The American Chemical Society (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable conducted a study to elucidate the value of continuous processing, which had been defined as a key research area for green engineering. In the course of defining the business case for continuous processing, individual cases were collected and evaluated to determine specific drivers to implement continuous processing and to find key success factors. The magnitude and timing of effects and the relation to the principles of green chemistry were investigated.

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This paper describes the development of a continuous, high yielding, and scalable enolization, oxidation, and quench process for the hydroxylation of the azapirone psychtropic agent buspirone to afford 6-hydroxybuspirone (6-hydroxy-8-[4-(4-pyrimidin-2-yl-piperazin-1-yl)-butyl]-8-aza-spiro[4.5]decane-7,9-dione). Two feed streams were reacted continuously using an in-line static mixer followed by oxidation in a continuous flow trickle-bed reactor. The laboratory reactor operation was demonstrated at steady state for over 40 h. The process was scaled up using both volumetric (enolization) and numbering-up (oxidation) scale-up strategies. A pilot-plant reactor was developed and successfully implemented in a three-batch campaign (47 kg input per batch).

Biotransformation of mutilin and pleuromutilin by microbial cultures was investigated to provide a source of 8-hydroxymutilin or 8-hydroxypleuromutilin. LC/MS analysis of culture broths showed that several strains gave M+16 products from mutilin and one culture gave an M+16 product from pleuromutilin, suggesting addition of oxygen. Biotransformation products were extracted from culture broths with ethyl acetate, dried, and purified by chromatography on silica gel. Streptomyces griseus strains SC 1754 and SC 13971 (ATCC 13273) converted mutilin to (8S)-, (7S)-, and (2S)-hydroxymutilin. Cunninghamella echinulata SC 16162 (NRRL 3655) gave (2S)-hydroxymutilin or (2R)-hydroxypleuromutilin from biotransformation of mutilin or pleuromutilin, respectively. The biotransformation of mutilin by S. griseus strain SC 1754 was scaled up in 15-, 60-, and 100-L fermentations to produce a total of 49 g of (8S)-hydroxymutilin (BMS-303786), 17 g of (7S)-hydroxymutilin (BMS-303789) and 13 g of (2S)-hydroxymutilin (BMS-303782) from 162 g of mutilin.

A thermal runaway potential was identified for the conversion of a tertiary alcohol to a hydroxypyrrolotriazine intermediate in the synthesis of brivanib alaninate. A continuous process was developed to mitigate the potential thermal runaway and allow for safer scale-up. This paper describes the hazard analysis, process development, reactor development, reaction engineering model development, and scale-up of the continuous process. The process includes three separate and stable feed streams that are mixed in distinct order using in-line static mixers. Heat exchangers are arranged and connected to facilitate a "plug flow" reactor scheme allowing sufficient residence time for reaction completion. The process has been scaled-up to the pilot plant and to manufacturing.