Semi-synthetic antibiotics such as cephalexin are commonly used to treat certain infections. Chemical route for their production faces drawbacks such as low operating temperatures and organic solvents. Enzymatic synthesis offers a green alternative and is the prevalent method of manufacturing. Combining the synthesis with in situ crystallization leads to improvement in the yield and selectivity by suppressing the product hydrolysis. Another way to improve this process efficiency and sustainability is by exploiting the benefits of continuous manufacturing including the ability to process higher concentrations and shorter downtime. Operating this process continuously can enhance process attributes such as productivity and space-time yield.<br/><br/>Here, we will describe a model-based approach to the design and development of a pilot plant for producing &gt; 1 g/h of cephalexin monohydrate crystals. With combined enzymatic reaction and crystallization, simulations point to a trade-off between process parameters such as pH and residence time, leading to a non-trivial optimization to obtain optimum conversion and productivity. Using simulations to guide the operation, we have illustrated the continuous production of cephalexin monohydrate crystals at &gt; 99% purity, with a productivity of 1-4 g/h for over 20 h of operation. Focusing on the quality attributes of the product, we will discuss the possibility of product contamination with a byproduct or other species in the system. Unlike common light scattering and attenuated total reflectance sensors, Raman and IR, which suffer from weak and overlapping signals for the species present, direct observation of the slurry by an in situ camera provides a robust method for detecting product contaminations.

Model-based process development for continuous manufacturing of beta-lactam antibiotics by enzymatic reactive crystallization: A pilot plant study

ACS Fall 2021

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