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Membrane processes suffer limitations such as low product yield and high solvent consumption, hindering their widespread application in the pharmaceutical and fine chemicals industries. In the present work, the authors propose an efficient purification methodology employing a two-stage cascade configuration coupled to an adsorptive solvent recovery unit, which addresses the two limitations. The process has been validated on purification of active pharmaceutical ingredient (API) from genotoxic impurity (GTI) using organic solvent nanofiltration (OSN). The model system selected for study comprises roxithromycin macrolide antibiotic (Roxi) with 4-dimethylaminopyridine (DMAP) and ethyl tosylate (EtTS) as API and GTIs, respectively. By implementing a two-stage cascade configuration for membrane diafiltration, the process yield was increased from 58% to 95% while maintaining less than 5 ppm GTI in the final solution. Through this yield enhancement, the membrane process has been "revamped" from an unfeasible process to a highly competitive unit operation when compared to other traditional processes. The advantage of size exclusion membranes over other separation techniques has been illustrated by the simultaneous removal of two GTIs from different chemical classes. In addition, a solvent recovery step has been assessed using charcoal as a non-selective adsorbent, and it has been shown that pure solvent can be recovered from the permeate. Considering the costs of solvent, charcoal, and waste disposal, it was concluded that 70% solvent recovery is the cost-optimum point. Conventional single-stage diafiltration (SSD) and two-stage diafiltration (TSD) configurations were compared in terms of green metrics such as cost, mass and solvent intensity, and energy consumption. It was calculated that implementation of TSD, depending on the batch scale, can achieve up to 92% cost saving while reducing the mass and solvent intensity up to 73%. In addition, the advantage of adsorptive solvent recovery has been assessed revealing up to 96% energy reduction compared to distillation and a 70% reduction of CO 2 footprint.

Reducing solvent consumption in the chemical industries is increasingly becoming a topic of interest. The field of organic solvent nanofiltration (OSN) has markedly evolved in the past decade, and effective membranes are now available that can withstand aggressive solvents while completely rejecting small solutes at the lower end of the nanofiltration range (100–2000 g·mol–1). With such membranes in hand and the advantages of membrane modularity, it is now possible to design innovative configurations to drastically reduce solvent consumption and enhance sustainability of downstream processes. Notably, a membrane-based solvent recovery configuration reported in our group has opened a new market for OSN membranes. In this work, the current state-of-the-art OSN membranes are screened, and a possible operation window for solvent recovery is identified. In tandem, to tackle the high solvent consumption challenge of membrane-based separation, we improved the solvent recovery configuration by combining both solute separation and solvent recovery in situ. The resultant system effectively performs the desired separation without any addition of extra solvent, thereby reducing solvent consumption to nearly zero. A model system comprising roxithromycin pharmaceutical and triphenylmethanol impurity is employed to illustrate that the proposed configuration allows constant volume diafiltration to be performed without any addition of fresh solvent. Parameters affecting the separation have been identified and validated experimentally or via modeling, and theoretical limitations are critically analyzed. The operability and carbon footprint have been compared with conventional solvent recovery units (e.g., distillation and adsorption). The present work reinforces that OSN is a leading separation technology in the process intensification movement of the fine chemicals sector.

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Organic Solvent Nanofiltration (OSN) technology is a membrane process for molecular separation in harsh organic media. However, despite having well-documented potential applications, development hurdles have hindered the widespread uptake of OSN technology. One of the most promising areas of application is as an iterative synthesis platform, for instance for oligonucleotides or peptides, where a thorough purification step is required after each synthesis cycle, preferably in the same working solvent. In this work, we report a process development study for liquid-phase oligonucleotide synthesis (LPOS) using OSN technology. Oligonucleotide (oligo) based drugs are being advanced as a new generation of therapeutics functioning at the protein expression level. Currently, over one hundred oligo based drugs are undergoing clinical trials, suggesting that it will soon be necessary to produce oligos at a scale of metric tons per year. However, there are as yet no synthesis platforms that can manufacture oligos at >10 kg batch-scale. With the process developed here, we have successfully carried out 8 iterative cycles of chain extension and synthesized 5-mer and 9-mer 2'-O-methyl oligoribonucleotide phosphorothioates, all in liquid phase media. This paper discusses the key challenges, both anticipated and unexpected, faced during development of this process, and suggests solutions to reduce the development period. An economic analysis has been carried out, highlighting the potential competitiveness of the LPOS-OSN process, and the necessity for a solvent recovery unit.

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