Four-zone Simulated Moving Bed Research Articles

Development of a stepwise solvent-gradient SMB process for continuous-mode purification of methoxyethyl nucleoside phosphoramidites to be used as the key building blocks of oligonucleotide drugs

One of the commercially proven oligonucleotide-based drugs that can treat a variety of life-threatening diseases through gene-expression control is 2′-O-methoxyethyl (MOE) oligonucleotide. To keep the economical production of the MOE-oligonucleotide stable, it is important to establish an efficient process for recovering its corresponding monomer (MOE nucleoside phosphoramidites) in a large quantity at high purity from the output of the phosphitylation reaction based on using MOE nucleoside as a starting component. To address this issue, we pursued the development of an efficient simulated-moving-bed (SMB) process for continuous-mode recovery of monomer from the considered reaction output. First, the intrinsic parameters of monomer and impurities present in the reaction output were obtained through an inverse method using silica gel as an adsorbent. The resulting intrinsic parameters were then applied to the optimal design of the SMB process for monomer recovery, which revealed that its optimal configuration was a four-zone open-loop SMB configuration based on the installation of regeneration and re-equilibration zones for implementing a stepwise solvent-gradient method. Under such configuration, the optimal SMB operation parameters to maximize throughput while keeping high purity stable were determined using the relevant optimization tool based on column model and genetic algorithm. It was confirmed through the experimental run that the optimized SMB process could enable the continuous recovery of monomer from the considered reaction output with 99.6% purity while keeping the monomer loss close to zero. Finally, the developed SMB process in this article was found to increase throughput by more than 33 times, and reduce solvent usage by more than 89%, compared to the plant-scale batch chromatographic process currently in operation in related industries.

Unified design of chromatographic separation processes: Partial separations and waste fractions

Chromatographic batch and simulated moving-bed (SMB) processes where products are collected in less than 100% purity, or part of the effluent is discarded as waste, were analyzed. The Unified Design method was used to visualize the regions of feasible operating parameters under ideal and non-ideal conditions. Binary separations with linear and Langmuir isotherms were considered. The feasible regions of batch chromatography and the classical four-zone SMB are identical for partial separations under ideal conditions. For Langmuir isotherms, the feasible region of an ideal batch column is an excellent approximation for an efficient SMB process when purity constraints are low. Chromatographic processes with waste fractions are represented by two operating points on the Unified Design operating parameter plane. In contrast to batch chromatography, introducing an additional waste stream to an SMB process was found to not improve its performance.

On-line optimization of four-zone simulated moving bed chromatography using an equilibrium-dispersion model: I. Simulation study

Simulated moving bed (SMB) chromatographic processes have been successfully applied to petrochemical, pharmaceutical, and fine chemical industries to separate the target products with high purity and yield since it was introduced in 1960s. Conventional four-zone SMB chromatography and its advanced variants are nowadays the most promising continuous processes for the separation of chiral active pharmaceutical ingredients (APIs). However, the design and optimization of SMB processes are still challenging issues due to their structural complexity and operational sensitivity. In this work, the equilibrium-dispersion model with nonlinear adsorption isotherms was applied for model based on-line optimization. The proposed optimization technique estimates the process states including the isotherm and kinetic parameters. The operating conditions are dynamically optimized ‘switch-by-switch’ in order to separate binary mixtures up to 99% product purity.

Model Predictive Control of Simulated Moving Bed Chromatography for Binary and Pseudo-binary Separations: Simulation Study

Simulated moving bed (SMB) processes have been applied to petrochemical, pharmaceutical, and fine chemical industries to separate products in high purity and yield since it was introduced in 1960s. Owing to process complexity and operational sensitivity, the control and dynamic optimization of the SMB process are still challenging issues. In this work, a simplified process model with linear isotherms was introduced to estimate process states of conventional four-zone SMB chromatography. In a simulation study, a controller can estimate current process states and find the optimal operating conditions ‘switch by switch’ up to moderately nonlinear ranges of the competitive Langmuir isotherms. Furthermore, the controller works for the process with system void volumes and delayed feedback information.

Improvement of the performances of a tandem simulated moving bed chromatography by controlling the yield level of a key product of the first simulated moving bed unit

One of the trustworthy processes for ternary separation is a tandem simulated moving bed (SMB) process, which consists of two subordinate four-zone SMB units (Ring I and Ring II). To take full advantage of a tandem SMB as a means of recovering all three products with high purities and high economical efficiency, it is important to understand how the separation condition in Ring II is affected by that in Ring I, and further to reflect such point in the stage of designing a tandem SMB. In regard to such issue, it was clarified in this study that the Ring I factors affecting the Ring II condition could be represented by the yield level of a key product of Ring I (YkeyRing I). As the YkeyRing I level became higher, the amount of the Ring I key-product that was reloaded into Ring II was reduced, which affected favorably the Ring II separation condition. On the other hand, the higher YkeyRing I level caused a larger dilution for the stream from Ring I to Ring II, which affected adversely the Ring II separation condition. As a result, a minimum in the desorbent usage of a tandem SMB occurred at the YkeyRing I level where the two aforementioned factors could be balanced with each other. If such an optimal YkeyRing I level was adopted, the desorbent usage could be reduced by up to 25%. It was also found that as the throughput of a tandem SMB became higher, the factor related to the migration of the Ring I key-product into Ring II was more influential in the performances of a tandem SMB than the factor related to the dilution of the stream from Ring I to Ring II.

Effects of a malfunctional column on conventional and FeedCol-simulated moving bed chromatography performance

The effects of a malfunctional column on the performance of a simulated moving bed (SMB) process were studied experimentally and theoretically. The experimental results of conventional four-zone SMB (2-2-2-2 configuration) and FeedCol operation (2-2-2-2 configuration with one feed column) with one malfunctional column were compared with simulation results of the corresponding SMB processes with a normal column configuration. The malfunctional column in SMB processes significantly deteriorated raffinate purity. However, the extract purity was equivalent or slightly improved compared with the corresponding normal SMB operation because the complete separation zone of the malfunctional column moved to a lower flow rate range in zones II and III. With the malfunctional column configuration, FeedCol operation gave better experimental performance (up to 7%) than conventional SMB operation because controlling product purity with FeedCol operation was more flexible through the use of two additional operating variables, injection time and injection length. Thus, compared with conventional SMB separation, extract with equivalent or slightly better purity could be produced from FeedCol operation even with a malfunctional column, while minimizing the decrease in raffinate purity (less than 2%).

Three-port operation in three-zone simulated moving bed chromatography

A new operating method, namely three-port operation in a three-zone simulated moving bed (TT-SMB), was developed to improve the separation performance of simulated moving bed (SMB) chromatography. In the TT-SMB, the switching period consists of two steps; extract outlet port is closed at the first step for raffinate production and raffinate outlet port is closed at the second step for extract production. As a result, three ports were used in each step of the three-zone SMB operation. The separation performance of TT-SMB was compared with conventional three- and four-zone SMBs in terms of purity, recovery, productivity, and eluent consumption. A conventional three-zone SMB operation usually produced the contaminated portion at the product outlet node during the switching period. However, such phenomenon could be prevented by using the TT-SMB operation because one product outlet port was closed at each step. Compared to the conventional three-zone SMB, all performance parameters improved with the use of TT-SMB, and the improvement in purity and recovery was significant (up to 7%). Adjusting the step ratio played a key role in the trade-off between the performance parameters. The purity, recovery, and productivity of TT-SMB at well-designed step ratio conditions are up to 3% higher than those of the conventional four-zone methods (1-1-1-1 configuration).

Backfill-simulated moving bed operation for improving the separation performance of simulated moving bed chromatography

The Backfill-SMB (BF-SMB) strategy was designed to improve the separation performance of simulated moving bed (SMB) chromatography. In the BF-SMB operation, a limited amount of products from raffinate and/or extract was re-fed to the SMB circuit as a backfill-feed. Two additional operating variables, backfill ratio (BR) and backfill length (BL), were suggested to determine the amount and injection length of backfill-feed. This strategy was applied to a four-zone SMB with one column (1-1-1-1) and two columns (2-2-2-2) per zone using a binary mixture with a nonlinear isotherm. Various BF-SMB operational methods were designed to supply backfill-feed to the feed node and/or intermediate node. The separation performances of conventional SMB and BF-SMB were compared in terms of purity, recovery, and eluent consumption. The BF-SMB successfully improved the separation performance of the conventional SMB because backfill-feed led to the rich condition of the main component at each product withdrawal node. Due to the ‘TMB effect’ caused by backfill-feed, the BF-SMB operation was more efficient in the 1-1-1-1 configuration than in the 2-2-2-2 configuration, showing maximum improvement of 5–7% purity and recovery from the performance of conventional SMB. In addition, partial recycling of eluent by backfill-feed resulted in a decrease in eluent consumption up to 10% even with improved purity and recovery in BF-SMB.

Improving performance of a tandem simulated moving bed process for sugar separation by making a difference in the adsorbents and the column lengths of the two subordinate simulated moving bed units

A tandem simulated moving bed (SMB) process for removal of sulfuric acid and acetic acid from sugars has been developed previously. This process consisted of two four-zone SMB units (Ring I and Ring II), in which the same adsorbent (Dowex99 resin) and the same column length were used. To improve the performance of such a tandem SMB process for sugar separation, it is worth adopting the strategy of making a difference between the column lengths of Ring I and Ring II. The results showed that such strategy could allow the adsorbent beds of both Ring I and Ring II to be fully utilized at the same time, which was impracticable in the previous tandem SMB mode. As a result, the tandem SMB based on such strategy could achieve higher productivity than the previous tandem SMB mode. In addition, the use of different adsorbents (Amberchrom-CG161C in Ring I and Dowex99 in Ring II) was proposed as the second strategy, which was confirmed to be highly effective in improving the productivity of the tandem SMB for sugar separation. Finally, a third strategy was proposed by combing the first and the second strategies. It was found that compared to the previous tandem SMB mode, the third strategy led to more than eleven times the productivity under the constraint of pressure drop ≤100psi. This was mostly because the third strategy had a remarkable advantage over the previous tandem SMB mode in the aspects of bed utilization and selectivities, which stemmed from the use of different column lengths and the use of different adsorbents respectively.

IgY (Immunoglobulin Yolk) 분리를 위한 3-영역 SMB (Simulated Moving Bed)와 4-영역 SMB 비교전산모사

난황에 포함된 IgY는 포유동물에 있는 바이러스나 항원에 반응하는 항체와 같은 역할을 한다. 난황을 전처리한 후 3-zone와 4-zone SMB를 이용하여 지질단백질들로 부터 IgY를 분리하는 전산모사연구를 수행하였다. 회분식 크로마토그래피에서 전산모사 매개변수와 흡착 등온식 SMB 전산모사 변수를 얻었다. Aspen simulator를 이용하여 전산모사를 수행하여 IgY를 분리할 수 있는 3-zone과 4-zone SMB 운전조건을 비교하여 다음과 같은 결과를 얻었다. IgY와 다른 단백질의 농도와 순도를 모두 고려할 때, 꼭지점인 좌표(<TEX>$m_2$</TEX>, <TEX>$m_3$</TEX>=0.1, 1.1)에서 3-zone SMB가 최적의 조건으로 생각된다. IgY 만을 고려하면 4-zone SMB가 좌표(<TEX>$m_2$</TEX>, <TEX>$m_3$</TEX>=0.06, 0.5)에서 가장 높게 IgY를 분리할 수 있었다. recycle이 없는 3-zone SMB는 꼭지점 좌표에서 좌표이동이 extract의 지질 단백질 농도에 큰 영향을 주었다. IgY (Immunoglobulin Yolk) is a specific antibody in egg yolk, and it protects human body from virus and antigen. There are a lot of egg yolk components such as lipoprotein and protein. To separate IgY, HPLC (High Performance Liquid Chromatography) and precipitation were used in a batch mode and SMB (Simulated Moving Bed) was adopted for continuous purification of yolk proteins. IgY and other proteins in yolk were separated by using three-zone and four-zone SMB chromatography. Before performing SMB experiments, batch chromatography simulation parameters and adsorption isotherms were obtained. The parameters of batch chromatography were used to simulate SMB using Aspen chromatography. To compare three-zone and four-zone SMB chromatography, simulations in <TEX>$m_2-m_3$</TEX> plane on the triangle theory were carried out. In terms of concentration and purity of both IgY and other lipoproteins, 3-zone SMB process is considered as ideal at the vertex of triangle (<TEX>$m_2$</TEX>, <TEX>$m_3$</TEX>=0.1, 1.1). 4-zone SMB yields the highest IgY purity at the coordinate (<TEX>$m_2$</TEX>, <TEX>$m_3$</TEX>=0.06, 0.5), which is the pure raffinate region. In 3-zone SMB without recycle, other lipoproteins in extract are largely affected in purity by small shift from the vertex of triangle (<TEX>$m_2$</TEX>, <TEX>$m_3$</TEX>=0.1, 1.1).

Separation of α-Tocopherol with a Two-Feed Simulated Moving Bed

A two-feed simulated moving bed (SMB) was proposed to utilize the stationary phase more effectively. Zone I is disconnected with zone II and zone III is disconnected with zone IV. Two feeds are added to zones I and III, while two desorbents are added to zones II and IV separately. The investigation on the movement of concentration bands indicated that the tail of the strong retained solute and the front of the weak retained solute were eluted from zones I and III orderly, so the streams from zones I and III could be cut into different fractions to give the products with high purity. The two-feed SMB was used to separate α-tocopherol from its homologue mixture successfully, and could double the productivity if both feeds were identical to the feed in the conventional four-zone SMB. The solvent consumption could be reduced by reusing the middle fraction without solutes.

Improved Performance of a Simulated Moving Bed Process by a Recycling Method in the Partial-Discard Strategy

The recycling partial-discard (RPD) strategy was developed to improve the performance of simulated moving bed (SMB) chromatography in partial-discard (PD) strategy by a simulation study. In the RPD operation, each discarded product portion of extract and raffinate is recycled as part of the feed. This strategy was applied to a binary mixture with a nonlinear isotherm in a four-zone SMB with two columns per zone. The two additional operating variables, recycle length (RL) and recycle flowrate (RF), were suggested for the RPD strategy in order to determine the time duration and flowrate of the recycle feed. Compared to those of the PD operation, extract and raffinate with higher purities can be produced from the RPD operation. Simultaneously, the losses in the other performance parameters (recovery, productivity, and eluent consumption) stemming from the PD operation could be favorably reduced by controlling the recycle length and recycle ratio in the RPD operation. The two variables, RL and RF, in the RPD ...

Novel Simulated Moving-Bed Cascades with a Total of Five Zones for Ternary Separations

Two simulated moving-bed (SMB) cascades are proposed for the separation of a ternary mixture containing the least, medium-, and most retained solutes (A, B, and C). Each cascade has a total of five zones. The first cascade combines two three-zone SMBs sharing zone III: the one SMB with zones I to III separates (A+B+C) into A and (B+C), and the other three-zone SMB with zones III to V separates (B+C) into B and C. The second cascade combines a four-zone SMB consisting of zones I to IV and a three-zone SMB comprising zones IV, V and I: the former separates (A+B+C) into (A+B) and C, and the latter separates (A+B) into A and B. Analysis of the concentration band movement together with a modeling study confirms the feasibilities of the two cascades, suggesting that the first cascade should be adopted if the separation of (A+B) and C is easier than that of A and (B+C), and otherwise, the second cascade should be used.

Recovery of ionic liquid and sugars from hydrolyzed biomass using ion exclusion simulated moving bed chromatography

Efficient recovery of ionic liquid (IL) from aqueous mixture of ILs and sugars (which derived from enzymatic or chemical catalyzed hydrolysis of ILs-pretreated biomass) is a major drawback for commercialization of biofuel and platform chemicals production from biomass utilized ILs as pretreatment solvent. In this study, simulated moving bed (SMB) chromatography equipped with ion exclusion column (containing [Emim]+ cation) was investigated to separate sugars (glucose and xylose) which are the main products from biomass hydrolysate and 1-Ethyl-3-methylimidazolium acetate (EmimAc) which is the ILs used for biomass pretreatment. A four-zone SMB system with a configuration of 2-2-2-2 (2 ion exclusion columns in each zone) was used to recover glucose, xylose and EmimAc from their aqueous mixture with yield of 71.38, 99.37 and 98.92%, respectively. Moreover, the optimization of SMB zone configuration by simulation results in a complete recovery of ILs. This result indicates that for the first time, ion exclusion SMB chromatography could be used for complete recovery of ILs from aqueous sugar mixture.

Enhanced performance of a tandem simulated moving bed process for separation of paclitaxel, 13-dehydroxybaccatin III, and 10-deacetylpaclitaxel by making a difference between the adsorbent particle sizes of the two subordinate simulated moving bed units

A tandem simulated moving bed (SMB) process, which consists of two four-zone SMB units (Ring I and Ring II) in series, has been developed previously for complete separation of a ternary bioproduct mixture. In all of previous studies on the optimization of such a tandem SMB process, the adsorbent particle sizes in Ring I and Ring II have been kept the same. To make a further improvement in the performance of a tandem SMB, one can adopt the strategy of making a difference between the adsorbent particle sizes of Ring I and Ring II, which was studied in this paper using the ternary paclitaxel-related mixture as an example separation system. The results showed that the proposed strategy led the adsorbent particle sizes in Ring I and Ring II to be selected in favor of reducing the product dilution of Ring I and reducing the pressure drop of Ring II, respectively. Such pattern of particle-size selection resulted in a marked improvement in the productivity of the tandem SMB of interest, which was confirmed for both the low-pressure and the high-pressure systems. Furthermore, such advantage of the proposed strategy became more pronounced as the selectivity related to the ternary separation was reduced.

Effect of dead volume on performance of simulated moving bed process

The volume of surrounding equipments (pipe transfer lines and valves) in the simulated moving bed (SMB) unit, which is called the dead volume, is modeled as bed-head, bed-tail and bed-line. Since the dead volume can be significant especially in industrial-scale SMB units, the consideration of dead volume has been required for high performance operation. In this study, a simple and unified approach based on the method of characteristics (MOC), called the extended node model, is established to solve fluid concentration dynamics within dead volumes. The computational efficiency of the approach is evaluated for three case studies of a standard four-zone SMB process with a linear adsorption equilibrium model. Insertion of one zone to flush the fluid trapped in extract bed-line into the standard four-zone SMB improves substantially purity, while recovery is kept constant.

Optimal design of a tandem simulated moving bed process for separation of paclitaxel, 13-dehydroxybaccatin III, and 10-deacetylpaclitaxel

Paclitaxel, 13-dehydroxybaccatin III (13-DHBIII), and 10-deacetylpaclitaxel (10-DAP), which came from the plant cell culture, have been regarded as highly valuable because of their efficacy in the anticancer treatments. Due to these values, the necessity for separating the three components in an economical way has been a matter of grave concern in industry. In this study, a tandem simulated moving bed (SMB) process that consisted of two four-zone SMB units in series was applied to such a ternary separation. First, a series of pulse injection experiments were performed for estimation of the adsorption isotherm and mass-transfer parameters. The estimated parameters were utilized in the tandem SMB optimization tool that was prepared based on the standing wave design principle. During the optimization of interest, the throughput of the tandem SMB was maximized while meeting the requirements on product purities and pressure drop. The results proved that the most economical strategy of utilizing the tandem SMB was to recover paclitaxel in the first SMB unit and then separate the remaining two components (13-DHBIII and 10-DAP) in the second SMB unit. Furthermore, such a strategy was also found to result in better tandem SMB performances over the entire region of a pressure drop limit.

Optimal design and experimental validation of a modified four-zone SMB process for the separation of a ternary amino acid mixture

For a standard four-zone simulated moving bed (SMB) chromatography, several process modifications have been made in previous studies such that its application scope could be extended to a ternary separation. One of the effective modifications reported was to (1) replace its closed-loop configuration with an open-loop configuration and (2) utilize the extract port for collecting both the intermediate-affinity and the highest-affinity components in regular sequence in every switching period. Most of previous researches on such a modified four-zone SMB (MF-SMB) have been limited to process simulation and optimization. The experimental validation of the MF-SMB process with linear isotherms was attempted in this article for the first time using a ternary amino acid mixture as a model system. First, the intrinsic parameters of three amino acids were estimated from a series of multiple-frontal experiments. The estimated parameter values were then used in the stage of the MF-SMB optimization, which was assisted by an up-to-date genetic algorithm. Based on the optimized conditions, the MF-SMB experiment was conducted and the assay results for product samples verified the attainment of a ternary separation. The experimental purities and concentrations were also found to agree closely with the model predictions.

Analysis of “focusing” effect in four-zone SMB (Simulated Moving Bed) unit for separation of xylose and glucose from biomass hydrolysate

Analysis of “focusing” effect in four-zone SMB (Simulated Moving Bed) unit for separation of xylose and glucose from biomass hydrolysate

Separation of D‐psicose and D‐fructose using simulated moving bed chromatography

Simulated moving bed (SMB) processes have been widely used in the sugar industries with ion-exchange resin as a stationary phase. D-psicose, a rare monosaccharide known as a valuable pharmaceutical substrate, was synthesized by the enzymatic conversion from D-fructose. The SMB process was adopted to separate D-psicose from D-fructose. Before the SMB experiment, the reaction mixture including D-psicose and D-fructose was treated by a deashing process to remove contaminants, such as buffers, proteins, and other organic materials. Four columns packed with Dowex 50WX4-Ca2+ (200-400 mesh) ion-exchange resins were used in the four-zone SMB. Single-step frontal analysis was performed to estimate the isotherm parameters of each monosaccharide. The operating conditions of the SMB process were determined based on the Equilibrium Theory. According to the simulation of the SMB process, the purity and yield of extract product (D-psicose) achieved were 99.04 and 97.46%, respectively and those of raffinate product (D-fructose) were 99.06 and 99.53%, respectively. Under the optimized operating condition, complete separation (extract purity = 99.36%, raffinate purity = 99.67%) was achieved experimentally.