Implementation of Near-Infrared Spectroscopy for In-Line Monitoring of a Dehydration Reaction in a Tubular Laminar Reactor

Production of active pharmaceutical ingredients (APIs), fine chemicals, food products, and so on has in recent years been focused on implementing process intensification and process optimization tools. Lower costs and higher selectivity as well as better sustainability and competitiveness are the main benefits. A good approach to achieve this is to perform continuous manufacturing together with satisfying process analytical technology (PAT) requirements. The example studied here is the dehydration reaction of 9-allyl-2-chlorothioxanthen-9-ol (“N714-allylcarbinol”) to give a mixture of <i>cis</i>- and <i>trans</i>-9<i>H</i>-thioxanthene, 2-chloro-9-(2-propenylidene)-(9CI) (“N746-butadienes”). A simplified procedure for designing mesoscale tubular reactors is demonstrated together with performance outside of the normal operation windows (higher pressures and temperatures above normal boiling points of solvents). Noninvasive in-line real-time monitoring was established by using Fourier transform near-infrared (FT-NIR) spectroscopy and a suitable partial least squares (PLS) model. High prediction accuracy was achieved and additionally validated by using at-line FT-NIR spectroscopy and off-line HPLC analysis. The presence of impurities was noticed and partly identified in the form of polymers. It is important to note that substrates and products in this work are API intermediates in the production of zuclopenthixol, a product of H. Lundbeck A/S

Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical

The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active pharmaceutical ingredient, and ended with finished tablets. The entire process was run on several occasions, with the data presented herein corresponding to a 240 h run at a nominal throughput of 41 g h[superscript –1] of aliskiren. The first reaction was performed solvent-free in a molten condition at a high temperature, achieving high yields (90%) and avoiding solid handling and a long residence time (due to higher concentrations compared to dilute conditions when run at lower temperatures in a solvent). The resulting stream was worked-up inline using liquid–liquid extraction with membrane-based separators that were scaled-up from microfluidic designs. The second reaction involved a Boc deprotection, using aqueous HCl that was rapidly quenched with aqueous NaOH using an inline pH measurement to control NaOH addition. The reaction maintained high yields (90–95%) under closed-loop control despite process disturbances.Novartis (Firm