A continuous oleuropein isolation process using imprinted materials coupled with nanofiltration-based solvent recovery utilising olive leaf waste.

In this work we introduce a sustainable membrane-based synthesis–separation platform for enantioselective organocatalysis. An azido derivatized cinchona-squaramide bifunctional catalyst was synthesized and subsequently grafted to the surface of a polybenzimidazole-based nanofiltration membrane. The favorable effect of the covalent graftingdue to the change in geometry and increased secondary interactionson the catalytic activity due to conformational changes was confirmed by quantum chemical calculations. Asymmetric Michael and aza-Michael reactions of 1,3-dicarbonyl and indole, pyrazole, and triazole derivatives to β-nitrostyrene were performed with as high as 99% enantiomeric excess. This report on the enantioselective aza-Michael reaction of pyrazoles and triazoles opens new frontiers in the application of squaramide-based cinchona catalysts. A catalytic membrane cascade reactor was developed for an integrated synthesis–purification process allowing at least 98% product and substrate recovery, and quantitative in situ solvent recycling. The sustainability of the synthetic methodology was assessed through E-factor and carbon footprint.

Solvent usage in the pharmaceutical sector accounts for as much as 90 % of the overall mass during manufacturing processes. Consequently, solvent consumption poses significant costs and environmental burdens. Continuous processing, in particular continuous‐flow reactors, have great potential for the sustainable production of pharmaceuticals but subsequent downstream processing remains challenging. Separation processes for concentrating and purifying chemicals can account for as much as 80 % of the total manufacturing costs. In this work, a nanofiltration unit was coupled to a continuous‐flow rector for in situ solvent and reagent recycling. The nanofiltration unit is straightforward to implement and simple to control during continuous operation. The hybrid process operated continuously over six weeks, recycling about 90 % of the solvent and reagent. Consequently, the E‐factor and the carbon footprint were reduced by 91 % and 19 %, respectively. Moreover, the nanofiltration unit led to a solution of the product eleven times more concentrated than the reaction mixture and increased the purity from 52.4 % to 91.5 %. The boundaries for process conditions were investigated to facilitate implementation of the methodology by the pharmaceutical sector.

For separation of a two-component mixture, a three-stage organic solvent nanofiltration (OSN) process is presented which comprises of a two-stage membrane cascade for separation with a third membrane stage added for integrated solvent recovery, i.e. solvent recycling. The two-stage cascade allows for increased separation selectivity whilst the integrated solvent recovery stage mitigates the otherwise large solvent consumption of the purification. This work explores the effect of washing the solvent recovery unit at intervals in order to attain high product purities with imperfect solvent recovery membranes possessing less than 100 % rejection of the impurity. This operation attains a purity of 98.7 % through semi-continuous operation with two washes of the solvent recovery stage, even when imperfect membranes are used in a closed-loop set-up. This contrasts favourably with the 83.0 % maximum purity achievable in a similar set-up with a single continuous run. The process achieves slightly lower (-0.7 %) yield of around 98.2 % compared to a continuously operated process without solvent recovery but consumes approx. 85 % less solvent (theoretical analysis suggests up to 96 % reduction is possible). 9 different membranes, both commercial (GMT, Novamem, SolSep) and in-house fabricated, are screened and tested on a separation challenge associated with the synthesis of macrocycles -amongst the membrane materials are polyimide (PI), polybenzimidazole (PBI) and, polyetheretherketone (PEEK).3

It is well-known that solvent treatment and preconditioning play an important role in rejection and flux performance of membranes due to solvent-induced swelling and solvent adsorption. Investigations into the effect of solvent treatment are scarce and application specific, and were limited to a few solvents only. This study reveals the trend in solvent treatment based on solvent polarity in a systematic investigation with the aim to harness such effect for intensification of membrane processes. Nine solvents with polarity indices ranging from 0.1 to 5.8 (hexane to acetonitrile) were used as treatment and process solvents on commercial Borsig GMT-oNF-2, Evonik Duramem 300, and emerging tailor-made polybenzimidazole membranes. TGA-GCMS, HS-GC-FID, and NMR techniques were employed to better understand the effect of solvent treatment on the polymer matrix of membranes. In this work, apart from the solvent treatment's direct effect on the membrane performance, a subsequent indirect effect on the ultimate separation process was observed. Consequently, a pharmaceutical case study employing chlorhexidine disinfectant and antiseptic was used to demonstrate the effect of solvent treatment on the nanofiltration-based purification. It is shown that treatment of polybenzimidazole membranes with acetone resulted in a 25% increase in product recovery at 99% impurity removal. The cost of the process intensification is negligible in terms of solvent consumption, mass intensity, and processing time.

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