Steady-state Recycling Research Articles

Global optimization of batch and steady-state recycling chromatography based on the equilibrium model

A bi-level approach is presented for the optimal design of batch and steady-state recycling (SSR) chromatography. On the first level, an efficient formulation as mixed-integer problem (MIP) is applied to obtain optimal fractionation times for chromatograms simulated by the equilibrium model. On the second level, the optima are evaluated against a parametrized objective function. The combination of model and optimization method provides a computationally very efficient tool. A comprehensive example study demonstrates that batch chromatography achieves the highest productivities at the cost of limited yields, which is optimal only for vanishing feed costs. In other instances, the more flexible SSR concept provides larger profits. The results reveal also new optimal operating policies for SSR processes with segmented product fractions and waste streams.

Steady-state recycling chromatography in the purification of weakly acidic lignocellulosic hydrolysates

Abstract Purification of monosaccharides from lignocellulosic hydrolysates using mixed recycle steady-state recycling chromatography (SSR) was studied experimentally on a pilot scale and via simulations. A hydrophilic, weak cation exchange resin was used as separation material, enabling the removal of lignin, formic acid, acetic acid, hydroxymethyl furfural, and furfural in a single step. Lignin concentration had only a minor effect on separation efficiency. The exchange of the Na+ ions of the resin with Ca2+ ions from the hydrolysates was found to decrease separation efficiency. The full recovery of separation efficiency could be obtained via a natrium citrate treatment of the resin. Very strong sorption of some lignin molecules led to coloring of the resin but did not affect separation efficiency. Simulations showed that depending on the monosaccharide concentration of the hydrolysates, the SSR mode yielded 13–20% higher monosaccharide productivity than the batch mode. The experimental investigation of the fractionation on a pilot scale revealed that viscous fingering due to a highly concentrated feed (≥360 g/L) lowered the separation efficiency in single-column batch mode but not in SSR mode. Thus, in practice, SSR is even more efficient than the batch process than was suggested by the simulations.

Chromatographic separation of ethyl-β-d-glucopyranoside and d-glucose with steady-state recycling chromatography

Abstract Mixed-recycle steady-state recycling chromatography (SSR) is an efficient and simple chromatographic process scheme that can be used to improve the separation efficiency of single-column batch process in binary separations. Despite many theoretical and numerical simulation studies, experimental investigations of the mixed-recycle SSR mode, which is the most straightforward to design and implement, are still rather scarce. In this work, the use of SSR was investigated under strongly non-ideal conditions. A novel design method for determining the cut times of the recycle fraction of SSR was derived for systems with components having linear sorption isotherms. This method allows determination of the cut times directly from chromatograms obtained with the batch process in the same operating conditions as would be used in SSR. The applicability of the method was investigated with chromatographic separation of ethyl β- d -glucopyranoside (BEG) and glucose. The performance of SSR was investigated experimentally and by simulations. The design method was found to be well applicable in this case as BEG and glucose fractions fulfilling the set purity requirements (98 wt% for both) could be obtained. SSR was found to be over 50% more efficient than the batch process with respect to specific productivities and water (eluent) consumption. Numerical optimization of SSR with respect to flow rate and column loading gave the same optimal operation point as was obtained experimentally. At this global optimum, SSR was 20% more efficient with respect to productivity than the batch process at its global optimum with a single cut separation, and only 14.5% less efficient than a 4-zone SMB (1:1:1:1 configuration). The results demonstrate the efficiency of SSR over batch process, and show that SSR is a viable option for 4-zone SMB process due to low investment costs and simple operation.

Steady state recycling chromatography with an integrated solvent removal unit – Separation of glucose and galactose

A process concept where a solvent removal unit is integrated to a steady-state recycling chromatography process (SSR–SR) offers a possibility to significantly increase the performance of single column chromatographic separation. The advantages of solvent removal for a difficult separation task at conditions typical for industrial scale chromatography were demonstrated by investigating the performance of SSR–SR in separation of glucose and galactose. Two limits for the extent of solvent removal were imposed: maximum total concentration of the solution fed into the column (viscosity limit) and the maximum total concentration achievable in the solvent removal unit (solubility or osmotic pressure limit). The process was optimized using numerical simulation. Three SSR–SR configurations with different positions of the solvent removal unit were compared with (1) the conventional batch process, (2) SSR without solvent removal, and (3) batch process with solvent removal. SSR–SR was found to always improve the productivity. In addition, solvent removal reduced eluent consumption in most cases. The concentration limits and the concentration of the fresh feed were shown to determine which SSR–SR configuration yields the best performance.

Steady State Recycling Chromatography in Acid–Sugar Separation on an Ion-Exchange Resin

Separation of sulphuric acid and glucose using steady-state recycling chromatography (SSR) was investigated experimentally and by simulations. The application is relevant for the recovery of fermentable monosaccharides from lignocellulosic hydrolysates. Choosing appropriate cut times beforehand was found to be challenging because of complex phase equilibrium behavior. An empirical isotherm model that accounts for co-operative sorption was used in simulations. SSR provided 60% higher productivity with 45% lower eluent consumption than batch when equal flow rates were used. Productivity of SSR was strongly improved without a significant increase in eluent consumption by simultaneously increasing flow rate and injection volume.

Simplified design of steady-state recycling chromatography under ideal and nonideal conditions

In a recent contribution a design method for steady-state recycling chromatography in the so-called mixed-recycle mode (MR-SSR) has been proposed by Sainio and Kaspereit (2009). The method holds under ideal, dispersion-free conditions for chromatographic systems with competitive Langmuir adsorption isotherms. Here this approach is extended to practically relevant nonideal conditions with significant dispersive effects and convex-upward adsorption isotherms in general. The developed shortcut design method allows designing MR-SSR processes based on a simple procedure applied to a single conventional chromatogram. The method is validated experimentally for the separation of two cycloketones on a polymeric stationary phase. The performance of the MR-SSR process is compared to batch chromatography by means of a simulation study.

Theoretical analysis of steady state recycling chromatography with solvent removal

The possibility to enhance the process performance of steady state recycling (SSR) chromatography by removing solvent was investigated in the framework of the equilibrium theory. A method was developed to choose a priori the relevant cut times corresponding to arbitrary purity constraints and to predict the steady state of the process without performing dynamic simulations. The amount of fresh feed introduced per cycle and the injection width were identified as the only free operating parameters. A relationship was derived between the amount of fresh feed and the solvent removal capacity required to achieve the chosen purities. The performance of three different process configurations was analyzed: solvent removal applied to (I) the fresh feed, (II) the recycle fraction, and (III) their mixture. It was found that solvent removal facilitates treating more fresh feed per cycle than is possible in a conventional SSR process. In addition, it was shown that the three SSR-SR configurations have identical performance with the same operating parameters. In contrast, the configurations differ with respect to the maximum amount of fresh feed that can be processed per cycle, as well as to the range of feasible injection widths. It was shown that SSR with solvent removal can yield higher productivity and lower eluent consumption than an optimized batch chromatography process that employs solvent removal.

Supercritical fluid chromatography and steady‐state recycling: Phase appropriate technologies for the resolutions of pharmaceutical intermediates in the early drug development stage

The use of phase appropriate technologies is critical for efficiently moving drug candidates forward in the early stages of drug discovery and development. Phase appropriate purification technology develops the analytical method and subsequently scales up the method and turns the sample around quickly (Kennedy et al., J Chromatogr A 2004; 1046:55). In this article, separation results and conditions from supercritical fluid chromatography (SFC), high-performance liquid chromatography (HPLC), and steady-state recycling (SSR) for the resolutions of three pharmaceutical intermediates in the early stage of the drug development are discussed. The first study used SFC and SSR to separate an impurity for a Good Manufacturing Practice (GMP) campaign. The analytical method development and scale-up conditions are discussed. Productivity, solvent usage, and sample solubility under SFC and SSR conditions are also compared. The second study compared SFC to batch HPLC in separating a diastereomer. Due to higher separation efficiency, SFC was able to resolute multiple peaks. The third study involved the addition of dichloromethane as a co-solvent in SFC purification--improving sample selectivity and solubility. From the separation results of these purifications, SFC and SSR are clearly phase appropriate technologies in the early drug development stage.

Streamlined, two-column, simulated countercurrent chromatography for binary separation

We report on a numerical and experimental study of two-column versions of streamlined, multicolumn, semi-continuous chromatography for binary separation. The systems combine a flexible node design, cyclic flow-rate modulation, and relayed operation of the inlet/outlet ports to extend the mass-transfer zone over the largest possible length, while keeping it inside the system at all times. One advantage of these streamlined designs is the simplicity of their physical realization: regardless of the number of columns, they only require two pumps to supply feed and desorbent into the system, while the flow rates of liquid withdrawn from the system are controlled by material balance using simple two-way valves. In one case, an extra pump is needed to recirculate the fluid in closed-loop. A rigorous model-based optimization approach is employed in the optimal design of the cycles to generate solutions that are physically realizable in the experimental set-ups. The optimized schemes for two-column operation supply fresh feed into the middle of the system where the composition of the circulating fluid is closest to that of the feedstock fluid, and recover the purified products, extract and raffinate, alternately at the downstream end of the unit, while desorbent is continuously supplied into the upstream end of the system. By internally recycling part of the non-pure cut fraction, the scheme with a step of closed-loop recycling significantly reduces its solvent consumption. The feasibility and effectiveness of the reported two-column processes have been verified experimentally on the linear separation of nucleosides by reversed phase subject to 99% purity constraints on both products. It is shown that our processes compare favorably against single-column batch chromatography, steady-state recycling, and four-column, open-loop SMB, for the same amount of adsorbent; they are also better than the four-column, closed-loop SMB at high feed throughputs.

Analysis of steady state recycling chromatography using equilibrium theory

This paper presents a method for analysis and design of steady state recycling (SSR) chromatography under arbitrary purity or yield requirements. The approach applies to SSR processes in mixed-recycle operation and allows for the direct prediction of the steady state and the design parameters without performing dynamic simulations. Therefore, it simplifies optimal design of SSR processes and evaluation of process performance, while allowing minimizing the startup time of the process. It was shown that, when the purity and/or yield of the product fractions is specified, the total injection width is the only free operating parameter in mixed-recycle SSR chromatography. Theoretical analysis of the process revealed that the productivity is necessarily lower than that of an optimized separation by batch chromatography. On the other hand, the SSR process always outperforms batch chromatography in terms of eluent consumption and product concentrations.

Improvement in industrial re-chromatography (recycling) procedure in solvent gradient bio-separation processes

Re-chromatography or recycling impure products obtained from the batch runs of solvent gradient chromatography is commonly practiced in industry to improve product yield. However, as the re-chromatography steps are carried out at the expense of running fresh batches, any improvement in the yield comes as a trade-off with the production time, and hence productivity. In recent studies, on the other hand, it has been suggested that with a properly designed recycling process one can not only improve the yield, but the productivity as well. That study, however, considered a steady-state recycling process, a technology yet to be implemented with bio-chromatographic systems. In the present paper we are reporting a study made on non-steady-state recycling or re-chromatography, as it is typically done in industrial practice. The results point out an amendment to the standard way of designing solvent gradients, which is necessary to improve both the yield and the productivity of an industrial run with recycle. Although the test case used here was the separation of an industrial peptide, Calcitonin, in a reversed-phase column, the general methodology of gradient manipulation, needless to say, is also valid for other solvent gradient processes like ion-exchange, HIC, etc.

The application of preparative batch HPLC, supercritical fluid chromatography, steady‐state recycling, and simulated moving bed for the resolution of a racemic pharmaceutical intermediate

This article discusses the chromatographic resolution of a racemic pharmaceutical intermediate. Preparative batch high performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC), steady-state recycling (SSR), and simulated moving bed (SMB) were used to resolve a total of 12.2 kg of a racemic pharmaceutical intermediate. In this study, a first batch of 0.8 kg of racemate was separated on the preparative batch HPLC and SFC, and subsequently another 5.9 kg of racemate was separated on the SSR. Lastly, a third batch of 5.5 kg was separated on the SMB. The separation conditions and results of these techniques are discussed. The productivities and solvent costs of SFC versus HPLC are compared. The productivities and solvent costs of SMB, SSR, and HPLC are also compared. The analytical method development and process optimization of these processes are also discussed in this article.

Optimization of steady state recycling parameters utilizing polarimetry in chiral separations

Processing gram to kilogram quantities of target analytes has led to the exploration of several high-throughput separation techniques. Among those investigated is steady state recycling (SSR). Similar to simulated moving bed (SMB) fractions are collected from the leading and trailing edges of a chromatographic profile while sample material is injected into the interior. Purifying large amounts of sample in the semi-preparative stage is ideal for these groups. SSR allows for development of methods capable of separating 50 g to kilograms and even greater amounts of product efficiently. Using polarimetry to optimize the SSR method further improves the efficiency of method development, providing comprehensive data leading to incisive development decisions. Accurate sample injection allowed continual 99% enantiomer separation after polarimetry optimization. We have developed an efficient SSR optimization methodology that offers rapid development of chiral separation by SSR.

Large GLUT4 Vesicles Are Stationary While Locally and Reversibly Depleted During Transient Insulin Stimulation of Skeletal Muscle of Living Mice

OBJECTIVE—Insulin stimulates glucose transport in skeletal muscle by GLUT4 translocation from intracellular compartments to sarcolemma and t-tubules. We studied in living animals the recruitment of GLUT4 vesicles in more detail than previously done and, for the first time, analyzed the steady-state recycling and subsequent re-internalization of GLUT4 on an insulin bolus. RESEARCH DESIGN AND METHODS—A confocal imaging technique was used in GLUT4-enhanced green fluorescent protein–transfected superficial muscle fibers in living mice. RESULTS—During the first 30 min of insulin stimulation, very few superficially or deeply located GLUT4 storage vesicles (>1 μm) moved in toto. Rather, big vesicles were stationary in their original position at sarcolemma or t-tubules and were locally depleted of GLUT4 by budding off of smaller vesicles. Photobleaching experiments revealed that during initial translocation and steady-state recycling, GLUT4 microvesicles (<1 μm) move from perinuclear GLUT4 depots out along the plasma membrane. Furthermore, after photobleaching of t-tubule areas, recovery of GLUT4 was slow or absent, indicating no recycling of GLUT4 from perinuclear or adjacent (1 μm) or more distant (20 μm) t-tubule areas. During waning of insulin effect, GLUT4 was re-internalized to basal stores with a delay in t-tubules compared with sarcolemma, probably reflecting delayed disappearance of insulin from t-tubules. CONCLUSIONS—In skeletal muscle, insulin reversibly stimulates local depletion of GLUT4 storage vesicles at sarcolemma and t-tubules rather than inducing movement of intact storage vesicles. During steady-state stimulation, recycling of GLUT4-containing microvesicles over longer distances (10–20 μm) takes place between perinuclear depots and sarcolemma but not at t-tubules.

Rapid and high throughput separation technologies—Steady state recycling and supercritical fluid chromatography for chiral resolution of pharmaceutical intermediates

The SSR and SFC techniques were used for the enantiomeric resolution of three pharmaceutical intermediates at various sample scales. The separation conditions, the sample purities and yields, the productivities and the solvent consumptions were discussed in three case studies in this paper. In case (I), the SSR process was used for a low selectivity resolution of 2.0 kg of pharmaceutical intermediate. By using this separation process, a productivity of 750 g racemate/kg stationary phase/day was achieved, while solvent usage was minimized (∼200 l/kg racemate). Case (II) pertained to the effectiveness of the SSR process. Productivity using SSR techniques increased by a factor of 4.5, while solvent usage decreased by a factor of 4.1 when compared to the productivity and solvent usage of batch HPLC. Case (III) compared SFC purification to HPLC purification. The SFC process was more effective in terms of an increase in productivity and a reduction in solvent usage. Based on these results, it appears that SSR and SFC are very useful choices at the early stage of the drug development for a high throughput and a rapid turn around of samples.

Resolution of a racemic pharmaceutical intermediate: A comparison of preparative HPLC, steady state recycling, and simulated moving bed

Preparative HPLC and simulated moving bed (SMB) chromatography were used to resolve significant quantities of a racemic pharmaceutical intermediate. In addition, smaller scale studies using closed-loop recycling and steady state recycling (SSR) were performed so that a meaningful comparison of all these techniques could be made using the same real world separation. A highly optimized, six-column SMB process was clearly the superior technique and was used for the process-scale (247 kg of racemate) resolution. At the more moderate lab-scale (33 kg of racemate and 19 kg of racemate), a frequently used but less optimized eight-column SMB process was used. It was found that SSR was comparable to the lab-scale SMB process in productivity and solvent consumption. Thus, it appears that SSR can be a useful choice at such moderate scales. Finally, at moderate scales when neither SSR nor SMB is available, it was found that acceptable results were obtained with both closed-loop recycling and with a two-step preparative process.

Modeling of separations by closed-loop steady-state recycling chromatography of a racemic pharmaceutical intermediate

Closed-loop steady-state recycling (SSR) is a cyclic, one-column process that is similar to simulated moving bed (SMB) chromatography in several respects. Both processes are cyclic. In both SMB and SSR, fractions are collected from the leading and trailing portions of the circulating chromatographic profile, and fresh sample is injected into the interior of the profile. However, SMB is a continuous process whereas SSR is a discontinuous, repetitive process. This paper presents a model for the closed-loop SSR process and its experimental validation in a case of practical importance. For this last purpose, we used the closed-loop SSR separation of the enantiomers of a racemic pharmaceutical intermediate. The experimental determination of the competitive adsorption equilibria was performed by frontal analysis in a system composed of a chiral HPLC column as the stationary phase and pure acetonitrile as the mobile phase. All the adsorption data were well correlated by the Langmuir model. The Langmuir model was used to calculate overloaded band profiles corresponding to the separation of racemic mixtures at both analytical and preparative scales. Theoretical band profiles were calculated using the equilibrium–dispersive model. With proper corrections for the contributions of the sources of extra-column band broadening, the model properly predicts the experimental band profiles obtained in the closed-loop SSR setup and demonstrates that a cyclic steady-state develops after the completion of a finite number of cycles. The results also show that the extra-column effects must be accounted for in order to model the closed-loop SSR process accurately.

The second law, the fourth law, recycling and limits to growth

Despite counter examples in nature, it has been argued that total recycling is impossible for an industrial society as a consequence of the second law of thermodynamics. In this paper it is shown that there is no such limitation. However, it is also shown that there must be a large stockpile of inactive materials as well as an exogenous source of exergy (e.g. from the sun) for a stable steady-state recycling system to function. The paper also discusses (briefly) some of the implications for economic growth.

Separation of a racemic pharmaceutical intermediate using closed-loop steady state recycling

Closed-loop steady state recycling (formerly called closed-loop recycling with periodic intra-profile injection or CLRPIPI) is similar to simulated moving bed (SMB) chromatography. Both steady state recycling (SSR) and SMB are steady state, binary chromatographic techniques in which fresh sample is injected into the interior of the circulating chromatographic profile and two fractions or product streams are collected from either end of the profile. However, SMB is a continuous process, whereas SSR is a repetitive, though discontinuous, process. Underlying mechanisms of closed-loop SSR were studied using the separation of a racemic pharmaceutical intermediate. We have found that creation of a stable steady state chromatographic profile is crucial to obtaining high purity fractions. The structure of the steady state profile, also called the steady state inventory, is controlled by the size of the fractions collected and by the location of the injection points. These SSR parameters have corresponding SMB parameters. For example, increasing the size of Fraction 1 in SSR is equivalent to increasing the raffinate flow-rate in SMB; increasing the distance from the injection point to fraction 1 in SSR is equivalent to increasing the size of zone III in SMB; etc. Finally, the SSR results were compared to those of an SMB separation of the same racemic pharmaceutical intermediate. Using the same chiral stationary phase (CSP) and mobile phase, the production rates (SSR, 255 g racemate/kg CSP/day; SMB, 240 g racemate/kg CSP/day), purities (SSR, 98% e.e. for both enantiomers; SMB, 98% e.e. for both enantiomers), and recoveries (SSR, 99% for both enantiomers; SMB, 99% for both enantiomers) for the two techniques were similar, but SSR used more mobile phase per gram of racemate than SMB. SSR, however, used less mobile phase than batch HPLC.

The Creation and Preservation of Archaean Continental Crust

Thirty years ago Armstrong (1968) proposed that the crust of the Earth was formed by 4.0 Ga and since this time steady-state recycling has maintained it at a constant volume at the surface of the Earth. In his model, the small proportion of old rocks preserved at the surface today were simply remnants of crust that survived the recycling process. More recent models of crustal growth (i.e. All~gre and Rousseau, 1984; McCulloch and Bennett, 1994) invoke the gradual growth of continental crust, punctuated by a series of peaks in production. The latter models imply a relatively simple process of progressive depletion of the upper mantle and growth of crust, in which, by the end of the Al'chaean (2,5 Ga), only 50-60% of the crust had been formed. The input parameters to the models are the radiogenic isotopes of Sr, Nd and Pb, and, to a lesser extent constraints from U/Pb zircon distribution. The Pb and U balance of crust, OIB and MORB provide important constraints on the amount of sediment that is recycled into the mantle, and, based on current fluxes, most models cannot accommodate >10% of recycled sediment. In recent years improvements in analytical techniques have made it possible to obtain reliable estimates of key trace element ratios in Archaean basaltic and ultramafic material (i.e. Jochum et al., 1991) and these authors argue that the sub-chondritic ratios of Nb/U and the depletion in epsilon-Nd in the early Earth are consistent with extraction of a proto-crust, since destroyed. In recent years several authors have stressed the role of accreted large igneous provinces, rather than arc accretion in crustal growth (Kusky and Kidd, 1992, Abouchami et al., 1990). These arguments were in large part based on the identification of the giant mafic-ultramafic basaltic provinces in the ocean basins (Coffin and Eldholm, 1994), and the detection of large tracts of geochemically juvenile material with oceanic plateau characteristics in ancient greenstone sequences.