Simulated Moving Bed Chromatography Research Articles

Industrial SMB chromatography as an alternative to the conventional refining of raw cane sugar

Simulated moving bed (SMB) chromatography is a well-established and widespread unit operation in the beet sugar industry and has been practiced commercially for more than thirty years. SMB chromatography has proven to be very efficient at removing inorganic ash components and colorants from sugar liquors, particularly those colorants with relatively high molecular masses. Recent optimization of the separation using raw sugar with a color ranging from 2000 IU up to 4000 IU has focused on minimizing the capital and operating costs of a chromatography system to replace the various purification and decolorization steps in conventional raw cane sugar refining. Decolorization levels exceeding 89% have been reliably achieved in the extract fraction from chromatography, along with ash removals ranging from 92% to 97%. As only water is added to purify the sugar, the application of this technology, in combination with modern industrial heat pumps and mechanical vapor recompression, allows for a powerful CO2-neutral process, with all the associated benefits regarding permits and marketability. The potential of this technology includes integration into new refinery projects (either standalone or back-end) by replacing affination, carbonatation and ion exchange decolorization (with raw sugar colors of up to 5000 IU), to expansion of existing refinery sites for slip stream processing of raw sugar syrups or refinery run-off syrups after clarification, and to the introduction of new process steps, such as direct liquid sugar production from cane raw sugar.

Short-Cut Design of Double-Layer Simulated Moving Bed Chromatography for Continuous Ternary Mixture Separation: Langmuir Isotherms

Short-Cut Design of Double-Layer Simulated Moving Bed Chromatography for Continuous Ternary Mixture Separation: Langmuir Isotherms

Bayesian optimization for quick determination of operating variables of simulated moving bed chromatography

The Simulated Moving Bed (SMB) is a continuous chromatographic separation process that operates on the principle of counter-current movement between the solid and liquid phases. Due to periodic switching of feed and product ports across numerous connected columns, adjusting SMB operating variables such as feed and product flow rates and switching time to achieve desired separations is challenging. While equilibrium theory can help narrow the search space, obtaining essential information such as accurate adsorption isotherms is crucial. This requirement, combined with often highly stringent production specifications, makes it challenging to identify even a feasible operating condition, let alone an optimal one. Trial-and-error-based approaches are often impractical as reaching cyclic steady state can be time-consuming, and any waste produced during this period can lead to significant economic losses. While rigorous dynamic models are available, they are computationally intensive and often do not accurately mirror actual process behavior. To address these challenges, the use of Bayesian Optimization (BO) is proposed to sequentially approach optimal SMB operation. Furthermore, it is suggested to employ the simpler True Moving Bed (TMB) model as a prior for the BO, which significantly accelerates convergence. This approach is demonstrated on an SMB process for cresol separation. Initially, the effectiveness of the BO using the TMB model is examined to gain insights into its behavior. Subsequently, we apply BO to the rigorous SMB model, informed by prior knowledge from the TMB model. Our results show that the developed BO framework rapidly converges to the optimal operating parameters that satisfy the purity constraints. We examine the efficiency improvements over various search algorithms and highlight the advantages of using the TMB model as a prior.

Conjugated linoleic acid from Suaeda salsa improves the intestinal health in T2DM mice by regulating colonic barrier function, intestinal glycolipid transporters and intestinal flora

Metabolic diseases such as obesity and diabetes are increasing rapidly, leading to adverse effects on patients’ intestinal function and health. In this study, high-purity conjugated linoleic acid (CLA) was extracted using glycerol from Suaeda salsa, followed by purification using simulated moving bed chromatography technique. Subsequently, type 2 diabetic mellitus (T2DM) mice were administered c9,t11-CLA (100 mg/kg), t10,c12-CLA (100 mg/kg), or varying doses of high-purity CLA diet (100, 600, or 1800 mg/kg) for a duration of five weeks. The impact on intestinal function was evaluated through morphological and tissue function studies combined with 16S rDNA sequencing technology and other techniques. The results demonstrated that the CLA was purified to 97.81% and significantly reduced blood glucose and lipid levels in T2DM mice by inhibiting the expression of small intestinal glucose and lipid transporters; enhanced colon barrier function by upregulating the expression of colon tight junction proteins; activated Jnk-c-Jun pathway to suppress intestinal cell apoptosis thereby improving survival rate; improved intestinal microecological health by modulating intestinal flora composition and metabolic function. These findings demonstrate the potential advantageous impact and mechanism of CLA derived from S. salsa in enhancing intestinal health among individuals with T2DM, providing a substantial theoretical and practical foundation for investigating the hypoglycemic effects of CLA and addressing global public health concerns.

Micro simulated moving bed chromatography-mass spectrometry as a continuous on-line process analytical tool.

Continuous manufacturing is becoming increasingly important in the (bio-)pharmaceutical industry, as more product can be produced in less time and at lower costs. In this context, there is a need for powerful continuous analytical tools. Many established off-line analytical methods, such as mass spectrometry (MS), are hardly considered for process analytical technology (PAT) applications in biopharmaceutical processes, as they are limited to at-line analysis due to the required sample preparation and the associated complexity, although they would provide a suitable technique for the assessment of a wide range of quality attributes. In this study, we investigated the applicability of a recently developed micro simulated moving bed chromatography system (µSMB) for continuous on-line sample preparation for MS. As a test case, we demonstrate the continuous on-line MS measurement of a protein solution (myoglobin) containing Tris buffer, which interferes with ESI-MS measurements, by continuously exchanging this buffer with a volatile ammonium acetate buffer suitable for MS measurements. The integration of the µSMB significantly increases MS sensitivity by removing over 98% of the buffer substances. Thus, this study demonstrates the feasibility of on-line µSMB-MS, providing a versatile PAT tool by combining the detection power of MS for various product attributes with all the advantages of continuous on-line analytics.

Green cannabigerol purification through simulated moving bed chromatography

Green cannabigerol purification through simulated moving bed chromatography

Possibilities of Optimizing the Purity of Mannose in Continuous Chromatographic Separation

AbstractThe development of separation technology based on continuous simulated moving bed chromatography in sugar technology is described. This is a potential economic alternative method both in terms of separation efficiency and process performance, and in terms of the high purity of the resulting products. This work focuses in detail on the isolation of mannose from natural polysaccharides, such as galactomannans; however, the developed procedures and equipment can be further applied to the separation of various liquid mixtures of carbohydrates. The main aim was to find optimal operating conditions for hydrolytic and separation steps of the whole technology. The obtained results provide a basic data set for further development of the industrial application.

Bamboo leaf: A review of traditional medicinal property, phytochemistry, pharmacology, and purification technology.

Bamboos are perennial evergreen plants that belong to the subfamily Bambusoideae of the true grass family Poaceae, with more than thousands of species distributed around the world. They are used as a traditional medicine with demonstrated effects of anti-oxidation, free radical scavenging, anti-inflammatory, liver protection and ameliorating cognitive deficits. Bamboo leaf is mainly used for the treatment of atherosclerotic, diabetic and nervous system diseases. This review aims to provide up-to-date information on the traditional medicinal properties, phytochemistry, pharmacology, and purification technologies of bamboo leaf. Relevant information on bamboo leaf was obtained by an online search of worldwide accepted scientific databases (Web of Science, ScienceDirect, Elsevier, SpringerLink, ACS Publications, Wiley Online Library and CNKI). More than 100 chemical compounds, including flavonoids and flavonoid glycosides, volatile components, phenolic acids, polysaccharide, coenzyme Q10, phenylpropanoid and amino acids have been reported to be present. These compounds were usually extracted by column chromatography and membrane separation technologies. Preparative high performance liquid chromatography (PHPLC), high-speed counter-current chromatography (HSCCC), simulated moving bed chromatography (SMB) and dynamic axial compression chromatography (DAC) were the advanced separation technologies have been used to isolate C-glycosides from bamboo leaf flavonoid, the main bioactive ingredient of bamboo leaf. Currently, bamboo leaf is mainly used for the treatment of atherosclerotic, diabetic, hepatic diseases and nervous system related symptoms, which are attributed to the presence of bioactive components of bamboo leaf. Phytochemical and pharmacological analyses of bamboo leaf have been revealed in recent studies. However, most of the pharmacological studies on bamboo leaf have focused on bamboo leaf flavonoids. Further studies need to pay more attention to other phytochemical components of bamboo leaf. In addition, there is lack of sufficient clinical data and toxicity studies on bamboo leaf. Therefore, more clinical and toxicity researches on this plant and constituents are recommended.

Development of a 3D printed micro simulated moving bed chromatography system

In the 1960s, chromatography processes were revolutionized by the invention of simulated moving bed chromatography. This method not only enhances the separation performance and resin utilization in comparison to batch-chromatography, it has also a much lower buffer consumption. While simulated moving bed chromatography nowadays is applied for a wide range of industrial applications, it was never transferred to the micro-scale (in regards to column and system volume). In our opinion a micro simulated moving bed chromatography system (µSMB) would be a useful tool for many applications, ranging from early process development and long term studies to downstream processing of speciality products. We implemented such a µSMB with a 3D printed central rotary valve and a microfluidic flow controller as flow source. We tested the system with a four zone open loop setup for the separation of bovine serum albumin and ammonium sulfate with size exclusion chromatography. We used four process points and could achieve desalting levels of BSA ranging from 94% to 99%, with yields ranging form 65% to 88%. Thus, we were able to achieve comparable results to common lab scale processes. With a total dead volume of 358 µL, including all sensors, connections and the valve, this is, to the best of our knowledge, the smallest SMB system that was ever built and we were able to perform experiments with feed flow rates reaching as low as 15 µL/min.

High-purity tri-alpha-linolenin isolation from silkworm pupae oil using sequential simulated moving bed chromatography

High-purity tri-alpha-linolenin isolation from silkworm pupae oil using sequential simulated moving bed chromatography

Separation of nadolol racemates by high pH reversed-phase fixed-bed and simulated moving bed chromatography

The separation of nadolol racemates under high pH reversed-phase using both the fixed-bed (FB) and the simulated moving bed (SMB) preparative chromatographic techniques is reported after the previous published work [1] where the Waters XBridge C18 adsorbent and an ethanol:water:diethylamine solvent mixture were validated to allow the separation of the multicomponent feed mixture composed by four nadolol stereoisomers into two pure racemates (two pairs of enantiomers).In this work, the experimental preparative separations using one commercial fixed-bed preparative HPLC Azura system equipped with one sole column of preparative dimensions (30 mm ID × 250 mm L) and one lab-scale SMB apparatus (the FlexSMB-LSRE pilot unit) equipped with six semi-preparative columns (19 mm ID × 100 mm L) are presented. Both systems use the Waters XBridge C18 adsorbent of 10 μm particle diameter. The screening of the mobile phase composition elected the 30:70:0.1 (v/v/v) ethanol:water:diethylamine solvent mixture to perform both FB and SMB preparative operations.A large set of experimental, modelling and simulation results are presented, including pulses, measurement and modelling of the adsorption equilibrium isotherms, and its validation through breakthroughs measurements. The modelling and simulation steps allowed the prediction and the optimization of both the FB and SMB operating conditions.For FB, using a feed concentration of 9 g/L of an equimolar mixture of the two nadolol racemates, both were recovered almost pure (at least 99.9 %), with a global system productivity of 3.06 gfeed/(Lbed.hr) and a solvent consumption of 4.21 Lsolvent/gfeed. For SMB, the pilot unit’s pressure drops limits imposed a maximum internal flow-rate of only 5 mL/min and, for a nadolol feed concentration of 2 g/L, both racemates were recovered 100 % pure, with a system productivity of 0.13 gfeed/(Lbed.hr) and a solvent consumption of 6.19 Lsolvent/gfeed. Additional simulation results showed that a SMB preparative unit can perform the 9 g/L nadolol racemate separation with a system productivity of 3.61 gfeed/(Lbed.hr) and a solvent consumption of only 1.95 Lsolvent/gfeed using the same average internal flow-rate as in FB operation. Even better SMB productivities can still be obtained using the same feed or solvent flow-rates as in FB operation if the internal SMB flow-rates are allowed and not limited by the system pressure drop.The experimental results presented in this work validate the strategy of separating a four nadolol stereoisomers mixture into two pure nadolol racemates, each one composed by a pair of nadolol enantiomers, using an achiral C18 adsorbent through FB and SMB chromatographic techniques. Each nadolol racemate can later be purified into pure nadolol stereoisomers using standard binary chiral FB and SMB chromatography. In this way, this works introduces a real and experimental solution for the complete multicomponent preparative separation of the four nadolol stereoisomers.

Addressing Atropisomerism in the Development of Sotorasib, a Covalent Inhibitor of KRAS G12C: Structural, Analytical, and Synthetic Considerations.

ConspectusNearly a century after its first description, configurationally stable axial chirality remains a rare feature in marketed drugs. In the development of the KRASG12C inhibitor sotorasib (LUMAKRAS/LUMYKRAS), an axially chiral biaryl moiety proved a critical structural element in engaging a “cryptic” protein binding pocket and enhancing inhibitor potency. Restricted rotation about this axis of chirality gave rise to configurationally stable atropisomers that demonstrated a 10-fold difference in potency. The decision to develop sotorasib as a single-atropisomer drug gave rise to a range of analytical and synthetic challenges, whose resolution we review here.Assessing the configurational stability of differentially substituted biaryl units in early inhibitor candidates represented the first challenge to be overcome, as differing atropisomer stability profiles called for differing development strategies (e.g., as rapidly equilibrating rotamers vs as single atropisomers). We relied on a range of NMR, HPLC, and computational methods to assess atropisomer stability. Here, we describe the various variable-temperature NMR, time-course NMR, and chiral HPLC approaches used to assess the configurational stability of axially chiral bonds displaying a range of rotational barriers.As optimal engagement of the “cryptic” pocket of KRASG12C was ultimately achieved with a configurationally stable atropisomeric linkage, the second challenge to be overcome entailed preparing the preferred (M)-atropisomer of sotorasib on industrial scale. This synthetic challenge centered on the large-scale synthesis of an atropisomerically pure building block comprising the central azaquinazolinone and pyridine rings of sotorasib. We examined a range of strategies to prepare this compound as a single atropisomer: asymmetric catalysis, chiral chromatographic purification, and classical resolution. Although chiral liquid and simulated moving bed chromatography provided expedient access to initial multikilo supplies of this key intermediate, a classical resolution process was ultimately developed that proved significantly more efficient on metric-ton scale. To avoid discarding half of the material from this resolution, this process was subsequently refined to enable thermal recycling of the undesired atropisomer, providing an even more efficient commercial process that proved both robust and green.While the preparation of sotorasib as a single atropisomer significantly increased both the analytical and synthetic complexity of its development, the axially chiral biaryl linkage that gave rise to the atropisomerism of sotorasib proved a key design element in optimizing sotorasib’s binding to KRASG12C. It is hoped that this review will help in outlining the range of analytical techniques and synthetic strategies that can be brought to bear in addressing the challenges posed by such axially chiral compounds and that this account may provide helpful guidelines for future efforts aimed at the development of such single atropisomer, axially chiral pharmaceutical agents.

Supervisory system for automated simulated moving bed (SMB) liquid chromatography (LC)

Praziquantel (PZQ) is a racemic mixture prescribed for Schistosomiasis disease treatment. However, only the enantiomer (R)-PZQ presents demonstrated efficiency against infirmity; the (S)-PZQ causes sickness and vomiting due to its bitter taste. The simulated moving bed chromatography system (SMB) is a well-established separation process applied in many branches of the chemical industry from drug purification stages to food processing systems. In order to implement and operate an SMB for the PZQ separation, allowing the production of medication with proven efficiency and without side effects, a LabVIEW supervisory system was developed. The automated software remotely controlled all equipment in the operational unit, such as automatic pumps, multi-position valves for flow rate alignments, and a chiral detector. Two experiments were conducted to characterize the system’s operational properties and efficiency. The first set of results demonstrated that the data acquisition programming retrieved information constantly, evidencing a direct correlation between the internal liquid pressure and the valve system position, with mean pressure values of approximately 50 bar. The second set of results demonstrated the SMB efficiency, with the raffinate stream producing (R)-PZQ of 100% purity.

Dual switch simulated moving bed chromatography: An optimal two‐fraction yielding separation process

Conventional Simulated Moving Bed Chromatography (C-SMBC) characterized by a single operating point comprising of the internal flow rates and switching period, yields a single fraction of the extract and raffinate, at cyclic steady state. In the current work, we deal with two-fraction yielding Dual Switch SMBC (DS-SMBC) characterized by two operating points implemented during alternate switches. The higher degrees of freedom in Dual Switch SMBC give it the potential of obtaining a higher average extract purity, for one of its two fractions, compared to conventional SMBC, at a certain minimum feed flow rate and minimum average extract recovery. This becomes possible with a trade-off in the average purity of the other extract fraction of Dual Switch SMBC, without any addition to the conventional SMBC equipment. We solve a multi-objective optimization problem wherein we maximize the average purity of one of the extract fractions of Dual Switch SMBC, with the requirement of certain minimum feed flow rate, minimum average extract recovery and minimum average purity of the non-objective extract fraction. One of the aims of the current work is deduction of the working principle of Dual Switch SMBC, that facilitates superior average extract purity. Next, we analyze the trade-offs due to the said process bounds on the objective i.e. average purity of objective extract fraction of Dual Switch SMBC. This has been done for the two case studies of separation: 1) linear isotherm based separation of fructose-glucose in deionized water on cation exchange resin 2) non-linear isotherm based separation of enantiomers of Tröger’s base in ethanol on microcrystalline cellulose triacetate. The findings from the trade-offs in the multi-objective optimization problem, further corroborate our understanding of the working principle.

Advances and challenges in the pharmacokinetics and bioanalysis of chiral drugs.

Enantioselective analytical approaches are essential for monitoring pharmacokinetics and acquiring accurate data to better understand the role of stereochemistry in pharmacokinetics. Enantioselectivity significantly impacts the pharmacokinetics of chiral drugs, especially in metabolic profile, leading to toxicity of enantiomer. Consequently, there is a need to study the pharmacokinetics of enantiomerically pure drugs and racemates as they differ in affinity with enzymes and proteins. Combining the best enantioseparation conditions with the specified biological matrix and the intended purpose of the analysis is a challenging task. This review discusses the importance of chirality in stereoselective pharmacokinetics with more relevant examples, various enantioselective analytical techniques, and stationary phases employed. Challenges such as lack of universal chiral columns, biological inversion of the isomers, and others have been discussed. Further presented the recent advances in the screening of chiral drugs and innovative improvements in the analytical approaches for chiral molecule analysis such as supercritical fluid chromatography, simulated moving bed chromatography, and other techniques are discussed.

D-Allulose (d-psicose) biotransformation from d-glucose, separation by simulated moving bed chromatography (SMBC) and purification by crystallization

d-Allulose (or d-Psicose), a C-3 epimer of d-fructose, is a low-calorie rare sugar with excellent physiological functions. The recombinant Escherichia coli expressing d-allulose 3-epimerase for d-allulose conversion from d-fructose was constructed. Under the optimal conditions, 139.3 g/L d-allulose was produced from 500 g/L of d-fructose. In order to decrease the cost for mass production, one-pot reaction method by using immobilized glucose isomerase and recombinant E. coli expressing d-allulose 3-epimerase to produce d-allulose from d-glucose was developed. The immobilized glucose isomerase (200 g/L) and the recombinant E. coli cells (OD600 2) were mixed and used to transform d-glucose into d-allulose, and 228.5 g/L d-glucose, 216.3 g/L d-fructose and 90.7 g/L d-allulose were obtained from 550 g/L d-glucose after 3 h reaction. After that, d-allulose was separated from the reaction mixture by using simulated moving bed chromatography (SMBC) with the purity of 99.6%. Finally, crystallization was made to obtain the d-allulose crystals with 99.8% purity. The combination of enzyme and catalytic cells in biotransformation greatly expand the flexibility and capability of the catalytic reactions. This method developed in this study can be easily scaled up for mass production of highly purified d-allulose.

Separation of p-xylene and m-xylene by simulated moving bed chromatography with MIL-53(Fe) as stationary phase

The separation of p-xylene (PX) and m-xylene (MX) isomers with near boiling points is a worldwide problem. The metal-organic framework material is an ideal stationary phase for chromatographic separation because of its high porosity, homogeneous pore diameter and good chemical stability. In this paper, a simulated moving bed (SMB) chromatography system with MIL-53(Fe) as the stationary phase and petroleum ether-dichloromethane as the mobile phase was designed to separate PX and MX at ambient temperature. Firstly, according to the elution curves of a single column, nonlinear competitive Langmuir adsorption isotherm equation was confirmed by equilibrium dispersive chromatography model. Then, the SMB separation zone was determined based on triangle theory, and the SMB operating conditions were optimized. Finally, the purity, recovery and productivity of PX reached 100.0%, 99.1% and 93.1 g/L/h, respectively; the purity, recovery and productivity of MX reached 96.4%, 100.0% and 23.5 g/L/h, respectively; the solvent consumption was 0.42 L/g.

Magnetic/flow controlled continuous size fractionation of magnetic nanoparticles using simulated moving bed chromatography.

The use of magnetic nanoparticles shows a steadily increasing technical importance. Particularly in medical technology disciplines such as cancer treatment, the potential of these special particles is increasing rapidly. Magnetic nanoparticles are particles with a submicron size, and consist mostly of magnetite-containing composites. An important quality parameter of such particles is a particle size distribution as narrow as possible, which can only be obtained to a certain degree by synthesis. Apart from ultracentrifugation, there are so far only methods on an analytical scale to narrow the size distribution as a post-processing step. We present a method based on magnetic chromatography, by which high separation efficiencies at yields of up to 99.9% are achieved. The novel technique is based on a competition between the magnetic interaction of the nanoparticles and the separation matrix, as well as the hydrodynamic forces. Furthermore, the method is extended using a continuous mode, namely simulated moving bed chromatography, to obtain potent space-time yields of up to 2.94g/(L*h). For those reasons, this novel continuous magnetic chromatography method offers high potential for large-scale refinement of magnetic nanoparticles while fulfilling sophisticated quality criteria for high-technology applications.

Dynamic modeling and machine learning of commercial-scale simulated moving bed chromatography for application to multi-component normal paraffin separation

Analysis and improvement of simulated moving bed chromatography (SMB) were conducted to separate multi-components of C10–14 normal paraffin (n-paraffin) from kerosene. Owing to the complexities of the feed composition and operational variables, a mathematical dynamic model using limited experimental parameters and data-driven machine learning using real industrial data were both employed to evaluate SMB performance. The developed dynamic model could evaluate the purity, recovery, and solvent consumption. Under standard operating conditions, the simulation results indicated that the extracted n-paraffin purity was 99.6%; and the recoveries of nC10, nC12, and nC14 were 95.7%, 88.9%, and 81.6%, respectively. The analysis of the counter-current ratio in each zone suggested that recovery can be enhanced by decreasing the Zone I and IIb ratios and increasing the Zone III ratio. In particular, controlling the Zone III became more important as the carbon-chain-length increased. An additional second desorbent stream in the n-paraffin SMB, known as zone flush, played an important role in further improving the purity of the extracted n-paraffin. The machine learning results clearly presented the importance of zone flush on impurity removal, which could not be sufficiently estimated from the dynamic model. The increase in p-xylene content in the zone flush contributed to a reduction in aromatic impurities in the extract. Owing to the nature of the industrial data obtained in a limited operation range, it was recommended that the mathematical and data-driven models should be used complementarily. Since the subsequent fractionation section consumed a significantly larger amount of energy than the SMB itself, an exergy analysis was conducted on the overall n-paraffin SMB process integrated with the fractionation section and potential improvements were suggested. The results will contribute to the establishment of design and operation guidelines for improving n-paraffin SMB performance.

Mobile Phase Composition Effects on Optimal Performance of Isocratic and Gradient Simulated Moving Bed Chromatography

Mobile Phase Composition Effects on Optimal Performance of Isocratic and Gradient Simulated Moving Bed Chromatography