**3. Gradient Variant**

The performance of the conventional four-zone SMB could be optimized by adjusting the adsorption behavior of each zone, which can be achieved by introducing a gradient parameter to change the operating conditions, such as temperature or solvent composition. Three kinds of gradient variants are frequently used: concentration gradient (or solvent gradient), temperature gradient and pressure gradient. Among them, the concentration gradient is most widely used and its operating conditions are relatively easier to achieve and fewer restrictions exist. The latter two variants are applicable to specific fluid phases and operating conditions.

#### *3.1. Concentration Gradient*

The separation in a conventional four-zone SMB is largely influenced by the adsorption affinity (or isotherm parameters) of the two components. To improve the performance of the SMB, the idea of distributing different isotherm parameters in different zones is applied by introducing different solvent intensities in the desorbent and feed, which resulted in different solvent intensities along the bed. Specifically, a concentration gradient is formed, and the elution ability of zones I–IV is gradually decreased. The elution intensity in zone II (between the extract port and the feed port) is greater than that in zone III (between the feed port and the raffinate port). The solute can, therefore, move forward in zone II and backward in zone III; thus, separation is achieved in these two zones. The solvent strength is commonly controlled by the concentration of the organic modifier in the fluid phase. The higher the concentration of the modifier, the lower the adsorption affinity (or isotherm parameter). Therefore, the concentration of the modifier in the desorbent should usually be set higher than the concentration in the feed material [57–60].

Wang et al. [60] used a concentration gradient SMB to separate paclitaxel and cephalosporin. The solvent composition, zone flow rate and switching time in the feed and desorbent were optimized using a non-dominated sequencing genetic algorithm with elite and jump genes (NSGA-II-JG) and rate model simulations. Compared to conventional SMB, optimal solvent gradient SMBs have substantially higher productivity and lower solvent consumption. Meanwhile, gradient SMBs can further improve productivity by eliminating limitations of flow rates in each zone.

Mun [61] applied the solvent gradient mode for the separation of phenylalanine and tryptophan. The amino acid separation process of SG-SMB was optimized to maximize the production efficiency under the constraints of pump capacity and purity. The inlet and outlet flow rates, switching times and local distribution of liquid phase along the chromatographic bed were optimized using genetic algorithms and rate model simulations. The results showed that the yield was increased, the desorbent consumption was reduced and the product concentration was increased compared to the conventional SMB. Specifically, in this case, the productivity of amino acid was increased up to 110%, and meanwhile the desorbent consumption was reduced up to 53%.

Compared to the conventional four-zone SMB, the concentration gradient SMB has higher productivity and lower desorbent consumption and, meanwhile, relatively high separation purity and efficiency could be obtained. Most operating designs employ an open-loop structure; the eluent flows out from the end of zone IV and is no longer circulated into zone I. However, in the concentration gradient mode, the mobile phase composition is not constant, which leads to cyclic steady-state characteristics when the inlet and outlet ports are switched periodically. Similarly, the internal adsorption equilibrium relationship of the solute also shows cyclic steady-state variations, which will reduce the stability of the system and thus make the process design more difficult.

#### *3.2. Temperature Gradient*

Conventional SMB units are operated under isothermal and isobaric conditions with constant adsorption intensities in all zones. Low adsorption intensities are favorable for zones I and II, while high adsorption intensities are favorable for zones III and IV. Therefore, it is desirable to introduce a gradient of adsorption intensity to improve the unit productivity and solvent consumption performance of the SMB. For the liquid fluid phase, the adsorption intensity can be effectively adjusted by changing the temperature [62–64].

Wankat et al. [62] combined the principles of SMB and thermal swing adsorption (TSA) and developed a traveling wave mode thermally assisted moving bed. A heat exchanger was used to control the fluid temperature, which resulted in a thermal wave passing through the column. As shown in Figure 11, the fluid is heated or cooled before it enters each adiabatic column, and the temperature within the column varies in each zone, thereby affecting the solute adsorption capacity and optimizing the performance of the SMB. Thermally assisted SMBs can be used to separate mixtures that are thermally stable and where the isotherm significantly shifts with temperature.

**Figure 11.** Schematic diagram of temperature gradient.

Yu et al. [65] investigated the feasibility of internal temperature gradient SMB for the enantiomeric binary separation process by introducing the temperature difference between feed and desorbent. The result demonstrated that a temperature gradient with a 20 K difference could significantly improve the productivity of the SMB device by 20%. In addition, increasing the flow rate ratio in zone IV could effectively reduce the solvent consumption.

In conclusion, the advantages of temperature gradient SMB are: (1) There are no restrictions on heat exchange rate, and the SMB and simulation system can be easily scaled up. (2) The adsorption intensity of each zone can be adjusted by changing the temperature to enhance the separation performance of the SMB. Nevertheless, some disadvantages are: (1) Although the traveling wave mode solves the serious heat transfer limitation problem, the external dead volume is increased by heat exchanger, and thus the hysteresis time is increased. (2) As the isotherm of separation mixture is certainly affected by temperature, its application scope is limited.

#### *3.3. Pressure Gradient*

The pressure gradient mode is, currently, mainly applied to supercritical fluid simulated moving beds (SF-SMB). Morbidelli et al. [66] designed a pressure gradient SMB, in which different pressure levels were applied in the four zones. Pressure control valves were, respectively, installed after each column and between the outlet and inlet valves, which could adjust different pressure values in the two adjacent zones. As a result, the Henry's constant of the components and their retention times were increased due to the decreased density of the supercritical fluid phase with decreasing pressure. Thus, the

separation process could be optimized by introducing a decreased pressure gradient from zone I to zone IV to form a decreased gradient in the elution intensity of the fluid phase. When a pressure gradient is used, the product purity is increased by up to 2.3% and the productivity is increased by 0.29 g/kg compared to the isobaric mode.

Since the fluid phase of this variant uses supercritical fluids instead of conventional organic solvents, it has the obvious advantage of being green and environmentally friendly; meanwhile, the desorbent cost is lower than conventional SMB. However, it is not widely applicable due to the special fluid phase.

#### **4. Feed or Operation Variant**

Another modification method is to improve the performance of the conventional SMB by only changing the feed or operation mode, without altering the SMB configuration. Ten different variants are investigated below, which can be used either alone or in combination of two or more to improve the separation performance of SMBs in applications.

#### *4.1. ModiCon*

"ModiCon" feed mode, also called varying concentration feed model. Schramm et al. [67] proposed adjusting the feed concentration with a certain rule within the transition cycle appropriately. Then, the concentration spectral band changes its movement rate as it flows through the feed port and is usually applicable to nonlinear adsorption. Compared to conventional SMB, the ModiCon could regulate the feed concentration and increase productivity by about 50% and reduce solvent consumption by about 25% [64]. In the Langmuir adsorption model, the higher the concentration, the faster the concentration point moves. For the more retained component, when it passes through the inlet, its flow rate can be reduced by reducing the feed concentration, so that the less retained component with higher purity can be obtained [68,69].

When the ModiCon mode is used exclusively, the improvement of SMB performance is not obvious. Therefore, it usually needs to be combined with VariCol or other processes to improve the separation performance. After this combination, the separation efficiency can be improved and the solvent consumption can be reduced compared to the conventional SMB.

## *4.2. VariCol*

VariCol, the asynchronous switching mode, is shown in Figure 12. In VariCol mode, only one inlet or outlet is switched within each switching time and each port is switched independently. This makes the length of the zone different for each stage; that is, the length of each zone is not fixed, and changes over time. According to the characteristics of the mixture and the spectral band distribution of the separation process, the column length can be adjusted timely to make the distribution reasonable and the separation more efficient [70–75].

**Figure 12.** Schematic diagram of VariCol.

Supelano et al. [76] compared the separation performance of three SMB modes, ModiCon, VariCol, and ModiCon + VariCol, in terms of maximum throughput for a given product purity by using the resolution of guaiacol glycerol ether as an example. It was found that the separation performance was not significantly improved when only the ModiCon feed mode was applied, while when both ModiCon + VariCol feed modes were used in combination the throughput, number of columns, and the separation efficiency were obviously improved compared to the conventional SMB, due to the larger zone I and zone II.

Zhang et al. [72] conducted a systematic multi-objective optimization study of the SMB and VariCol processes for the chiral resolution of racemic pindolol using the NSGA-II-JG algorithm. The result showed that, under the condition of higher feed concentration and lower feed flow rate, a relatively high product purity can be obtained without consuming more desorption agent and, meanwhile, a better performance can be obtained by increasing the number of columns. When the VariCol process was used, the product recovery was generally improved by 0.15–0.56% and the product purity was generally improved by 0.1–0.52% compared to the conventional SMB [72]. It was finally proven that the VariCol process outperforms conventional SMB in terms of desorbent consumption with the same separation requirements.

Lin et al. [77] designed and optimized the operating conditions for the enantiomeric separation of aminoglutamine by SMB and VariCol methods using a mass transfer-diffusion model, while considering the intraparticle mass transfer resistance and axial dispersion effects. It was also verified that the separation performance of VariCol process was superior to the conventional SMB.

In summary, the VariCol process allows more flexibility in the chromatographic column use and breaks the limitations of constant zone length and constant solids flow rate. Compared to the conventional SMB, the VariCol mode can obtain higher productivity and lower desorbent consumption.

#### *4.3. PowerFeed*

PowerFeed is the separation process with variable feed flow rate. When the mixture solution flows through the feed port position, the feed flow rate is changed in each switching interval, which affects the components' movement rate in each zone by changing the concentration spectrum band. In this way, different components in a mixture are gradually separated [78–80].

The PowerFeed mode is similar to the ModiCon mode mentioned above, in which both methods achieve the separation purpose by changing the concentration of the spectral band. The ModiCon changes the feed concentration directly, whereas PowerFeed changes the concentration by adjusting the flow rate [81–83]. Similarly, PowerFeed generally needs to be used in conjunction with other modes to improve the separation performance.

The three feed variant modes mentioned above, ModiCon, VariCol and PowerFeed, have one thing in common; all of them improve the performance of SMB by increasing the degrees of freedom. All three types of feed modes can lead to improved separation efficiency and performance, and the performance can be further improved by effectively combining these three variants.

#### *4.4. Intermittent Simulated Moving Bed (ISMB)*

ISMB is fully known as intermittent SMB. In the ISMB process, as shown in Figure 13, each switching time ts is divided into two sub steps with durations αts and (1−α)ts, respectively. In step 1, the ISMB also contains two inlets and two outlets, while zone IV is isolated. In step 2, all inlets and outlets are closed, and the liquid phase circulates along the column with the same flow rate in all four zones, thus redistributing the concentration profiles and adjusting the position of each component [84,85].

**Figure 13.** Schematic diagram of the ISMB process with port switching occurring at the end of Step 2 and the beginning of Step 1.

Mazzotti et al. [86–88] proposed a three-column ISMB as a new semi-continuous chromatographic process. Higher throughput can be achieved while using fewer columns due to the timely recycling of less retained components. The experiments were conducted for the binary separation process, and the ternary separation by using the three-column ISMB cascade chromatography was studied and designed. The final product purity of up to 97.8% was obtained with a productivity of 2.10 g/L/h and a solvent consumption of 12 g/L, which proved better than that of the conventional SMB process. The cascade operation could provide greater flexibility, better simulation accuracy, and improved purity and performance of the ISMB.

In conclusion, better concentration distribution could be obtained by reasonably designing the time interval in the ISMB process. In addition, complex separation tasks such as ternary separation can be conducted, which indicates the great application potential of ISMB. In summary, the main advantages of ISMB are: (1) High separation efficiency and performance can be obtained with a simple operation mode. (2) High operating flexibility. (3) The feasibility in multiple mixtures' separation process.

#### *4.5. Sequential Simulated Moving Bed (SSMB)*

SSMB is called sequential simulated moving bed, and its process is shown in Figure 14. SSMB divides the conventional SMB into three phases: "feeding", "circulation" and "elution". In the feeding phase, the feed solution and eluent, respectively, enter zones III and I simultaneously, while zones II and IV are isolated. In the second phase, all inlets and outlets are closed, and all the columns are connected into a closed loop. The liquid phase is circulated in this system and redistributes the concentration profiles. In the third "elution" phase, the eluent is passed into zones I to III, while zones IV is isolated. The extract products are collected in both the feed and elution phases, and the raffinate products are collected only in the feed phase [26,89].

For example, Li et al. [26,90] applied SSMB to the separation of glucose and fructose and compared the separation performance to the conventional SMB. The results revealed that the solvent consumption of SSMB was significantly less than that of SMB for the same purity and recovery requirements, which further proved the technical and economic superiority of the SSMB process [90]. In addition, the feasibility of SSMB for the separation and purification of xylo-oligosaccharides (XOS) under different constraints and objectives with multi-objective optimization was also investigated.

SSMB is not only an improvement of the conventional SMB, but also a modification of the ISMB. The main advantages are: (1) High utilization of the mobile phase and low water consumption can effectively reduce the cost, so the SSMB is suitable for industrial production. (2) When separating some specific mixtures, the separation performance of SSMB is significantly higher than that of SMB. (3) The back mixing problem existing in the separation process of SMB can be effectively solved by SSMB. (4) Ternary separation can be achieved by adding the inlet and outlet ports. In addition, SSMB also possesses some disadvantages: (1) The operation is more complicated and increases the control difficulty. (2) The utilization rate of the stationary phase is lower. (3) The flow rate ratio (m value) is influenced by various factors and is not constant during the switching time, which indicates that the SSMB cannot be directly designed by using the m value.

**Figure 14.** Schematic diagram of the SSMB process.
