Imperial College London



Iterative peptide synthesis in membrane cascades: untangling operational decisionsWenqian Chen, Mahdi Sharifzadeh, Nilay Shah, Andrew G. LivingstonDepartment of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United KingdomAbstractMembrane enhanced peptide synthesis (MEPS) combines liquid-phase synthesis with membrane filtration, avoiding time-consuming separation steps such as precipitation and drying. Although performing MEPS in a multi-stage cascade is advantageous over a single-stage membrane system in terms of overall yield, the advantage is offset by the complex combination of operational variables such as the diavolume and recycle ratio in each diafiltration process. The current work aims to tackle this problem using dynamic process simulation. The results suggest that the two-stage membrane cascade improves the overall yield of MEPS significantly from 72.2% to 95.3%, although more washing is required to remove impurities as the second-stage membrane retains impurities together with the anchored peptide. This clearly indicates a link between process configuration and operation. While the case study is based on the comparison of single-stage and two-stage MEPS, the results are transferable to other biopolymers such as oligonucleotides and to more complex system configurations (e.g. three-stage membrane cascade).KeywordsMembrane enhanced peptide synthesis, biopolymer, membrane cascade, dynamic process model.NomenclatureAmembrane area (m2)Bmembrane permeance (m ? s-1 ? bar-1)cconcentration (mol ? m-3)Fvolumetric flow rate (m3 ? s-1)kreaction constant (unit is case-dependent)nmolar quantity (mol)Pgauge pressure (barg)?Ptransmembrane pressure difference (bar)Rrejection (dimensionless)ttime (s)Vvolume (m-3)Vdiadiavolume (dimensionless)AbbreviationAAamino acidCSTRcontinuous stirred-tank reactorMEPSmembrane enhanced peptide synthesisPFRplug flow reactorSPPSsolid phase peptide synthesisSubscript1stage 12stage 2 iinteger (starting from 1)jinteger (starting from 1)kinteger (starting from 1)Ninteger (user defined)Panchored peptideSerror sequenceIntroductionBiopolymers such as peptides and oligonucleotides have specific biological functions that originate from their unique monomer sequences. The chemical synthesis of these biopolymers is iterative, involving stepwise addition of monomers to a growing polymer chain, followed by post-reaction purification ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/0471220523", "ISBN" : "9780471220527", "abstract" : "This chapter opens with an historical perspective of step-growth polymers. We then present a few general but important parameters of step-growth polymerization. References are provided throughout the chapter for further information.", "author" : [ { "dropping-particle" : "", "family" : "Rogers", "given" : "Martin E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Long", "given" : "Timothy E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Synthetic Methods in Step-Growth Polymers", "id" : "ITEM-1", "issue" : "October 2015", "issued" : { "date-parts" : [ [ "2003" ] ] }, "number-of-pages" : "1-16", "title" : "Synthetic Methods in Step-Growth Polymers", "type" : "book" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1126/science.1238149", "ISBN" : "0002-7863", "ISSN" : "0036-8075", "PMID" : "14611205", "abstract" : "On the basis of the distance-dependence of DNA-templated reductive amination reactions and of recent findings of D. Lynn and co-workers, we developed DNA-templated polymerizations of synthetic peptide nucleic acid (PNA) aldehydes. The coupling reactions proceed in a highly efficient and sequence-specific manner, even in the presence of mixtures of PNA aldehydes of different sequence. Synthetic peptide nucleic acid polymers containing as many as 40 PNA units (representing 10 consecutive coupling reactions) were formed efficiently. The ease of preparing PNAs containing tailor-made functional groups together with these findings raises the possibility of evolving synthetic sequence-defined polymers by iterated cycles of translation, selection, PCR amplification, and diversification previously available only to biological macromolecules.", "author" : [ { "dropping-particle" : "", "family" : "Lutz", "given" : "J.-F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ouchi", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "David R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sawamoto", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Science", "id" : "ITEM-2", "issue" : "6146", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "1238149-1238149", "title" : "Sequence-Controlled Polymers", "type" : "article-journal", "volume" : "341" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Lutz et al., 2013; Rogers and Long, 2003)", "plainTextFormattedCitation" : "(Lutz et al., 2013; Rogers and Long, 2003)", "previouslyFormattedCitation" : "(Lutz, Ouchi, Liu, & Sawamoto, 2013; Rogers & Long, 2003)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Lutz et al., 2013; Rogers and Long, 2003). There are two main challenges for the precise control of polymer sequence. Firstly, the chemistry should ensure each reaction proceeds to completion without side reactions. In the context of peptide, this goal can be achieved with the Fmoc chemistry from conventional solid phase peptide synthesis (SPPS) for most peptides ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISBN" : "0824703596", "abstract" : "This volume provides the information needed to synthesize peptides by solid-phase synthesis (SPS) - employing polymeric support (resins), anchoring linkages (handles), coupling reagents (activators), and protection schemes. It presents strategies for creating a wide variety of compounds for drug discovery and analyzes peptides, DNA, carbohydrates, conjugates of biomolecules, and small molecules.", "author" : [ { "dropping-particle" : "", "family" : "Albericio", "given" : "Fernando", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2000" ] ] }, "publisher" : "CRC Press", "title" : "Solid-phase synthesis: a practical guide", "type" : "book" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1038/nprot.2007.454", "ISBN" : "1750-2799 (Electronic)\\r1750-2799 (Linking)", "ISSN" : "1754-2189", "PMID" : "18079725", "abstract" : "This protocol for solid-phase peptide synthesis (SPPS) is based on the widely used Fmoc/tBu strategy, activation of the carboxyl groups by aminium-derived coupling reagents and use of PEG-modified polystyrene resins. A standard protocol is described, which was successfully applied in our lab for the synthesis of the corticotropin-releasing factor (CRF), >400 CRF analogs and a countless number of other peptides. The 41-mer peptide CRF is obtained within approximately 80 working hours. To achieve the so-called difficult sequences, special techniques have to be applied in order to reduce aggregation of the growing peptide chain, which is the main cause of failure for peptide chemosynthesis. Exemplary application of depsipeptide and pseudoproline units is shown for synthesizing an extremely difficult sequence, the Asn(15) analog of the WW domain FBP28, which is impossible to obtain using the standard protocol.", "author" : [ { "dropping-particle" : "", "family" : "Coin", "given" : "Irene", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beyermann", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bienert", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Protocols", "id" : "ITEM-2", "issue" : "12", "issued" : { "date-parts" : [ [ "2007" ] ] }, "page" : "3247-3256", "title" : "Solid-phase peptide synthesis: from standard procedures to the synthesis of difficult sequences.", "type" : "article-journal", "volume" : "2" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1021/cr100048w", "ISBN" : "0009266515206890", "ISSN" : "00092665", "PMID" : "21866984", "abstract" : "In recent years, peptide-coupling reactions have significantly advanced in parallel with the development of new peptide- coupling reagents, which have been covered in a number of valuable reviews.111\\nThe procedures used to combine two amino acid residues to form a peptide are referred to as coupling methods. Coupling involves attack by the amino group of one residue at the carbonyl carbon atom of the carboxy-containing component that has been activated by the introduction of an electron-withdrawing group, X (Scheme 1).\\nThe activated form may be a shelf-stable reagent, such as some active esters; a compound of intermediate stability, such as an acyl halide, azide, or a mixed or symmetrical anhydride, which may or may not be isolated; or a transient intermediate, indicated in Scheme 1 by brackets, which is neither isolable nor detectable. The latter im- mediately undergoes aminolysis to give the peptide, or it may react with a second nucleophile that originates from the reactants or that was added for the purpose to give the more stable active ester or symmetrical anhydride, whose aminolysis then generates the peptide.", "author" : [ { "dropping-particle" : "", "family" : "El-Faham", "given" : "Ayman", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Albericio", "given" : "Fernando", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Chemical Reviews", "id" : "ITEM-3", "issue" : "11", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "6557-6602", "title" : "Peptide coupling reagents, more than a letter soup", "type" : "article", "volume" : "111" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1002/psc.2836", "ISSN" : "10991387", "PMID" : "26785684", "abstract" : "Today, Fmoc SPPS is the method of choice for peptide synthesis. Very-high-quality Fmoc building blocks are available at low cost because of the economies of scale arising from current multiton production of therapeutic peptides by Fmoc SPPS. Many modified derivatives are commercially available as Fmoc building blocks, making synthetic access to a broad range of peptide derivatives straightforward. The number of synthetic peptides entering clinical trials has grown continuously over the last decade, and recent advances in the Fmoc SPPS technology are a response to the growing demand from medicinal chemistry and pharmacology. Improvements are being continually reported for peptide quality, synthesis time and novel synthetic targets. Topical peptide research has contributed to a continuous improvement and expansion of Fmoc SPPS applications. Copyright \u00a9 2015 European Peptide Society and John Wiley & Sons, Ltd.", "author" : [ { "dropping-particle" : "", "family" : "Behrendt", "given" : "Raymond", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "White", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Offer", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Peptide Science", "id" : "ITEM-4", "issue" : "1", "issued" : { "date-parts" : [ [ "2016" ] ] }, "page" : "4-27", "title" : "Advances in Fmoc solid-phase peptide synthesis", "type" : "article", "volume" : "22" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Albericio, 2000; Behrendt et al., 2016; Coin et al., 2007; El-Faham and Albericio, 2011)", "plainTextFormattedCitation" : "(Albericio, 2000; Behrendt et al., 2016; Coin et al., 2007; El-Faham and Albericio, 2011)", "previouslyFormattedCitation" : "(Albericio, 2000; Behrendt, White, & Offer, 2016; Coin, Beyermann, & Bienert, 2007; El-Faham & Albericio, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Albericio, 2000; Behrendt et al., 2016; Coin et al., 2007; El-Faham and Albericio, 2011). Secondly, the purification step should ensure the complete removal of excess monomers as well as excess reagents and by-products in order to avoid side reactions in the subsequent steps due to carry-over ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Chen", "given" : "Wenqian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharifzadeh", "given" : "Mahdi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shah", "given" : "Nilay", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew Guy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Industrial & Engineering Chemistry Research", "id" : "ITEM-1", "issue" : "23", "issued" : { "date-parts" : [ [ "2017" ] ] }, "page" : "6796-6804", "publisher" : "ACS Publications", "title" : "The Implication of Side-reactions in Iterative Biopolymer Synthesis: The Case of Membrane Enhanced Peptide Synthesis (MEPS)", "type" : "article-journal", "volume" : "56" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Chen et al., 2017)", "plainTextFormattedCitation" : "(Chen et al., 2017)", "previouslyFormattedCitation" : "(Chen, Sharifzadeh, Shah, & Livingston, 2017)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Chen et al., 2017). Membrane enhanced peptide synthesis (MEPS) addresses this purification challenge with the membrane process, which has been used for various applications ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/cssc.201701120", "ISSN" : "1864564X", "abstract" : "The 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 burden. Continuous processing, in particular continuous-flow reactors have a great potential in the sustainable production of pharmaceuticals but subsequent downstream processing remains challenging. Separation processes for the concentration and purification of 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 recycle. The nanofiltration unit is straightforward to implement and control in a continuous operation. The hybrid process was continuously operated over 6 weeks recycling about 90% of the solvent and the reagent. Consequently, the E-factor and the carbon footprint were reduced by 91% and 19%, respectively. Moreover, the nanofiltration unit concentrated the product 11 times and simultaneously 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.", "author" : [ { "dropping-particle" : "", "family" : "Fodi", "given" : "Tamas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Didaskalou", "given" : "Christos", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kupai", "given" : "Jozsef", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Balogh", "given" : "Gyorgy T.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huszthy", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Szekely", "given" : "Gyorgy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "ChemSusChem", "id" : "ITEM-1", "issue" : "17", "issued" : { "date-parts" : [ [ "2017" ] ] }, "page" : "3435-3444", "title" : "Nanofiltration-Enabled In Situ Solvent and Reagent Recycle for Sustainable Continuous-Flow Synthesis", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.memsci.2017.02.008", "ISSN" : "18733123", "abstract" : "Membranes that enable the recovery of organic compounds from dilute aqueous solution are desired for applications such as biobutanol production. The polymer of intrinsic microporosity PIM-1 shows promise for organophilic separations and here it is incorporated into thin film composite (TFC) membranes in order to increase the flux of permeate. Asymmetric polyvinylidene fluoride (PVDF) supports were prepared with pore sizes at the surface in the size range 25\u201355\u00a0nm and fractional surface porosities in the range 0.38\u20130.69, as determined by atomic force microscopy (AFM). The addition of phosphoric acid to the PVDF dope solution helped to control the pore size and porosity. Supports were coated with PIM-1 to form TFC membranes with active layer thicknesses in the range 1.0\u20132.9\u00a0\u00b5m. Membranes were tested for the pervaporation of a 1-butanol/water mixture (5\u00a0wt%). At 65\u00a0\u00b0C, values of total flux up to 9\u00a0kg\u00a0m\u22122\u00a0h\u22121were obtained, with separation factors up to 18.5 and values of pervaporation separation index (PSI) up to 112\u00a0kg\u00a0m\u22122\u00a0h\u22121.", "author" : [ { "dropping-particle" : "", "family" : "Gao", "given" : "Lei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alberto", "given" : "Monica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gorgojo", "given" : "Patricia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Szekely", "given" : "Gyorgy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Budd", "given" : "Peter M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Membrane Science", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2017" ] ] }, "page" : "207-214", "title" : "High-flux PIM-1/PVDF thin film composite membranes for 1-butanol/water pervaporation", "type" : "article-journal", "volume" : "529" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "ISSN" : "0976-3961", "abstract" : "In the last decades the rapid advancement of solvent-resistant membranes and catalysis led to the development of more efficient and sustainable materials and processes. The present article critically assesses membrane-assisted catalysis in organic media, which is a multidisciplinary field combining materials science, reaction engineering, organic chemistry, and membrane science and technology. The membranes act either as catalysts directly accelerating the rate of the reaction or as selective barriers for separating homogeneous catalysts from the reaction mixture. The discussions are grouped based on the catalyst type, and introductory tables given for each group allow direct comparison of the literature with regards to reaction type, solvent(s) employed, type of membrane, catalyst rejection, highest conversion and volumetric productivity. Major achievements, limitations and inconsistencies in the field are presented along with future research directions and requirements.", "author" : [ { "dropping-particle" : "", "family" : "Cseri", "given" : "Levente", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fodi", "given" : "Tamas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kupai", "given" : "Jozsef", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Balogh", "given" : "Gyorgy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Garforth", "given" : "Arthur", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Szekely", "given" : "Gyorgy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Advanced Materials Letters", "id" : "ITEM-3", "issued" : { "date-parts" : [ [ "2016" ] ] }, "title" : "Membrane-assisted catalysis in organic media", "type" : "article-journal" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1016/j.cherd.2016.02.005", "ISSN" : "02638762", "abstract" : "Three commercial spiral-wound membrane modules of different sizes, from 1.8\u2033 \u00d7 12\u2033 to 4.0\u2033 \u00d7 40\u2033, are used to concentrate a solution of sucrose octaacetate in ethyl acetate under different operating conditions. A mathematical model to describe the batch concentration process is developed, based on a combination of the classical solution diffusion membrane transport model and the film theory, to account for the mass transfer effects. The model was implemented using the \"OSN Designer\" software tool. The membrane transport model parameters as well as all parameters in the pressure drop and mass transfer correlations for the spiral-wound modules were obtained from regression on a limited number of experimental data at steady state conditions. Excellent agreement was found between the experimental and multi-scale modelling performance data under various operating conditions. The results illustrate that the performance of a large scale batch concentration process with spiral-wound membrane modules can be predicted based on laboratory crossflow flat sheet test data when the fluid dynamics and mass transfer characteristics in the module, and the necessary channel geometry are known. In addition, the effects of concentration polarisation, pressure drop through feed and permeate channels, and thermodynamic non-ideality of the solution at large scale batch concentration are also investigated.", "author" : [ { "dropping-particle" : "", "family" : "Shi", "given" : "Binchu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peshev", "given" : "Dimitar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marchetti", "given" : "Patrizia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Shengfu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Chemical Engineering Research and Design", "id" : "ITEM-4", "issued" : { "date-parts" : [ [ "2016" ] ] }, "page" : "385-396", "title" : "Multi-scale modelling of OSN batch concentration with spiral-wound membrane modules using OSN Designer", "type" : "article-journal", "volume" : "109" }, "uris" : [ "" ] }, { "id" : "ITEM-5", "itemData" : { "DOI" : "10.1016/j.desal.2016.08.025", "ISBN" : "0011-9164", "ISSN" : "00119164", "abstract" : "Proper industrial-scale module design for seawater desalination by means of direct contact membrane distillation (DCMD) can be aided by module simulation. Accordingly, two open-source simulators (of flat sheet membranes and hollow fibre membranes) were developed on the Matlab GUI platform to supplement DCMD module scale-up. A coupled \u201ctanks-in-series\u201d and \u201cblack box\u201d mathematical approach was developed not only to yield accurate simulation, but also to produce profiles of all the key parameters versus membrane length. Using laboratory-scale experimental results in one configuration as simulation inputs, the developed simulators were able to predict large-scale DCMD module performance in both co-current and counter-current configurations. These predictions exhibited good accuracy in both laboratory-scale and large-scale. Design considerations informing appropriate module scale-up for the DCMD process were demonstrated using the simulators. Key design criteria for industrial-scale module design were identified and evaluated. The results presented in this study offer general and practical guidance for proper module scale-up to deliver optimal pure water productivity for industrial-scale seawater desalination using the DCMD process. More importantly, the developed simulators are open-source, available for all researchers to develop specific DCMD module scale-up strategies for their own membranes.", "author" : [ { "dropping-particle" : "", "family" : "Dong", "given" : "Guangxi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "Jeong F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "Ji Hoon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Drioli", "given" : "Enrico", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "Young Moo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Desalination", "id" : "ITEM-5", "issued" : { "date-parts" : [ [ "2017" ] ] }, "page" : "72-87", "title" : "Open-source predictive simulators for scale-up of direct contact membrane distillation modules for seawater desalination", "type" : "article-journal", "volume" : "402" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Cseri et al., 2016; Dong et al., 2017; Fodi et al., 2017; Gao et al., 2017; Shi et al., 2016)", "plainTextFormattedCitation" : "(Cseri et al., 2016; Dong et al., 2017; Fodi et al., 2017; Gao et al., 2017; Shi et al., 2016)", "previouslyFormattedCitation" : "(Cseri et al., 2016; Dong, Kim, Kim, Drioli, & Lee, 2017; Fodi et al., 2017; Gao, Alberto, Gorgojo, Szekely, & Budd, 2017; Shi, Peshev, Marchetti, Zhang, & Livingston, 2016)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Cseri et al., 2016; Dong et al., 2017; Fodi et al., 2017; Gao et al., 2017; Shi et al., 2016). The valuable peptide is grown attached to a soluble anchor ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Castro", "given" : "Vida", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Noti", "given" : "Christian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "Wenqian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cristau", "given" : "Michele", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livignston", "given" : "Andrew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodriguez", "given" : "Hortensia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Albericio", "given" : "Fernando", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Macromolecules", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2017" ] ] }, "page" : "1626-1634", "publisher" : "ACS Publications", "title" : "Novel Globular Polymeric Supports for Membrane-Enhanced Peptide Synthesis", "type" : "article-journal", "volume" : "50" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1021/cr960064l", "ISBN" : "0009-2665", "ISSN" : "0009-2665", "PMID" : "11848880", "abstract" : "A review with 148 refs. including discussion of peptide, oligonucleotide, oligosaccharide and small mol. syntheses. 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The soluble anchor aids the retention of the peptide by the membrane during diafiltration (Figure 1) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "So", "given" : "Sheung", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peeva", "given" : "Ludmila G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tate", "given" : "Edward W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leatherbarrow", "given" : "Robin J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Chemical Communications", "id" : "ITEM-1", "issue" : "16", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "2808-2810", "publisher" : "Royal Society of Chemistry", "title" : "Membrane enhanced peptide synthesis", "type" : "article-journal", "volume" : "46" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1021/op1001403", "ISBN" : "1083-6160", "ISSN" : "10836160", "PMID" : "20369190", "abstract" : "This communication reports a new technology platform that advantageously combines organic solvent nanofiltration (a newly emerging technology capable of molecular separations in organic solvents) with solution phase peptide synthesis-Membrane Enhanced Peptide Synthesis (MEPS).", "author" : [ { "dropping-particle" : "", "family" : "So", "given" : "Sheung", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peeva", "given" : "Ludmila G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tate", "given" : "Edward W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leatherbarrow", "given" : "Robin J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Organic Process Research and Development", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "1313-1325", "title" : "Organic solvent nanofiltration: A new paradigm in peptide synthesis", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(So et al., 2010a, 2010b)", "plainTextFormattedCitation" : "(So et al., 2010a, 2010b)", "previouslyFormattedCitation" : "(So, Peeva, Tate, Leatherbarrow, & Livingston, 2010a, 2010b)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(So et al., 2010a, 2010b). As a result, the excess monomers, reagents and by-products permeate through the membrane, while the anchored peptide remains in the system for further elongation. It was demonstrated previously that this process (and a similar approach for oligonucleotides) can achieve high yield and purity, while offering scalability and ease of monitoring of the impurity level ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "So", "given" : "Sheung", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peeva", "given" : "Ludmila G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tate", "given" : "Edward W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leatherbarrow", "given" : "Robin J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Chemical Communications", "id" : "ITEM-1", "issue" : "16", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "2808-2810", "publisher" : "Royal Society of Chemistry", "title" : "Membrane enhanced peptide synthesis", "type" : "article-journal", "volume" : "46" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1021/op1001403", "ISBN" : "1083-6160", "ISSN" : "10836160", "PMID" : "20369190", "abstract" : "This communication reports a new technology platform that advantageously combines organic solvent nanofiltration (a newly emerging technology capable of molecular separations in organic solvents) with solution phase peptide synthesis-Membrane Enhanced Peptide Synthesis (MEPS).", "author" : [ { "dropping-particle" : "", "family" : "So", "given" : "Sheung", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peeva", "given" : "Ludmila G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tate", "given" : "Edward W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leatherbarrow", "given" : "Robin J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Organic Process Research and Development", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "1313-1325", "title" : "Organic solvent nanofiltration: A new paradigm in peptide synthesis", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1021/acs.oprd.6b00139", "ISSN" : "1520586X", "abstract" : "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 ...", "author" : [ { "dropping-particle" : "", "family" : "Kim", "given" : "Jeong F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gaffney", "given" : "Piers R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Valtcheva", "given" : "Irina B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Williams", "given" : "Glynn", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buswell", "given" : "Andrew M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Anson", "given" : "Mike S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Organic Process Research and Development", "id" : "ITEM-3", "issue" : "8", "issued" : { "date-parts" : [ [ "2016" ] ] }, "page" : "1439-1452", "title" : "Organic Solvent Nanofiltration (OSN): A New Technology Platform for Liquid-Phase Oligonucleotide Synthesis (LPOS)", "type" : "article-journal", "volume" : "20" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1002/chem.201402186", "ISBN" : "1215421109", "ISSN" : "15213765", "PMID" : "22393313", "abstract" : "A new strategy to access highly monodisperse, heterobifunctional linear polyethylenglycols (PEGs) has been designed. This was built around unidirectional, iterative chain extension of a 3-arm PEG homostar. A mono-(4,4'-dimethoxytriphenylmethyl) octagol building block, DmtrO-EG8-OH, was constructed from tetragol. After six rounds of chain extension, the monodisperse homostar reached the unprecedented length of 56 monomers per arm (PEG2500). The unique architecture of the synthetic platform greatly assisted in facilitating and monitoring reaction completion, overcoming kinetic limitations, chromatographic purification of intermediates, and analytical assays. After chain terminal derivatisation, mild hydrogenolytic cleavage of the homostar hub provided heterobifunctional linear EG56 chains with a hydroxyl at one end, and either a toluene sulfonate, or a tert-butyl carboxylate ester at the other. A range of heterobifunctional, monodisperse PEGs was then prepared having useful cross-linking functionalities (-OH, -COOH, -NH2, -N3) at both ends. A rapid preparation of polydisperse PEG homostars, free of multiply cross-linked chains, is also described. The above approach should be extendable to other high value oligomers and polymers.", "author" : [ { "dropping-particle" : "", "family" : "Sz\u00e9kely", "given" : "Gy\u00f6rgy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schaepertoens", "given" : "Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gaffney", "given" : "Piers R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Chemistry - A European Journal", "id" : "ITEM-4", "issue" : "32", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "10038-10051", "title" : "Beyond PEG2000: Synthesis and functionalisation of monodisperse pegylated homostars and clickable bivalent polyethyleneglycols", "type" : "article-journal", "volume" : "20" }, "uris" : [ "" ] }, { "id" : "ITEM-5", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Castro", "given" : "Vida", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Noti", "given" : "Christian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "Wenqian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cristau", "given" : "Michele", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livignston", "given" : "Andrew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodriguez", "given" : "Hortensia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Albericio", "given" : "Fernando", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Macromolecules", "id" : "ITEM-5", "issue" : "4", "issued" : { "date-parts" : [ [ "2017" ] ] }, "page" : "1626-1634", "publisher" : "ACS Publications", "title" : "Novel Globular Polymeric Supports for Membrane-Enhanced Peptide Synthesis", "type" : "article-journal", "volume" : "50" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Castro et al., 2017; Kim et al., 2016; So et al., 2010a, 2010b; Sz\u00e9kely et al., 2014)", "plainTextFormattedCitation" : "(Castro et al., 2017; Kim et al., 2016; So et al., 2010a, 2010b; Sz\u00e9kely et al., 2014)", "previouslyFormattedCitation" : "(Castro et al., 2017; Kim et al., 2016; So et al., 2010a, 2010b; Sz\u00e9kely, Schaepertoens, Gaffney, & Livingston, 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Castro et al., 2017; Kim et al., 2016; So et al., 2010a, 2010b; Székely et al., 2014). Figure 1. Membrane enhanced peptide synthesis (MEPS).The configuration of the membrane system and the operation of the diafiltration are important for the purification of anchored peptide in MEPS. It was shown previously that diafiltration in a single-stage nanofiltration system can lead to significant yield loss in order to achieve high purity. This can be overcome by operating diafiltration in a two-stage membrane cascade, where the anchored peptide permeating through the first-stage membrane is recovered by the second-stage membrane ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.seppur.2013.05.050", "ISSN" : "13835866", "abstract" : "Organic Solvent Nanofiltration (OSN) is a relatively new molecular separation technology used for separating solutes present in an organic solvent. Although there are many potential applications in industrial processes, obtaining a sharp separation between two molecules which are both in the nanofiltration range from 100 to 2000gmol\u22121 remains a challenge. This is because the differences in rejection of the solutes by the membrane are often insufficient for them to be separated in a single filtration stage. Membrane cascades can meet this challenge and have potential for process intensification (PI) allowing more sustainable membrane units. The membrane cascade concept was proposed in the early 1940s, but to date several implementation challenges such as control difficulties have presented major hurdles and only few experimental data have been reported. Here we present a simplified-control cascade process that not only overcomes previous implementation issues, but also minimizes the product loss and maximizes the purity. The process operates using a single high pressure pump as the primary pressure source, and has no need for a buffer tank between membrane stages. The process was tested on an organic solution of polyethyleneglycol 400 (PEG-400) and PEG-2000 in acetonitrile which is a challenging model, as the flexible chains make it difficult to obtain 100% rejection of any PEG. Polyimide and polybenzimidazole membranes were screened for the cascade process. Using this process it was possible to increase the final yield of PEG-2000 from 59% to 94%, and the solvent-consumption/productivity ratio was also reduced. The process has been analyzed using a model developed to predict the cascade performance. It was found experimentally that the recycle ratio, as well as the trans-membrane pressure, affect the process yield significantly, in agreement with the model predictions. Model analysis and experimental validation are presented.", "author" : [ { "dropping-particle" : "", "family" : "Kim", "given" : "Jeong F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freitas da Silva", "given" : "Ana M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Valtcheva", "given" : "Irina B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Separation and Purification Technology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "277-286", "title" : "When the membrane is not enough: A simplified membrane cascade using Organic Solvent Nanofiltration (OSN)", "type" : "article-journal", "volume" : "116" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "abstract" : "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 \u201crevamped\u201d 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.", "author" : [ { "dropping-particle" : "", "family" : "Kim", "given" : "Jeong F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sz\u00e9kely", "given" : "Gy\u00f6rgy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Valtcheva", "given" : "Irina B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Green Chemistry", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "133-145", "publisher" : "Royal Society of Chemistry", "title" : "Increasing the sustainability of membrane processes through cascade approach and solvent recovery-pharmaceutical purification case study", "type" : "article-journal", "volume" : "16" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Kim et al., 2014, 2013)", "plainTextFormattedCitation" : "(Kim et al., 2014, 2013)", "previouslyFormattedCitation" : "(Kim, Freitas da Silva, Valtcheva, & Livingston, 2013; Kim, Sz\u00e9kely, Valtcheva, & Livingston, 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Kim et al., 2014, 2013).Membrane cascades have been widely studied for applications such as desalination, water purification and the fractionation of solutes in mixture ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Ebara", "given" : "Katsuya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ogawa", "given" : "Toshio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Takahashi", "given" : "Sankichi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nishimura", "given" : "Sigeoki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kikkawa", "given" : "Seiichi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Komori", "given" : "Shinji", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sawa", "given" : "Toshio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1978" ] ] }, "number" : "4080289", "publisher-place" : "U.S.", "title" : "Apparatus for treating waste water or solution", "type" : "patent" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1021/jp984020n", "ISBN" : "1089-5647", "ISSN" : "1520-6106", "abstract" : "Multiwalled carbon nanotubes were purified and size-separated by a multistep microfiltration process through a sequence of track-etched polycarbonate membranes of various pore sizes in both dead-ended and cross-flow mode. For this cascade microfiltration, the electric arc derived raw multiwalled samples were suspended in an aqueous solution of sodium dodecyl sulfate in deionized water. By examining the deposits on the membrane surfaces and in the permeate suspensions with scanning electron microscopy and atomic force microscopy, the nanotube fractionation was confirmed and analyzed. These scanning techniques showed that the components of the crude sample, which included carbon nanotubes, polyhedral nanoparticles, and large aggregates, were separated from each other during the filtration. In addition, fractionation of the multiwalled carbon nanotubes according to length was possible.\\nMultiwalled carbon nanotubes were purified and size-separated by a multistep microfiltration process through a sequence of track-etched polycarbonate membranes of various pore sizes in both dead-ended and cross-flow mode. For this cascade microfiltration, the electric arc derived raw multiwalled samples were suspended in an aqueous solution of sodium dodecyl sulfate in deionized water. By examining the deposits on the membrane surfaces and in the permeate suspensions with scanning electron microscopy and atomic force microscopy, the nanotube fractionation was confirmed and analyzed. These scanning techniques showed that the components of the crude sample, which included carbon nanotubes, polyhedral nanoparticles, and large aggregates, were separated from each other during the filtration. In addition, fractionation of the multiwalled carbon nanotubes according to length was possible.", "author" : [ { "dropping-particle" : "", "family" : "Abatemarco", "given" : "Thomas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stickel", "given" : "Jonathan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Belfort", "given" : "Jonathan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frank", "given" : "Brian P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ajayan", "given" : "P. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Belfort", "given" : "Georges", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of Physical Chemistry B", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "1999" ] ] }, "page" : "3534-3538", "title" : "Fractionation of Multiwalled Carbon Nanotubes by Cascade Membrane Microfiltration", "type" : "article-journal", "volume" : "103" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Mellal", "given" : "Mounir", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hui Ding", "given" : "Lu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Y. Jaffrin", "given" : "Michel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Delattre", "given" : "Cedric", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Michaud", "given" : "Philippe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Courtois", "given" : "Josiane", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Separation Science and Technology", "id" : "ITEM-3", "issue" : "2", "issued" : { "date-parts" : [ [ "2007" ] ] }, "page" : "349-361", "publisher" : "Taylor & Francis", "title" : "Separation and fractionation of oligouronides by shear-enhanced filtration", "type" : "article-journal", "volume" : "42" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1016/j.seppur.2009.10.002", "ISBN" : "13835866", "ISSN" : "13835866", "abstract" : "This paper examines the use of multi-stage or cascade ultrafiltration systems for continuous fractionation of model proteins human serum albumin (HSA) and human immunoglobulin G (HIgG). A three-stage, countercurrent ultrafiltration system was able to generate continuous HSA and HIgG streams with high purity and recovery. Pulsed sample injection ultrafiltration experiments showed that selectivity could be significantly affected by protein-protein interactions. The molar ratio of proteins in the feed was affected by the sieving coefficients of the proteins, particularly that of the preferentially transmitted one. Simulated results obtained with effective sieving coefficient data from pulsed sample injection ultrafiltration which factored in protein-protein interactions were found to be in good agreement with experimental results. The selectivity and hydraulic permeability as a function of time in a continuous fractionation process run under optimized conditions were determined to examine the feasibility of operation for extended duration. Crown Copyright ?? 2009.", "author" : [ { "dropping-particle" : "", "family" : "Mayani", "given" : "Mukesh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mohanty", "given" : "Kaustubha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Filipe", "given" : "Carlos", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghosh", "given" : "Raja", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Separation and Purification Technology", "id" : "ITEM-4", "issue" : "2", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "231-241", "title" : "Continuous fractionation of plasma proteins HSA and HIgG using cascade ultrafiltration systems", "type" : "article-journal", "volume" : "70" }, "uris" : [ "" ] }, { "id" : "ITEM-5", "itemData" : { "DOI" : "10.1016/j.desal.2008.01.061", "ISBN" : "0011-9164", "ISSN" : "00119164", "abstract" : "In this study, the aim is to remove micropollutants (pesticides) from water completely while removing only a small fraction of salts. To achieve the latter, loose commercial nanofiltration (NF) membranes were selected (Desal51HL, N30F and NF270). To realize a high removal of organic compounds, combined with a low salt rejection, cascades of NF stages are proposed. Experiments with pesticides (aldrin, atrazine, bentazone, dieldrin, and propazine) and NaCl confirmed that a nearly complete rejection of pesticides is possible, depending on specific properties of the solutes such as molecular size and chemical structure (e.g. hydrophobicity). Salt rejection was highly dependent on the specifications of the membrane and on the ion charge, and ranged from low to high values. Through modeling based on transport equations and mass balances, it was shown that the separation was significantly improved by adopting the principle of an integrated cascade of NF membranes. ?? 2008 Elsevier B.V. All rights reserved.", "author" : [ { "dropping-particle" : "", "family" : "Caus", "given" : "Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vanderhaegen", "given" : "Stefaan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Braeken", "given" : "Leen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruggen", "given" : "Bart", "non-dropping-particle" : "Van der", "parse-names" : false, "suffix" : "" } ], "container-title" : "Desalination", "id" : "ITEM-5", "issue" : "1-3", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "111-117", "title" : "Integrated nanofiltration cascades with low salt rejection for complete removal of pesticides in drinking water production", "type" : "article-journal", "volume" : "241" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Abatemarco et al., 1999; Caus et al., 2009; Ebara et al., 1978; Mayani et al., 2009; Mellal et al., 2007)", "plainTextFormattedCitation" : "(Abatemarco et al., 1999; Caus et al., 2009; Ebara et al., 1978; Mayani et al., 2009; Mellal et al., 2007)", "previouslyFormattedCitation" : "(Abatemarco et al., 1999; Caus, Vanderhaegen, Braeken, & Van der Bruggen, 2009; 4080289, 1978; Mayani, Mohanty, Filipe, & Ghosh, 2009; Mellal et al., 2007)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Abatemarco et al., 1999; Caus et al., 2009; Ebara et al., 1978; Mayani et al., 2009; Mellal et al., 2007). The design and operation of membrane cascades can be complex due to the many combinations of design and operation variables. As a result, computer-aided process simulation and optimisation are useful tools and design aids ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "(96)00319-5", "ISSN" : "0376-7388", "abstract" : "A novel methodology has been developed which enables optimization of membrane separations. In multi-component separation processes, sieving coefficients for the individual solutes, defined as the ratio of the filtrate and feed concentrations, tend to reach optimum values under different process conditions. It is not possible to determine a priori the pair of sieving coefficients which will give the best combination of product yield and purification for a given application. A purification factor-yield diagram for such an optimization has been developed which utilizes a family of curves representing two dimensionless numbers plotted on yield versus purification-factor coordinates. Analysis can be performed with knowledge of only three experimental variables: the filtrate flux and the two solute sieving coefficients. Complete optimization of membrane processes can be achieved by combining these variables with membrane area, process time, and retentate-volume constraints. The methodology should be applicable to ultrafiltration, microfiltration, and high-performance tangential flow (selective) filtration processes.", "author" : [ { "dropping-particle" : "", "family" : "Reis", "given" : "Robert", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Saksena", "given" : "Skand", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Membrane Science", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "1997" ] ] }, "page" : "19-29", "title" : "Optimization diagram for membrane separations", "type" : "article-journal", "volume" : "129" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.memsci.2010.03.019", "ISBN" : "03767388", "ISSN" : "03767388", "abstract" : "A comprehensive modeling approach is proposed for the dynamic simulation and operation optimization of batch diafiltration processes. We provide a unified technology for water utilization control that addresses generality versus special cases. A rigorous dynamical model of the diafiltration process with concentration-dependent rejections of solutes is developed. We determine the optimal time-dependent profile of the diluant flow for the entire process using dynamic optimization methods. The results show that optimal process operation needs not to be any of the conventional diafiltration concepts. The presented optimization technique is a useful tool for improving the performance of a membrane diafiltration process. ?? 2010 Elsevier B.V. All rights reserved.", "author" : [ { "dropping-particle" : "", "family" : "Fikar", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kov\u00e1cs", "given" : "Z.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Czermak", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Membrane Science", "id" : "ITEM-2", "issue" : "1-2", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "168-174", "title" : "Dynamic optimization of batch diafiltration processes", "type" : "article-journal", "volume" : "355" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1080/01496397608085339", "ISBN" : "0037-2366", "ISSN" : "0037-2366", "abstract" : "Abstract Preliminary consideration suggests that process time in diafiltration can be optimized. A mathematical derivation of the optimum time gives a surprisingly simple general relationship between the bulk concentration and the membrane surface concentration. Experimental values confirm that an optimum value can indeed be obtained.", "author" : [ { "dropping-particle" : "", "family" : "Ng", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lundblad", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mitra", "given" : "Gautam", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Separation Science", "id" : "ITEM-3", "issue" : "5", "issued" : { "date-parts" : [ [ "2007" ] ] }, "page" : "499-502", "title" : "Optimization of Solute Separation by Diafiltration", "type" : "article-journal", "volume" : "11" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1016/0011-9164(96)00054-9", "ISSN" : "00119164", "abstract" : "The present design of nanofiltration systems is based mostly on the design of reverse osmosis systems including such aspects as Christmas tree configurations, six spiral-wound modules per pressure vessel, and no recirculation of the brine. However, the feed and osmotic pressure of NF systems are much lower compared to RO systems due to the lower salt concentration of the feed and the lower rejection for monovalent ions. Therefore the hydraulic pressure losses in NF systems are no longer negligible as they are in RO systems. Thus the configuration of NF systems could be different from RO systems. In order to improve the performance of NF systems by optimizing the configuration and operating conditions, a mathematical model has been developed. The model describes the mass transfer through the membranes by using the homogeneous solution model, which is improved by including the concentration polarization. Hydraulic pressure losses are calculated using a modified Darcy-Weisbach equation. In order to optimize the performance of NF systems, the influence of recirculation on recovery, rejection, permeate production per element, and energy consumption has been studied. First results of this study showed that for a given recovery, a one-stage installation with recirculation produces more permeate per element than a two-stage installation without recirculation. However, application of recirculation leads to a slightly increasing energy consumption and permeate concentration. ?? 1996, All rights reserved.", "author" : [ { "dropping-particle" : "", "family" : "Meer", "given" : "W. G J", "non-dropping-particle" : "van der", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aeijelts Averink", "given" : "C. W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dijk", "given" : "J. C.", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" } ], "container-title" : "Desalination", "id" : "ITEM-4", "issue" : "1-2", "issued" : { "date-parts" : [ [ "1996" ] ] }, "page" : "25-31", "title" : "Mathematical model of nanofiltration systems", "type" : "article-journal", "volume" : "105" }, "uris" : [ "" ] }, { "id" : "ITEM-5", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Overdevest", "given" : "Pieter E M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hoenders", "given" : "Marc H J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "van't Riet", "given" : "Klaas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Padt", "given" : "Albert", "non-dropping-particle" : "der", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keurentjes", "given" : "Jos T F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "AIChE journal", "id" : "ITEM-5", "issue" : "9", "issued" : { "date-parts" : [ [ "2002" ] ] }, "page" : "1917-1926", "publisher" : "Wiley Online Library", "title" : "Enantiomer separation in a cascaded micellar-enhanced ultrafiltration system", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] }, { "id" : "ITEM-6", "itemData" : { "DOI" : "10.1016/j.memsci.2003.08.012", "ISBN" : "0376-7388", "ISSN" : "03767388", "abstract" : "High-resolution protein-protein fractionation is an important and expensive activity in the biotechnological industry. Ultrafiltration (UF), a membrane-based separation process which combines high throughput of product with ease of scale-up is widely used for protein desalting and concentration. In recent years, the potential for achieving high-resolution protein fractionation using ultrafiltration has been demonstrated. However, there has been limited success in translating these into industrial processes. One of the reasons for this is the unsuitability of currently used ultrafiltration process configurations for carrying out high-resolution protein fractionation. These configurations are particularly unsuitable in situations where recovery of pure protein fractions in both permeate and retentate streams is required. This paper discusses a novel three-stage cascade ultrafiltration configuration designed specifically for continuous, high-resolution protein-protein fractionation. The advantages of this configuration over other types are discussed based on results of binary protein fractionation simulation studies. By suitably adjusting the flow streams within this novel configuration it is possible to achieve high recovery as well as high purity of each of the target proteins. The results of simulation show that it is not just the use of the three stages, but how the permeation rates of these three stages are optimized that actually results in high purity and recovery. ?? 2003 Elsevier B.V. All rights reserved.", "author" : [ { "dropping-particle" : "", "family" : "Ghosh", "given" : "Raja", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Membrane Science", "id" : "ITEM-6", "issue" : "1-2", "issued" : { "date-parts" : [ [ "2003" ] ] }, "page" : "85-99", "title" : "Novel cascade ultrafiltration configuration for continuous, high-resolution protein-protein fractionation: A simulation study", "type" : "article-journal", "volume" : "226" }, "uris" : [ "" ] }, { "id" : "ITEM-7", "itemData" : { "DOI" : "10.1016/j.memsci.2003.11.014", "ISBN" : "03767388 (ISSN)", "ISSN" : "03767388", "abstract" : "Recent studies have demonstrated that membrane ultrafiltration can be used to separate proteins with very similar size, but these investigations have been performed with model binary mixtures. This study examined the use of a two-stage tangential flow filtration system for the purification of both ??-LA and ??-LG from whey protein isolate. Separation was achieved using 100 and 30kDa membranes in series, with the buffer concentration and filtration velocity for each stage adjusted to give optimal separation. Two purification strategies were examined: one using the 100kDa membrane followed by the 30kDa and one with the reverse order. In both cases, the ??-LA purification was greater than 10-fold at 90% yield. The recovery of ??-LG was more challenging since it was obtained in the permeate from one stage and the retentate from the other. The results provide important insights into the development of staged membrane systems for the purification of complex protein mixtures. ?? 2003 Elsevier B.V. All rights reserved.", "author" : [ { "dropping-particle" : "", "family" : "Cheang", "given" : "Beelin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zydney", "given" : "Andrew L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Membrane Science", "id" : "ITEM-7", "issue" : "1-2", "issued" : { "date-parts" : [ [ "2004" ] ] }, "page" : "159-167", "title" : "A two-stage ultrafiltration process for fractionation of whey protein isolate", "type" : "article-journal", "volume" : "231" }, "uris" : [ "" ] }, { "id" : "ITEM-8", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Lightfoot", "given" : "E N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Separation science and technology", "id" : "ITEM-8", "issue" : "4", "issued" : { "date-parts" : [ [ "2005" ] ] }, "page" : "739-756", "publisher" : "Taylor & Francis", "title" : "Can membrane cascades replace chromatography? Adapting binary ideal cascade theory of systems of two solutes in a single solvent", "type" : "article-journal", "volume" : "40" }, "uris" : [ "" ] }, { "id" : "ITEM-9", "itemData" : { "DOI" : "10.1021/ie200665g", "abstract" : "Scarcity of freshwater resources and increasingly stringent environmental regulations on industrial effluents have motivated the process industry to identify and develop various water recovery strategies. This work proposes the use of detailed model representation for water regeneration network synthesis, in which nonlinear mechanistic models of the regeneration units are embedded within an overall mixed-integer nonlinear programming (MINLP) optimization framework. The superstructure-based MINLP framework involves both continuous variables for water flow rates and contaminant concentrations and 0\u20131 variables for selection of piping interconnections. The nonlinear regeneration model produces a rigorous cost-based relation, instead of a \u201cblack box\u201d model, that is incorporated within the overall MINLP representing a network of numerous water sources and water sinks. Hence, such an approach enables a simultaneous evaluation of both direct water reuse/recycle and regeneration\u2013reuse/recycle opportunities. To demonstrate the proposed approach, an industrial case study is illustrated that incorporates a mechanistic model of reverse osmosis network (RON) for water regeneration for an operating refinery in Malaysia. The results indicate a potential of 58% savings in freshwater use. The capital investment for the water regeneration network is reported as $8,960,000 with a payback period of 2.1 years, thus providing economic support to pursue the RON retrofit option.", "author" : [ { "dropping-particle" : "", "family" : "Khor", "given" : "Cheng Seong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foo", "given" : "Dominic C Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "El-Halwagi", "given" : "Mahmoud M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tan", "given" : "Raymond R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shah", "given" : "Nilay", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Industrial & Engineering Chemistry Research", "id" : "ITEM-9", "issue" : "23", "issued" : { "date-parts" : [ [ "2011" ] ] }, "page" : "13444-13456", "title" : "A Superstructure Optimization Approach for Membrane Separation-Based Water Regeneration Network Synthesis with Detailed Nonlinear Mechanistic Reverse Osmosis Model", "type" : "article-journal", "volume" : "50" }, "uris" : [ "" ] }, { "id" : "ITEM-10", "itemData" : { "DOI" : "10.1016/j.desal.2012.02.024", "ISBN" : "0011-9164", "ISSN" : "00119164", "abstract" : "Optimal plant operation of brackish water reverse osmosis (BWRO) desalination is studied in this work to reduce specific energy consumption (SEC). A comprehensive first-principles based mathematical model, which explicitly accounts for membrane area and hydraulic permeability, pump characteristic curves, and pressure drops along the RO train, is developed and validated by plant data. A constrained nonlinear optimization is formulated and solved for two RO trains with different service times. It is shown that a 16% reduction in SEC is possible by optimizing operating conditions within the normal operating range of the pump while maintaining the same permeate rate. Results are discussed using dimensionless parameters derived in the author's previous work. Suggestions are made to further reduce SEC in BWRO plant operation. ?? 2012 Elsevier B.V.", "author" : [ { "dropping-particle" : "", "family" : "Li", "given" : "Mingheng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Desalination", "id" : "ITEM-10", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "61-68", "title" : "Optimal plant operation of brackish water reverse osmosis (BWRO) desalination", "type" : "article-journal", "volume" : "293" }, "uris" : [ "" ] }, { "id" : "ITEM-11", "itemData" : { "DOI" : "(96)00294-3", "ISSN" : "0376-7388", "abstract" : "A design method for reverse osmosis desalination plants has been developed. It incorporates rigorous mathematical models for the prediction of the performance of various process units (reverse osmosis modules, pumps, energy recovery turbines) employed in the flowsheet and taken into account the network structure using an appropriate superstructure, which represents various reverse osmosis networks. Cost equations relating the capital and operating cost to the design variables, as well as the structural variables of the designed network have been introduced in the objective function. The total cost of the plant is minimized in order to determine the optimal operating and structural variables. The model is accurate enough to describe the process and yet simple enough to be used for design purposes. During the simulation and optimization studies, several structures for multistage reverse osmosis systems have been found. Results concerning the economics of the process are presented. Optimal results have also been used for the derivation of design curves concerning the effect of quality and quantity of produced water to the total annualized cost of the plant for various types of membrane modules.", "author" : [ { "dropping-particle" : "", "family" : "Voros", "given" : "N G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maroulis", "given" : "Z B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marinos-Kouris", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Membrane Science", "id" : "ITEM-11", "issue" : "1", "issued" : { "date-parts" : [ [ "1997" ] ] }, "page" : "47-68", "title" : "Short-cut structural design of reverse osmosis desalination plants", "type" : "article-journal", "volume" : "127" }, "uris" : [ "" ] }, { "id" : "ITEM-12", "itemData" : { "DOI" : "10.1021/acs.iecr.5b01803", "ISSN" : "0888-5885", "abstract" : "Strict environmental regulations and social pressures have created the need for water and energy minimization in the process industries. Therefore, this work looks at the incorporation of a detailed reverse osmosis network (RON) superstructure within a water network superstructure in order to simultaneously minimize water, energy, operation, and capital costs. The water network consists of water sources, water sinks, and RO units for the partial treatment of the contaminated water. An overall mixed-integer nonlinear programming framework is developed that simultaneously evaluates both water recycle\u2013reuse and regeneration reuse\u2013recycle opportunities. The solution obtained from optimization provides the optimal connections between various units in the network arrangement, size and types of RO units, booster pumps, as well as energy recovery turbines. The paper looks at four cases to highlight the importance of including a detailed regeneration network within the water network instead of the traditional \u201cbla...", "author" : [ { "dropping-particle" : "", "family" : "Buabeng-Baidoo", "given" : "Esther", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Majozi", "given" : "Thokozani", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Industrial & Engineering Chemistry Research", "id" : "ITEM-12", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "150915083245002", "title" : "Effective Synthesis and Optimization Framework for Integrated Water and Membrane Networks: A Focus on Reverse Osmosis Membranes", "type" : "article-journal" }, "uris" : [ "" ] }, { "id" : "ITEM-13", "itemData" : { "DOI" : "", "ISSN" : "0376-7388", "abstract" : "Abstract 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 (\u22120.7%) 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 \u2013 amongst the membrane materials are polyimide (PI), polybenzimidazole (PBI) and, polyetheretherketone (PEEK). ", "author" : [ { "dropping-particle" : "", "family" : "Schaepertoens", "given" : "Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Didaskalou", "given" : "Christos", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "Jeong F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Szekely", "given" : "Gyorgy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Membrane Science", "id" : "ITEM-13", "issued" : { "date-parts" : [ [ "2016" ] ] }, "page" : "646-658", "title" : "Solvent recycle with imperfect membranes: A semi-continuous workaround for diafiltration", "type" : "article-journal", "volume" : "514" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Buabeng-Baidoo and Majozi, 2015; Cheang and Zydney, 2004; Fikar et al., 2010; Ghosh, 2003; Khor et al., 2011; Li, 2012; Lightfoot, 2005; Ng et al., 2007; Overdevest et al., 2002; Schaepertoens et al., 2016; van der Meer et al., 1996; van Reis and Saksena, 1997; Voros et al., 1997)", "plainTextFormattedCitation" : "(Buabeng-Baidoo and Majozi, 2015; Cheang and Zydney, 2004; Fikar et al., 2010; Ghosh, 2003; Khor et al., 2011; Li, 2012; Lightfoot, 2005; Ng et al., 2007; Overdevest et al., 2002; Schaepertoens et al., 2016; van der Meer et al., 1996; van Reis and Saksena, 1997; Voros et al., 1997)", "previouslyFormattedCitation" : "(Buabeng-Baidoo & Majozi, 2015; Cheang & Zydney, 2004; Fikar, Kov\u00e1cs, & Czermak, 2010; Ghosh, 2003; Khor, Foo, El-Halwagi, Tan, & Shah, 2011; Li, 2012; Lightfoot, 2005; Ng, Lundblad, & Mitra, 2007; Overdevest, Hoenders, van\u2019t Riet, der Padt, & Keurentjes, 2002; Schaepertoens, Didaskalou, Kim, Livingston, & Szekely, 2016; van der Meer, Aeijelts Averink, & van Dijk, 1996; van Reis & Saksena, 1997; Voros, Maroulis, & Marinos-Kouris, 1997)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Buabeng-Baidoo and Majozi, 2015; Cheang and Zydney, 2004; Fikar et al., 2010; Ghosh, 2003; Khor et al., 2011; Li, 2012; Lightfoot, 2005; Ng et al., 2007; Overdevest et al., 2002; Schaepertoens et al., 2016; van der Meer et al., 1996; van Reis and Saksena, 1997; Voros et al., 1997).Membrane-enhanced synthesis of biopolymers in membrane cascades is an interesting area of research due to the semi-batch and iterative nature of the process (vs continuous operation for most of the existing studies), as well as the interesting interplay between reaction and purification. However, its complexity in terms of design and operation is a barrier for its adoption in manufacturing in general. This study presents the advantages of operating an iterative peptide synthesis in a two-stage membrane cascade through process simulations. A dynamic process model was first developed and validated with the experimental data of MEPS in a single-stage system. The process model was then extended to MEPS in a two-stage membrane cascade and an operational variable analysis was performed to show how operating in a two-stage membrane cascade could improve the overall yield of the process. Materials and methodsThe materials and experimental procedures for the MEPS of a model hexapeptide (sequence: Pyr-Ser(Bzl)-Ala-Phe-Asp-Leu-NH2 (Figure S1 in supplementary information)) were reported previously ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Chen", "given" : "Wenqian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharifzadeh", "given" : "Mahdi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shah", "given" : "Nilay", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew Guy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Industrial & Engineering Chemistry Research", "id" : "ITEM-1", "issue" : "23", "issued" : { "date-parts" : [ [ "2017" ] ] }, "page" : "6796-6804", "publisher" : "ACS Publications", "title" : "The Implication of Side-reactions in Iterative Biopolymer Synthesis: The Case of Membrane Enhanced Peptide Synthesis (MEPS)", "type" : "article-journal", "volume" : "56" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Chen", "given" : "Wenqian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2015" ] ] }, "publisher" : "Imperial College London", "title" : "Membrane Enhanced Peptide Synthesis (MEPS) \u2013 Process Development and Application", "type" : "thesis" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Chen, 2015; Chen et al., 2017)", "plainTextFormattedCitation" : "(Chen, 2015; Chen et al., 2017)", "previouslyFormattedCitation" : "(Chen, 2015; Chen et al., 2017)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Chen, 2015; Chen et al., 2017). The anchor used in this experiment was 2,4-didocosyloxybenzalcohol with Rink functionality (Figure S2 in supplementary information). The experimental data were used for the development and validation of the process model of MEPS.Dynamic process simulationA dynamic process model of MEPS in a single-stage system was developed with an equation-oriented simulation platform, gPROMS, based on the experimental data reported previously ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Chen", "given" : "Wenqian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharifzadeh", "given" : "Mahdi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shah", "given" : "Nilay", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew Guy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Industrial & Engineering Chemistry Research", "id" : "ITEM-1", "issue" : "23", "issued" : { "date-parts" : [ [ "2017" ] ] }, "page" : "6796-6804", "publisher" : "ACS Publications", "title" : "The Implication of Side-reactions in Iterative Biopolymer Synthesis: The Case of Membrane Enhanced Peptide Synthesis (MEPS)", "type" : "article-journal", "volume" : "56" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Chen et al., 2017)", "plainTextFormattedCitation" : "(Chen et al., 2017)", "previouslyFormattedCitation" : "(Chen et al., 2017)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Chen et al., 2017).The MEPS process was performed in the batch modes iteratively (according to the number of amino acids in the sequence), where cycles of reaction and filtration were performed in the same single-stage system that comprises mainly a membrane circuit and a feed tank. The operation time for each reaction and diafiltration is an important process variable that determines the purity and yield of each intermediate product at the end of the reaction or diafiltration. The model was validated with the experimental results for overall yield and purity of anchored peptide. The validated model was then extended to MEPS in a two-stage membrane cascade. All the simulation inputs can be found in the supplementary information section. In addition, the simulation file can be downloaded in the supplementary information section.Single-stage membrane system: process description The single-stage membrane system has the simplest design of its kind, comprising nine units (Figure 2). The membrane circuit consists of five units: a circulation pump, three pipes and a membrane unit. The feed pump pushes the liquid from the feed tank into the membrane circuit, whereas the circulation pump ensures the direction of flow as well as good mixing within the membrane circuit. The backpressure valve sets the operating pressure of the membrane circuit by releasing some liquid into the feed tank (i.e. the recycle), when the feed pump pushes liquid into the membrane circuit and causes the pressure to go beyond the set value. The waste tank collects the permeate from the membrane unit as waste. This simple configuration can be easily turned into a multi-stage system by adding more membrane circuits in sequence.Figure 2. Single-stage membrane system in gPROMS.Mass balance during reactionsThe current dynamic model calculates the mass balance of each chemical component during reactions and diafiltrations in all unit operations (i.e. the tanks, valves, pumps, pipes and membrane unit in Figure 1). All reactions are modelled dynamically throughout the process, even during diafiltrations where the reactant concentrations drop significantly. This allows the current model to capture the complex nature of the transition between reactions and diafiltrations. For the addition of each amino acid onto the peptide chain, the anchored peptide first undergoes N-terminus deprotection with piperidine and then coupling with the activated amino acid (Figure 1). The total number of reactions for synthesising a peptide sequence with N amino acids and Fmoc-protection at the N-terminus is therefore equal to 2 N – 1. In this study, the synthesis of the hexapeptide (i.e. N = 6) involves 11 reactions (i.e. 5 deprotections and 6 couplings).The key components for the peptide synthesis include piperidine, amino acids and anchored peptides (i.e. the target product of reaction (i), where i = 1, 2, 3 … 2 N – 1). In the mass balance, all the amino acids and anchored peptides are assigned specific numbers (i.e. AAi where i = 1, 2, 3 … N and Pj where j = 1, 2, 3 … 2 N – 1). This allows the identification of individual components for analysis purposes.For example, in the MEPS of hexapeptide in this study, AA(1) and AA(6) are the first and last amino acids to participate in the couplings, whereas P(1) and P(11) refer to Fmoc-AA(1)-Anchor and Fmoc-AA(6)-AA(5)-AA(4)-AA(3)-AA(2)-AA(1)-Anchor respectively. For illustration, the mass balance of piperidine, amino acids and anchored peptide intermediates during reactions in a continuous stirred-tank reactor (CSTR) is explained in detail. These calculations are adopted for the different units in the membrane system according to their configurations (i.e. CSTR or plug flow reactor (PFR)). More information can be found in the supplementary information section.Mass balance for piperidinePiperidine is not consumed in all reactions. As a result, the rate of accumulation must be equal to the difference between the rates of piperidine entering and leaving the CSTR as shown in Equation 1, where VCSTR is the tank volume (m3), cinlet,piperidine, coutlet,piperidine and cCSTR,piperidine are the concentrations of piperidine at the inlet, outlet and inside the tank (mol ? m-3), Finlet and Foutlet are the volumetric flow rates at the inlet and outlet of the tank (m3 ? s-1).VCSTR×dcCSTR,piperidinedt = Finlet×cinlet,piperidine-Foutlet×coutlet,piperidine 1Reaction network of amino acids and anchored peptidesAs reported previously ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Chen", "given" : "Wenqian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharifzadeh", "given" : "Mahdi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shah", "given" : "Nilay", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew Guy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Industrial & Engineering Chemistry Research", "id" : "ITEM-1", "issue" : "23", "issued" : { "date-parts" : [ [ "2017" ] ] }, "page" : "6796-6804", "publisher" : "ACS Publications", "title" : "The Implication of Side-reactions in Iterative Biopolymer Synthesis: The Case of Membrane Enhanced Peptide Synthesis (MEPS)", "type" : "article-journal", "volume" : "56" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Chen et al., 2017)", "plainTextFormattedCitation" : "(Chen et al., 2017)", "previouslyFormattedCitation" : "(Chen et al., 2017)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Chen et al., 2017), a complex reaction network of amino acids and anchored peptides exits due to the formation of error sequences when a deprotected anchored peptide reacts with the residual amino acids from previous couplings. For example, in the second coupling (i.e. n = 2), H2N-AA(1)-Anchor can react with residual AA(1) to form the error sequence AA(1)-AA(1)-Anchor. The current process model includes the formation of error sequences, so that the extent of removal of amino acids during diafiltration has a direct impact on the final purity of the anchored peptide. Mass balance for amino acidsIn each coupling, a specific amino acid is added into the system for reacting with the deprotected N-terminus of the anchored peptide. However, this amino acid can undergo two more side reactions in the following steps. The first is the side reaction with piperidine during deprotection, as it was observed experimentally that piperidine consumes activated amino acids in this study. The second side reaction is the formation of error sequence in the following coupling ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Chen", "given" : "Wenqian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharifzadeh", "given" : "Mahdi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shah", "given" : "Nilay", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew Guy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Industrial & Engineering Chemistry Research", "id" : "ITEM-1", "issue" : "23", "issued" : { "date-parts" : [ [ "2017" ] ] }, "page" : "6796-6804", "publisher" : "ACS Publications", "title" : "The Implication of Side-reactions in Iterative Biopolymer Synthesis: The Case of Membrane Enhanced Peptide Synthesis (MEPS)", "type" : "article-journal", "volume" : "56" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Chen et al., 2017)", "plainTextFormattedCitation" : "(Chen et al., 2017)", "previouslyFormattedCitation" : "(Chen et al., 2017)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Chen et al., 2017).As a result, the mass balance of each amino acid is calculated by Equation 2, where P2i-2 is the anchored peptide to be coupled with the amino acid AAi to give the correct sequence. VCSTR×dcCSTR,AAidt = Finlet×cinlet,AAi-Foutlet×coutlet,AAi-VCSTR×kcoupling×cCSTR,AAi×cCSTR,P2i-2- VCSTR×kcoupling×cCSTR,AAi×cCSTR,P2i- VCSTR×kside-reaction×cCSTR,AAi×cCSTR,piperidine 2Mass balance for anchored peptidesThere are two types of anchored peptides. One has Fmoc-protected N-terminus after coupling and the other is the deprotected form after deprotection. In the mass balance, the anchored peptides are designated as Pj where j = 1, 2, 3 … 2 N – 1. The Fmoc-protected anchored peptides correspond to Pj when j is an odd number, whereas the deprotected anchored peptides correspond to Pj when j is an even number.Each Fmoc-protected anchored peptide is formed by the prior deprotected anchored peptide during coupling and is then consumed in the deprotection. Therefore, the mass balance for the Fmoc-protected anchored peptide is calculated by Equation 3, where j is an odd number (i.e. 1, 3, 5 …). VCSTR×dcCSTR,Pjdt = Finlet×cinlet,Pj-Foutlet×coutlet,Pj+VCSTR×kcoupling×cCSTR,AAj+12×cCSTR,Pj-1- VCSTR×kdeprotection×cCSTR,Pj×cCSTR,piperidine 3On the other hand, the deprotected anchored peptide is formed during deprotection and is then consumed in the following coupling. In addition, it is also consumed by the side-reaction with residual amino acid from the previous coupling. Therefore, the mass balance for the deprotected anchored peptide is calculated by Equation 4, where j is an even number (i.e. 2, 4, 6 …). VCSTR×dcCSTR,Pjdt = Finlet×cinlet,Pj-Foutlet×coutlet,Pj+VCSTR×kdeprotection×cCSTR,Pj-1×cCSTR,piperidine- VCSTR×kcoupling×cCSTR,AAj+22×cCSTR,Pj- VCSTR×kside-reaction×cCSTR,AAj2×cCSTR,Pj 4Mass balance for error sequencesThe error sequences are formed by the side-reaction between residual amino acid and deprotected anchored peptide ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Chen", "given" : "Wenqian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharifzadeh", "given" : "Mahdi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shah", "given" : "Nilay", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew Guy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Industrial & Engineering Chemistry Research", "id" : "ITEM-1", "issue" : "23", "issued" : { "date-parts" : [ [ "2017" ] ] }, "page" : "6796-6804", "publisher" : "ACS Publications", "title" : "The Implication of Side-reactions in Iterative Biopolymer Synthesis: The Case of Membrane Enhanced Peptide Synthesis (MEPS)", "type" : "article-journal", "volume" : "56" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Chen et al., 2017)", "plainTextFormattedCitation" : "(Chen et al., 2017)", "previouslyFormattedCitation" : "(Chen et al., 2017)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Chen et al., 2017). The mass balance of these error sequences can be calculated by Equation 5, where Sk represents the error sequence and k is 1, 2, 3 … N for synthesising a peptide with N amino acids. VCSTR×dcCSTR,Skdt = Finlet×cinlet,Sk-Foutlet×coutlet,Sk+VCSTR×kside-reaction×cCSTR,AAk×cCSTR,P2k 5Mass balance during diafiltrationPost-reaction diafiltration is necessary for the removal of all excess reagents (i.e. amino acid and piperidine) through the membrane, which is modelled as two CSTRs connected by a membrane interface (Figure 3(a)). This is based on the assumption that perfect mixing is achieved within both the retentate and permeate compartments due to flow turbulence. When the two compartments are at the same pressure, there is no liquid flow through the membrane and the liquid flows into the retentate compartment of the membrane through the inlet and then exits through the outlet (retentate) (Figure 3 (b)). In this case, no mass transfer takes place through the membrane. Figure 3. (a) Membrane unit. (b) Liquid flow without cross-membrane pressure difference.When the retentate compartment has a higher pressure than the permeate compartment, part of the liquid entering from the inlet passes through the membrane and then exits the permeate compartment through the permeate outlet (Figure 4(a)). Figure 4. (a) Liquid flow in the retentate compartment with cross-membrane pressure difference. (b) Liquid flow in the permeate compartment with cross-membrane pressure difference.Assuming perfect mixing, the retentate compartment is modelled after a conventional CSTR, whose general mass balance is described by Equation 6. The transmembrane flow rate, Ftransmembrane (m3 ? s-1), is calculated by Equation 7. The permeance is a physical property of the membrane and can only be changed by using different kind of membrane. The membrane area can be increased by having a bigger module or multiple parallel modules, while the cross-membrane pressure difference (i.e.?P=Pretentate-Ppermeate) is an operating variable. For a nanofiltration membrane, the maximum value of cross-membrane pressure difference is normally 40 – 50 bar.Vretentate × dcrdt = Ffeed×cfeed-Fretentate×cretentate- Ftransmembrane×ctransmembrane+ Vretentate ×rategeneration 6where Ffeed and Fretentate (m3 ? s-1) are the volumetric flow rates through the inlet and outlet, Ftransmembrane (m3 ? s-1) is the volumetric flow rate through the membrane, Vretentate (m3) is the volume of the retentate compartment, cr, cfeed, cretentate and ctransmembrane (mol ? m-3) are the concentrations of the compound inside the compartment, at the inlet and outlet, and on the permeate side of the membrane tank respectively. Ftransmembrane=B×A×Pretentate-Ppermeate 7where Ftransmembrane (m3 ? s-1) is the volumetric flow rate through the membrane, B (m ? s-1 ? bar-1) is the permeance of the membrane, A (m2) is the membrane area, and Pretentate and Ppermeate (barg) are the gauge pressure of the retentate and permeate compartments respectively. Similarly, the mass balance in the permeate compartment of the membrane unit (Figure 4(b)) can be calculated by Equation 8, where Ftransmembrane and Fpermeate (m3 ? s-1) are the volumetric flow rates through the membrane and outlet, Vpermeate (m3) is the volume of the permeate compartment, cp, ctransmembrane and cpermeate are the concentrations of the compound inside, entering and leaving the compartment. The concentration of the compound entering the permeate compartment is correlated to the concentration at the outlet of the retentate compartment by Equation 9, where R is the rejection of the compound by the membrane. Vpermeate × dcpdt = Ftransmembrane×ctransmembrane-Fpermeate×cpermeate+ Vpermeate ×rategeneration 8R = 1-ctransmembranecretentate 9MEPS in two-stage membrane cascadeAfter the development and validation with experimental data, the process model was extended to the two-stage membrane cascade, which has an additional membrane circuit (Figure 5). The second-stage membrane serves to recover the anchored peptide that permeates through the first-stage membrane and recycle it back to the feed tank. As a result, less anchored peptide leaves the entire membrane system as waste.Figure 5. Two-stage membrane cascade in gPROMS.Variables for performance analysisDue to the large number of variables in the process simulation, several consolidating variables were introduced to analyse the process performance, including synthesis scale, yield, purity, conversion, diavolume, extent of removal, recycle ratio and minimum selling price of the anchored peptide.Since one mole of deprotected peptide forms one mole of extended N-terminus-protected peptide in a coupling and one mole of N-terminus-protected peptide forms one mole of deprotected peptide in a deprotection, the synthesis scale (mol) is defined as the quantity of anchor used in the first coupling (nanchor,initial) (mol) (Equation 10).synthesis scale=nanchor,initial 10The yield of anchored peptide (yieldPi) (%) is defined as the quantity of anchored peptide (nPi) (mol) normalised by the quantity of anchor used in the first coupling (nanchor,initial) (mol) (Equation 11).yieldPi=nPinanchor,initial×100 % 11The purity of anchored peptide (purityPi) (%) is defined as the quantity of anchored peptide (nPi) (mol) normalised by the total quantity of chemical components in the system (ntotal) (mol) including amino acids, piperidine, side products and anchored peptides (Equation 12).purityPi=nPintotal×100 % 12The conversion of anchored peptide in a reaction (i.e. coupling or deprotection) (ConversionPi) (%) is defined as the quantity of the resulting anchored peptide (nPi+1) (mol) normalised by the quantity of the starting anchored peptide (nPi) (mol) (Equation 13).ConversionPi=nPi+1nPi×100 % 13In constant volume diafiltration, diavolume (Vdia) is a dimensionless term for quantifying the total volume of permeate with respect to the system volume (Vsystem) (Equation 14) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.seppur.2013.05.050", "ISSN" : "13835866", "abstract" : "Organic Solvent Nanofiltration (OSN) is a relatively new molecular separation technology used for separating solutes present in an organic solvent. Although there are many potential applications in industrial processes, obtaining a sharp separation between two molecules which are both in the nanofiltration range from 100 to 2000gmol\u22121 remains a challenge. This is because the differences in rejection of the solutes by the membrane are often insufficient for them to be separated in a single filtration stage. Membrane cascades can meet this challenge and have potential for process intensification (PI) allowing more sustainable membrane units. The membrane cascade concept was proposed in the early 1940s, but to date several implementation challenges such as control difficulties have presented major hurdles and only few experimental data have been reported. Here we present a simplified-control cascade process that not only overcomes previous implementation issues, but also minimizes the product loss and maximizes the purity. The process operates using a single high pressure pump as the primary pressure source, and has no need for a buffer tank between membrane stages. The process was tested on an organic solution of polyethyleneglycol 400 (PEG-400) and PEG-2000 in acetonitrile which is a challenging model, as the flexible chains make it difficult to obtain 100% rejection of any PEG. Polyimide and polybenzimidazole membranes were screened for the cascade process. Using this process it was possible to increase the final yield of PEG-2000 from 59% to 94%, and the solvent-consumption/productivity ratio was also reduced. The process has been analyzed using a model developed to predict the cascade performance. It was found experimentally that the recycle ratio, as well as the trans-membrane pressure, affect the process yield significantly, in agreement with the model predictions. Model analysis and experimental validation are presented.", "author" : [ { "dropping-particle" : "", "family" : "Kim", "given" : "Jeong F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freitas da Silva", "given" : "Ana M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Valtcheva", "given" : "Irina B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Separation and Purification Technology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "277-286", "title" : "When the membrane is not enough: A simplified membrane cascade using Organic Solvent Nanofiltration (OSN)", "type" : "article-journal", "volume" : "116" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Kim et al., 2013)", "plainTextFormattedCitation" : "(Kim et al., 2013)", "previouslyFormattedCitation" : "(Kim et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Kim et al., 2013). Vdia= A × B × ?P×t Vsystem 14where B (m ? s-1 ? bar-1) is the permeance of the membrane, A (m2) is the membrane area, ?P is the cross-membrane pressure difference (bar) as in Equation 7, t (s) is the diafiltration time and Vsystem (m3) is the system liquid volume.During constant volume diafiltration, chemical components permeate through the membrane with the solvent. As a result, the extent of removal of a particular chemical component increases with the diavolume. The extent of removal for component i (Extent of removali) is defined as the quantity of the chemical component (ni) (mol) at the end of diafiltration normalised by its quantity at the beginning of the diafiltration (ni,initial) (mol) (Equation 15). Extent of removali=nini,initial×100 % 15As pointed out in a previous study, the recycle ratio (recycle) (%) is an important higher-order variable in membrane cascade operation ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.seppur.2013.05.050", "ISSN" : "13835866", "abstract" : "Organic Solvent Nanofiltration (OSN) is a relatively new molecular separation technology used for separating solutes present in an organic solvent. Although there are many potential applications in industrial processes, obtaining a sharp separation between two molecules which are both in the nanofiltration range from 100 to 2000gmol\u22121 remains a challenge. This is because the differences in rejection of the solutes by the membrane are often insufficient for them to be separated in a single filtration stage. Membrane cascades can meet this challenge and have potential for process intensification (PI) allowing more sustainable membrane units. The membrane cascade concept was proposed in the early 1940s, but to date several implementation challenges such as control difficulties have presented major hurdles and only few experimental data have been reported. Here we present a simplified-control cascade process that not only overcomes previous implementation issues, but also minimizes the product loss and maximizes the purity. The process operates using a single high pressure pump as the primary pressure source, and has no need for a buffer tank between membrane stages. The process was tested on an organic solution of polyethyleneglycol 400 (PEG-400) and PEG-2000 in acetonitrile which is a challenging model, as the flexible chains make it difficult to obtain 100% rejection of any PEG. Polyimide and polybenzimidazole membranes were screened for the cascade process. Using this process it was possible to increase the final yield of PEG-2000 from 59% to 94%, and the solvent-consumption/productivity ratio was also reduced. The process has been analyzed using a model developed to predict the cascade performance. It was found experimentally that the recycle ratio, as well as the trans-membrane pressure, affect the process yield significantly, in agreement with the model predictions. Model analysis and experimental validation are presented.", "author" : [ { "dropping-particle" : "", "family" : "Kim", "given" : "Jeong F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freitas da Silva", "given" : "Ana M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Valtcheva", "given" : "Irina B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Separation and Purification Technology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "277-286", "title" : "When the membrane is not enough: A simplified membrane cascade using Organic Solvent Nanofiltration (OSN)", "type" : "article-journal", "volume" : "116" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Kim et al., 2013)", "plainTextFormattedCitation" : "(Kim et al., 2013)", "previouslyFormattedCitation" : "(Kim et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Kim et al., 2013). The recycle ratio (recycle) (%) at the second-stage membrane circuit (Figure 5) is defined as the percentage of the volumetric flow through the first-stage membrane (F1) (m3 ? s-1) (Equation 16) that is recycled back to the feed tank. The recycle ratio is correlated to both design (A1 and A2) (m2) and operating variables (?P1 and ?P2) (bar) (Equation 18b). A high recycle ratio (i.e. close to 100%) means most of the volumetric flow through the first-stage membrane is recycled back to the feed tank.F1=B1×A1×?P1 16F2=B2×A2×?P2 17recycle=F1-F2F1×100 %=B1×A1×?P1-B2×A2×?P2B1×A1×?P1×100 18aSince the same type of membrane is used in both stage 1 and 2, B1=B2:recycle=A1×?P1-A2×?P2A1×?P1×100 % 18bwhere recycle (%) is the recycle ratio, F1 and F2 (m3 ? s-1) are the volumetric flow rate through the membranes of stage 1 and 2 respectively (Figure 5), B (m ? s-1 ? bar-1) is the permeance, A (m2) is the membrane area and ?P (bar) is the cross-membrane pressure difference. The minimum selling price (Euro ? g-1) of the anchored peptide is used to evaluate the economic performance of the process (Equation 19). It includes the amortisation of capital investment, maintenance of equipment, membrane replacement, chemicals, labour and electricity ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1089/ees.2000.17.61", "ISSN" : "1092-8758", "abstract" : "A model is presented for estimating costs of crossflow ultrafiltration and microfiltration processes. The model incorporates separate correlations for several major components of capital costs, thus accounting for different economies of scale associated with different equipment and facilities. In contrast to previous cost-modeling exercises that have inherently assumed an economy of scale for capital costs based on current design estimates, this work considers an economy of scale for the en- tire membrane system that changes with the design mix as the capacity of the facility increases. The calibrated model is used to explore the impacts of raw water quality, plant capacity, and operating variables on treatment costs. Capital costs amortized per unit of production decrease with plant ca- pacity due to economies of scale. The overall economies of scale associated with a membrane sys- tem are considered as a function of the raw water quality and the resultant permeate flux. When permeate flux is limited due to concentration polarization and cake growth, treatment costs are pre- dicted to demonstrate relatively lower economies of scale. Selection of a combination of design and operating parameters such as membrane radius, transmembrane pressure, and system recovery, which results in higher permeate fluxes for a given raw water quality, is predicted to lower total treatment costs. Key", "author" : [ { "dropping-particle" : "", "family" : "Sethi", "given" : "Sandeep", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wiesner", "given" : "Mark R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Environmental Engineering Science", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2000" ] ] }, "page" : "61-79", "title" : "Cost Modeling and Estimation of Crossflow Membrane Filtration Processes", "type" : "article-journal", "volume" : "17" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.memsci.2015.04.065", "ISSN" : "18733123", "abstract" : "The profitability of a reverse osmosis application has been evaluated by using a well-known economic model based on experimental data, where additional operating costs were considered to represent a more realistic estimation. A calculation template was included to provide an easy-access to a preliminary economic evaluation of a specific membrane installation. The response of the model was checked with a real reverse osmosis application as this is the condensate recovery from a dairy ultra-high-temperature plant. A sensitivity analysis was performed to show the model behaviour when subjected to some process parameter fluctuations. The base case, which considers a design flow of 20m³/h, produced a payback period of 3.3 years, being a cost-effective facility for the amortization period studied. The recovery rate proved to be a relevant parameter of influence in the economic viability of the process, as an increase of 20% produced an improvement of 48.6% in the net present value estimated.", "author" : [ { "dropping-particle" : "", "family" : "Su\u00e1rez", "given" : "Adri\u00e1n", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fern\u00e1ndez", "given" : "Pablo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ram\u00f3n Iglesias", "given" : "Jos\u00e9", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Iglesias", "given" : "Estefan\u00eda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Riera", "given" : "Francisco A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Membrane Science", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "389-402", "title" : "Cost assessment of membrane processes: A practical example in the dairy wastewater reclamation by reverse osmosis", "type" : "article-journal", "volume" : "493" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Sethi and Wiesner, 2000; Su\u00e1rez et al., 2015)", "plainTextFormattedCitation" : "(Sethi and Wiesner, 2000; Su\u00e1rez et al., 2015)", "previouslyFormattedCitation" : "(Sethi & Wiesner, 2000; Su\u00e1rez, Fern\u00e1ndez, Ram\u00f3n Iglesias, Iglesias, & Riera, 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Sethi and Wiesner, 2000; Suárez et al., 2015). The details of the economic model can be found in Section S6 in the supplementary information as well as the previous literature ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Chen", "given" : "Wenqian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015" ] ] }, "publisher" : "Imperial College London", "title" : "Membrane Enhanced Peptide Synthesis (MEPS) \u2013 Process Development and Application", "type" : "thesis" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Chen, 2015)", "plainTextFormattedCitation" : "(Chen, 2015)", "previouslyFormattedCitation" : "(Chen, 2015)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Chen, 2015).Minimum selling price = (AC + CMC + CMA)AP + (CE + CC + CL)CP (19)where AC(Euro ? year-1) is the amortisation constituent, CMC(Euro ? year-1) is the cost of membrane replacement, CMA(Euro ? year-1) is the cost of maintenance, CE (Euro ? cycle-1) is the cost of energy, CC (Euro ? cycle-1) is the cost of chemicals, CL (Euro ? cycle-1) is the cost of labour, AP (g ? year-1) is the annual production rate of product and CP (g ? cycle-1) is the cycle production rate of product.Results and discussionsIn this section, the process model of MEPS in a single-stage membrane system was validated with experimental data and then extended to a two-stage membrane cascade. The dynamic quantities of intermediate products (i.e. the growing anchored peptide chain), as well as the overall yield for single-stage and two-stage systems were compared in order to show the advantage of performing MEPS in a two-stage cascade. Operational variable analysis was then performed to show the overall yield can change with operating variables such as the diavolume of post-coupling diafiltration and recycle ratio.Validation of process model in single-stage membrane systemThe process model enables the dynamic simulation of all couplings, N-terminus deprotection and post-reaction diafiltrations. The simulation inputs for single-stage MEPS are summarised in Section S2 in the supplementary information. The structural analysis of the gPROMS model shows that there are 711 variables, of which 209 are assigned and the remaining 502 are calculated. The model has 502 equations, of which 180 are ordinary differential equations and 322 are algebraic equations. In order to solve the system of equations, 180 initial conditions are provided. As a result, the degree of freedom is zero. Unlike other software such as MATLAB, it is not necessary to specify the calculation sequence in gPROMS, since it is handled by the software internally. The assumptions for the calculation of mass balance are listed below:Tubes behave as PFR.Tanks and compartments in membrane units behave as CSTR.Membrane has constant rejection for each component and constant permeance.The reactions are first-order with respect to each participating reactant.The coupling reactions have the same rate constant.The N-terminus deprotection reactions have the same rate constant.Assumption 1 and 2 are valid due to the high flow rates within the system. Assumption 3 is valid for ceramic membrane that was used in the current study, but may not be invalid for polymeric membrane during compression. Assumption 4 is valid due to the known chemistry of coupling and N-terminus deprotection, but should be modified if the reactions follow more complicated pathways. Assumption 5 and 6 are valid for the reactions with short peptide, but could be invalid for longer ones whose properties are more dependent on peptide length. The process model of MEPS in a single-stage membrane system is validated with the results in Table 1. This table shows that there is a close agreement between the overall yield and purity of the anchored peptide (structure shown in Figure S3 of supplementary information) calculated by the model (72.2 % and 89.1 % respectively) and their corresponding experimental values (71.2 % and 88.1 % respectively). Table 1. Experimental and modelling results of single-stage MEPS.ExperimentalModellingOverall yield* (%) 71.272.2Final purity (%)88.189.1%*The overall yield was before cleavage and global deprotection (i.e. the peptide was still bound to the anchor).Figure 6 shows that the current process model accurately captures the dynamic interactions between two consecutive anchored peptides. Except for the anchored peptides with the full sequence, all the other anchored peptides go through three general stages in MEPS: Formation through the coupling reactionPurification by diafiltrationConsumption as the next peptide in the sequence is formedWhen put together, the rise and fall in the quantity of each anchored peptide over time forms a wave pattern in Figure 6. Each operation (i.e. coupling, N-terminus deprotection, post-coupling diafiltration and post-N-terminus-deprotection) had a fixed processing time based on the experimental values, which are specified in Table S2 and S3 in the supplementary information.Using Fmoc-AA(1)-Anchor as an example, its quantity increases from zero to the synthesis scale (i.e. 33.6 mmol) in the first coupling, as the anchor reacts with Fmoc-AA(1). In the post-coupling diafiltration, its quantity decreases slightly due to its permeation through the membrane. Its quantity diminishes rapidly in the next deprotection, where it reacts with piperidine to form the next anchored peptide, H2N-AA(1)-Anchor. The general downward trend of anchored peptide quantities over time was mainly due to the mass loss through the membrane during diafiltrations. Figure 6. Quantities of anchored peptides during MEPS in a single-stage membrane system.Extension of process model to two-stage membrane cascadeThe data in Table 1 provide confidence in the accuracy of the process model, which was next extended to the two-stage configuration. The simulation inputs for two-stage MEPS are summarised in Section S3 in the supplementary information. Table 2 presents the modelling results for MEPS in both single-stage and two-stage membrane systems. With the same synthesis scale (33.6 mmol), the system volume and total membrane area increase by 124% and 90% respectively from the single-stage system to the two-stage cascade due to the additional membrane circuit. The second-stage membrane successfully recovers the anchored peptide that permeates through the first-stage membrane, improving the overall yield significantly (i.e. 32%). However, the second-stage membrane also retains part of the excess reagents such as amino acids and piperidine that permeate through the first-stage membrane. As a result, a larger diavolume is needed (i.e. 33% more) to achieve the same purity of anchored peptide before reactions, leading to a 25% increase in process time.As shown in Figure 7, the two-stage cascade successfully reduces the yield loss during diafiltrations by recovering the anchored peptides which permeate through the first-stage membrane due to incomplete rejection. Each operation (i.e. coupling, N-terminus deprotection, post-coupling diafiltration and post-N-terminus-deprotection) had fixed operation time as indicated in Table S3 and S4 in the supplementary information. As a result of the improved overall yield, the minimum selling price of the anchored peptide is reduced by 10% (Table 2). Table 2. Modelling results for MEPS in single-stage and two-stage membrane systems.Single-stageTwo-stageChanges*Synthesis scale (mmol)33.633.50 %System volume (mL)400894+ 124 %Total membrane area (Atotal) (m2)0.05120.0973+ 90 %Total diavolume92122+ 33 %Total process time (h)5265+ 25 %Overall yield (%)72.295.3+ 32 %Final purity (%)89.195.8+ 8 %Minimum selling price (Euro ? g-1)3733- 10 %*Change with respect to MEPS in a single-stage system.Figure 7. Quantities of anchored peptides during MEPS in single-stage and two-stage membrane systems.Operational variable analysis Operational variable analysis illustrates how the overall yield of anchored peptide depends on the operational variables, including the diavolumes employed for the post-coupling and post-deprotection diafiltrations, as well as the recycle ratio in the two-stage membrane cascade. The diavolume is linearly proportional to the diafiltration process time (Equation 14), whereas the recycle ratio is collectively determined by the cross-membrane pressure differences in the first- and second-stage membranes (Equation 18b). The diavolume and recycle ratio are interrelated for achieving a target purity of the anchored peptide at the end of the diafiltration process. A higher recycle ratio means more anchored peptide that permeates through the first-stage membrane as well as impurities are covered by the two-stage system, and hence a higher diavolume is required to achieve the same purity. However, the resulting yield can either increase or decrease based on the specific combination of the diavolume and recycle ratio. This means the yield and purity have a complex relationship in the case of two-stage membrane cascade, which can be studied with the current dynamic process model. Dynamic simulations were performed, where the selected variable was perturbed while keeping all others constant. The reference value for each variable was the original input value for the simulations discussed in the previous sections. Details of the original inputs for the simulations can be found in the supplementary information. The relationships between the overall yield of anchored peptide and operational variables are different for single-stage and two-stage MEPS.Sensitivity with respect to the diavolume employed for post-coupling diafiltrations Activated amino acid is used in slight excess (0.05 equivalent) to drive each coupling to completion. At the end of each coupling, the system contains unreacted amino acid which will participate in side-reactions during the N-terminus deprotection and consumes the anchored intermediate products. The post-coupling diafiltrations serve to remove the unreacted amino acid in the system before the N-terminus deprotection. The diavolume in two-stage MEPS is with respect to the stage 1 system volume, which includes the feed tank, pipe 1, 2 and 3, as well as the retentate compartment of the stage 1 membrane unit (Figure 5). As the diavolume of every post-coupling diafiltration increases, the percentage of unreacted amino acid (normalised by the production scale) decreases from 5% to less than 1% for MEPS in both single-stage and two-stage membrane systems (Figure 8). However, the removal of unreacted amino acid is less efficient in the two-stage process, since the second-stage membrane not only retains the anchored intermediate product, but also the unreacted amino acid. As a result, the two-stage MEPS requires 1.4 times diavolume for post-reaction diafiltration in order to achieve the same purity level as in single-stage MEPS.Figure 8. The quantity of unreacted amino acid at the beginning of each N-terminus-deprotection normalised by the production scale as the effect of changing the diavolume employed for every post-coupling diafiltration for single-stage and two-stage MEPS. Although increasing the diavolume reduces the amount of unreacted amino acid in the system, and hence reduces the extent of side-reactions during the subsequent N-terminus deprotection, it also increases the loss of the anchored intermediate product through the membrane. The effect on the overall yield is therefore a combination of these two effects. As shown in Figure 9, the overall yield decreases by 8% (i.e. from 77.6% to 72.2%) as the diavolume increases from zero to four for single-stage MEPS. This shows that the impact of the loss of anchored intermediate products during diafiltrations outweighs that of the side-reactions. Interestingly, the effect of increasing the diavolume of every post-coupling diafiltration on the overall yield is the opposite for two-stage MEPS, as the overall yield increases slightly from 94.4% to 95.3% (Figure 9). This is because the second-stage membrane not only retains the anchored intermediate products, but also the unreacted amino acids, which leads to a greater extent of side-reactions. A larger diavolume in two-stage MEPS reduces the quantity of unreacted amino acid in the system and therefore the extent of the resulting side-reactions. Figure 9. The effect of changing the diavolume of every post-coupling diafiltration on the overall yield for single-stage and two-stage MEPS.Sensitivity with respect to the diavolume employed for post-deprotection diafiltrationsPiperidine is used in large excess to drive the N-terminus deprotection to completion, but it must be removed thoroughly by diafiltration before the next coupling. Otherwise, residual piperidine will consume the activated amino acid, leading to the formation of error sequences due to incomplete couplings and ultimately a lower overall yield. Figure 10 shows that 14 diavolumes for the first post-deprotection diafiltration in the single-stage process can reduce the quantity of residual piperidine (normalised by the quantity of excess amino acid at the beginning of the following coupling) to 2.9%. Reducing this diavolume to 10 results in a higher normalised quantity of piperidine (34.9%). Similar to the removal of excess amino acid in post-coupling diafiltration, the removal of piperidine in the two-stage process is less efficient than in its single-stage counterpart. Even with 17 diavolumes, the normalised quantity of piperidine is relatively high (i.e. 65.6%). Decreasing the diavolume will results in a rapid increase in the normalised amount of piperidine (Figure 10).Figure 10. Quantity of residual piperidine at the end of the first post-deprotection diafiltration normalised by the quantity of excess amino acid at the beginning of the following coupling.Figure 11 shows that the overall yield increases sharply from 0 to 7 diavolumes for single-stage MEPS and from 0 to 11 diavolumes for two-stage MEPS. These results demonstrate clearly that, unlike their post-coupling counterparts, post-deprotection diafiltrations are crucial for achieving high overall yield in both single-stage and two-stage MEPS by avoiding incomplete couplings due to the presence of residual piperidine. This result is consistent with the previous study ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Chen", "given" : "Wenqian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharifzadeh", "given" : "Mahdi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shah", "given" : "Nilay", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew Guy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Industrial & Engineering Chemistry Research", "id" : "ITEM-1", "issue" : "23", "issued" : { "date-parts" : [ [ "2017" ] ] }, "page" : "6796-6804", "publisher" : "ACS Publications", "title" : "The Implication of Side-reactions in Iterative Biopolymer Synthesis: The Case of Membrane Enhanced Peptide Synthesis (MEPS)", "type" : "article-journal", "volume" : "56" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Chen et al., 2017)", "plainTextFormattedCitation" : "(Chen et al., 2017)", "previouslyFormattedCitation" : "(Chen et al., 2017)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Chen et al., 2017).Figure 11. The effect of changing the diavolume of every post-deprotection diafiltration on the overall yield for single-stage and two-stage MEPS.Sensitivity with respect to the recycle ratio in two-stage MEPSIn the two-stage process, the recycle ratio during diafiltration (Equation 18a & 18b) is another important variable that greatly influences the overall yield. It was found previously that a higher recycle ratio always results in a higher yield for the purification of polyethylene glycol 2000 (PEG 2000) from polyethylene glycol 400 (PEG 400) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.seppur.2013.05.050", "ISSN" : "13835866", "abstract" : "Organic Solvent Nanofiltration (OSN) is a relatively new molecular separation technology used for separating solutes present in an organic solvent. Although there are many potential applications in industrial processes, obtaining a sharp separation between two molecules which are both in the nanofiltration range from 100 to 2000gmol\u22121 remains a challenge. This is because the differences in rejection of the solutes by the membrane are often insufficient for them to be separated in a single filtration stage. Membrane cascades can meet this challenge and have potential for process intensification (PI) allowing more sustainable membrane units. The membrane cascade concept was proposed in the early 1940s, but to date several implementation challenges such as control difficulties have presented major hurdles and only few experimental data have been reported. Here we present a simplified-control cascade process that not only overcomes previous implementation issues, but also minimizes the product loss and maximizes the purity. The process operates using a single high pressure pump as the primary pressure source, and has no need for a buffer tank between membrane stages. The process was tested on an organic solution of polyethyleneglycol 400 (PEG-400) and PEG-2000 in acetonitrile which is a challenging model, as the flexible chains make it difficult to obtain 100% rejection of any PEG. Polyimide and polybenzimidazole membranes were screened for the cascade process. Using this process it was possible to increase the final yield of PEG-2000 from 59% to 94%, and the solvent-consumption/productivity ratio was also reduced. The process has been analyzed using a model developed to predict the cascade performance. It was found experimentally that the recycle ratio, as well as the trans-membrane pressure, affect the process yield significantly, in agreement with the model predictions. Model analysis and experimental validation are presented.", "author" : [ { "dropping-particle" : "", "family" : "Kim", "given" : "Jeong F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freitas da Silva", "given" : "Ana M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Valtcheva", "given" : "Irina B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livingston", "given" : "Andrew G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Separation and Purification Technology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "277-286", "title" : "When the membrane is not enough: A simplified membrane cascade using Organic Solvent Nanofiltration (OSN)", "type" : "article-journal", "volume" : "116" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "(Kim et al., 2013)", "plainTextFormattedCitation" : "(Kim et al., 2013)", "previouslyFormattedCitation" : "(Kim et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Kim et al., 2013). However, higher recycle ratio does not always result in higher overall yield for two-stage MEPS. Figure 12 shows that increasing the recycle ratio from 10% to 90% results in an initial increase in overall yield from 95.3% to 98.2% (for recycle ratio from 10% to 40%), which is followed by a slight decrease from 98.2% to 94.6%. In other words, a recycle ratio of 40% is sufficient to improve the overall yield significantly compared to the single-stage process (i.e. from 72.2% to 98.2%). Increasing the recycle ratio further is not necessary, since this will only retain more impurities in the system and increase the diavolume required for achieving the same purity of intermediate product after each diafiltration. As mentioned in the previous sections, the increased diavolume results in lower overall yield. Figure 12. The effect of recycle ratio on the overall yield two-stage MEPS.ConclusionA dynamic process model was developed for the mass balance of chemical components involved in the single-stage MEPS of a model hexapeptide. The model accounts for side reactions that can happen in the presence of residual amino acid and piperidine due to their incomplete removal during diafiltrations. The process model was validated with experimental data, showing close agreement between the simulation results and the experimental results for the overall yield and purity of the anchored peptide. The extended two-stage MEPS model shows that it is indeed advantageous over single-stage MEPS, as the second-stage membrane recovers the anchored peptide that permeates through the first-stage membrane due to the incomplete retention of anchored peptide by membrane (i.e. rejection = 99.7%), leading to a significant improvement of overall yield from 72.2% to 95.3%. However, the more complex operation presented by two-stage MEPS is the trade-off for the enhanced yield, as the second-stage membrane also increases the retention of impurities (i.e. residual amino acid and piperidine) during diafiltration, resulting in more diavolumes being required (i.e. more fresh solvent and time). Operational variable analysis shows that the post-deprotection diafiltration is crucial for ensuring high overall yield. Converse to the previous study that shows a higher recycle ratio always results in higher overall yield for non-reacting systems (i.e. PEG 2000 and PEG 400), operational variable analysis shows a recycle ratio of 40% is optimal for the current two-stage MEPS, as higher recycle ratio results in higher retention of piperidine which impedes couplings. As a result, more diavolumes are required for post-deprotection diafiltrations in order to maintain a low level of residual piperidine, sacrificing the overall yield. The current dynamic model in gPROMS can be easily extended to more complex system configurations and the iterative synthesis of biopolymers in general by adapting it accordingly (the simulation file is downloadable as supplementary information of this article). For example, similar modelling and optimization frameworks can be performed for the synthesis of oligonucleotides by adding the relevant reaction rate equations into the mass balance of the model and more complex configurations such as three-stage membrane cascade can be easily constructed with an additional membrane circuit to the permeate compartment of the second-stage membrane unit. ORCIDWenqian Chen: 0000-0001-8867-3012Mahdi Sharifzadeh: 0000-0002-7895-5646Nilay Shah: 0000-0002-8906-6844Andrew G. Livingston: 0000-0003-0074-1426DeclarationThe authors declare no competing financial interest.AcknowledgmentPart of the current work was supported by the European Community's Seventh Framework Programme (FP7/2007-2013) [grant number 238291].ReferenceADDIN Mendeley Bibliography CSL_BIBLIOGRAPHYAbatemarco, T., Stickel, J., Belfort, J., Frank, B.P., Ajayan, P.M., Belfort, G., 1999. Fractionation of Multiwalled Carbon Nanotubes by Cascade Membrane Microfiltration. J. Phys. Chem. B 103, 3534–3538. , F., 2000. Solid-phase synthesis: a practical guide. CRC Press.Behrendt, R., White, P., Offer, J., 2016. Advances in Fmoc solid-phase peptide synthesis. J. Pept. Sci. , E., Majozi, T., 2015. Effective Synthesis and Optimization Framework for Integrated Water and Membrane Networks: A Focus on Reverse Osmosis Membranes. Ind. Eng. Chem. Res. 150915083245002. , V., Noti, C., Chen, W., Cristau, M., Livignston, A., Rodriguez, H., Albericio, F., 2017. 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