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A general design methodology for chromatographic three fraction separation by application of the three column intermittent simulated moving bed (3C-ISMB) cascade is proposed and experimentally validated by studying the purification of an intermediately retained stereoisomer of nadolol, from an equimolar mixture of its four stereoisomers. The theoretical part shows that the 3C-ISMB cascade can be easily designed by applying Triangle Theory. Moreover, a re-scaling approach for the second stage is proposed so as to account for the fact that the feed flow rates to stage 2 are generally higher as compared to stage 1 due to dilution in the latter. Scaling the columns of the second stage accordingly enables to run both stages under optimal conditions with respect to switching time and step ratio, which is an important advantage as compared to integrated ternary processes. The experimental part starts with studying the linear adsorption behavior of nadolol in heptane/ethanol/DEA on Chiralpak AD for varying ratios of heptane and ethanol. Based on that, a solvent composition of Hept/EtOH/DEA 30/70/0.3 (v/v/v) is selected and the competitive multi-component Langmuir isotherm of the quaternary mixture is determined by frontal analysis. The resulting isotherm parameters are used to design several first stage experiments aiming at removal of the most retained component. The resulting ternary intermediate product is reprocessed in several second stage experiments studying various configurations. Finally, the dilution of the intermediate product with Hept/DEA yielding a solvent composition of Hept/EtOH/DEA 60/40/0.3 (v/v/v) is examined showing that the resulting increase in retention is beneficial for final product purities. Moreover, the reduction in viscosity compensates for the dilution as it enables higher flow rates. Dilution of the intermediate product is hence the best option, yielding highest overall cascade productivity (2.10 gl−1 h−1) and highest product purity (97.8%) requiring a specific solvent consumption of 12 l/g of product.

In liquid chromatography, adsorption and desorption lead to velocity variations within the column if the adsorbing compounds make up a high volumetric ratio of the mobile phase and if there is a substantial difference in the adsorption capacities. An equilibrium theory model for binary systems accounting for these velocity changes is derived and solved analytically for competitive Langmuir isotherms. Characteristic properties of concentration and velocity profiles predicted by the derived model are illustrated by two exemplary systems. Applicability of the model equations for the estimation of isotherm parameters from experimental data is investigated, and accurate results are obtained for systems with one adsorbing and one inert compound, as well as for systems with two adsorbing compounds.

The intermittent simulated moving bed (I-SMB) process is a modification of the conventional SMB process that has been recently analyzed theoretically [1] . Here, we present a comparative analysis of the two processes, each operated in a six column 1-2-2-1 configuration (one column in sections 1 and 4 and two columns in sections 2 and 3) and in a four-column 1-1-1-1 configuration. Experiments are carried out on a properly modified laboratory unit to separate racemic mixtures of the enantiomers of Troger’s base in ethanol on ChiralPak AD at a total feed concentration of 1 g/L. Simulations are carried out for the same system using the equilibrium dispersive model and a bi-Langmuir isotherm, whose parameters have been preliminarily estimated from pulse and breakthrough experiments. Experiments and simulations are fully consistent and demonstrate that the four-column I-SMB process (but not the four-column SMB process) can separate the two enantiomers at very high purity and achieve a productivity twice as large as that of the six-column I-SMB and conventional SMB processes with the same solvent consumption.

We report about a new type of composition front in nonlinear chromatography that is called delta-shock, which has to be added to the family of classical transitions, i.e. simple waves, shocks and semi-shocks. Recently, the occurrence of delta-shocks in the case of mixed competitive-cooperative isotherms of the following type n(i) = H(i)c(i)/(1 - K1c1 + K2c2) (i = 1, 2), (with H2 > H1, where components 1 and 2 have anti-Langmuir and Langmuir adsorption behavior, respectively) was predicted theoretically and their behavior was analyzed in the frame of the equilibrium theory of chromatography. The delta-shock can be viewed as a growing traveling spike superimposed to the discontinuity separating the initial and the feed state, which propagates along the column at constant speed and constant rate of growth. In this work we complement these findings from an experimental point of view. The binary system consisting of phenetole (component 1) and 4-tert-butylphenol (component 2) in methanol-water (about 2:1, v/v) on a Zorbax 300StableBond-C18 column from Agilent has been shown, through a series of overloaded pulse experiments and of frontal analysis experiments with the pure compounds, to be subject to the competitive-cooperative isotherm of the type above, up to rather large concentrations. This system does exhibit a delta-shock when the operating conditions are chosen according to theory, namely when phenetole initially saturating the column is displaced by 4-tert-butylphenol, both at high concentrations (the minimum concentrations exhibiting a fully developed delta-shock in this series of experiments were c1 = 20 g/L and c2 = 75 g/L). The propagation of the delta-shock matches the theoretical predictions in terms of both the effect of concentration and the effect of column length. This is the first experimental observation ever of a delta-shock in chromatography. It is noteworthy that the proof of the occurrence of the delta-shock reported here has been obtained in both laboratories cooperating in this project.

In order to better exploit the economic potential of the simulated moving bed chromatography a 'cycle to cycle' controller which only requires the information about the linear adsorption behavior and the overall average porosity of the columns has been proposed. Recently, an automated on-line HPLC monitoring system which determines the concentrations in the two product streams averaged over one cycle, and returns them as feedback information to the controller was implemented. The new system allows for an accurate determination of the average concentration of the product streams even if the plant is operated at high concentrations. This paper presents the experimental implementation of the 'cycle to cycle' control concept to the separation of guaifenesin enantiomers under nonlinear chromatographic conditions, i.e. at high feed concentrations. Different case studies have been carried out to challenge the controller under realistic operation conditions, e.g. introducing pump disturbances and changing the feed concentration during the operation. The experimental results clearly demonstrate that the controller can indeed deliver the specified purities and improve the process performance.

A novel method to estimate adsorption isotherm parameters is presented and its applicability is studied through synthetic as well as experimental data. This approach assumes a linear dependency of the UV absorption intensity on the solute concentration in the fluid phase, at least in certain ranges of the UV spectra. It was demonstrated that by fitting the absorption profiles, i.e. the new direct inverse method, and by fitting the concentration profiles, i.e. the classical inverse method, very similar adsorption isotherm parameters can be obtained. The findings presented in this work have as important implication the elimination of the requirement of converting a measured absorption intensity into a concentration value, i.e. the elimination of the calibration of the UV signal.

The intermittent SMB (I-SMB) process is a multi-column chromatographic process, which is a modification of the conventional SMB process, has been applied so far only in the sugar industry and is claimed to achieve higher productivity. In the I-SMB process the time interval between two port switches is divided in two sub-intervals, and only during the first the product streams are collected. The potential of the I-SMB technology is demonstrated in the case of the separation of a binary mixture subject to the linear isotherm by using both the equilibrium theory of chromatography and detailed simulations. It is shown that a I-SMB with only four columns can achieve much higher separation performance than a SMB unit with four columns.

In continuous chromatography simulated moving bed (SMB) is a firmly established powerful technique for the separation of fine chemicals and enantiomers. The use of a controller could improve the operation conditions and increase the productivity of an SMB unit. However, the performance of any controller is greatly affected by the reliability and the quality of the feedback information from the plant. Therefore, to overcome the limitations of optical detectors, such as UV and polarimeter, an automated on-line HPLC monitoring system was developed and installed to monitor the product streams. The performance of the system is tested experimentally separating a mixture of guaifenesin enantiomers on Chiralcel OD columns with ethanol as mobile phase in our laboratory SMB unit under both linear and nonlinear chromatographic conditions. The results show that the new monitoring system provides precise and accurate data about the concentration of the components in the two product streams. Moreover, they prove that despite disturbances a combination of the controller and the new on-line monitoring system allows to fulfill the product specifications and to improve the performance of the process in terms of feed throughput and solvent consumption.

Simulated moving bed (SMB) chromatography, a continuous multi-column chromatographic process, has become one of the preferred techniques for the separation of the enantiomers of a chiral compound. Several active pharmaceutical ingredients, including blockbuster drugs, are manufactured using the SMB technology. Compared to single column preparative chromatography, SMB separations achieve higher productivity and purity, while reducing the solvent consumption. The SMB technology has found applications both at small and large scales. Design methods have been developed for robust operation and scale-up, using data obtained from analytical experiments. In the last few years, rapid developments have been made in the areas of design, improved process schemes, optimization and robust control. This review addresses these developments, as well as both the fundamentals of the SMB science and technology and some practical issues concerning the operation of SMB units. Particular emphasis is placed on the consolidation of the "triangle theory", a design tool that is used both in the academia and industry for the design of SMB processes.

In the absence of a suitable controller, currently simulated moving beds (SMBs) are operated suboptimally to cope with system uncertainties and to guarantee robustness of operation. Recently, we have developed a 'cycle to cycle' optimizing controller that not only makes use of minimal system information, i.e. only the Henry constants and average bed voidage, but also optimizes the process performance and taps the full economic potential of the SMB technology. The experimental implementation of the 'cycle to cycle' optimizing controller had been carried out for achiral separation. For chiral separation however, application of any online controller has not been possible because an appropriate online monitoring system has not been available. This work reports and discusses the first experimental implementation of the 'cycle to cycle' optimizing control for chiral separations. A mixture of guaifenesin enantiomers is separated on Chiralcel OD columns with ethanol as mobile phase in a eight-column four sections laboratory SMB unit. The results show that the controller, although using minimal information about the retention of the two enantiomers, is able to meet product and process specifications, can optimize the process performance, and is capable of rejecting disturbances that may occur during the operation of the SMB plant.

The separation of the enantiomers of 1-phenyl-1-propanol by supercritical fluid chromatography on a chiral stationary phase, which consists of cellulose tris (3,5-dimethylphenylcarbamate) coated on a silica support (Chiralcel-OD), is studied under overloaded, non-linear chromatographic conditions. Pulse experiments are performed at a temperature of 30 ° C using supercritical CO2 modified with methanol as a mobile phase. The parameters of the binary Langmuir adsorption isotherm are determined by the inverse method, comparing experimental and simulated peak responses. Isotherm parameters are derived for modifier concentrations between 1 and 5% (w/w) and operating pressures between 125 and 185 bar, and the dependency of the isotherm parameters, namely the Henry constant and the saturation capacity, on operating conditions is investigated.

The existing literature of continuous chromatographic process indicates the scarcity of processes which allow the continuous separation of a ternary mixture and which also exploit the power of modifier gradients and counter-currency. A new process filling this gap is presented and analyzed using an equilibrium theory model and linear isotherms. The analysis leads to the explicit formulation of an operating region, where 100% purity and yield can be obtained. A normalized flow rate ratio is introduced, which allows an easy description and understanding of the process behavior. The gained insights are verified using a detailed simulation model, where the influence of changes in the normalized flow rate ratios on the unit performance is investigated.

In a previous theoretical analysis based on equilibrium theory it has been shown how differences in the sample and elution modifier concentrations can lead to unexpected behavior of the solute eluted peaks such as retention time distortion, peak deformation and peak doubling. All these features are verified experimentally in this work using the polypeptide calcitonin and a variant of a specific monoclonal antibody as chromatographic model systems. For both experimental systems, the retention time distortion can be predicted with high accuracy by the solution of the equilibrium theory model. For the polypeptide, the predictions from the theory about the occurrence of peak deformation and double peaks has been successfully verified by a series of tailored experiments with positive as well as negative modifier perturbations.

Experimental implementation of an optimizing controller based on identified model for the separation of nucleosides in a laboratory scale simulated moving bed (SMB) unit is reported in this study. The manipulative variables are the three external and one internal flow rates while the outputs are productivity, solvent consumption, and purities of extract and raffinate streams averaged over a switching period. The feedback information is the concentration profile of extract and raffinate measured online using two ultraviolet (UV) detectors. Experimental results show that the designed controller is able to operate the SMB units under optimal condition fulfilling the purity requirements. Besides, the controller demonstrated excellent performance in terms of rejecting disturbances that may occur during SMB operations.

The enantioseparation of 1-phenyl-1-propanol through the supercritical fluid-simulated moving bed (SF-SMB) process is studied. Non-linear isotherms were measured on an analytical column, and used together with the triangle theory for SMB design to select operating conditions for the SF-SMB. Experiments were carried out on a pilot-scale SF-SMB plant at conditions that corresponded to the non-linear range of the isotherm. Under conditions of low feed concentration, complete separation (extract purity = 99.5%; raffinate purity = 98.4%) was achieved. Under conditions of larger feed concentration, the best separation corresponded to an extract purity of 98.0% and a raffinate purity of 94.0%, and yielded a productivity of 110 g of racemate per kg stationary phase per day.

The operation of simulated moving beds (SMBs) at their optimal operating conditions is difficult and not robust. Therefore, it is common practice to operate SMB units far from their economic optimum in order to tolerate uncertainties in the system and minimize the effect of disturbances. Recently, we have proposed an on-line optimization based SMB control scheme that allows to exploit the full economic potential of SMB technology. The goal of this work is two-fold. Firstly, to experimentally evaluate and demonstrate the capability of the controller to optimize and operate the SMB units, thus delivering the products with maximum productivity and minimum solvent consumption. Secondly, to show the suitability of the controller even using a minimum of system information, thus making the detailed isotherm measurements redundant and saving time in the separation design phase. This paper reports and discusses the first experimental implementation of the control concept on a high purity separation of nucleosides (uridine, guanosine) with an eight-column four-section SMB where the species to be separated are retained on the source 30RPC stationary phase according to a linear isotherm.

Batch liquid chromatographic columns are often equilibrated with an eluent stream being a mixture of inert compounds and so-called modifiers. The sample injected into the eluent stream usually consists of the solutes to be separated and of a mixture of the same solvents as in the eluent but in general with different concentration values. This results in two groups of peaks moving along the column: the solute peaks and the modifier pertubations. If the adsorptivity of the solute depends strongly on the modifier, as it is often the case in biochromatography, the interference between the two groups of peaks leads to peculiar phenomena like double peaks, split peaks, distorted peaks with anti-Langmurian shape, etc. In this work, these phenomena are analyzed based on an analytical solution of the equilibrium theory model and the results are compared with detailed simulations and experimental data. It is shown that the qualitative behavior is well predicted in the frame of equilibrium theory and general guidelines how to avoid these kinds of interactions are developed.

The supercritical fluid chromatography (SFC) separation of the enantiomers of 1-phenyl-1-propanol on the chiral stationary phase Chiralcel OD under linear conditions is studied. Supercritical CO2 modified with methanol is used as a mobile phase. The effect of modifier concentration, pressure and temperature is studied. An empirical isotherm to account for the effect of density of the mobile phase and modifier concentration has been used to model the experimental results. It was observed that the selectivity and resolution were higher at 30 ° C as compared to those at 40 ° C.

A new experimental set-up and a new simulated moving bed (SMB) operation are presented in this work. A desktop SMB unit developed as a modification of the commercial AKTA explorer working platform has been utilized for the separation of different mixtures of nucleosides. Both two fraction and three fraction SMB separations have been carried out, the latter made possible by the adoption of a new SMB configuration and operating mode (three fraction SMB, 3F-SMB, operation). Experiments demonstrate the feasibility of the 3F-SMB operation, and confirm the trends predicted based on considerations about retention of the components to be separated along the unit.

This works deals with the development of a model for the description of the chromatographic behavior of enantiomers forming dimers on achiral stationary phases. The model describes the formation of both homochiral and heterochiral dimers by introducing two equilibrium constants, K(homo) and K(hetero), which have to be independently estimated. The adsorption of both monomeric and dimeric species is described by a bi-Langmuir isotherm. Both adsorption and dimerization equilibrium models are implemented in a standard equilibrium-dispersive model of the chromatographic column. The isotherm parameters are determined by fitting of pulses constituted either of the pure enantiomers or of non racemic mixtures of both enantiomers. The validity of the model is then assessed by application to the binaphthol case.

A possible way to improve the separation performance of simulated moving bed (SMB) units is to change the internal and external liquid flow-rates during the switching period. This operation mode, referred to as PowerFeed, is examined in this work through a model analysis. Similar to the Varicol process, which allows for the asynchronous movement of the ports, the PowerFeed process exhibits more degrees of freedom than the classical SMB process and therefore allows more room for optimization. Using an optimization technique based on a genetic algorithm, all three processes have been optimized for a few case studies in order to determine their relative potentials. It is found that PowerFeed and Varicol provide substantially equivalent performances, which are however significantly superior to those of the classical SMB process.

Chromatography is a key technique for the analytical, preparative, and production scale separation of enantiomers, particularly in the pharmaceutical and fine chemicals industries. Although it is common belief that this separation can be accomplished only using a chiral stationary phase, it has been recently shown that under certain circumstances a non-racemic mixture of specific chiral compounds can be separated in two fractions which differ in enantiomeric excess (e.e.) also on an achiral stationary phase. In this work we show that in the case of the enantiomers of binaphthol in chloroform achiral chromatography on LiChrospher 100 NH2 furnishes two fractions constituted of the pure enantiomer present in excess and of the racemic mixture, respectively. This is demonstrated by on-line monitoring the concentration of both enantiomers at the outlet of a chromatographic column fed with a non-racemic pulse of the two enantiomers by using a UV detector and a polarimeter in series. Furthermore, we provide experimental evidence of the presence of homo- and hetero-dimers in solution through NMR experiments and develop a consistent physico-chemical model of the solution itself and of the competitive achiral adsorption equilibria. When combined with a standard rate model of the chromatographic column this not only confirms the possibility of achieving 100% e.e. through achiral chromatography, but also allows for a qualitative and quantitative description of all the experimentally observed phenomena. Among these, the effect of the enantiomeric excess and of the overall concentration of the injected pulse on the chromatographic behaviour are worth mentioning.

The simulated moving bed (SMB) technology offers the possibility of scaling up single column, batch chromatographic separations to continuous operation. This has proved particularly effective for the separation of enantiomers, and has been applied in the liquid and gas phase, as well as using a supercritical fluid as eluent (SF-SMB). In the last case, the main performance improvements are due to the possibility of tuning the elution strength of the mobile phase, by changing the pressure in the four sections of the SMB unit. Thus a SF-SMB can be operated in two modes, i.e. the isocratic and the pressure gradient mode. In this research, design criteria for these two operating modes have been developed, which can be applied to systems described by linear as well as nonlinear Langmuir adsorption isotherms. The role and effect of an appropriate modifier in increasing solubility and reducing retention times have been investigated. The results reported allow to identify the operating conditions, including the pressure levels and the modifier concentration, which lead to optimal separation performance in terms of productivity and desorbent requirement.

Simulated moving bed chromatography is a key technology for the pilot and production scale separation of enantiomers of chiral chemical species. Product quality control is probably the most important issue in this kind of separation at both scales, and for this it is clear that on-line monitoring of absolute enantiomer concentrations plays a major role. In this work, an on-line system consisting of a UV detector and a polarimeter in series is used to monitor the composition of the extract and raffinate streams of a laboratory SMB unit. The model system adopted is the separation of the enantiomers of the Tröger's base on microcrystalline cellulose triacetate (CTA) using ethanol as mobile phase. The technique is effective and accurate, thus providing promising perspectives for SMB process control and dynamic optimization.

The gas chromatographic enantiomer separation of alpha-ionone was studied with three different chiral stationary phases using as chiral selectors: (1) heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin, dissolved in polysiloxane PS-086, (2) octakis(2,6-di-O-pentyl-3-O-trifluoroacetyl)-gamma-cyclodextrin and (3) octakis(2,6-di-O-pentyl-3-O-butanoyl)-gamma-cyclodextrin, both dissolved in polysiloxane SE-54. The influence of the concentration of the chiral selector in the polysiloxane, coated on Chromosorb P AW-DMCS 80-100 mesh, is described and discussed, as well as the effect of Chromosorb loading. The feasibility of the preparative gas chromatographic separation of the enantiomers of alpha-ionone is considered; in order to provide a term of comparison, the estimated performances are compared with those achieved in the separation of the enantiomers of the inhalation anaesthetic enflurane.

Simulated Moving Bed (SMB) technology is receiving more and more attention as a convenient technique for the production scale continuous chromatographic separation of fine chemicals. Thanks to the efficient simulated countercurrent contact between the stationary and the fluid phase, SMB units can operate under high productivity overload conditions. These lead to nonlinear competitive adsorption behavior, which has to be accounted for when designing and optimising new SMB separations. The so called `Triangle Theory', which is briefly revised here, provides explicit criteria for the choice of the operating conditions of SMB units to achieve the prescribed separation of a mixture characterized by Langmuir, modified Langmuir and bi-Langmuir isotherms. In all these cases, the effect of increasing nonlinearity of the separation, due to increased feed concentration can be predicted. In this paper, the use of this approach for the design of linear and nonlinear SMBs is considered, with reference to examples reported previously. Alternative strategies have been proposed in the literature, which are based on the use of safety factors for linear systems and on an adaptation of this for nonlinear ones. In the cases considered, which involve experimental data for a linear system and numerical experiments for a nonlinear Langmuir system, it is shown that `Triangle Theory' allows attainment of a better understanding of and a deeper insight into the behavior of SMB units.

The separation of the enantiomers of the racemic inhalation anesthetic enflurane was achieved by continuous gas phase simulated moving bed chromatography (GC–SMB). The productivity of the unit and the enantiomeric excess of the obtained streams were somehow low mainly because of the high operating temperature, i.e., T =50°C. As chiral stationary phase, an unpurified cyclodextrin derivative, consisting of various isomers and homologues and dissolved in an apolar polysiloxane matrix, was used. The competitive adsorption isotherms of ( R )-(−)-enflurane and ( S )-(+)-enflurane were determined by gas chromatographic measurements at increasing values of the pulse concentration in the range from linear to overload conditions. It has been shown that the adsorption behavior of the two enantiomers can be explained by considering enantioselective and non-enantioselective sites on the stationary phase. These results demonstrate the feasibility of the chiral resolution of enflurane by GC–SMB.

Several important theoretical results have been previously obtained to predict the behaviour of continuous chromatographic separation units in the case of Langmuirian type of isotherms. Concerning separation of binary mixtures in a non-adsorbable carrier with SMB units, stoichiometric and non-stoichiometric Langmuir and modified Langmuir have been considered in the frame of equilibrium theory. For these isotherms explicit constraints on the operating parameters have been found to achieve complete separation (M. Mazzotti, G. Storti, M. Morbidelli, J. Chromatogr. A 769 (1997) 3; M. Mazzotti, G. Storti, M. Morbidelli, AIChE J. 42 (1996) 2784; M. Mazzotti, M. Pedeferri, M. Morbidelli, in: Chiral Europe '96 Symposium, Spring Innovations Limited, Stockport, UK, 1996); the design of the SMB unit was then reduced to the analysis of the so-called region of complete separation for the operating parameters. In this paper, the same result is presented for the bi-Langmuir case, which can avoid the constant selectivity limit of the Langmuir isotherms. Langmuir and bi-Langmuir isotherms fitting the same set of data taken from the literature were then used here to show the difference in the prediction of the region of complete separation. Finally an analysis of non-linearity effects on performance parameters is presented as a useful criterion for optimization of the separation performances.

Continuous chromatographic separation processes have gained increasing industrial importance for fine chemical and pharmaceutical applications. These are based on the simulated moving bed (SMB) technology, of which the implementation using a supercritical eluent (SF-SMB) is dealt with in this work. Criteria for the choice of the operating conditions of SF-SMBs to achieve optimal separation performance are derived. Through these a thorough analysis of the two operating modes of these units, isocratic and pressure gradient mode, is made. The theoretical findings are supported by comparison with experimental data previously published in the literature.

The simulated moving bed (SMB) technology is receiving more and more attention as a convenient technique for the production scale continuous chromatographic separation of fine chemicals. Characteristic features of SMBs are improved performances with respect to preparative chromatography and nonlinear competitive adsorption behavior. The selection of the operating conditions to achieve high separation performances under nonlinear conditions is acknowledged to be the major problem in running a SMB unit for a new application. This problem is solved in this paper, where a general theory is developed which provides explicit criteria for the choice of the operating conditions of SMB units to achieve the prescribed separation of a mixture characterized by both constant selectivity Langmuir isotherms and variable selectivity modified Langmuir isotherms. The space of the operating parameters, i.e. the fluid to solid flow-rate ratios, is divided in regions with different separation regimes. The effect of increasing nonlinearity of the system on the operating conditions and the separation performances, namely desorbent requirement, enrichment, productivity and robustness of the separation, is thoroughly analyzed. The obtained results are shown to provide a very convenient tool to find both optimal and robust operating conditions of SMB units. Finally, a comparison between model predictions and experimental data dealing with the resolution of different racemic mixtures assesses the reliability and accuracy of the obtained theoretical findings.