera indica L. using Design of Experiments (DOE) Strategy

Abstract

Introduction: Improved Traditional Medicines (ITMs), a recent concept by the World Health Organization (WHO) was introduced to promote the rational use of herbal medicine for primary health care in developing countries. The ITM by WHO andAIPO have categorized into 4 categories with respect to the quality of the active ingredient. However, this category needs more research in finding a greater variety of acceptable dosage forms. There is a need to account for formulation and process variables in these dosage forms to maintain product properties hence performance of plant extract, ensuring consistent quality. One of the methods to account for formulation and process variables is by using the Design of Experiments (DoE) approach.
 Objective: The main objective of this work was to optimize the formulation of a category 2 Improved Traditional Medicine containing Mangifera indica L. stem bark aqueous extract using Design of Experiments.
 Methods: Mangifera indica L. stem bark was collected and identified at the National herbarium. It was dried, ground and the powder used for extraction using digestion method using water as solvent (at 70°C). Phytochemical screening was done on the extract. The extract then proceeded unto pharmaceutical development. The formulation optimization of Mangifera indica aqueous stem bark extract (MIABE) started with the definition of the Quality Target Product Profile (QTPP) that was expected for the final product; which is an orodispersible tablet that will facilitate patient compliance and promote a rapid disintegration. These QTPPs formed the basis of the Critical Quality Attributes (CQAs) which were identified (as hardness, disintegration time and mass uniformity) and used for all experiments. The experimental part was divided into 2 main manufacturing processes; direct compression and wet granulation techniques. Each process was investigated for drug product optimization. 
 A risk assessment was undertaken to identify the formulation variables that impact product quality.
 For direct compression, a 32 full factorial Design of Experiment (DoE) was used to investigate the effect of superdisintegrant (25%) and lubricant level (0.25-5%) on powder flow characteristics. For wet granulation, a 22 full factorial DoE was used to investigate the effect of superdisintegrant (2-5%) and binder (5-10%) on flow properties and tablet properties.
 Results: The design and evaluation of the formulations in this study resulted in successful formulation optimization of an Improved Traditional Medicine. DoE proved to be an excellent method to optimize formulations of ITMs, providing several tools that increase a much better understanding of the formulation and manufacturing process. Further studies on this formulation DoE are needed to evaluate the effect of more process variables (compression force and speed) and more formulation variables such as palatability.
 Conclusion: Optimization models were developed for the various responses (disintegration time, wetting time and hardness) showing the influence of formulation variables on these responses. Therefore, the formulation optimization of a category 2 ITM containing Mangifera indica L. stem extract using Design of Experiment is a suitable approach to save time, money and improve drug product understanding.