(368bb) Green, Renewable, and Continuous Manufacturing of the Active Pharmaceutical Ingredient Paracetamol

My research focuses on developing new methods to manufacture paracetamol (i.e. acetaminophen) continuously using renewable feedstocks with a focus on improving the Green Chemistry metrics of the process. Broadly speaking, I have experience in multi-phase reactions, reaction engineering/kinetics, continuous reactor design, mechanochemistry, and organic synthesis. I am interested in developing sustainable processes in industry.

Paracetamol, the active ingredient in Tylenol®, is one of the most widely produced active pharmaceutical ingredients (API) worldwide and is listed on the WHO List of Essential Medicines. Current methods to synthesize paracetamol use non-renewable petrochemical feedstocks, hazardous reagent, and operate in batch configuration, resulting in poor Green Chemistry metrics. New processes toe paracetamol would ideally by renewable, green, safe, and operate continuously. To that end, lignin derived phenol and its derivatives are a potential source of the raw material needed to synthesize many APIs, including paracetamol.

An important challenge in paracetamol synthesis is the side reaction of the intermediate 4-aminophenol, which is difficult to obtain selectively because of its high reactivity. I first conducted a limited substrate scope for potential routes to paracetamol, with a focus on renewable feedstocks, high selectivity, and viability for continuous scale-up. Out of three potential feedstocks tested (hydroquinone, p-benzoquinone, and 4-nitrophenol), the hydrogenation of 4-nitrophenol proved the most promising in terms of Green Chemistry metrics as well as potential for continuous manufacturing. Traditional hydrogenation methods operate using pressurized batch reactors at high temperature, pressure, and solvent loading, leading to safety issues and poor Green Chemistry metrics. As such, I next explored novel reactor designs to conduct hydrogenations in a safe, efficient, and scalable manner.

Careful design of the reaction conditions was necessary to achieve the high selectivity paramount to the synthesis of a pharmaceutical ingredient, as the key reaction intermediate 4-aminophenol was highly prone to side reactions. I showed that simultaneous hydrogenation and acetylation of 4-aminophenol in one vessel was highly effective for improving selectivity in a fed-batch mechanochemical reactor. This reactor introduced several novel concepts, including fed-batch vapor phase reagent delivery (bypassing limitations of fed-batch delivery of liquid reagents into a vibrating vessel), ambient mechanochemical hydrogenation using hydrogen flow (improving safety), as well as a one-pot reaction configuration (improving selectivity and reducing equipment complexity). Through this novel reactor design, I was able to synthesize paracetamol with a high selectivity of up to 99% and a low process mass intensity (PMI) of <7, up to an order of magnitude less than the traditional batch pressurized hydrogenation process.

I then implemented important reaction engineering strategies learned during the design of the mechanochemical reactor, such as the fed-batch one-pot reaction configuration, into a multi-phase flow reactor. Paracetamol was continuously synthesized with high selectivity and at high concentrations through a multi-stage packed bed reactor with tuned stage-by-stage acetic anhydride addition, resulting in a process with consistent product quality, volumetric productivity, and Green Chemistry metrics. In addition, the safety of the process was improved compared to batch synthesis methods.