Chromatographic Reactor Research Articles

Reactive Chromatography for the Synthesis of 2-Ethylhexyl Acetate

Reactive chromatography (RC) combines reaction and chromatography in a single unit. Due to simultaneous separation of products it can be advantageously used for reversible reactions to obtain the enhanced performance. It is a promising alternative to reactive distillation when the components are temperature sensitive and less volatile. In the present work, we study the application of RC for the synthesis of 2-ethylhexyl acetate through esterification of acetic acid with 2-ethylhexanol. Amberlyst-15 has been used as a catalyst/adsorbent. Several aspects such as reaction kinetics, multicomponent adsorption equilibria, and reaction-separation study using fixed bed chromatographic reactor are covered. The kinetics was studied in a stirred batch reactor. The effects of various parameters such as speed of agitation, particle size, temperature, mole ratio of reactants, and catalyst loading have been investigated. Kinetic modeling was performed using modified activity based Langmuir-Hinshelwood-Hougen-Watson (LHHW) model. Non-reactive binary adsorption experiments were performed to determine the parameters of Langmuir adsorption isotherm by minimizing the errors between the experimental and predicted breakthrough curves. Further, the reactive chromatography experiments were performed to obtain the reactive breakthrough curves which indicate a clear potential for the use of reactive chromatography for this reaction. The obtained data has been compared with the predictions of mathematical model of the chromatographic reactor.

A high-temperature liquid chromatographic reactor approach for investigating the solvolytic stability of a pharmaceutical compound and an investigation of its retention behavior on a C18-modified zirconia stationary phase

The solvolysis kinetics of a developmental active pharmaceutical ingredient (API) were investigated using a high temperature (HT)-HPLC reactor approach to determine whether it might be possible to use the technique to efficiently screen the relative stabilities of typical APIs (particularly those that are stable at the column temperatures achievable on most HPLC systems and over durations of less than 60 min—a reasonable upper limit for typical method run time). It was discovered that the on-column API degradation kinetics better obeyed a second-order model than a first-order one. Employing a newly developed mathematical treatment, the apparent activation energy for the process was determined to be 85.7 ± 1.6 kJ/mol; the apparent frequency factor was found to be (3.9 ± 0.4) × 10 4 s −1. The retention mechanism of the API on the C18-modified zirconia column (ZirChrom ® Diamondbond™-C18) was investigated using a van’t Hoff analysis. It was discovered that the logarithm of the retention factor (following correction for the gradient elution of the assay method) exhibited a quadratic dependence on the reciprocal of the absolute temperature. While the retention was found to be predominantly enthalpically driven over the majority of temperatures investigated in this study (ranging from 40 to 200 °C), a regression fit of the curve predicted a maximum at ∼20 °C, indicative of a transition from predominantly enthalpically controlled retention to a mainly entropically driven mechanism. A table summarizing the thermodynamic retention parameters at each experimental column temperature is provided. Finally, the preliminary application of the HT-HPLC reactor approach to the study of degradation kinetics of other APIs is discussed in terms of some unexpected findings obtained using the zirconia column.

Feasibility studies and dynamics of catalytic liquid phase esterification reactions in a micro plant

We present a new micro reactor concept which is suitable for investigations of heterogeneously catalyzed liquid phase reactions. In the set-up two reactants are mixed in a commercially available interdigital micro mixer. The outlet of the micro mixer is connected to a modular micro reactor that consists of stacked plates. Each plate contains a milled meandering channel filled with catalyst beads. By using a variable number of plates the residence time can be manipulated and thus adjusted for a specific task. The synthesis of butyl acetate is considered as a model reaction since it has been investigated in detail in conventional reaction systems. In a first step, some experimental results of the heterogeneously catalyzed reaction are presented. In the second part, the set-up is operated as a chromatographic reactor. Dynamic behaviour is investigated applying the frontal analysis mode and the elution chromatography mode.

Thermal effects in reactive liquid chromatography

Thermal effects in unsteady-state liquid phase chromatographic reactors were investigated experimentally in a thermally insulated column. In the case of an exothermic esterification reaction catalyzed by an acidic ion-exchange resin, a self-amplifying positive thermal wave was found to develop in the reactor. This improved the reactor performance considerably when compared to isothermal conditions: both conversion of reactants and the mole ratio of the desired and undesired products in a product fraction increased. The heat of reaction, enthalpy of adsorption, and heat of mixing all contribute to the thermal behavior of the reactor. The coupling between the concentration fronts and thermal waves was elucidated by means of numerical simulations. The solid phase to fluid phase heat capacity ratio was found to be an important parameter because it affects the magnitude and propagation velocities of the thermal waves.

Comparison between simulated moving bed and reverse flow chromatographic reactors for equilibrium limited reactions

A staged linear model, containing five parameters, is developed to compare equivalent simulated moving bed chromatographic reactors (SMBCR) and reverse flow chromatographic reactors (RFCR). A first order reversible reaction and linear adsorption equilibrium, with preferential adsorption of the reactant is assumed. The analysis uses simple, easily computable analytical solutions that rigorously represents the transients in the cyclic steady state for both the RFCR and the SMBR. A comparison between the two types of reactors is carried out to determine the maximum conversion attainable and the range of operation where these systems have advantages over conventional steady state reactors. It is found that the maximum conversion of both reactors is similar. The range of operation in terms of amount of catalyst and range of switching times favors the RFCR, while the conversion at low separation factors favors the SMBCR.

Immobilized tyrosinase reactor for on-line HPLC application: Development and characterization

Mushroom tyrosinase was covalently bonded with glutaraldehyde, as activating agent, to aminopropyl-controlled pore glass support by “in situ” immobilization technique. The Schiff's base double bond reduction with sodium cyanoborohydride was made as innovation. Catalytic activity and stability of the chromatographic reactor were evaluated using d,l-3,4-dihydroxyphenylalanine as substrate. The tyrosinase-IMER was characterized by investigation of various parameters influencing the enzymatic activity (pH, temperature, ionic strength and organic solvents). In addition kinetic measurements showed that, by removal of the external diffusional limitation, the enzyme selectivity towards substrate was improved whereas the activity was comparable with respect to that of free enzyme.

Chromatographic Reactors with Reactive Desorbents

The possibility of introducing, as a desorbent in a chromatographic reactor, a reactive desorbent that removes the most strongly retained component by chemical reaction and not by purely physical desorption has been investigated. The principle is demonstrated in the case of the esterification of glycerol with acetic acid using a mixture of acetic acid and acetic anhydride as the desorbent and a polymeric acidic resin as the stationary phase. It is shown that reacting the most strongly retained component, water, with acetic anhydride allows for a significant improvement in the column regeneration process, thus improving the process performance in terms of both productivity and desorbent requirements.

Esterification of acrylic acid with methanol by reactive chromatography: Experiments and simulations

The esterification of acrylic acid with methanol using Amberlyst 15 as a stationary phase has been investigated using a chromatographic reactor. Several experimental runs at various operating conditions have been conducted on a batch column. A classical reactive chromatography model including lumped kinetics, a linear driving force transport model and a heterogeneous kinetic model for the catalytic reaction has been developed. The additional dispersion of concentration fronts due to density gradient effects has been accounted for in the model. The model parameters have been determined in a fast and reliable way by directly fitting the batch column experiments. In general, a good agreement between experimental and calculated results is obtained. The evaluation of the covariance of the fitted model parameters reveals important insights about the system behavior. Based on the detailed batch column model, a complete model of a simulated-moving-bed reactor has been implemented and its optimal point of operation for the synthesis of methyl acrylate from acrylic acid has been determined. Particularly when considering the low-operating temperature, we can regard this process as a possible competition for current technologies.

An HPLC chromatographic reactor approach for investigating the hydrolytic stability of a pharmaceutical compound

The solution-phase hydrolysis kinetics of the Aprepitant (Emend™) prodrug, Fosaprepitant Dimeglumine, were investigated using an HPLC chromatographic reactor approach. The term ‘chromatographic reactor’ refers to the use of an analytical-scale column as both a flow-through reactor and, simultaneously, as separation medium for the reactant(s) and product(s). Recently, we reported a novel mathematical treatment for the kinetic data obtained from chromatographic reactors, which we believe is superior to other treatments in terms of its accuracy, robustness and ease of implementation. In this work, we demonstrate that our treatment may be applied equally well to HPLC reactors, as previously we studied only GC reactors. It is found that the hydrolysis of Fosaprepitant Dimeglumine (FD) has an apparent activation energy of 107 kJ/mol when the reaction is investigated on-column, using the gradient elution conditions of the validated HPLC impurity profile method for this compound. For comparison, the activation energy determined for the same reaction occurring in a quiescent solution consisting of a fixed ratio of acetonitrile–0.1% v/v aqueous H 3PO 4 (50:50, v/v) is 91 kJ/mol, calculated using direct application of the Arrhenius equation. The data presented show that, when used as a screening tool, chromatographic reactors may be feasible for use in the pharmaceutical industry to quickly gauge the relative stabilities of various compounds with similar degradation pathways.

Enhanced hydrogenation in a reverse flow chromatographic reactor

AbstractAn experimental study of the reverse flow chromatographic reactor is carried with the equilibrium limited hydrogenation of 1,3,5‐trimethylbenzene (mesitylene, MES) to 1,3,5‐trimethylcyclohexane. The reaction is pseudo first‐order when carried out in excess hydrogen. A simple experimental setup is used to evaluate the effects of carrier flow, reactant feed concentration, and amount of catalyst on conversion. Conversions exceeding the thermodynamic equilibrium conversion are obtained for a wide variety of switching times, catalyst amounts, carrier flow rates, and reactant concentrations, showing the robustness of the system. While the qualitative features of the process can be predicted for a simple linear adsorption equilibrium model, the experimental results are best fitted by assuming a linear adsorption isotherm combined with an adjusted interfacial mass‐transfer resistance. The experimental results are very similar to those reported in previous research of the same reaction in a simulated moving‐bed chromatographic reactor. © 2006 American Institute of Chemical Engineers AIChE J, 2006

Formula omitted] removal in forced unsteady-state chromatographic reactors

The feasibility of the selective catalytic reduction (SCR) of NO x with ammonia in unsteady-state reactors is investigated by means of numerical simulations. A reactors network (RN) with periodical change of the feeding position is shown to be an alternative to the well investigated reverse-flow reactor (RFR) in order to fulfil the requirements on NO x conversion and ammonia emissions. Non-isothermal operation was studied, with low temperature feed, and the influence of the switching time on the mean outlet concentration of NH 3 and NO x was investigated, as well as the response of these devices to perturbations in the pollutant feed concentration.

Analysis of Ester Hydrolysis Reactions in a Chromatographic Reactor Using Equilibrium Theory and a Rate Model

In this paper, a new methodology for the conceptual design of chromatographic reactors is proposed and illustrated for ester hydrolysis reactions in a fixed-bed chromatographic reactor with a pulse injection of the ester. In the first step, an extended equilibrium theory approach for chromatographic reactors is used to study the feasibility, i.e., to clarify whether total conversion of the reactant and total separation of the products are possible. In the second step, the required column length is calculated using a rate based model, which takes into account the finite reaction kinetics and axial dispersion. Finally, the theoretical predictions are compared with the experimental results.

Dynamics of reaction separation processes in the limit of chemical equilibrium

AbstractA new approach for analyzing and understanding the dynamics of combined reaction separation processes with fast chemical reactions was proposed recently. The approach is based on transformed concentration variables which were first introduced by Doherty and co‐workers for the steady‐state design of reactive distillation processes. Application was demonstrated for reactive distillation processes and fixed bed, as well as moving‐bed chromatographic reactors. The focus was on simple reactions of type 2A ⇋ B + C. This approach is further extended and applied to some real—fairly complex—multireaction systems. Applications to be considered are a reactive enantiomeric separation process in a fixed‐bed chromatographic reactor, and an industrial reactive distillation column. Finally, application to membrane reactors is discussed. © 2005 American Institute of Chemical Engineers AIChE J, 2006

Use of a Reverse-Flow Chromatographic Reactor To Enhance Productivity in Consecutive Reaction Systems

A reverse-flow chromatographic reactor can be used to improve the yield and selectivity for a consecutive reaction system (A - B - C) beyond the values obtained from conventional plug-flow reactors (PFRs) in the case where the reactants are more strongly adsorbed than the products. It is also simpler than conventional chromatographic, moving, and simulated moving beds and other systems that combine reaction and adsorption separation. The results of the study show the robustness and stability of the system, its capacity to significantly improve the range of yield and selectivity that can be achieved, and the advantage of decoupling the relationship between yield and selectivity found in a PFR.

Phenol Hydroxylation with TS-1 in a Chromatographic Reactor

ABSTRACTPhenol hydroxylation with TS-1 was studied in a chromatographic reactor. TS-1 not only acts as the catalyst for the reaction but also the adsorbent for the separation. The reaction/separation was carried out at 60°C with water and 0.2wt% of aqueous H2O2 as the desorbent. Separation of hydroquinone (HQ) can be achieved in all cases. With water as the desorbent, separation of catechol (CT) depends on the phenol feed concentration, which has been confirmed from both reaction/separation in the chromatographic reactor and equilibrium competitive adsorption experiment. Some unknown by-products not commonly reported in batch experiments have been observed here. TS-1 can also be regenerated using just water. With the aqueous mixture of H2O2 as the desorbent, separation of HQ and CT is possible. Reactive separation schemes based on the simulated counter-current technology have been proposed according to the experimental results.

Thermal decomposition of tert‐butyl peroxide in a gas chromatographic reactor: A comparison of kinetic approaches

AbstractThe thermal decomposition of tert‐butyl peroxide is investigated utilizing both the column and the injection port of a commercial gas chromatograph (GC) as chemical reactors. Using the injector liner as the reactor, the chromatographic peak areas of the reactant, measured at various injector temperatures, are used in the determination of the activation energy of the decomposition (Ea). With the column serving as the reactor, both the reactant peak areas and the product peak shapes are similarly utilized for this purpose. Values of Ea obtained using different mathematical treatments for each of the three approaches are found to range from 115 to 164 kJ/mol. Of these methods, the column reactor approach utilizing peak area measurements (referred to as PACR, for “peak area, column reactor”) is found to be far superior in terms of its speed, robustness, and its accuracy in determining Ea. The PACR method's effectiveness can be largely attributed to the mathematical treatment that is described in the approach. © 2004 Wiley Periodicals, Inc. Int J Chem Kinet 36: 386–393, 2004

Development of a chromatographic bioreactor based on immobilized β-glucuronidase on monolithic support for the determination of dextromethorphan and dextrorphan in human urine

We here reported the development and application of an immobilized enzyme reactor (IMER) based on β-glucuronidase to the on-line determination of urinary molar ratios of dextromethorphan (DOMe)/dextrorphan (DOH) for the assessment of the metabolic activity of CYP2D6, a genetically variable isoform of cytochrome P-450 (CYP). β-Glucuronidase was immobilized on an HPLC monolithic aminopropyl silica support. Catalytic activity and stability of the chromatographic reactor were evaluated using 8-hydroxyquinoline glucuronide (8-HQG) as substrate. The IMER was coupled through a switching valve to a reversed-phase column (C8) for the simultaneous determination of dextromethorphan and its main metabolite dextrorphan. On purpose a selective reversed-phase ion pair HPLC method coupled with fluorescence detection was developed. Urine samples were first centrifuged to remove insoluble materials and then aliquots of the supernatants were injected into the coupled-column analyser. Linearity, precision and accuracy of the method were established. The method reliability was verified by comparing our data with previous data of a phenotyping study carried out by the Poison Control Centre of Pavia-Clinical Toxicology Division.

Analysis of Heterogeneously Catalyzed Ester Hydrolysis Performed in a Chromatographic Reactor and in a Reaction Calorimeter

A discontinuously operated chromatographic reactor and a reaction calorimeter were used to study experimentally and theoretically the heterogeneously catalyzed hydrolysis reactions of four esters (methyl formate, methyl acetate, ethyl formate, and ethyl acetate). Two different batches of an acidic ion-exchange resin were used as catalyst and adsorbent. The relevant distribution equilibria were quantified using pulse chromatographic experiments. The reaction rates were quantified from (a) the shape of the elution profiles and (b) the course of the heat fluxes. To this end, systematic experiments were carried out using fixed beds packed with the catalysts and a reaction calorimeter containing catalyst suspensions. Advantages and disadvantages of these two types of experimental approaches in terms of their potential to extract reliable kinetic parameters were evaluated. A simplified pseudohomogeneous model and the determined parameters were found to be capable of describing the concentration profiles in the chromatographic reactor for all reactions studied under diverse operation conditions.

Equilibrium theory and nonlinear waves for reactive distillation columns and chromatographic reactors

A general framework for analyzing and understanding the dynamics of reactive separation processes is developed. The theory is based on the assumption of simultaneous phase and reaction equilibrium. It makes use of transformed concentration variables, which were first introduced by Doherty and co-workers for the steady state design of reactive distillation processes (Proc. Roy. Soc. London A 413 (1987a) 459). It is shown that these transformed variables can be directly generalized to the dynamic problem considered here. Further, they can also be applied to other reactive separation processes like fixed bed as well as countercurrent chromatographic reactors, for example. They provide profound insight into the dynamic behavior of these processes and reveal bounds of feasible operation caused by reactive azeotropy. It is shown that reactive azeotropy, which is a well-known phenomenon in reactive distillation (Proc. Roy. Soc. London A 413 (1987b) 443) may also rise under very similar conditions in other reactive separation processes like chromatographic reactors for example.

Analysis of the reverse flow chromatographic reactor

A reverse flow chromatographic reactor with side feed (RFCR) can be used to improve the conversion and selectivity for irreversible and reversible reaction systems beyond the values obtained from conventional steady-state reactors in the case where the reactants are more strongly adsorbed than the products. It is also simpler than conventional chromatographic, moving, and simulated moving beds and other systems that combine reaction and adsorption separation. The results of the study show the robustness and stability of the system, as well as its capacity to significantly improve conversion and selectivity for several reaction systems, including consecutive reactions. Simulation results of this mathematical model for the hydrogenation of 1,3,5-trymethylbenzene (MES) compare well with previous studies, using countercurrent moving-bed reactors and simulated countercurrent bed reactors. © 2004 American Institute of Chemical Engineers AIChE J, 50: 2266–2275, 2004