Synthesis and evaluation of pharmaceutical and fine chemicals processes for intensification and sustainability benefits

Abstract

In the face of global competition and tighter safety and environmental regulations, the pharmaceutical industry is exploring new areas and technologies that could potentially bring about step change in process performance. Process intensification has the potential to improve early development by introducing new process options, which are capable of achieving green and sustainable benefits in production. In this thesis, the objective is to demonstrate the synthesis and evaluation of pharmaceutical processes for intensification and sustainability benefits. This is illustrated with two main processes – the amidation process and the ortho-lithiation process. Based on the experiences gained at the end of the case studies, a general framework that summarizes the approach to Process Intensification (PI) for pharmaceutical processes is developed. Firstly, the amidation process has been successfully intensified with the implementation of a number of PI options, which are proven feasible in lab-scale experiments. These options are represented in terms of three intensified cases - the intensified batch case, the continuous reaction case and the continuous process case, are compared to the batch base case. To compare their sustainability performance, the respective plants are designed at a hypothetical throughput of 3 tons per year. Overall, the intensified batch case provided the most benefits, with cost savings of up to 40%, and more than 70% improvements in total material efficiency and E-factor compared to the batch base case. This also indicates that batch mode operation in this particular process is more suitable than continuous mode. The second case study on the ortho-lithiation process consists of three parts. The first part investigates ortho-lithiation reaction in continuous flow reactors at ambient temperature. The findings demonstrated that the highest reaction yield of 99% was obtained in a T-reactor as a result of short residence time and good mixing. The Spinning Disc Reactor (SDR) also showed distinct advantage in handling this reaction with mild solid precipitation. The second part focuses on the comparison of the T-reactor, the SDR and the Stirred Tank Reactor (STR) based on the sustainability metrics. The results showed that the T-reactor process achieved 66% and 11% reduction in energy consumption and operating expenditure respectively as compared to the STR process. The last part of the ortho-lithiation process focuses on the study of the whole process including workup. To avoid dealing with inefficient separation process, consecutive reaction has been attempted by avoiding the isolation of ortho-lithiation crude product and directly transferring it into the next reactor for subsequent reaction. This is experimentally proven feasible and resulted in a greener process.