Combined ultrasound-microwave assisted synthesis of aripiprazole: Process optimization using RSM-ANN

Abstract

The current work demonstrates combined microwave and ultrasonic assisted synthesis of aripiprazole (ARZ) drug from carbostyril intermediate with piperazine moiety in the presence of a mixture of a green medium. The traditional cooking (TC) technique is time-consuming (≥ 16.45 h), accounts for a significant number of contaminants (≥ 2.63%), and has the drawback of additional repetitive purification stages. The intensification tool simultaneous microwave-ultrasonic irradiation has been employed to overcome these challenges. Response surface methodology (RSM), along with central composite design (CCD), was used to assess the impact of different process parameters on process yield (ϒc) and total impurity content (ὶ). A consistent process yield (≥ 91%) with less total impurity content (≤ 1.45%) was obtained at the optimum condition of reactant mole ratio (1:1), base mole ratio (2.4:1), reaction temperature (85°C) and process time (188 min). Among the exercised numerical tools, a neural network was found to be more precise than RSM for the current system. The synthesis of ARZ followed a second-order kinetic model. The activation energy was found to be 79.61 kJ/mol. Eventually, the qualitative analysis shows a good resemblance between the synthesized products obtained by these two techniques.