Optimization of the synthesis reaction and establishing the reference standard of Fenofibrate impurity C (USP)

1-methylethyl 2-[[2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl propanoyl]oxy]-2-methylpropanoate (or fenofibrate impurity C, United States Pharmacopoeia [USP]) is an impurity in fenofibrate raw material. To date, publications on synthesis of fenofibrate impurity C (ImpC) have reported low yield and purity, so far. The purpose of this study is to optimize the conditions for synthesis of ImpC using Central Composite Design (CCD) approach and standardization of ImpC as reference substance. ImpC was synthesized from the reaction between fenofibric acid and isopropyl 2-bromo-2-methylpropanoate in dimethyl sulfoxide in the presence of potassium carbonate. Four factors were investigated: temperature, reaction time, mole ratio of potassium carbonate and isopropyl 2-bromo-2-methylpropanoate. A CCD model was constructed to predict and provide optimal conditions for the reaction. The structure of synthesized ImpC was determined by infrared spectroscopy, mass spectrometry and nuclear magnetic resonance spectroscopy. The procedure for establishing reference standards for ImpC followed the guidelines of ISO 13528:2022. The third-order regression model was developed to predict the yield of reaction using Design Expert software. The optimal conditions were determined: reaction temperature 87°C reaction time 3.64 hours; mole ratio of fenofibric acid and potassium carbonate was 1:4.30; mole ratio of fenofibric acid and isopropyl 2-bromo-2-methylpropanoate was 1:5.95. Under theses conditions, the yield was 89.53%. The structure of ImpC was confirmed. The reference standard of ImpC was established with the assigned value of 99.483%. ImpC was successfully synthesized and standardized as reference standard. The optimal condition for its synthesis was also determined.