Gyorgy Szekely

Sustainability assessment of organic solvent nanofiltration: from fabrication to application

Can Organic Solvent Nanofiltration (OSN) be considered green? Is OSN greener than other downstream processing technologies? These are the two main questions addressed critically in the present review. Further questions dealt with in the review are as follows: What is the carbon footprint associated with the fabrication and disposal of membrane modules? How much solvent has to be processed by OSN before the environmental burden of OSN is less than the environmental burden of alternative technologies? What are the main challenges for improving the sustainability of OSN? How can the concept of Quality by Design (QbD) improve and assist the progress of the OSN field? Does the scale have an effect on the sustainability of membrane processes? The green aspects of OSN membrane fabrication, processes development and scale-up as well as the supporting concept of QbD, and solvent recovery technologies are critically assessed and future research directions are given, in this review.

Sustainable wastewater treatment and recycling in membrane manufacturing

It is widely accepted that membrane technology is a green and sustainable process; however, it is not well known that the membrane fabrication process itself is quite far from green, with more than 50 billion liters of wastewater being generated every year contaminated with toxic solvents such as DMF and NMP. This urgent challenge is often overlooked and recent attempts to improve the sustainability of membrane fabrication have been limited to the replacement of toxic solvents with greener alternatives. Our recent survey from membrane industries indicates that such wastewater contributes to more than 95% of the total waste generated during the membrane fabrication process, and their disposal is considered cumbersome. Hence, recycling wastewater in the membrane industry is a pressing challenge to be resolved to augment the rapidly growing membrane market. In this work, a continuous wastewater treatment process is proposed and the quality of the recycled water was validated through membrane fabrication and performance tests. Seven different classes of adsorbents—graphene, polymers with intrinsic microporosity, imprinted polymers, zeolites, metal organic frameworks, activated carbon, and resins—were evaluated. The isotherm and kinetic behaviors of the best adsorbents have been fully characterized and the adsorbent regenerability without any performance loss has been confirmed for up to 10 wastewater treatment cycles. It has been demonstrated that over 99% of the organic impurities in the wastewater can be successfully removed and the recycled water can be reused without adverse effects on the final membrane performance. The proposed wastewater treatment technique can reduce the process mass intensity (PMI) of membrane fabrication by 99.9% per m2 of the membrane produced. The required energy duty for different regeneration methods and wastewater treatment methods revealed that the adsorption technology is the most effective method, with the lowest energy requirement of about 1200 kJ per m2 of the membrane produced.

Fabrication of hybrid polymer/metal organic framework membranes: mixed matrix membranes versus in situ growth

Hybrid polymer/metal organic framework (MOF) membranes have been prepared using either a mixed matrix membrane (MMM) or in situ growth (ISG) approach and were evaluated for application in organic solvent nanofiltration (OSN). MMMs were produced by dispersing pre-formed particles of the MOF HKUST-1 in polyimide P84 dope solutions. MMMs demonstrated both (i) higher rejections of styrene oligomers and (ii) lower flux decline than the polymeric control membranes. Furthermore, an alternative hybrid membrane fabrication methodology – in situ growth (ISG) of HKUST-1 in integrally skinned asymmetric polymer membrane supports – has been successfully demonstrated. Ultrafiltration support membranes were submerged in HKUST-1 precursor solutions in order to promote the growth of MOF within the porous structure of the polymer membranes. The presence of HKUST-1 in the membranes was proven with X-ray powder diffraction (XRPD). Energy-dispersive X-ray spectroscopy (EDX) was used to reveal the distribution of HKUST-1 throughout the ISG membranes, and was found to be even across the surface and throughout the cross-section. The ISG membranes also had higher solute rejections and lower flux decline than the MMMs.

Increasing the sustainability of membrane processes through cascade approach and solvent recovery ? pharmaceutical purification case study

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 CO2 footprint.

Valorisation of agricultural waste with an adsorption/nanofiltration hybrid process: from materials to sustainable process design

Downstream processing is considered to be the bottleneck in pharmaceutical manufacturing because its development has not kept pace with upstream production. In some cases, the lack of efficient downstream processing capacity can seriously affect both the sustainability and profitability of a pharmaceutical product and even result in its failure. Minimising solvent and raw material consumption, as well as utilising waste, can make a significant difference towards environmentally benign and economically viable chemical production. In this work, the authors present the development and modelling of a continuous adsorption process with in situ solvent recovery for the isolation of oleuropein from olive leaves, an agricultural waste. Waste utilisation in agriculture has gained increasing attention because this economic sector is ranked as the 2nd highest global greenhouse gas emission contributor. Imprinted polymers were developed for the selective scavenging of oleuropein from olive leaf extracts using green solvents. The mild temperature-swing (25–43 °C) process allows the continuous isolation of oleuropein at 1.75 g product per kg of adsorbent per hour with an unprecedented 99.7% purity. In situ solvent recovery was realized with a solvent-resistant nanofiltration membrane allowing 97.5% solvent recycle and 44.5% total carbon footprint reduction, while concentrating both the product stream for crystallisation and the waste stream for disposal.

Role of chirality and macroring in imprinted polymers with enantiodiscriminative power.

Enantioselective discrimination of chiral amines is of great importance as their biological properties often differ. Therefore, here we report the development of synthetic receptors for their enantioselective recognition and pH-sensitive drug release. This paper reports the preparation of three pyridine and two benzene derivatives containing an allyloxy group [(S,S)-5, 6-9] as well as their evaluation as functional monomer anchors for chiral imprinting of amines. The enantiomeric enriching ability and controlled release of the imprinted polymers (IPs) were evaluated using racemic mixture of 1-(1-naphthyl)ethylamine hydrogen perchlorate (1). The effect of the enantiomeric purity of the template on the enantioseparation performance was investigated. Racemic template in combination with enantiomerically pure macrocyclic anchors and vice versa yields IPs with excellent enantiomeric recognition. In vitro drug delivery, enantiomeric enrichment and pH-sensitive release were investigated through kinetic models.

Genotoxic Impurities in Pharmaceutical Manufacturing: Sources, Regulations, and Mitigation

Regulations, and Mitigation Gyorgy Szekely,*,† Miriam C. Amores de Sousa,‡ Marco Gil, Frederico Castelo Ferreira,*,‡ and William Heggie* †School of Chemical Engineering & Analytical Science, The University of Manchester, The Mill, Sackville Street, Manchester M13 9PL, United Kingdom ‡Department of Bioengineering and Institute for Bioengineering and Biosciences (iBB), Instituto Superior Tećnico, Universidade de Lisboa, Avenida Rovisco Pais, 1049-001, Lisbon, Portugal Hovione FarmaCiencia SA, R&D, Sete Casas, 2674-506, Loures, Portugal

Nanofiltration-enabled in situ solvent and reagent recycle for sustainable continuous-flow synthesis

Abstract 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.

Iterative synthesis of monodisperse PEG homostars and linear heterobifunctional PEG

Highly monodisperse, heterobifunctional poly(ethylene glycol) (PEG) was prepared by iterative chain extension of a PEGylated homostar using an octagol (EG8) building block to give MeO–EG24–OH in high purity. The branched structure facilitated purification of intermediates by chromatography, and mono-functionalization of the chain termini. This approach should be extendable to other classes of oligomers.

Robust Covalently Cross-linked Polybenzimidazole/Graphene Oxide Membranes for High-Flux Organic Solvent Nanofiltration

Robust, readily scalable, high-flux graphene oxide (GO) mixed matrix composite membranes were developed for organic solvent nanofiltration. Hydroxylated polybenzimidazole was synthesized by N-benzylation of polybenzimidazole with 4-(chloromethyl)benzyl alcohol, which was confirmed by FTIR and NMR spectroscopy. Flat-sheet composite membranes comprising of polybenzimidazoles and 1 or 2 wt % GO were fabricated via conventional blade coating and phase inversion. Subsequently, GO was covalently anchored to the hydroxyl groups of the polymer using a diisocyanate cross-linking agent. The even distribution of GO in the membranes was mapped by visible-light microscopy. Hydroxylation and incorporation of GO in the polymer matrix increased the permeance up to 45.2 ± 1.6 L m-2 h-1 bar-1 in acetone, nearly 5 times higher than the unmodified benchmark membrane. The enhancement in permeance from the addition of GO did not compromise the solute rejection. The composite membranes were found to be tight in seven organic solvents, having molecular weight cut-offs (MWCO) as low as 140 g mol-1. Permeance increased with increasing solvent polarity, while rejection of a 420 g mol-1 pharmaceutical remained over 93%. The covalent anchoring resulted in robust composite membranes that maintained constant performance over 14 days in a continuous cross-flow configuration.