Synthesis, Formulation and Analytical Method Validation of Rutin Prodrugs

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سرحان, تالا محمد أحمد
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An-Najah National University
Background: Rutin is a plant extract that belongs to the flavonoid group of compounds. Many studies showed that Rutin has a potential pharmacological uses such as antioxidant, anti-inflammatory and antihypertensive activities. Rutin is widely used as medicinal product and food supplement and marketed in different pharmaceutical dosage formulations. However, rutin suffered from low systemic bioavailability due to its low absorption from the gastrointestinal tract and its low water solubility. In this study, we aimed to improve the water solubility and consequently its dissolution profile by synthesizing a more soluble derivative of rutin. Method: Decaacetylated ester of rutin was first synthesized. Then selective partial deacetylation was performed to produce the hexaacetylated ester of rutin. Water solubility of the new derivative as well as its dissolution was compared to rutin. An evaluation of the antioxidant activity of the hexaacetylated derivative was tested using 2,2-diphenyl-1-picrylhydrazyl reduction method. Moreover, A Ultraviolet/Visible spectrophotometric method was developed and validated for the analysis of a tablet formulation of the newly synthesized derivative. An ultraviolet spectrophotometric quantitative analytical method for rutin derivative as active particle ingredient and in a tablet dosage form was developed and validated according to the International Conference on Harmonization and international guidelines. Results: The hexaacetylated ester derivative of rutin was successfully synthesized and the derivative structure was confirmed by nuclear magnetic resonance. Moreover, the water solubility and the dissolution profile were improved by approximately two fold increase compared to that of the original rutin. Water solubility of the partially acetylated product has been increased from 0.07 to 0.15 mg/mL and its dissolution increased from 22% to 37.5% compared to the original rutin. Moreover, the antioxidant activity results showed that the newly synthesized derivative preserved the antioxidant activity of the original rutin. An easy and feasible analytical method was developed and validated. The developed method was found to be linear, precise, accurate and selective with a lowest limit of detection and lowest limit of quantification of 0.00854 and 0.0259 mg/mL respectively. The formulated tablets of hexaacetylated rutin in our research laboratory were found to be stable under accelerated conditions as well as long term conditions for three months. Conclusion: An improvement on the solubility of rutin was achieved by selective acetylation of some of the OH groups of rutin. The tablet formulation of the partially acetylated ester derivative of rutin gives a better dissolution over the already marketed rutin tablets.