Microsoft Word - szolcs_eloszo.doc HUNGARIAN JOURNAL OF INDUSTRIAL CHEMISTRY VESZPRÉM Vol. 32. pp. 13-21 (2004) STUDY OF OPEN–LOOPED SIMULATED MOVING BED (SMB) CHROMATOGRAPHIC PROCESS M. NAGY1, Z. MOLNÁR1, L. HANÁK1, J. ARGYELÁN1, T. SZÁNYA1, B. RAVASZ1, G. TURZA1 A. ARANYI2 and K. TEMESVÁRI2 1University of Veszprém, Department of Chemical Engineering POB 158, Veszprém, H-8201, HUNGARY 2Gedeon Richter Rt., POB 27 Budapest 10, H-1475, HUNGARY In this experimental work laboratory scale four-column simulating moving bed (SMB) equipment (L=25 cm, ID=1 cm) was planned and constructed for separation of a steroid mixture [1] using YMC S-50 silica gel as adsorbent, with the co-operation of Central Mechanical Workshop, University of Veszprém. The effect of switching time change (5.5 min, 9 min, 11.5 min, 22.5 min) on component separation was examined. During our measurements the amount of acetone in dichloromethane was 55 % v/v in the fresh eluent and pure dichloromethane in the feed. Product purity and other specifications (yield, productivity, eluent consumption) were measured by gas chromatography. An equilibrium mathematical model of the SMB process for open and closed eluent loops was constructed by means of a computer program [2, 3]. Adsorption equilibrium, and kinetic data, theoretical plate number measurement, frontal and elution adsorption-desorption measurements for determination of the optimum conditions for the SMB process and for construction of the mathematical model were measured by means of laboratory experiments. Finally results coming from simulation program were compared to measurement results. Our conclusion is that the measured and the calculated data agreed well and we have produced more than 99.9 % m/m purity and 90 % yield, at productivity 1300-3000 g “B” component/ kg adsorbent within a day using 60 g dm-3 inlet steroid composition in case of 1:1:2:0 column configuration. Keywords: SMB, preparative liquid chromatography, simulated moving bed chromatography, Introduction The most recent developments in preparative chromatographic processes are the simulated moving bed processes; these will probably be widely used, mostly for the production of high purity materials or materials otherwise difficult to isolate in pharmaceutical industry, fine chemical and biotechnological separation tasks. If materials are difficult to separate (α ≈1), the process efficiency is disadvantageous, as in case of a component of a mixture being strongly adsorbed (k’»). The process becomes uneconomical when a large volume of eluent must be used. The SMB process was developed in the early 1960s by Brougthon and Gerhold [4] and has been used for many years in the petrochemical and sugar industries for large scale separation. Recently, the separation of enantiomers due to the demand for high purity products becomes necessary [5]. The SMB (Fig.2.) is a continuous unit operated mode in cyclic which reproduces the performance of the equivalent true moving bed (TMB) unit (Fig.1.). The SMB is divided into four sections, each constituted of a counter current adsorption column which plays a specific role in the separation. Let us consider a feed mixture consisting of a more retained species (A) and a less retained one (B) dissolved in the eluent. The separation is obtained in the two central sections, where B is carried by the mobile phase to the raffinate outlet. The fresh eluent is fed to the bottom of the section I, so as to desorb A and regenerate the adsorbent solid, before it is recycled to section IV. On the other hand B is 14 Fig. 1. True Moving Bed (TMB) Fig. 2. Simulated Moving Bed (SMB) retained in section IV and the pure eluent is recycled to section I. In practice the movement of the solid is not feasible and the TMB is replaced by the SMB configuration where the adsorption beds are fixed and the counter-current solid-liquid movement is simulated by periodical switching the inlet and outlet ports of the unit [6]. Use of gradient elution is recommended, likewise the conditions change during the separation. The applied gradient can be the pressure, temperature or solution composition. The third out of theses is usually chosen, and the process is known as solution composition changing gradient SMB. The literature reveals that four scientific „schools” study this subject, the Kluyer Laboratory for Biotechnology at Delft University of Technology in the Netherlands [7-9], ETH Zürich, Inst. Verfahrenstechnik in Switzerland [10,11], the MPI Magdeburg Inst. Dyn. Komplex Techn. System in Germany [12,13] and there are significant scientific results in France, too. We calculated the initial parameters with the method of Morbidelli et al. [14]. After the authors in a two components system can be determined a mII-mIII area from the geometric data of the SMB equipment, the volumetric velocities, the parameters of Langmuir-type isotherms and the concentrations of the mixture to be separated. The actual operating conditions determined a point on the mII-mIII diagram. The variable operating conditions are: fresh eluent, recirculated eluent, feed, extract and raffinate flow rates, switching time. Experiments Equilibria Measurements Adsorption equilibria data for acetone (Fig. 3.) and for steroids “A” and “B” (Fig. 4.) were determined on YMC S-50 silica gel with 1:1 (v/v) acetone- dichloromethane at 293 K at Richter Rt, Department of Preparative Chromatography. Monitoring happened by analytical HPLC with a multistepped frontal saturating method. 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0 200 400 600 800 1000 c acetone (g dm -3 eluent) q ac et on e (g g -1 s ili ca g el ) q acetone measured q acetone calculated a*Acetone= 1.543 cm 3 liquid cm-3 solid silica gel b*Acetone= 0.001517 cm 3 liquid mg-1 acetone Fig. 3. Adsorption equilibria measurement of acetone Acetone in Dichloromethane YMC S-50 silica gel, 20°C, measurements of G. R. I. Feed (A+B) Extract (A) Raffinate (B) IV. III. II. A ds or be nt r ec ir cu la ti on L iq ui d re ci rc ul at io n S (E-F+R) D=S+REC REC Fresh eluent I II III IV D=S+REC E (A) F (A+B) R (B) Liquid phase Adsorbent phase 15 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 0.16 0.18 0.20 0 5 10 15 20 25 30 35 40 45 c (g dm-3 eluent) q B , q A (g g -1 a ds or be nt ) qB calculated qB measured qA calculated qA measured aB= 6.4747 cm 3 liquid g-1 adsorbent bB= 0.016711 cm 3 liquid mg-1 B steroid aA= 14.4086 cm 3 liquid g-1 adsorbent bA= 0.041481 cm 3 liquid mg-1 A steroid Fig. 4. Adsorption equilibria measurement of „A” and „B” components Steroid A, B adsorption, YMC S - 50 silica gel in 1:1 (v/v) acetone-dichloromethane, 20°C, measurements of G. R. Langmuir constants used for calculations are given below (Table 1.): Calculation for the three-component mixture: Adsorption isotherm of acetone: 1 acetone acetone acetoneacetone acetoneacetone acetone gmg0.0015171 1.543 1 − + = + = c c cb ca q (1) Adsorption isotherm for steroid B in 1:1 (v/v) acetone-dichloromethane: 1 B B B gmg0.0016711 6.474 − + = c c q (2) For the competitive Langmuir: BBacetoneacetone BB B 1 cbcb ca q ++ = (3) If cB ≈ 0, the first derivative of the isotherm is: acetoneacetone B B B d d cb a c q + = 1 (4) We obtained new Langmuir constants when the acetone-dichloromethane volume is additive and cacetone=396 g dm-3 : 13* B * B g36.10 396001517.01 474.6 −= ⋅+ = cma a (5) 13* B * B mg02675.0 396001517.01 01671.0 −= ⋅+ = cmb b (6) Calculation method for steroid A is similar. Table 1. Adsorption isotherms on YMC-S-50 silica gel Langmuir constants for acetone in dichloromethane silicagelg volumefreeliquid .*Acetone 3 5431 cm a = neacetomg volumefreeliquid .*Acetone 3 0015170 cm b = Langmuir constants for steroids 1: 1 (v/v) acetone -dichloromethane silicagelg volumefreeliquid .B 3 4746 cm a = componentBmg volumefreeliquid .B 3 016710 cm b = silicagelg volumefreeliquid .A 3 08614 cm a = componentAmg volumefreeliquid .A 3 041480 cm b = Langmuir constants of three-component compound silicagelg volumefreeliquid .*Acetone 3 5431 cm a = neacetomg volumefreeliquid .*Acetone 3 0015170 cm b = silicagelg volumefreeliquid .*B 3 3610 cm a = componentBmg volumefreeliquid .B * 3 026750 cm b = silicagelg volumefreeliquid .*A 3 5522 cm a = componentAmg volumefreeliquid .A * 3 066400 cm b = Determination of Number of Theoretical Plates (NTP) – Height of Equivalent Theoretical Plate (HETP) A Supelco chromatographic column (ID=1 cm, L=25 cm) was filled with YMC S-50 silica gel (8 g) with the aid of a column-packing vibrator. Air was removed from the column by means of 1:1 16 (v/v) acetone-dichloromethane and an LMIM D- 167 pump. A Rheodyne injection valve with 100 µL loop was connected to the column inlet and a Waters UV detector to the outlet, where we monitored the signal from 0.2 % (v/v) acetophenone in eluent on 300 nm wavelength. We evaluated the retention time density function with the triangle method. The flow rates during the measurements were in the range of 1-13 cm3 min-1. The equation of the trendline is NTP/25(cm)= 1522.4v0(cm3 min-1)-0,707 , the regression value is R2= 0.9639. Frontal Adsorption - Elution Measurement Measurement was performed with a chromatographic column (ID=0.735 cm, L=42 cm) packed with YMC S-50 silica gel. Air was removed from the column by means of 1:1 (v/v) acetone- dichloromethane at 293 K, directed upwards by means of an LMIM-D167 piston pump. 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 0 50 100 150 200 250 30 V (cm3) C (g d m -3 ) Measured "B" Measured "A" Calculated "B" Calculated "A" 50 % v/v acetone 50 % v/v dichloromethane 4 g B dm-3 1 g A dm-3 135 cm3 50% v/v acetone, 50% v/v dichloromethane Fig. 5. Frontal adsorption-desorption measurement of steroids 385 390 395 400 405 0 50 100 150 200 250 V (cm3) C a ce to ne (m g cm -3 ) Aceton konc. számított Aceton konc. mért acetone calculated acetone measured Fig. 6. Frontal adsorption-desorption measurement of acetone During frontal adsorption an 80:20 % (m/m) mixture of steroids B+A (total concentration 5 g dm-3) was applied downwards to the column at a flow of 2.47 cm3 min-1 at 293 K. Application of the mixture of A and B was stopped after 55 min (135 cm3 liquid) and pure eluent (1:1 (v/v) acetone- dichloromethane) was let to the column at a flow rate 2.85 cm3 min-1 (Fig. 5. and Fig. 6.). The outlet liquid was collected in cooled (273 K) sample collectors and the concentration was measured by analytical gas chromatography. Frontal Adsorption - Desorption Simulation Data Parameters in KROM-N software with solvent adsorption-desorption (Table 2.). Table 2. Input data of the software Number of components: k = 3 Column inner diameter: ID=0.735 cm Column length: L=42 cm Free volume coefficient: EPS= 0.8018 cm3 liquid free volume cm-3 column Feed: B=2.47 cm3 min-1 Bulk density: ROH= 0.4045 g silica gel cm-3column Langmuir constants: (same as in Table 1 ) Sample feeding time: 55 min (135.85 cm3) Sample concentration: cAcetone=396 mg cm-3 cB=4 mg cm-3 cA=1 mg cm-3 Eluent concentration: cAcetone=396 mg cm-3 cB=cA=0 mg cm-3 Number of Theoretical Plates NTP=400 End of elution time: 112 min SMB Equipment Planning, Construction and Installation The SMB preparative liquid chromatographic equipment with four columns, four sectors and open eluent loops were constructed in the Central Mechanical Workshop of University of Veszprém (Fig. 7.). 17 Fig. 7. SMB equipment photo During installation the four preparative liquid chromatographic columns were filled with YMC S-50 silica gel applying vibration method ( ~ 60 min filling time). The column packing density was 0.405 g cm-3, the free volume factor was 0.8018. Each column was filled with approximately 7.95 g silicagel. Stainless steel fritts (2 µm) were placed at the top and bottom of each column. Before measurements air was removed with dichloromethane. Parameters of SMB-LC Measurements We applied an 1-1-2-0 column configuration in SMB system. This way the steroid B has “bigger space” along the length of the columns. In this case we did not use the raffinate pump, we adjusted the flow rate in segment III so that the steroid B appeared in the LROUT flow in the open-looped SMB system. The function of segment I is the regeneration of the adsorbent and the production of the steroid A in the extract. We used 1,2:1 (v/v) acetone - dichloromethane (gradient) like fresh eluent in the segment I. The function of segment II is the separation of steroid A and B and the extraction of the steroid A in this segment. The function of segment III is to separate steroid A and B and to produce steroid B in the LROUT flow. We fed the mixture of steroid A and B into the third segment, the steroids were soluted in pure dichloromethane because this improved the solution of the steroids and helped us to use gradient SMB. Each of the columns in the four-column SMB equipment were previously equilibrated with pure dichloromethane at 293 K, we wanted to separate the mixture of 42 g dm-3 steroid B and 18 g dm-3 steroid A in the same solvent. The flow rate of the steroid sample input was 0.8 cm3 min-1. Steroid A was extracted with 2.2 cm3 min-1 parameter, so the LROUT flow was 4.25 cm3 min-1 and the switching time was 22.5 min. Process parameters have been determined by Morbidelli method (Fig. 8.). Fig. 8. The measurements points placed in the Morbidelli triangle at different switching times When we decreased the switching time to 11.25 min, we doubled the original flow rates. When we used 5.5 min for switch time, we doubled once again the flow rates. In case of 9 min switching time, we used computer simulation to optimize the work point to get as close to the points of Morbidelli triangle as it was possible. Simulation Data of 1:1:2:0 Column Configuration SMB Simulation was done by SMB-KROM-N software. The input data are summarized in Table 3. The software takes into account the solvent adsorption- desorption phenomena, too. 18 Table 3. Input data of the software Number of components k = 3 Column inner diameter ID.=1 cm Column length L=25 cm Number of columns N=4 Free volume coefficient EPS= 0.8018 cm3 liquid free volume cm-3 column Bulk density ROH= 0.4045 g silica gel cm-3 column Langmuir constants (same as on page ) Feed concentration liquid cmacetonemg -3Facetone 0=c liquid cmcomponentBmg -3FB 42=c liquid cmcomponentAmg -3FA 18=c Flow rates * Optimized by simulation liquidmLcomponentAorBmg0 1SA S B −== cc Simulation SMB 8/41 SMB 8/42 SMB 8/46* SMB 8/44 Switching time(min) 22.5 11.25 9 5.5 F (cm3 min-1) 0.8 1.6 1.8 3.2 D (cm3 min-1) 4.25 8.5. 14.4 17.0 E (cm3 min-1) 2.2 4.4 7.8 8.8 R (cm3 min-1) 0 0 0 0 Fresh eluent liquid cmacetonemg. -3Facetone 6435=c Number of Theoretical Plates NTP=200 / 25 cm column Calculation time 585 min Results Measurement Results of 1:1:2:0 Column Configuration SMB Compared to Simulation In the Figs. 9. 10. 11. 12. those measurements are marked with grey colour where the desired results can be seen, with white colours the measurements which are out of our requirements. The result of the experiments shows that the decrease of the switching time highly improves the productivity, especially at the optimized 9 min switching time experiment. In this case the eluent consumption is also properly low. Numerically describe the above GSMB 8/41 and GSMB 8/46, the productivity was increased from 0.95 mg steroid B g-1 adsorbent min-1 to 2.64 mg steroid B g-1 adsorbent min-1. The eluent consumption was changed from 0.12 cm3 eluent mg-1 steroid B to 0.18 cm3 eluent mg-1 steroid B. 0 20 40 60 80 100 Prep. HPLC GSMB8/41 (22.50 min) GSMB8/42 (11.25 min) GSMB8/44 (5.50 min) GSMB8/46 (9.00 min) pu ri ty " B "( % m /m ) Raffinate > 99.9 % m/m B ηB > 90 % Raffinate < 99.9 % m/m B vagy ηB < 90 % Fig. 9. Comparing the purity of steroid B in different measurements 19 0 10 20 30 40 50 60 70 80 90 100 Prep. HPLC GSMB8/41 (22.50 min) GSMB8/42 (11.25 min) GSMB8/44 (5.50 min) GSMB8/46 (9.00 min) yi el d "B "( % ) Raffinate > 99.9 % m/m B ηB > 90 % Raffinate < 99.9 % m/m B vagy ηB < 90 % Fig. 10. Comparing the yield of steroid B in different measurements 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Prep. HPLC GSMB8/41 (22.50 min) GSMB8/42 (11.25 min) GSMB8/44 (5.50 min) GSMB8/46 (9.00 min) P B ( m g B g -1 s ili ca g el m in ) Raffinate > 99.9 % m/m B ηB > 90 % Raffinate < 99.9 % m/m B vagy ηB < 90 % Fig. 11. Comparing the productivity of steroid B in different measurements 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 Prep. HPLC GSMB8/41 (22.50 min) GSMB8/42 (11.25 min) GSMB8/44 (5.50 min) GSMB8/46 (9.00 min) SF B (d m 3 el ue nt g -1 B ) Raffinate > 99.9 % m/m B ηB > 90 % Raffinate < 99.9 % m/m B vagy ηB < 90 % Fig.12. Comparing the eluent consumption of steroid B in different measurements We achieved the best favourable result in the RG-1040-GSMB 8/46 measurement at 9 min switching time. In this case calculated values of measurement were compared to data given in Table 4. We note that the LROUT 1, 2 are given by halving the LROUT liquid stream for 0-4,5 min and 4,5-9 min fractions. Conclusion Our conclusion on the basis of laboratory measurements is that varying the switching time of SMB process results big changes in productivity. In our case we get the highest productivity at 9 min switching time. We significantly increased the operation results according to the preparative HPLC measurement (Table 5.). We achieved 700% productivity increase and 50 % eluent consumption decrease beside more than 99.9 % m/m B purity and 90 % B yield. It could be seen, that the developed SMB process was outstandingly economic, the value of the productivity was successfully increased to 3.082 kg B/ kg silica gel within a day. Acknowledgement The authors express their gratitude to the Chemical Engineering Institution Co-operation Research Centre, Veszprém, the Széchenyi Project of National Research and Development Project, and the Gedeon Richter Ltd. for financial support of this research. 20 Table 4. Results of the RG 1040 GSMB 8/46 measurement compared to result of the simulation Measurement Simulation Purity of raffinate (LROUT) LROUT1 96.96 %m/m B LROUT2 > 99.9 %m/m B LROUT 1 +LROUT 2 > 99.9 %m/m B Purity of extract (E) 88.89 %m/m A 93.5 %m/m A Yield LROUT1 6.46 %B LROUT2 92.6 %B Extract 68.1 %A LROUT 1 +LROUT 2 > 99.99 % 98.3 % Productivity LROUT 2 2.14 mingelsilicag Bmg Extract 0.54 mingelsilicg Amg LROUT 1 +LROUT 2 2.16 mingelsilicag Bmg Extract 0.69 mingelsilicg Amg Eluent consumption LROUT 2 0.134 Bmg eluentfreshcm3 Extract 0.403 Amg eluentfreshcm3 LROUT 1 +LROUT 2 0.197 Bmg eluentfreshcm3 Extract 0.61 Amg eluentfreshcm3 Table 5. Results of the RG 1040 GSMB 8/46 measurement compared to preparative HPLC measurement Preparative HPLC RG1040 SMB8/46 measurement (9 min) Purity of raffinate (LROUT 2) >99.9 % m/m B >99.9 % m/m B Yield (LROUT 2) ~ 95 % B >92.6 % B Productivity (LROUT 2) 0.303 mingelsilicag Bmg 2.14 mingelsilicag Bmg Eluent consumption (LROUT 2) 0.354 Bmg eluentfreshcm3 0.134 Bmg eluentfreshcm3 21 SYMBOLS qAcetone adsorbent concentration of acetone, mg g-1 aAcetone Langmuir constant of acetone, cm3 liquid free volume g-1 silica gel bAcetone Langmuir constant of acetone, cm3 liquid free volume mg-1 acetone cAcetone concentration of acetone, g dm-3 qB adsorbent concentration of steroid B, mg g-1 aB Langmuir constant of steroid B, cm3 liquid free volume g-1 silica gel bB Langmuir constant of steroid B, cm3 liquid free volume mg-1 B component cB concentration of steroid B, g dm-3 qA adsorbent concentration of steroid A, mg g-1 aA Langmuir constant of steroid A, cm3 liquid free volume g-1 silica gel bA Langmuir constant of steroid A, cm3 liquid free volume mg-1 A component cA concentration of steroid A, g dm-3 k number of components k’ capacity factor ID column inner diameter, cm L column length, cm F flow rate of feed, cm3 min-1 D flow rate of fresh eluent, cm3 min-1 E flow rate of extract, cm3 min-1 R flow rate of raffinate, cm3 min-1 LROUT outlet liquid at 1:1:2:0 column configuration at R=0 T switching time, min ε free volume coefficient, cm3 liquid free volume cm-3 column ROH bulk density, g silica gel cm-3column NTP Number of Theoretical Plates REFERENCES 1. SZANYA T., ARGYELAN J., KOVATS S. and HANAK L.: J. Chromatogr. A, 2001, 908:265- 272 2. MIRON M., SZANYA T., HANAK L., ARGYELAN J. and MARTON GY.: Hung. J. Ind.Chem. 1995, 23:293-298. 3. KOVATS S., CSUKAS B., ARANYI A. and POZNA E.: Hung. J. Ind.Chem. 1998, 26: 44-53. 4. BROUGHTON D. B. and GERHOLD C. G.: US Pat. 2 985589, 1961. 5. JUPKE A., EPPING A. and SCHMIDT-TRAUB H.: J. Chromatogr. A, 2002 944:93-117 6. GIOVANNI O., MAZZOTTI M., MORBIDELLI M., DENET F., HAUCK W. and NICOUD R.: J. Chromatogr. A, 2001, 919:1-12 7. JENSEN T., REIJNS T., BILLIET H. and WIELEN L.: J. Chromatogr A, 2000, 873:149-162 8. HOUWING J., BILLIET H. and WIELEN L.: J. Chromatogr A, 2002, 944:189-201 9. HOUWING J., HATEREN S., BILLIET H. and WIELEN L.: J. Chromatogr A, 2002, 952:85-98 10. ABEL S., MAZZOTTI M. and MORBIDELLI M.: J. Chromatogr A, 2002, 944:23-29 11. GIOVANNI O., MAZZOTTI M., MORBIDELLI M., DENET F., HAUCK W. and NICOUD R.: J. Chromatogr A, 2001, 919:1-12 12. ANTOS D. and MORGENSTERN A.: J. Chromatogr., 2002, 944:77-91 13. ANTOS D. and MORGENSTERN A.: Chem. Eng. Sci., 2001, 56:6667-6682 14. MIGLIORINI C., MAZZOTTI M. and MORBIDELLI M.: J. Chromatogr. A, 1998, 827:2:161-173