(357ay) Continuous Enzymatic Reactive Crystallization of Beta-lactam Antibiotics

Overview: My PhD research revolves around the development of a pilot-scale pharmaceutical manufacturing process for improved process outcomes (e.g., productivity, green chemistry, product quality, etc.) to produce amoxicillin and cephalexin, two drugs consumed on a large scale worldwide. The process is at the intersection of enzymology, crystallization, continuous processing, and many other subjects.

Research Interests: After I receive my PhD, I wish to apply my technical skills to tackle problems related to process development in the pharmaceutical industry.

Expected Graduation: May 2023

PhD Research: Crystallization is often used as a method of product isolation towards the end of a pharmaceutical manufacturing process; however, there are some circumstances where crystallization may be exploited with other phenomena present in the process to improve process outcomes. In my work, we combine crystallization of an active pharmaceutical ingredient (API) with the enzymatic synthesis of the API in the same vessel to generate improvements in yield, selectivity, and productivity, as well as intensify a traditional two-vessel process configuration on a pilot scale. We also achieve this operating the process in continuous fashion, which leads to lower waste production, lower energy consumption, higher productivity, and smaller process footprint in comparison to a batch process.

The final process configuration consisted of two mixed-suspension mixed product-removal (MSMPR) vessels in series, with an external wet mill loop and enzyme separator (discussed below) associated with the first vessel. The first vessel contained enzyme and product crystals and the second was only a product slurry and was used to allow the product, amoxicillin, to deplete its supersaturation in solution and be driven into the solid phase. Downstream, post product isolation, we have incorporated recovery steps to isolate and recycle unreacted substrate. These can be conducted as the two substrates are sparingly soluble at different pH values. This recycle allows for much improved process outcomes, specifically higher conversions/yields and lower waste generation.

The use of an enzymatic catalyst in a continuous process was a challenge as we desired to recycle or retain it to reduce catalyst waste. This resulted in the presence of two solids within the reactor, one which was to be recycled/retained and the other to be isolated as product. We achieved this by using a size-based separation and a stainless-steel mesh sieve in conjunction with an external wet mill loop to decrease the size of product crystals. The mesh sieve was designed so that it was small enough to retain the enzyme support but large enough to allow milled product crystals to pass through. Studies were also conducted on the affect of enzyme support size on enzyme performance and the mesh size on product isolation efficiency.

Additionally, we have developed a model incorporating the enzyme kinetics and crystallization kinetics to study the process dynamics and identify improved process conditions. We are currently in the process of assessing these process conditions for improved outcomes.

Overall, we believe that the lessons learned from the developments in our pharmaceutical process may be applied to industrial production processes for the improvement of beta-lactam manufacturing or similar systems.