Continuous chemical production processes

John A. Glaser
2015 Clean Technologies and Environmental Policy  
The American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable recently reported its efforts to determine the value of continuous processing, in contrast to step-wise protocols, as a key area for green engineering. A group of 8 pharmaceutical firms participated in this study. The initial hurdle was to assemble information and agree on a procedure to assess the "business case for continuous manufacturing." The "business case" concept is expected to provide an estimate of the
more » ... ofitability of an investment opportunity through scenario analysis. Examples of continuous manufacturing were assembled from multiple member companies and ranged across the features of materials/waste savings, smaller footprint/ smaller plants, company goals (e.g., CO 2 emission control), investment for new processes/plants, and green reputation. A format for information was established for scoping the business case. Major benefits of this analysis were shown to be concentrated in investment saving, yield/quality improvement, safety, and speed of operation. Benefits to business analysis were recognized not as an end but a beginning of process development by the participants. Equipment and infrastructure issues important to continuous manufacturing could be risk-eliciting issues. An example of these directions to use continuous manufacturing can be found in the recently reported multistep synthesis and workup sequence for the small molecule, aliskiren hemifumarate (a direct renin inhibitor used as an antihypertensive drug). Starting with advanced intermediates, the synthesis plant completed the conversion through two synthetic steps to the final active pharmaceutical ingredient. The 1st step involved solvent-free, molten conditions at high temperature leading to 90 % yield. Solid handling and long residence times were avoided. The product stream was treated with inline liquid-liquid extraction with membrane-based separators scaled for microfluidic implementation providing continuous crystallization, filtration, and washing. The 2nd step used aqueous acid conditions to deprotect the substrate. Base neutralization completed the conversion chemistry in yields of 90-95 %. Multiple runs were conducted corresponding to a nominal throughput of 41 g/h over 240 h of operation. The authors emphasize that the plant demonstration revealed the necessity of undertaking a reevaluation of the entire pharmaceutical process when undertaking conversion to a continuous flow system since the steps for the flow process may be different than an established batch process.
doi:10.1007/s10098-015-0903-3 fatcat:7zvxfbcjrjfyfow2les4uo74bi