Design of a Continuous Solvent Recovery System for End-to-End Integrated Continuous Manufacturing of Pharmaceuticals

Abstract

Disadvantages of the traditional batch process have encouraged the pharmaceutical industry to explore continuous manufacturing, including end-to-end approaches, such as integrated continuous manufacturing (ICM). As the pharmaceutical industry is relatively solvent-intensive, solvent recovery is necessary to achieve the goal of sustainable manufacturing. A simple vapor−liquid equilibrium (VLE) setup was designed, and its reliability was assessed, from which the VLE data for a two-solvent system were obtained and, accordingly, the distillation columns were designed. The recovered solvent purities were >99.9 wt % for the first solvent (Solvent 1) and >99.8 wt % for the second solvent (Solvent 2), and the recovery yields were 94.9% and 98.3%, respectively. From the E-factor analysis, approximately 30% less waste was generated in the ICM process compared with a corresponding batch process. After integration of the solvent recovery system, the E-factors for both the batch and ICM processes decreased significantly, from 1.63 to 0.29 and from 0.77 to 0.21, respectively.

Design and Commercialization of an End-to-End Continuous Pharmaceutical Production Process: A Pilot Plant Case Study

“…System I collects, separates, and purifies the filtrate from the rotary filtration unit. 46 System II condenses and collects evaporated solvent from the drum dryer unit. Solvents 1 and 2 are stored in two central feed tanks.…”

“…There are two solvent recovery systems. System I collects, separates, and purifies the filtrate from the rotary filtration unit . System II condenses and collects evaporated solvent from the drum dryer unit.…”

“…The system consists of three thin-film evaporators (TFEs) and two distillation columns. 46 Purified solvents 1 and 2 (99.9 and 99.8% pure for solvents 1 and 2, respectively) are pumped back to their respective feed vessels after being processed. Solvent recovery II is comprised of a plate condenser equipped with a heat exchanger.…”

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

“…Motivated by the benefits shown in Fig. 1 [6][7][8][9][10], the pharmaceutical industry is transitioning to continuous processes, including end-to-end integrated continuous manufacturing (ICM) approaches [1,6,8,[10][11][12][13][14][15][16][17][18]. A first-of-its-kind research demonstration of an end-to-end ICM line was unveiled by MIT in 2011 [13].…”

Multi‐Step Synthesis of Miltefosine: Integration of Flow Chemistry with Continuous Mechanochemistry

“…A few of the most advanced examples include; the flow synthesis of quinolone antibiotic ciprofloxacin, [7] end‐to‐end manufacturing process for aliskiren hemifumarate [8] solid‐supported synthesis of imatinib [9] development of a single dedicated platform for the multiple drug molecules [10] flow synthesis of rolipram using heterogeneous catalyst [11] four‐step continuous flow process for antihistamines from bulk alcohols, [12] seven‐step continuous flow synthesis of linezolid molecule [13] and continuous flow synthesis and purification of ibuprofen [14] . The development and operation of fully automated pilot plant enables efficient and end‐to‐end integrated continuous manufacturing of the pharmaceutical product and small drug molecules, [15–17] including continuous solvent recovery for sustainable manufacturing [18] Recently, Kappe et al. has developed a real‐time analysis platform and fully integrated multistep synthesis of an active pharmaceutical ingredient, mesalazine [19] …”