Circular Economy Metrics for the Photo-High-p,T Continuous Multistep Synthesis of Vitamin D₃

The vitamin D3 flow-chemical process is a good route for exercising circularity in chemistry; as the complex chemistry of this reaction limits the highest yield to only 25%, a recycling operation becomes mandatory. In this context, this research applies, for the first time, a circular economy assessment to a flow chemistry process, including reaction and separation. This is undertaken on the example of the photo-flow-chemical synthesis of vitamin D3, previously developed by our group. In the research reported here, we develop a separation process to recycle the unreacted starting material 7-dehydrocholesterol after the photo-flow irradiation. We use acetonitrile for separation, instead of methanol, in the industrial process. In just one run, 90% of vitamin is extracted using dry acetonitrile as a separation solvent at 30 °C. A cumulative extraction efficiency of >99% is achieved after a second extraction step. The acetonitrile separation process connects directly to the subsequent vitamin crystallization using the same solvent. This eliminates the need to evaporate methanol in the industrial process; rather, the product is obtained just by cooling down. The Material Circular Indicator has been used as a central metric, and we needed to redefine this circularity metrics proposed by the Ellen MacArthur Foundation's CE100 program to the world of flow chemistry. Rather than being able to take the parameter of lifetime and utility used in the original C100 definition, the frequency and dose of usage of medicinal products are taken here, both of which are connected to chemical productivity and waste generation. To explore the application of this adapted methodology to other pharmaceutical production processes, the results for the proposed vitamin D3 flow-chemical process are compared with five processes for producing vitamins, painkillers, and an antibiotic. It is shown that the vitamin D3 flow chemistry process with the new separation achieves a Material Circular Indicator of 0.94, a recycled fraction mass above 0.95, and an energy demand reduction by a factor of 2.