# Analytical, Preparative, and Industrial-Scale Separation of Substances by Methods of Countercurrent Liquid-Liquid Chromatography

^{*}

## Abstract

**:**

## 1. Introduction

_{eff}is the effective number of theoretical stages; n is the number of perfectly mixed cells in a column (the axial mixing parameter); T = k

_{v}V

_{c}/F is the number of mass transfer units in the column (the mass transfer parameter): F is the volumetric flow rate of the mobile phase, k

_{v}is the mass transfer coefficient related to the volume of contacting liquids, V

_{c}is the column volume; K’ = K

_{D}S /(1−S) is the ratio of amounts of a solute in the stationary and mobile phases under the equilibrium conditions (the retention factor): K

_{D}= y*/x* is the partition coefficient of the solute; y* and x* are the equilibrium solute concentrations in stationary and mobile phases, respectively; and S is the fractional volume of the stationary phase in the column.

_{eff}stages according to formula (1) makes it possible to proceed from a simpler equilibrium model in the analysis of CCC separations.

## 2. Analytical Scale Separations

#### 2.1. Multiple Dual-Mode CCC Separations

#### 2.2. Multiple Dual-Mode CCC Separations with Variable Duration of Phase Elution Steps

#### 2.3. Modeling of Multiple Dual-Mode Countercurrent Chromatography Separations with Variable Duration of Phase Elution Steps and Single Sample Injection

#### 2.4. Modeling of Multiple Dual-Mode Countercurrent Chromatography Separations with Variable Duration of Phase Elution Steps and Multiple Sample Injection

#### 2.5. Closed-Loop Recycling CCC Separations

#### 2.6. Modeling and Design of Closed-Loop Recycling Countercurrent Chromatography Separations with Single Sample Injection

#### 2.7. CLR CCC Separations Using Recycling Systems with a Short Recycling Line

_{c}) is the dimensionless time; F is the volumetric flow rate of the mobile phase; V

_{c}is the column volume; and τ is the actual time.

#### 2.8. CLR CCC Separations Using Recycling Systems with a Long Recycling Line

_{ec}. The model has two additional parameters: b = V

_{ec}/V

_{c}—the ratio of the column volume V

_{c}and the volume of the recycling system V

_{ec}and N

_{ec}—the number of perfectly mixed cells characterizing the dispersion in the recycling system. To simulate the non-ideal CLR CCC processes, the following equation can be used [135,136]:

**n**for the non-ideal recycling mode of operation.

_{D1}= 0.3 and K

_{D2}= 0.5 is shown for different lengths (volumes) of the recycling system.

_{D}, N, N

_{ec}, and S, by using Equation (5), a given separation can be simulated, and the number of cycles and the periods of collection of fractions of solutes can be determined.

#### 2.9. Modeling and Design of Closed-Loop Recycling Countercurrent Chromatography Separations with Multiple Sample Injection

_{Dt}passes point A. These time points (t

_{rt}) are determined by the equations:

_{t}is the number of equilibrium stages in the column associated with the target compound; r is the number of the cycle (the number of passages of the target compound through the point A), after which the sample is re-injected; and t

_{R}is the position of the target compound peak on the time axis.

_{D}at the point B corresponding to the first sample injection at the time $\tau =0$ (t = 0). Equations (11) and (14) describe the elution profiles of the compound K

_{Dj}(j = 1,2,3) corresponding to the second X

_{n,1}and third X

_{n,2}sample injections. Equations (11), (12), (14) and (15) can be obtained by putting r = 1 and r = 2 in Equations (6) and (9), respectively. The resulting concentration profiles after two and three sample injections are described by the equations:

#### 2.10. Closed-Loop Recycling Dual-Mode CCC Separations

#### 2.11. Modeling and Design of Closed-Loop Recycling Dual Mode Countercurrent Chromatography Separations

_{y}/V

_{c}; the start time for the y-phase flow is τ = 0 (t = 0); and $Y=y/\overline{x}$ is the normalized concentration of a compound eluting with the mobile y-phase.

_{x}(t = t

_{x}).

## 3. Preparative and Industrial-Scale Separations

^{3}/h) than process-scale CCC columns. The complexity of CCC devices imposes restrictions on their scale. For example, the current CCC equipment cannot process large volumes of feed material formed during the industrial production of rare earth metals. The high-performance CCC plants for industrial-scale separations are to be developed on the basis of the currently available solvent extraction equipment [101,102,103,104,105,106].

#### 3.1. Modeling and Design of Non-Steady-State Preparative and Industrial Scale Countercurrent Chromatography Separations

_{s}(t

_{s}). To ensure high performance, it is necessary to load large volumes of the sample solution, which can be accomplished by increasing the loading time. Increasing the sample solution loading time from t

_{s}= 0.01 (impulse sample injection) to t

_{s}= 0.1 corresponds to a ten times increase in productivity.

#### 3.2. Conventional Elution Mode

_{D}after the sample, containing Q = x

_{s}F τ

_{s}amount of the compound, which has been introduced into the column with a feed stream (x

_{s}is the compound concentration in the feed stream; τ

_{s}is the sample loading time).

_{s}≤ 0.2–0.3), the much simpler Equation (21) can be applied to describe the conventional CCC separations [141].

_{D}=1):

#### 3.3. Multiple Dual-Mode CCC Separations with Variable Duration of Phase Elution Steps

#### 3.3.1. Single Sample Loading

#### 3.3.2. Multiple Samples Loading

#### 3.3.3. Closed-Loop Recycling CCC Separations

#### 3.3.4. Modeling of CLR CCC Separations with Single Sample Solution Loading

_{s}= τ

_{s}F/V

_{c}is the normalized sample solution loading time.

_{D}at the outlet of the column during the recycling from the first to the last cycle of the separation process n.

#### 3.3.5. Modeling of CLR CCC Separations with Multiple Sample Solution Loading

_{n,1}(t), X

_{n,2}(t), and X

_{n,ml}(t) are determined by Equation (24); the subscripts 1, 2, and ml denote the numbers of the sample solution loadings. The cycle numbers correspond to the numbers of passages of the target compound K

_{Dt}through the CCC device. Counting of time and cycles is carried out from the moment of the first loading of the sample solution.

_{D}corresponding to individual loading of the sample solution. Equation (25) describes the resulting concentration profiles after several loadings.

#### 3.4. Modeling and Design of Continuous Steady-State Preparative and Industrial Scale Countercurrent Chromatography Separations

_{s}(t

_{s}) and the interval between consecutive loads τ

_{in}(t

_{in}) are the free operating parameters of the SS CCC separation processes. The productivity and the separation efficiency are interconnected, and increasing the productivity can lead to the decrease in the purity of the separated products: for maximum performance and minimum solvent consumption, the interval between two consecutive loads of the sample solution τ

_{in}(t

_{in}) must be minimal but sufficient to ensure separation of the adjacent sample bands; on the other hand, for maximum performance, the duration of the loading periods τ

_{s}(t

_{s}) should be as long as possible, but it should not reduce the separation. To find the trade-off between product quality and process performance requires prior mathematical modeling to determine the optimal values of the sample solution loading time and the interval between consecutive loads. To simulate SS CCC separations, it is sufficient to have the theoretical description of the elution profiles after two consecutive sample solution loads.

#### 3.5. Conventional Steady-State Countercurrent Chromatography (SS CCC) Separations

_{Dj}, corresponding to the first and second consecutive sample solution loads and the resulting concentration profiles after two loads, can be calculated by the following equations [141,142]:

_{j}= x

_{js}Fτ

_{s}is the amount of the compound j loaded during the sample solution loading time τ

_{s}; x

_{js}is the concentration of the solution j in the sample solution; F is the volumetric flow rate of the fresh mobile phase and the sample solution; t

_{in}= τ

_{in}F/V

_{c}, (τ

_{in}) is the interval between consecutive sample solution loads.

#### 3.6. Steady-State Multiple Dual Mode Countercurrent Chromatography (SS MDM CCC) Separations

#### 3.7. Steady-State Closed-Loop Recycling Countercurrent Chromatography (SS CLR CCC) Separations

**τ**(

_{in}**t**) is continuously loaded into a CCC device over a constant time

_{in}**τ**(

_{s}**t**). The first loading starts at τ = 0 (t = 0). Obviously, the loop must be open during loading the sample solution into the column. After the first loading is finished, the loop is closed, and the solution of compounds circulates in the system until the desired degree of separation is achieved. After that, the loop is opened again; mobile phase is pumped into the column, and the elution of the separated fractions of compounds starts; at τ = τ

_{s}_{in}(t = t

_{in}), the second portion of the sample solution is continuously loaded into the column over the time

**τ**(

_{s}**t**); after the second loading is finished, the mobile phase is pumped into the column until the elution of the compounds of the first load is completed. After that, the loop is closed again, and the second portion of sample solution circulates in the system until the desired separation of compounds is achieved. Furthermore, the operations are repeated. To describe the band profiles after two consecutive loads, the following equations can be recommended [144]:

_{s}_{j}and N

_{efj}are the parameters defined by Equations (28) and (32), respectively; n is the number of cycles (the number of passages of the component j through the column) required to achieve the desired separation.

_{D}, N, S, etc.) obtained on the available CCC instrument with the selected solvent system.

## 4. Conclusions and Future Work

## Author Contributions

## Funding

## Conflicts of Interest

## References

- Orefice, M.; Audoor, H.; Li, Z.; Binnemans, K. Solvometallurgical route for the recovery of Sm, Co, Cu and Fe from SmCo permanent magnets. Separations Purif. Technol.
**2019**, 219, 281–289. [Google Scholar] [CrossRef] - Van De Voorde, M.; Van Hecke, K.; Binnemans, K.; Cardinaels, T. Separations of samarium and europium by solvent extraction with an undiluted quaternary ammonium ionic liquid: Towards high-purity medical samarium-153. RSC Adv.
**2018**, 8, 20077–20086. [Google Scholar] [CrossRef][Green Version] - Belova, V.; Voshkin, A.; Kholkin, A.; Payrtman, A. Solvent extraction of some lanthanides from chloride and nitrate solutions by binary extractants. Hydrometallurgy
**2009**, 97, 198–203. [Google Scholar] [CrossRef] - Belova, V.; Voshkin, A.; Egorova, N.; Kholkin, A. Solvent extraction of rare earth metals from nitrate solutions with di(2,4,4-trimethylpentyl)phosphinate of methyltrioctylammonium. J. Molecules Liq.
**2012**, 172, 144–146. [Google Scholar] [CrossRef] - Zakhodyaeva, Y.A.; Zinov’Eva, I.V.; Tokar, E.S.; Voshkin, A. Complex Extraction of Metals in an Aqueous Two-Phase System Based on Poly(Ethylene Oxide) 1500 and Sodium Nitrate. Molecules
**2019**, 24, 4078. [Google Scholar] [CrossRef][Green Version] - Zakhodyaeva, Y.A.; Izyumova, K.V.; Solov’Eva, M.S.; Voshkin, A. Extraction Separations of the components of leach liquors of batteries. Theor. Found. Chem. Eng.
**2017**, 51, 883–887. [Google Scholar] [CrossRef] - Gradov, O.M.; Zakhodyaeva, Y.A.; Zinov’Eva, I.; Voshkin, A. Some Features of the Ultrasonic Liquid Extraction of Metal Ions. Molecules
**2019**, 24, 3549. [Google Scholar] [CrossRef] - Tsivadze, A.Y. Selective Separation of Elements of the Periodic Table with Similar Chemical Properties as a Foundation for New Technologies. Her. Russ. Acad. Sci.
**2020**, 90, 214–224. [Google Scholar] [CrossRef] - Ito, Y.; Conway, W.D. High-Speed Countercurrent Chromatography; Wiley-Interscience: Amsterdam, The Netherlands, 1996. [Google Scholar]
- Conway, W.D. Counter-Current Chromatography: Apparatus, Theory and Applications; VCH Publishers Inc.: New York, NY, USA, 1990. [Google Scholar]
- Cazes, J. Centrifugal Partition Chromatography. Nat. Biotechnol.
**1988**, 6, 1398–1400. [Google Scholar] [CrossRef] - Berthod, A. Countercurrent Chromatography. The Support-Free Liquid Stationary Phase, Comprehensive Analytical Chemistry; Elsevier: Amsterdam, The Netherland, 2002; Volume 38. [Google Scholar]
- Menet, J.M.; Thiebaut, D. Countercurrent Chromatography; Chromatographic Science Series 82, 1st ed.; Marcel Dekker, Inc.: New York, NY, USA, 1999. [Google Scholar]
- Ito, Y. Golden rules and pitfalls in selecting optimum conditions for high-speed counter-current chromatography. J. Chromatogr. A
**2005**, 1065, 145–168. [Google Scholar] [CrossRef] - Sutherland, I.; Hawes, D.; Ignatova, S.; Janaway, L.; Wood, P. Review of Progress Toward the Industrial Scale-Up of CCC. J. Liq. Chromatogr. Relat. Technol.
**2005**, 28, 1877–1891. [Google Scholar] [CrossRef] - Friesen, J.B.; Pauli, G.F. Reciprocal Symmetry Plots as a Representation of Countercurrent Chromatograms. Anal. Chem.
**2007**, 79, 2320–2324. [Google Scholar] [CrossRef] [PubMed] - Berthod, A.; Friesen, J.B.; Inui, T.; Pauli, G.F. Elution−Extrusion Countercurrent Chromatography: Theory and Concepts in Metabolic Analysis. Anal. Chem.
**2007**, 79, 3371–3382. [Google Scholar] [CrossRef] [PubMed][Green Version] - Berthod, A.; Maryutina, T.; Spivakov, B.; Shpigun, O.; Sutherland, I.A. Countercurrent chromatography in analytical chemistry (IUPAC Technical Report). Pure Appl. Chem.
**2009**, 81, 355–387. [Google Scholar] [CrossRef][Green Version] - Conway, W.D. Counter-current chromatography: Simple process and confusing terminology. J. Chromatogr. A
**2011**, 1218, 6015–6023. [Google Scholar] [CrossRef] [PubMed] - Ignatova, S.; Sutherland, I. The 8th international conference on counter-current chromatography held at Brunel university London UK, July 23–25, 2014. J. Chromatogr. A
**2015**, 1425, 1–7. [Google Scholar] [CrossRef] - Friesen, J.B.; McAlpine, J.B.; Chen, S.-N.; Pauli, G.F. The 9th International Countercurrent Chromatography Conference held at Dominican University, Chicago, USA, August 1–3, 2016. J. Chromatogr. A
**2017**, 1520, 1–8. [Google Scholar] [CrossRef] - Kostanian, A. Modelling counter-current chromatography: A chemical engineering perspective. J. Chromatogr. A
**2002**, 973, 39–46. [Google Scholar] [CrossRef] - Kostanyan, A.E.; Berthod, A.; Ignatova, S.N.; Maryutina, T.A.; Spivakov, B.Y.; Sutherland, I.A. Countercurrent chromatographic Separations: A hydrodynamic approach developed for extraction columns. J. Chromatogr. A
**2004**, 1040, 63–72. [Google Scholar] [CrossRef] - Kostanyan, A.E. General regularities of liquid chromatography and countercurrent extraction. Theor. Found. Chem. Eng.
**2006**, 40, 587–593. [Google Scholar] [CrossRef] - Kostanyan, A.; Ignatova, S.; Sutherland, I.; Hewitson, P.; Zakhodjaeva, Y.A.; Erastov, A.A. Steady-state and non-steady state operation of counter-current chromatography devices. J. Chromatogr. A
**2013**, 1314, 94–105. [Google Scholar] [CrossRef] [PubMed] - Hewitson, P.; Sutherland, I.; Kostanyan, A.E.; Voshkin, A.A.; Ignatova, S. Intermittent counter-current extraction—Equilibrium cell model, scaling and an improved bobbin design. J. Chromatogr. A
**2013**, 1303, 18–27. [Google Scholar] [CrossRef] [PubMed] - Phansalkar, R.S.; Nam, J.-W.; Chen, S.-N.; McAlpine, J.B.; Leme, A.A.; Aydin, B.; Bedran-Russo, A.-K.; Pauli, G.F. Centrifugal partition chromatography enables selective enrichment of trimeric and tetrameric proanthocyanidins for biomaterial development. J. Chromatogr. A
**2017**, 1535, 55–62. [Google Scholar] [CrossRef] [PubMed] - Ward, D.P.; Hewitson, P.; Cárdenas-Fernández, M.; Hamley-Bennett, C.; Díaz-Rodríguez, A.; Douillet, N.; Adams, J.P.; Leak, D.J.; Ignatova, S.; Lye, G.J. Centrifugal partition chromatography in a biorefinery context: Optimisation and scale-up of monosaccharide fractionation from hydrolysed sugar beet pulp. J. Chromatogr. A
**2017**, 1497, 56–63. [Google Scholar] [CrossRef] - Boonloed, A.; Weber, G.L.; Ramzy, K.M.; Dias, V.R.; Remcho, V.T. Centrifugal partition chromatography: A preparative tool for isolation and purification of xylindein from Chlorociboria aeruginosa. J. Chromatogr. A
**2016**, 1478, 19–25. [Google Scholar] [CrossRef] - Kotland, A.; Chollet, S.; Diard, C.; Autret, J.-M.; Meucci, J.; Renault, J.-H.; Marchal, L. Industrial case study on alkaloids purification by pH-zone refining centrifugal partition chromatography. J. Chromatogr. A
**2016**, 1474, 59–70. [Google Scholar] [CrossRef] - Hopmann, E.; Goll, J.; Minceva, M. Sequential Centrifugal Partition Chromatography: A New Continuous Chromatographic Technology. Chem. Eng. Technol.
**2012**, 35, 72–82. [Google Scholar] [CrossRef] - Maciuk, A.; Renault, J.-H.; Margraff, R.; Trébuchet, P.; Zeches-Hanrot, M.; Nuzillard, J.-M. Anion-Exchange Displacement Centrifugal Partition Chromatography. Anal. Chem.
**2004**, 76, 6179–6186. [Google Scholar] [CrossRef] - Knight, M.; Lazo-Portugal, R.; Ahn, S.N.; Stefansson, S. Purification of semiconducting single-walled carbon nanotubes by spiral counter-current chromatography. J. Chromatogr. A
**2017**, 1483, 93–100. [Google Scholar] [CrossRef][Green Version] - Ito, Y.; Clary, R.; Sharpnak, F.; Metger, H.; Powell, J. Mixer-settler counter-current chromatography with multiple spiral disk assembly. J. Chromatogr. A
**2007**, 1172, 151–159. [Google Scholar] [CrossRef] - Ito, Y.; Qi, L.; Powell, J.; Sharpnack, F.; Metger, H.; Yost, J.; Cao, X.-L.; Dong, Y.-M.; Huo, L.-S.; Zhu, X.-P.; et al. Mixer-settler counter-current chromatography with a barricaded spiral disk assembly with glass beads. J. Chromatogr. A
**2007**, 1151, 108–114. [Google Scholar] [CrossRef] [PubMed] - Knight, M.; Finn, T.M. Spiral Countercurrent Chromatography Studies Using the Spiral Disk Assembly. J. Liq. Chromatogr. Relat. Technol.
**2009**, 32, 2669–2685. [Google Scholar] [CrossRef] - Wood, P.; Ignatova, S.; Janaway, L.; Keay, D.; Hawes, D.; Garrard, I.; Sutherland, I.A. Counter-current chromatography Separations scaled up from an analytical column to a production column. J. Chromatogr. A
**2007**, 1151, 25–30. [Google Scholar] [CrossRef] [PubMed] - Huang, X.; Pei, D.; Liu, J.-F.; Di, D.-L. A review on chiral Separations by counter-current chromatography: Development, applications and future outlook. J. Chromatogr. A
**2018**, 1531, 1–12. [Google Scholar] [CrossRef] [PubMed] - Brämer, C.; Lammers, F.; Scheper, T.; Beutel, S. Development and Testing of a 4-Columns Periodic Counter-Current Chromatography System Based on Membrane Adsorbers. Separations
**2019**, 6, 55. [Google Scholar] [CrossRef][Green Version] - Roehrer, S.; Minceva, M. Evaluation of Inter-Apparatus Separations Method Transferability in Countercurrent Chromatography and Centrifugal Partition Chromatography. Separations
**2019**, 6, 36. [Google Scholar] [CrossRef][Green Version] - Roehrer, S.; Minceva, M. Characterization of a centrifugal partition chromatographic column with spherical cell design. Chem. Eng. Res. Des.
**2019**, 143, 180–189. [Google Scholar] [CrossRef] - Hewitson, P.; Hewitson, P.; Sutherland, I.; Chen, L.; Ignatova, S. The effect of increasing centrifugal acceleration/force and flow rate for varying column aspect ratios on Separations efficiency in Counter-Current Chromatography. J. Chromatogr. A
**2018**, 80–90. [Google Scholar] [CrossRef] - Peng, A.; Hewitson, P.; Sutherland, I.; Chen, L.; Ignatova, S. How changes in column geometry and packing ratio can increase sample load and throughput by a factor of fifty in Counter-Current Chromatography. J. Chromatogr. A
**2018**, 1580, 120–125. [Google Scholar] [CrossRef] - Morley, R.; Minceva, M. Operating mode selection for the Separations of intermediately-eluting components with countercurrent and centrifugal partition chromatography. J. Chromatogr. A
**2019**, 1594, 140–148. [Google Scholar] [CrossRef] - Friesen, J.B.; Pauli, G.F. GUESS—A generally useful estimate of solvent systems in CCC. J. Liq. Chromatogr. Relat. Technol.
**2005**, 28, 2777–2806. [Google Scholar] [CrossRef] - Friesen, J.B.; Ahmed, S.; Pauli, G.F. Qualitative and quantitative evaluation of solvent systems for countercurrent Separations. J. Chromatogr. A
**2015**, 1377, 55–63. [Google Scholar] [CrossRef] [PubMed] - Liang, J.; Mengzhe, G.; Wu, D.; Guo, M.; Wu, S. A novel 9×9 map-based solvent selection strategy for targeted counter-current chromatography isolation of natural products. J. Chromatogr. A
**2015**, 1400, 27–39. [Google Scholar] [CrossRef] [PubMed] - Liu, Y.; Friesen, J.B.; Klein, L.L.; McAlpine, J.B.; Lankin, D.C.; Pauli, G.F.; Chen, S.-N. The Generally Useful Estimate of Solvent Systems (GUESS) method enables the rapid purification of methylpyridoxine regioisomers by countercurrent chromatography. J. Chromatogr. A
**2015**, 1426, 248–251. [Google Scholar] [CrossRef] [PubMed][Green Version] - Friesen, J.B.; McAlpine, J.B.; Chen, S.-N.; Pauli, G.F. Countercurrent Separations of Natural Products: An Update. J. Nat. Prod.
**2015**, 78, 1765–1796. [Google Scholar] [CrossRef][Green Version] - Wang, Y.; Zhang, L.; Zhou, H.; Guo, X.; Wu, S. K-targeted strategy for isolation of phenolic alkaloids of Nelumbo nucifera Gaertn by counter-current chromatography using lysine as a pH regulator. J. Chromatogr. A
**2017**, 1490, 115–125. [Google Scholar] [CrossRef] - Fang, Y.; Li, Q.; Shao, Q.; Wang, B.; Wei, Y. A general ionic liquid pH-zone-refining countercurrent chromatography method for Separations of alkaloids from Nelumbo nucifera Gaertn. J. Chromatogr. A
**2017**, 1507, 63–71. [Google Scholar] [CrossRef] - Friesen, J.B.; Pauli, G.F. Performance Characteristics of Countercurrent Separations in Analysis of Natural Products of Agricultural Significance. J. Agric. Food Chem.
**2008**, 56, 19–28. [Google Scholar] [CrossRef] - Peng, A.; Hewitson, P.; Ye, H.; Zu, L.; Garrard, I.; Sutherland, I.; Chen, L.; Ignatova, S. Sample injection strategy to increase throughput in counter-current chromatography: Case study of Honokiol purification. J. Chromatogr. A
**2016**, 1476, 19–24. [Google Scholar] [CrossRef][Green Version] - Esatbeyoglu, T.; Juadjur, A.; Wray, V.; Winterhalter, P. Semisynthetic Preparation and Isolation of Dimeric Procyanidins B1–B8 from Roasted Hazelnut Skins (Corylus avellanaL.) on a Large Scale Using Countercurrent Chromatography. J. Agric. Food Chem.
**2014**, 62, 7101–7110. [Google Scholar] [CrossRef] - Meng, J.; Yang, Z.; Liang, J.; Zhou, H.; Wu, S. Comprehensive multi-channel multi-dimensional counter-current chromatography for Separations of tanshinones from Salvia miltiorrhiza Bunge. J. Chromatogr. A
**2014**, 1323, 73–81. [Google Scholar] [CrossRef] [PubMed] - Zobel, S.; Helling, C.; Ditz, R.; Strube, J. Design and Operation of Continuous Countercurrent Chromatography in Biotechnological Production. Ind. Eng. Chem. Res.
**2014**, 53, 9169–9185. [Google Scholar] [CrossRef] - Zhang, X.; Ito, Y.; Liang, J.; Su, Q.; Zhang, Y.; Liu, J.; Sun, W. Preparative isolation and purification of five steroid saponins from Dioscorea zingiberensis C.H.Wright by counter-current chromatography coupled with evaporative light scattering detector. J. Pharm. Biomed. Anal.
**2013**, 84, 117–123. [Google Scholar] [CrossRef] [PubMed][Green Version] - Wang, X.; Liu, J.; Geng, Y.; Wang, D.; Dong, H.; Zhang, T. Preparative Separations of alkaloids from Nelumbo nucifera Gaertn by pH-zone-refining counter-current chromatography. J. Separations Sci.
**2010**, 33, 539–544. [Google Scholar] [CrossRef] [PubMed] - Hewitson, P.; Ignatova, S.; Ye, H.-Y.; Chen, L.; Sutherland, I. Intermittent counter-current extraction as an alternative approach to purification of Chinese herbal medicine. J. Chromatogr. A
**2009**, 1216, 4187–4192. [Google Scholar] [CrossRef] [PubMed] - Pauli, G.F.; Pro, S.M.; Friesen, J.B. Countercurrent Separations of Natural Products#. J. Nat. Prod.
**2008**, 71, 1489–1508. [Google Scholar] [CrossRef] [PubMed] - Vieira, M.N.; Costa, F.D.N.; Leitão, G.G.; Garrard, I.; Hewitson, P.; Ignatova, S.; Winterhalter, P.; Jerz, G. Schinus terebinthifolius scale-up countercurrent chromatography (Part I): High performance countercurrent chromatography fractionation of triterpene acids with off-line detection using atmospheric pressure chemical ionization mass spectrometry. J. Chromatogr. A
**2015**, 1389, 39–48. [Google Scholar] [CrossRef] - Figueiredo, F.S.; Celano, R.; Silva, D.S.; Costa, F.N.; Hewitson, P.; Ignatova, S.; Piccinelli, A.L.; Rastrelli, L.; Leitão, S.G.; Leitão, G.G. Countercurrent chromatography Separations of saponins by skeleton type from Ampelozizyphus amazonicus for off-line ultra-high-performance liquid chromatography/high resolution accurate mass spectrometry analysis and characterization. J. Chromatogr. A
**2017**, 1481, 92–100. [Google Scholar] [CrossRef] - Boudesocque-Delaye, L.; Forni, L.; Martinez, A.; Nuzillard, J.-M.; Giraud, M.; Renault, J.-H. Purification of dirucotide, a synthetic 17-aminoacid peptide, by ion exchange centrifugal partition chromatography. J. Chromatogr. A
**2017**, 1513, 78–83. [Google Scholar] [CrossRef] - Mandova, T.; Audo, G.; Michel, S.; Grougnet, R. Off-line coupling of new generation centrifugal partition chromatography device with preparative high pressure liquid chromatography-mass spectrometry triggering fraction collection applied to the recovery of secoiridoid glycosides from Centaurium erythraea Rafn. (Gentianaceae). J. Chromatogr. A
**2017**, 1513, 149–156. [Google Scholar] [CrossRef] - Liang, Y.; Hu, J.; Chen, H.; Zhang, T.; Ito, Y. Preparative Isolation and Purification of Four Compounds from Chinese Medicinal HerbGentiana ScabraBunge by High-Speed Countercurrent Chromatography. J. Liq. Chromatogr. Relat. Technol.
**2007**, 30, 509–520. [Google Scholar] [CrossRef] - Wu, W.; Ye, H.; Tang, M.; Peng, A.; Shi, J.; Li, S.; Zhong, S.; He, S.; Lai, H.; Zhao, J.; et al. Using High-Performance Counter-Current Chromatography Combined with Preparative High Performance Liquid Chromatogramphy for the Separations of Bioactive Compounds from the Water Extract ofGentiana macrophyllaPall. Separations Sci. Technol.
**2011**, 47, 762–768. [Google Scholar] [CrossRef] - Liang, J.; Ito, Y.; Zhang, X.; He, J.; Sun, W. Rapid preparative Separations of six bioactive compounds from Gentiana crass caulis Duthie ex Burk. using microwave-assisted extraction coupled with high-speed counter-current chromatography. J. Separations Sci.
**2013**, 36, 3934–3940. [Google Scholar] [CrossRef] [PubMed][Green Version] - Spórna-Kucab, A.; Wróbel, N.; Kumorkiewicz-Jamro, A.; Wybraniec, S. Separations of betacyanins from Iresine herbstii Hook. ex Lindl. leaves by high-speed countercurrent chromatography in a polar solvent system. J. Chromatogr. A
**2020**, 1626. [Google Scholar] [CrossRef] - Kim, C.Y.; Kim, J. Preparative isolation and purification of geniposide from gardenia fruits by centrifugal partition chromatography. Phytochem. Anal.
**2007**, 18, 115–117. [Google Scholar] [CrossRef] - Wang, J.; Liu, C.-M.; Li, L.; Bai, H.-L. Isolation of four high-purity dammaranesaponins from extract of Panax notoginseng by centrifugal partition chromatography coupled with evaporative light scattering detection in one operation. Phytochem. Anal.
**2011**, 22, 263–267. [Google Scholar] [CrossRef] - Chadwick, L.R.; Fong, H.H.S.; Farnsworth, N.R.; Pauli, G.F. CCC Sample Cutting for Isolation of Prenylated Phenolics from Hops. J. Liq. Chromatogr. Relat. Technol.
**2005**, 28, 1959–1969. [Google Scholar] [CrossRef] - Marston, A.; Hostettmann, K. Developments in the application of counter-current chromatography to plant analysis. J. Chromatogr. A
**2006**, 1112, 181–194. [Google Scholar] [CrossRef] - Liu, R.; Kong, L.; Li, A.; Sun, A. Preparative Isolation and Purification of Saponin and Flavone Glycoside Compounds from Clinopodium chinensis (Benth) O. Kuntze by High?Speed Countercurrent Chromatography. J. Liq. Chromatogr. Relat. Technol.
**2007**, 30, 521–532. [Google Scholar] [CrossRef] - Peng, J.; Dong, F.; Qi, Y.; Han, X.; Xu, Y.; Xu, L.; Xu, Q.; Liu, K.; Zhu, Z. Preparative Separations of four triterpene saponins from radix astragali by high-speed counter-current chromatography coupled with evaporative light scattering detection. Phytochem. Anal.
**2008**, 19, 212–217. [Google Scholar] [CrossRef] - Liang, J.; Yang, Z.; Cao, X.; Wu, B.; Wu, S. Preparative isolation of novel antioxidant flavonoids of alfalfa by stop-and-go counter-current chromatography and following on-line liquid chromatography desalination. J. Chromatogr. A
**2011**, 1218, 6191–6199. [Google Scholar] [CrossRef] [PubMed] - McAlpine, J.B.; Friesen, J.B.; Pauli, G.F. Separations of Natural Products by Countercurrent Chromatography. Bioinform. MicroRNA Res.
**2012**, 864, 221–254. [Google Scholar] [CrossRef] - Azevedo, L.; Faqueti, L.; Kritsanida, M.; Efstathiou, A.; Smirlis, D.; Franchi, G.C., Jr.; Genta-Jouve, G.; Michel, S.; Sandjo, L.P.; Grougnet, R.; et al. Three new trixane glycosides obtained from the leaves of Jungia sellowii Less. Using centrifugal partition chromatography. Beilstein J. Org. Chem.
**2016**, 12, 674–683. [Google Scholar] [CrossRef] [PubMed][Green Version] - Rho, T.; Jung, M.; Lee, M.W.; Chin, Y.-W.; Yoon, K.D. Efficient methods for isolating five phytochemicals from Gentiana macrophylla using high-performance countercurrent chromatography. J. Separations Sci.
**2016**, 39, 4723–4731. [Google Scholar] [CrossRef] [PubMed] - Sun, W.; Jin, Y.; Wang, C.; Zhao, S.; Wang, X.; Luo, M.; Yan, J.; Tong, S. Stereoselective Separations of isomeric sertraline with analytical countercurrent chromatography. J. Chromatogr. A
**2020**, 1617. [Google Scholar] [CrossRef] [PubMed] - Sun, S.-W.; Wang, R.-R.; Sun, X.-Y.; Fan, J.-H.; Qi, H.; Liu, Y.; Qin, G.-Q.; Wang, W. Identification of Transient Receptor Potential Vanilloid 3 Antagonists from Achillea alpina L. and Separations by Liquid-Liquid-Refining Extraction and High-Speed Counter-Current Chromatography. Molecules
**2020**, 25, 2025. [Google Scholar] [CrossRef] - Chen, L.; Xin, X.; Feng, H.; Li, S.; Cao, Q.; Wang, X.; Vriesekoop, F. Isolation and Identification of Anthocyanin Component in the Fruits of Acanthopanax Sessiliflorus (Rupr. & Maxim.) Seem. by Means of High Speed Counter Current Chromatography and Evaluation of Its Antioxidant Activity. Molecules
**2020**, 25, 1781. [Google Scholar] [CrossRef][Green Version] - Li, W.-X.; Wang, H.; Dong, A.-W. Preparative Separations of Alkaloids from Stem of Euchresta tubulosa Dunn. by High-Speed Counter-Current Chromatography Using Stepwise Elution. Molecules
**2019**, 24, 4602. [Google Scholar] [CrossRef][Green Version] - Wu, X.; Gao, X.; Zhu, X.; Zhang, S.; Liu, X.; Yang, H.; Song, H.; Chen, Q. Fingerprint Analysis of Cnidium monnieri (L.) Cusson by High-Speed Counter-Current Chromatography. Molecules
**2019**, 24, 4496. [Google Scholar] [CrossRef][Green Version] - Yang, F.; Qi, Y.; Liu, W.; Li, J.; Wang, D.; Fang, L.; Zhang, Y. Separations of Five Flavonoids from Aerial Parts of Salvia Miltiorrhiza Bunge Using HSCCC and Their Antioxidant Activities. Molecules
**2019**, 24, 3448. [Google Scholar] [CrossRef][Green Version] - Zhou, J.; Du, S.Y.; Dong, H.J.; Fang, L.; Feng, J.H. Preparative Separations of monoterpenoid indole alkaloid epimers from Ervatamia yunnanensis Tsiang by pH-zone-refining counter-current chromatography combined with preparative high-performance liquid chromatography. Molecules
**2019**, 24, 1316. [Google Scholar] [CrossRef] [PubMed][Green Version] - Sun, X.; Yan, H.-J.; Zhang, Y.; Wang, X.; Qin, D.; Yu, J.-Q. Preparative Separations of Diterpene Lactones and Flavones from Andrographis paniculate Using Off-Line Two-Dimensional High-Speed Counter-Current Chromatography. Molecules
**2019**, 24, 620. [Google Scholar] [CrossRef] [PubMed][Green Version] - Nahar, L.; Sarker, S.D. Droplet counter current chromatography (DCCC) in herbal analysis. Trends Phytochem. Res.
**2020**, 4, 201–202. [Google Scholar] - He, J.-M.; Huang, J.; Wu, W.-L.; Mu, Q. Unlimited recycling counter-current chromatography for the preparative Separations of natural products: Naphthaquinones as examples. J. Chromatogr. A
**2020**, 1626. [Google Scholar] [CrossRef] [PubMed] - Vogg, S.; Müller-Späth, T.; Morbidelli, M. Design space and robustness analysis of batch and counter-current frontal chromatography processes for the removal of antibody aggregates. J. Chromatogr. A
**2020**, 1619. [Google Scholar] [CrossRef] [PubMed] - Gong, Y.; Huang, X.; Pei, D.; Da Duan, W.-; Zhang, X.; Sun, X.; Di, D. The applicability of high-speed counter current chromatography to the Separations of natural antioxidants. J. Chromatogr. A
**2020**, 1623. [Google Scholar] [CrossRef] [PubMed] - Gomis-Fons, J.; Andersson, N.; Nilsson, B. Optimization study on periodic counter-current chromatography integrated in a monoclonal antibody downstream process. J. Chromatogr. A
**2020**, 1621. [Google Scholar] [CrossRef] - Lin, Y.; Luo, J.; Li, L.; Liu, X.; Wang, W.; Zhu, L.; Han, C.; Kong, L. Precise Separations of lysine-specific demethylase 1 inhibitors from Corydalis yanhusuo using multi-mode counter-current chromatography guided by virtual screening. J. Chromatogr. A
**2020**, 1625. [Google Scholar] [CrossRef] - Duan, W.; Li, Y.; Dong, H.; Yang, G.; Wang, W.; Wang, X. Isolation and purification of six aristolochic acids with similar structures from Aristolochia manshuriensis Kom stems by pH-zone-refining counter-current chromatography. J. Chromatogr. A
**2020**, 1613, 460657. [Google Scholar] [CrossRef] - Wang, C.; Sun, W.; Wang, X.; Jin, Y.; Zhao, S.; Luo, M.; Tong, S. Large-scale Separations of baicalin and wogonoside from Scutellaria baicalensis Georgi by the combination of pH-zone-refining and conventional counter-current chromatography. J. Chromatogr. A
**2019**, 1601, 266–273. [Google Scholar] [CrossRef] - Yang, Y.; Wang, Y.; Zeng, W.; Tian, J.; Zhao, X.; Han, J.; Huang, D.; Gu, D. A strategy based on liquid-liquid-refining extraction and high-speed counter-current chromatography for the bioassay-guided Separations of active compound from Taraxacum mongolicum. J. Chromatogr. A
**2020**, 1614. [Google Scholar] [CrossRef] [PubMed] - Yang, Z.; Guo, P.; Han, R.; Wu, D.; Gao, J.-M.; Wu, S. Methanol linear gradient counter-current chromatography for the Separations of natural products: Sinopodophyllum hexandrum as samples. J. Chromatogr. A
**2019**, 1603, 251–261. [Google Scholar] [CrossRef] [PubMed] - Song, X.; Li, K.; Cui, L.; Yu, J.; Ali, I.; Zhu, H.; Wang, Q.; Wang, X.; Wang, D. A simple and efficient linear gradient coupled with inner-recycling high-speed counter-current chromatography mode for the preparative Separations of flavonoid glycosides from leaves of custard apple. J. Chromatogr. A
**2020**, 1615. [Google Scholar] [CrossRef] [PubMed] - Jerz, G.; Winterhalter, P. The 10th international conference on countercurrent chromatography held at Technische Universität Braunschweig, Braunschweig, Germany, August 1–3, 2018. J. Chromatogr. A
**2020**, 1617. [Google Scholar] [CrossRef] - Morley, R.; Minceva, M. Operating mode and parameter selection in liquid–liquid chromatography. J. Chromatogr. A
**2020**, 1617. [Google Scholar] [CrossRef] - Macke, S.; Jerz, G.; Empl, M.T.; Steinberg, P.; Winterhalter, P. Activity-Guided Isolation of Resveratrol Oligomers from a Grapevine-Shoot Extract Using Countercurrent Chromatography. J. Agric. Food Chem.
**2012**, 60, 11919–11927. [Google Scholar] [CrossRef] - Kostanyan, A.E.; Voshkin, A. Pulsation cyclic liquid-liquid chromatography. Theor. Found. Chem. Eng.
**2009**, 43, 729–733. [Google Scholar] [CrossRef] - Kostanyan, A.E.; Voshkin, A.A.; Khol’kin, A.I.; Belova, V.V. Pulsating-cyclic Extraction Separation of Components Mix and Device to This End. Russia Patent 2403949, 20 November 2010. [Google Scholar]
- Kostanyan, A.E.; Voshkin, A.; Kodin, N.V. Controlled-cycle pulsed liquid–liquid chromatography. A modified version of Craig’s counter-current distribution. J. Chromatogr. A
**2011**, 1218, 6135–6143. [Google Scholar] [CrossRef] - Kostanyan, A.E.; Voshkin, A.; Kodin, N.V. Pulsed cyclic device for liquid countercurrent chromatography. Theor. Found. Chem. Eng.
**2011**, 45, 779–785. [Google Scholar] [CrossRef] - Kostanyan, A. Extraction Chromatographic Separations of Rare-Earth Metals in a Cascade of Centrifugal Extractors. Russ. J. Inorg. Chem.
**2018**, 63, 287–292. [Google Scholar] [CrossRef] - Kostanyan, A.; Erastov, A.A. Industrial countercurrent chromatography Separationss based on a cascade of centrifugal mixer-settler extractors. J. Chromatogr. A
**2018**, 1572, 212–216. [Google Scholar] [CrossRef] [PubMed] - Kostanyan, A.E.; Voshkin, A. Analysis of cyclic liquid chromatography. Theor. Found. Chem. Eng.
**2011**, 45, 68–74. [Google Scholar] [CrossRef] - Kostanyan, A.; Voshkin, A. Support-free pulsed liquid–liquid chromatography. J. Chromatogr. A
**2009**, 1216, 7761–7766. [Google Scholar] [CrossRef] [PubMed] - Delannay, E.; Toribio, A.; Boudesocque, L.; Nuzillard, J.-M.; Zèches-Hanrot, M.; Dardennes, E.; Le Dour, G.; Sapi, J.; Renault, J.-H. Multiple dual-mode centrifugal partition chromatography, a semi-continuous development mode for routine laboratory-scale purifications. J. Chromatogr. A
**2006**, 1127, 45–51. [Google Scholar] [CrossRef] [PubMed] - Ito, Y.; Goto, T.; Yamada, S.; Matsumoto, H.; Oka, H.; Takahashi, N.; Nakazawa, H.; Nagase, H.; Ito, Y. Application of dual counter-current chromatography for rapid sample preparation of N-methylcarbamate pesticides in vegetable oil and citrus fruit. J. Chromatogr. A
**2006**, 1108, 20–25. [Google Scholar] [CrossRef] [PubMed] - Kostanyan, A.E.; Belova, V.V.; Kholkin, A.I. Modeling CCC and dual CCC using longitudinal mixing cell and eluting countercurrent distribution models. J. Chromatogr. A
**2007**, 1151, 142–147. [Google Scholar] [CrossRef] [PubMed] - Rubio, N.; Ignatova, S.; Minguillón, C.; Sutherland, I. Multiple dual-mode countercurrent chromatography applied to chiral Separationss using a (S)-naproxen derivative as chiral selector. J. Chromatogr. A
**2009**, 1216, 8505–8511. [Google Scholar] [CrossRef] - Yang, Y.; Aisa, H.A.; Ito, Y. Mathematical model of computer-programmed intermittent dual countercurrent chromatography applied to hydrostatic and hydrodynamic equilibrium systems. J. Chromatogr. A
**2009**, 1216, 6310–6318. [Google Scholar] [CrossRef][Green Version] - Ignatova, S.; Hewitson, P.; Mathews, B.; Sutherland, I. Evaluation of dual flow counter-current chromatography and intermittent counter-current extraction. J. Chromatogr. A
**2011**, 1218, 6102–6106. [Google Scholar] [CrossRef] - Mekaoui, N.; Berthod, A. Using the liquid nature of the stationary phase. VI. Theoretical study of multi-dual mode countercurrent chromatography. J. Chromatogr. A
**2011**, 1218, 6061–6071. [Google Scholar] [CrossRef] - Hewitson, P.; Ignatova, S.; Sutherland, I. Intermittent counter-current extraction—Effect of the key operating parameters on selectivity and throughput. J. Chromatogr. A
**2011**, 1218, 6072–6078. [Google Scholar] [CrossRef] [PubMed] - Mekaoui, N.; Chamieh, J.; Dugas, V.; Demesmay, C.; Berthod, A. Purification of Coomassie Brilliant Blue G-250 by multiple dual mode countercurrent chromatography. J. Chromatogr. A
**2012**, 1232, 134–141. [Google Scholar] [CrossRef] [PubMed] - Morley, R.; Minceva, M. Trapping multiple dual mode centrifugal partition chromatography for the Separations of intermediately-eluting components: Throughput maximization strategy. J. Chromatogr. A
**2017**, 1501, 26–38. [Google Scholar] [CrossRef] [PubMed] - Hopmann, E.; Minceva, M. Separations of a binary mixture by sequential centrifugal partition chromatography. J. Chromatogr. A
**2012**, 1229, 140–147. [Google Scholar] [CrossRef] - Peng, A.; Ye, H.-Y.; Shi, J.; He, S.; Zhong, S.; Li, S.; Chen, L. Separations of honokiol and magnolol by intermittent counter-current extraction. J. Chromatogr. A
**2010**, 1217, 5935–5939. [Google Scholar] [CrossRef] - Du, Q.-Z.; Ke, C.-Q.; Ito, Y. Recycling High-Speed Countercurrent Chromatography for Separations of Taxol and Cephalomannine. J. Liq. Chromatogr. Relat. Technol.
**1998**, 21, 157–162. [Google Scholar] [CrossRef] - Oka, H.; Iwaya, M.; Harada, K.-I.; Suzuki, M.; Ito, Y. Recycling Foam Countercurrent Chromatography. Anal. Chem.
**2000**, 72, 1490–1494. [Google Scholar] [CrossRef] - Han, Q.-B.; Song, J.Z.; Qiao, C.F.; Wong, L.; Xu, H. Preparative Separations of gambogic acid and its C-2 epimer using recycling high-speed counter-current chromatography. J. Chromatogr. A
**2006**, 1127, 298–301. [Google Scholar] [CrossRef] - Ye, H.-Y.; Ignatova, S.; Luo, H.; Li, Y.; Peng, A.; Chen, L.; Sutherland, I. Preparative Separations of a terpenoid and alkaloids from Tripterygium wilfordii Hook. f. using high-performance counter-current chromatography. J. Chromatogr. A
**2008**, 1213, 145–153. [Google Scholar] [CrossRef] - Xie, J.; Deng, J.; Tan, F.; Su, J. Separations and purification of echinacoside from Penstemon barbatus (Can.) Roth by recycling high-speed counter-current chromatography. J. Chromatogr. B
**2010**, 878, 2665–2668. [Google Scholar] [CrossRef] - Tong, S.; Guan, Y.-X.; Yan, J.; Zheng, B.; Zhao, L. Enantiomeric Separations of (R, S)-naproxen by recycling high speed counter-current chromatography with hydroxypropyl-β-cyclodextrin as chiral selector. J. Chromatogr. A
**2011**, 1218, 5434–5440. [Google Scholar] [CrossRef] [PubMed] - Yang, J.; Ye, H.; Lai, H.; Li, S.; He, S.; Zhong, S.; Chen, L.; Peng, A. Separations ofanthraquinone compounds from the seed of Cassia obtusifolia L. using recycling counter-current chromatography. J. Separations Sci.
**2012**, 35, 256–262. [Google Scholar] [CrossRef] [PubMed] - Meng, J.; Yang, Z.; Liang, J.; Guo, M.; Wu, S. Multi-channel recycling counter-current chromatography for natural product isolation: Tanshinones as examples. J. Chromatogr. A
**2014**, 1327, 27–38. [Google Scholar] [CrossRef] [PubMed] - Chen, Y.; Yan, X.; Lu, F.; Jiang, X.; Friesen, J.B.; Pauli, G.F.; Chen, S.-N.; Li, D.-P. Preparation of flavone di-C-glycoside isomers from Jian-Gu injection (Premna fulva Craib.) using recycling counter-current chromatography. J. Chromatogr. A
**2019**, 1599, 180–186. [Google Scholar] [CrossRef] - Kostanyan, A.E. Increasing efficiency of the Separations of substance mixtures by methods of liquid–liquid chromatography. J. Anal. Chem.
**2020**, 75, 1384–1398. [Google Scholar] [CrossRef] - Kostanyan, A.; Erastov, A.A.; Shishilov, O.N. Multiple dual mode counter-current chromatography with variable duration of alternating phase elution steps. J. Chromatogr. A
**2014**, 1347, 87–95. [Google Scholar] [CrossRef] - Kostanyan, A.E. Multiple dual mode counter-current chromatography with periodic sample injection: Steady-state and non-steady-state operation. J. Chromatogr. A
**2014**, 1373, 81–89. [Google Scholar] [CrossRef] - Kostanyan, A.; Shishilov, O.N. An easy-to-use calculating machine to simulate steady state and non-steady-state preparative Separationss by multiple dual mode counter-current chromatography with semi-continuous loading of feed mixtures. J. Chromatogr. A
**2018**, 1552, 92–98. [Google Scholar] [CrossRef] - Kostanyan, A. Modeling of closed-loop recycling liquid–liquid chromatography: Analytical solutions and model analysis. J. Chromatogr. A
**2015**, 1406, 156–164. [Google Scholar] [CrossRef] - Kostanyan, A. Simple equations to simulate closed-loop recycling liquid–liquid chromatography: Ideal and non-ideal recycling models. J. Chromatogr. A
**2015**, 1423, 71–78. [Google Scholar] [CrossRef] - Kostanyan, A.; Galieva, Z.N. Modeling of closed-loop recycling dual-mode counter-current chromatography based on non-ideal recycling model. J. Chromatogr. A
**2019**, 1603, 240–250. [Google Scholar] [CrossRef] [PubMed] - Kostanyan, A.E. Theoretical study of Separations and concentration of solutes by closed-loop recycling liquid-liquid chromatography with multiple sample injection. J. Chromatogr. A
**2017**, 1506, 82–92. [Google Scholar] [CrossRef] [PubMed] - Kostanyan, A.; Martynova, M.; Erastov, A.; Belova, V. Simultaneous concentration and Separations of target compounds from multicomponent mixtures by closed-loop recycling countercurrent chromatography. J. Chromatogr. A
**2018**, 1560, 26–34. [Google Scholar] [CrossRef] [PubMed] - Kostanyan, A.; Belova, V.V. Closed-loop recycling dual-mode counter-current chromatography. A theoretical study. J. Chromatogr. A
**2019**, 1588, 174–179. [Google Scholar] [CrossRef] - Kostanyan, A. On influence of sample loading conditions on peak shape and Separations efficiency in preparative isocratic counter-current chromatography. J. Chromatogr. A
**2012**, 1254, 71–77. [Google Scholar] [CrossRef] - Kostanyan, A. Modeling of preparative closed-loop recycling liquid-liquid chromatography with specified duration of sample loading. J. Chromatogr. A
**2016**, 1471, 94–101. [Google Scholar] [CrossRef] - Kostanyan, A.; Belova, V.V. Theoretical study of industrial scale closed-loop recycling counter-current chromatography Separationss. J. Chromatogr. A
**2020**, 1633. [Google Scholar] [CrossRef] - Kostanyan, A.; Erastov, A.A. Steady state preparative multiple dual mode counter-current chromatography: Productivity and selectivity. Theory and experimental verification. J. Chromatogr. A
**2015**, 1406, 118–128. [Google Scholar] [CrossRef] - Kostanyan, A.; Martynova, M. Modeling of two semi-continuous methods in liquid–liquid chromatography: Comparing conventional and closed-loop recycling modes. J. Chromatogr. A
**2020**, 1614. [Google Scholar] [CrossRef]

**Figure 1.**Schematic diagram of the multiple dual mode (MDM) countercurrent (CCC) separation with variable duration of phase elution steps: all the solutes are completely eluting with one phase in a certain cycle.

**Figure 2.**Schematic diagram of the MDM CCC separation with variable duration of phase elution steps: individual solutes are completely removed from the column with different phase flows.

**Figure 3.**Schematic diagram of the mathematical model of multiple dual mode countercurrent chromatography with variable duration of phase elution steps and periodic sample injection.

**Figure 4.**Scheme and principle of the ideal recycling mode of a CLR CCC separation and the applied mathematical model.

**Figure 6.**Operating scheme and principle of the non-ideal recycling mode of a CLR CCC separation and the applied mathematical model.

**Figure 7.**Simulation by Equation (5) of the closed-loop recycling countercurrent chromatography (CRL CCC) separations of the solutes K

_{D1}= 0.3 and K

_{D2}= 0.5 for different values of parameter b: N = 200, N

_{ec}= 200, S = 0.5.

**Figure 8.**Schematic diagram of the closed-loop non-ideal recycling countercurrent chromatography with multiple sample injection.

**Figure 9.**Schematic diagram of the closed-loop recycling dual mode countercurrent chromatography separations and the applied mathematical model.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

## Share and Cite

**MDPI and ACS Style**

Kostanyan, A.A.; Voshkin, A.A.; Belova, V.V. Analytical, Preparative, and Industrial-Scale Separation of Substances by Methods of Countercurrent Liquid-Liquid Chromatography. *Molecules* **2020**, *25*, 6020.
https://doi.org/10.3390/molecules25246020

**AMA Style**

Kostanyan AA, Voshkin AA, Belova VV. Analytical, Preparative, and Industrial-Scale Separation of Substances by Methods of Countercurrent Liquid-Liquid Chromatography. *Molecules*. 2020; 25(24):6020.
https://doi.org/10.3390/molecules25246020

**Chicago/Turabian Style**

Kostanyan, Artak A., Andrey A. Voshkin, and Vera V. Belova. 2020. "Analytical, Preparative, and Industrial-Scale Separation of Substances by Methods of Countercurrent Liquid-Liquid Chromatography" *Molecules* 25, no. 24: 6020.
https://doi.org/10.3390/molecules25246020