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Ind. Eng. Chem. Res. 1996, 35, 1322-1331
PROCESS DESIGN AND CONTROL Integration of Wiped-Film Evaporation and Crossflow Microfiltration for the Purification of a Silylenol Ether Reaction Mixture: Process Issues and Scaleup Karen A. Larson,* A. Andrews, B. Snyder, C. Wightman, and E. Paul Chemical Engineering Research and Development, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065
The reaction between p-nitrobenzyl 2-diazoacetoacetate and trimethylchlorosilane (TMS-Cl) produces a toluene-soluble silylenol ether (SEE) product and insoluble byproduct salts (NaCl and triethylammonium hydroiodide). Purification of the SEE solution via removal of the salts and unreacted TMS-Cl is accomplished by integrating two unit operations [crossflow microfiltration and distillation in a wiped-film evaporator (WFE)] into a semicontinuous process. The process addresses the critical scale-up issues of potential exothermic activity near the operating temperature, water sensitivity of the product, and the avoidance of direct solids handling. Key to its successful scaleup from the laboratory (2 kg scale) to manufacturing (370 kg scale) was the development of a distributed control system which addresses characteristics unique to each of the unit operations. Crossflow operation at all scales exhibited a substantial increase and then a decrease in transmembrane pressure (TMP) which coincided with dissolved solids concentration and concomitant solution viscosity. Membrane fouling, which became apparent in manufacturing after repeated membrane use, was addressed by operational changes to minimize TMP and by incorporating a membrane cleaning procedure. Introduction Use of membranes for separations has become popular because they can be applied to a number of different separation problems. Improvements in membrane manufacture and membrane systems design as well as a better understanding of the causes and remedies for membrane fouling and flux decay have resulted in more large-scale use. Work aimed at a better understanding of the fouling process through experiments and modeling (Davis, 1992; Tarleton and Wakeman, 1994a,b; Wakeman, 1994; Foley et al., 1995) has resulted in new module designs which enhance turbulence through pulsatile flow (Bertram et al., 1993) or centrifugal instabilities, for example (Belfort and Heath, 1994). The problems with fouling and flux decay can be minimized in conventional modules by using backflushing, fastflushing, and chemical cleaning (Chen et al., 1991). Membrane processes are used in many biotechnology and environmental applications. They have been integrated into fermentators and bioreactors to facilitate gas transport; they are used in downstream purification steps often in conjuction with large-scale chromatography and solvent extraction; and when the membranes are modified with affinity ligands, they can be used in facilitated transport (Belfort and Heath, 1994). Crossflow filtration is used to treat industrial wastewater by concentrating pollutants. An additional separation technique is then required to treat this concentrated waste. This is much less energy intensive than an evaporation process (Mulder, 1994). In these examples, crossflow filtration is used in conjunction with other unit
operations to give an overall process which can be volumetrically more productive and less energy intensive and can minimize external contamination because of its closed system operation. Design of processes for the pharmaceutical and fine chemical industries typically consists of a a chemical reaction followed by appropriate purification and isolation steps (Paul and Rosas, 1990). Process conditions for each of these steps must be established that reflect both the chemical and physical properties of the process streams as well as establish safe and controllable manufacturing operations. Often, a direct scaleup of the original reaction and isolation laboratory process can meet all of the above criteria; however, in some cases, integration of steps is required to simultaneously meet all of the process requirements of a particular operation. Integration may include combinations of reactions with unit operations and/or simultaneous unit operations. The following describes a process design that integrates crossflow filtration and wiped-film evaporation into a semicontinuous process in which these operations are carried out simultaneously in order to satisfy several process requirements which include difficult filtration of a reaction byproduct, the need for closed system operation, and distillation of a thermally unstable intermediate. Successful scaleup to manufacturing required definition of process conditions for both operations as well as design of a control system that could run the process under normal conditions and, in addition, respond to abnormal conditions, particularly those that could lead to the possibility of thermal instability. Experimental Section
* To whom correspondence should be addressed. E-mail: KAREN
[email protected].
0888-5885/96/2635-1322$12.00/0
The conversion of p-nitrobenzyl 2-diazoacetoacetate (pNB-DAA) to SEE was carried out as described in © 1996 American Chemical Society
Ind. Eng. Chem. Res., Vol. 35, No. 4, 1996 1323 Table 1. Scale of Operations from Laboratory to Manufacturing
Figure 1. Process flow sheet for the SEE isolation for the pilot plant (30 kg scale). Crossflow filtration and continuous evaporation are integrated into a semicontinuous process. The filters retain the solids, while the permeate is sent to the WFE for acetonitrile and TMS-Cl removal. The concentrate is returned to the slurry tank until the batch volume has been reduced to 40% of the original volume at which point the SEE solution is recovered by diafiltration with toluene. After one last pass through the evaporator, the bottoms is sent to a holding tank for direct use in the next reaction.
Hughes (1994) and will briefly be overviewed in the Results and Discussion section. Compressibility studies of the NaCl/TEA‚HI cake were accomplished with a 1 L, 0.002 m2 Rosenmund pocket filter (Rosenmund Corp.). The reaction slurry was filtered to establish a cake, the cake height was measured, and the liquor was then refiltered so that the filtration rate for the established cake could be determined. This was repeated for a range of filtration pressures and cake depths. The semicontinuous purification process was run at three scales (2, 30, and 370 kg of SEE), as summarized in Table 1. At the laboratory scale (2 kg), shown in Figure 1, a 30 L jacketed, glass resin kettle served as the slurry tank. A single-element ceramic filter with a 1 or 0.2 µm pore size with 2.7 mm i.d. lumen and 0.14 m2 surface area (Millipore Model MSDN02100 or MSDN02020 filter element in housing Model MSDNS100Q,
scale of operations
pNB-DAA charge (kg)
TEA‚HI + NaCl formed (kg)
membrane area (m2)
WFE area (m2)
laboratory pilot plant manufacturing
2 30 370
1.7 26 318
0.14 0.39 5.2
0.023 1.3 4.2
Millipore Corp., Bedford, MA) was connected to the bottom of the vessel via a 25 L/min capacity diaphragm pump (Wildon Model M1, Colton, CA) for recirculation. The permeate was collected in a 1 L round-bottom flask which served as the surge tank. Fluxes were in the range 0.15-0.2 L/min (ca. 160 L(h‚m2)-1) as measured by a rotometer. Feed to the 0.023 m2 wiped-film evaporator (Artisan Industries Model “Rototherm”, Waltham, MA), equipped with a standard glass coil condenser, distillate receiver, and vacuum pump (Welsh Model 1376), was accomplished using the system vacuum. Concentrate was collected in one of two 12 L round-bottom flasks and recycled to the slurry tank or sent forward to a 18 L glass bottle using a peristaltic pump (Cole Parmer Masterflex Model 7520-25 with viton tubing). The equipment configuration in the pilot plant (30 kg scale) was similar to that of the laboratory (Figure 1). An 800 L glass-lined vessel served as the slurry tank. The slurry was recirculated with a standard centrifugal pump through a three-element filter housing (Millipore Model MSDNS3000, Bedford, MA) with 0.2 µm pore size membranes and 4 mm i.d. lumen (Millipore Model MSDN04020). The total filtration area was 0.39 m2. Permeate flux was measured by rotometer at 5.5-7.5 L/min (ca. 240 L(h‚m2)-1). The recirculation rate, maintained at 60 L/min, was measured using a Micromotion meter (Coriolis meter). Permeate was fed to a 10 gal portable tank which fed the 1.3 m2 WFE (VotatorTurba Film Processor Model 14-060, Chemetron, Corp., Louisville, KY) via residual vacuum. The jacket tem-
Figure 2. Crossflow filtration equipment and control scheme for manufacturing (370 kg scale). The control system for the crossflow takes into consideration the inherent variability of membrane operation. The primary control loops (boldface-dashed lines) allow the crossflow and WFE to operate independently. Small fluctuations in the permeate rate will not affect the feed to the WFE. In the event of a significant decrease in permeate rate, a secondary control system takes over (double-dashed lines) which directly links the permeate rate with the feed to the WFE. This method of control helps to minimize operator/supervisor intervention.
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chemists (Hughes, 1994), pNB-DAA slurried in 2:1 (v/ v) toluene/acetonitrile, is reacted with chlorotrimethylsilane (TMS-Cl; 1.14 equiv) in the presence of sodium iodide (NaI; 1.2 eq) and triethylamine (TEA; 1.18 equiv) to form the soluble product, silylenol ether (SEE). The reaction is carried out at 15-20 °C. Sodium chloride (NaCl) and triethylammonium hydroiodide (TEA‚HI) are formed as insoluble byproducts of the reaction, as shown in the following:
Figure 3. Equipment and control system for the wiped-film evaporator. With the feed to the WFE maintained at a constant rate, the calculation of the distillation cut includes feed and concentrate flow rates. Eight different distillate cut setpoints are used at various stages of processing. Key to successful operation of the WFE is the fast-responding control loops for the concentrate flow rate and heat exchanger. In the event of an emergency, fresh toluene is fed to the WFE to prevent product drying on the walls of the evaporator.
perature of the WFE was maintained at 30-35 °C. The vacuum was maintained at 18-30 mmHg using a threestage steam jet. Concentrate was collected in a 100 L glass-lined receiver (located at the outlet of the WFE). The level was maintained at 19 L by pumping via a positive displacement pump back to the slurry tank during the concentration step or forward to a holding tank during the diafiltration step to await the next reaction. A schematic representation of the equipment used in manufacturing (370 kg scale) is shown in Figures 2 and 3. The slurry tank was a 6000 L glass-lined vessel. A 37-element housing (Millipore Model MSDNS8000, Bedford, MA) contained 0.2 µm pore size membranes with 4 mm i.d. lumen (Millipore Model MSDN04020). The total filter area was 5.2 m2. At this scale, the standard “feed and bleed” method for recirculation was used (Ripperger, 1988): a centrifugal pump operating at a high circulation rate pumped slurry around the membranes at 700 L/min, while a second centrifugal pump fed slurry from RE-1680 to the recirculation loop at 135 L/min. The transcartridge pressure drop was maintained by a backpressure control valve in the recirculation loop which resulted in a return (bleed) of slurry to RE-1680. Permeate at 23 L/min [265 L(h‚m2)-1] was fed by gravity to the 750 L surge tank and then by a positive displacement pump to the 4.2 m2 WFE (LCI Corp., formerly LUWA Inc., Charlotte, NC). The jacket temperature was controlled with a glycol heat-exchange loop in the range 35-50 °C. Vacuum was maintained constant at 18 mmHg with a liquid ring seal vacuum pump and blower. Concentrate was sent back to RE1680 during the concentration step or forward to a holding tank during diafiltration via a positive displacement pump. Details of the control system will be described in the Results and Discussion section. Results and Discussion Chemistry and General Process Description. In the laboratory process, as received from the process
The purification of the SEE reaction mixture and its use as a toluene solution in the subsequent coupling reaction requires the removal of unreacted TMS-Cl and TEA, which are added in excess, and removal of the byproduct salts. The presence of these compounds interferes with the subsequent reaction. Thus, once the reaction is complete, as confirmed by 1H NMR, the slurry is diluted with toluene (to an approximate ratio of 4:1 toluene/acetonirile) to precipitate 85-90% of the TEA‚HI (this salt has some solubility in the toluene/ acetonitrile solvent system). A vacuum distillation/ concentration removes acetonitrile and the volatile TMS-Cl. Reduction of the acetonitrile content to less than 0.5% ensures that the remaining 10-15% TEA‚HI has precipitated. The slurry is then filtered to remove the byproduct salts, the salt cake is washed with toluene, and the wash is combined with the purified SEE solution. The streams for reaction (1) were evaluated for thermal activity using standard differential scanning calorimetry. This testing is carried out for all new processes prior to any pilot plant activity. The thermal evaluation of this step revealed exothermic decomposition in the starting pNB-DAA slurry as well as the SEE reaction mixture. The reaction itself is also exothermic. These exotherms have a magnitude of about 100 cal/g and initiate at a temperature of 75 °C. [Note: An exotherm of this magnitude is sufficient to bring the temperature of the reaction solution to the solvent boiling point and would then vaporize >75% of the solvent in an open, adiabatic system. Gas generated by the product decomposition could result in significant two-phase flow.] The reaction and isolation are further complicated by the necessity of maintaining anhydrous conditions (98% is achieved after diafiltering with >3.9 batch volumes of toluene. The SEE yield and quality for the first three manufacturing batches are compared with the laboratory and pilot-scale batches in Table 2. The yields achieved in manufacturing are comparable to those achieved in most of the pilot plant batches. The major improvement in the manufacturing-scale process is the reduced amount of pNB-DAA in the final toluene solution of SEE. The presence of pNB-DAA in the final solution is indicative of the intrusion of water into the process (as described in reaction (3)). Every pilot plant batch contained some pNB-DAA starting material at the end of the isolation even though conversion in the reaction was 100%. The disastrous effect that water can have is most notable in batch 7 (30 kg scale) which contained 24% pNB-DAA. Water backup from the vacuum steam jet contaminated this batch when the pilot plant tem-
A novel integration of two well-established unit operations into a semi-continuous process enabled the scaleup of a complex isolation process for a heat- and water-sensitive compound. The use of crossflow filtration in conjunction with a wiped-film evaporator addressed the critical scale-up issues of potential exothermic activity of the process streams as well as the issues of handling a large quantity of compressible byproduct salts. Optimal start-up procedures for the crossflow system as well as optimum distillation rate regimes in the WFE were identified in laboratory and pilot-scale experiments. Key to the successful scale-up to manufacturing was the design of the sequenced control system which addressed characteristics unique to each of the unit operations. This included a control system which was sufficiently flexible to handle the inherent variability in membrane performance with minimal outside intervention and a secondary control system to handle a “catastrophic” system upset. Characteristics of membrane performance identified in the pilot plant were very similar to those in manufacturing. The system experienced a substantial increase and then decrease in transmembrane pressure which coincided with the dissolved solids concentration (SEE concentration) and concomitant solution viscosity. An additional parameter, membrane permeability, became an important measure of membrane fouling which was especially apparent in manufacturing after repeated membrane use. Incorporation of aqueous washes of the membranes as well as some adjustments in the diafiltration regimen helped to improve productivity. Future development of processes which incorporate crossflow microfiltration should also include an evaluation of membrane fouling and the effects of long-term membrane use during the piloting phase. Acknowledgment The authors acknowledge the members of Process Research, Analytical Research, Technical Operations, Process Engineering, Chemical Engineering R & D, Automation and Instrumentation, and Factory Opera-
Ind. Eng. Chem. Res., Vol. 35, No. 4, 1996 1331
tions of Merck and Co., Inc., who contributed to the overall success of the project. Nomenclature DP ) transcartridge pressure drop pNB-DAA ) p-nitrobenzyl 2-diazoacetoacetate TEA ) triethylamine TEA‚HI ) triethylammonium hydroiodide TMP ) transmembrane pressure TMS-Cl ) trimethylchlorosilane SEE ) silylenol ether
Literature Cited Belfort, G.; Heath, C. Biotechnology Processes: Membrane Materials, Modules and Process Design. In Membrane Processes in Separation and Purification; Crespo, J., Boddeker, K., Eds.; Kluwer Academic Publishers: Amsterdam, The Netherlands, 1994; pp 3-7. Bertram, C. D.; et al. Flux Enhancement in Crossflow Microfiltration Using a Collapsible Tube Pulsation Generator. J. Membr. Sci. 1993, 84, 279-292. Bowen, W. R.; Gan, Q. Properties of Microfiltration MembranessFlux Loss During Constant Permeation of Bovine Serum Albumin. Biotechnol. Bioeng. 1991, 38, 688-698. Chen, A.; Flynn, J.; Cook, R.; Casaday, A. Removal of Oil, Grease, and Suspended Solids From Produced Water Using Ceramic Crossflow Microfiltration. Adv. Filtr. Sep. Technol. 1991, 3, 292-317. Davis, R. H. Modeling of Fouling of Crossflow Microfiltration Membranes. Separation and Purification Methods; Marcel Dekker, Inc., New York, 1993; Vol. 21 (2); pp 75-125. Foley, G., MacLoughlin, P.; Malone, D. Membrane Fouling during Constant Flux Crossflow Microfiltration of Dilute Suspensions of Active Dry Yeast. Sep. Sci. Technol., 1995, 30 (3), 383-99. Hughes, D. L. Process for the Preparation of 2-Diazo-3-Trisubstituted Silyloxy 3-Butenoates. U.S. Patent 5,340,927, Aug 23, 1994.
Lyons, C. C. Improved Triethylamine HCl Filtration Times Facilitated by the Cubic Rate Addition of an Organic Chloroformate. AIChE Annual Meeting, San Francisco, Nov 1994; Paper 140h. Ma, Y. H. Inorganic Membranes Show Promise for High Temperature Separation and Catalysis. Chem. Process. 1992, 31, 2126. McCallion, J. New materials, applications enter booming ceramic scene. Chem. Eng. 1988, May, 23-36. Mulder, N. Energy Requirements in Membrane Separation Processes. NATO ASI Ser., Ser. E 1994, 272, 445-75. Nagata, N.; Herouvis, D.; Dziewulski, D.; Belfort, G. Cross Flow Membrane Microfiltration of a Bacterial Fermentation Broth. Biotechnol. Bioeng. 1989, 34, 447-466. Paul, E. L.; Rosas, C. B. Challenges for Chemical Engineers in the Pharmaceutical Industry. Chem. Eng. Progr. 1990, December, 17-25. Perry’s Chemical Engineers’ Handbook; McGraw-Hill: New York, 1984; p 19-67. Ripperger, S. Engineering Aspects and Applications of Crossflow Microfiltration. Chem. Eng. Technol. 1988, 11, 17-25. Tarleton, E. S.; Wakeman, R. J. Understanding Flux Decline in Crossflow Microfiltration: Part IIsEffects of Process Parameters. Chem. Eng. Res. Des. 1994a, 72, 431-40. Tarleton, E. S.; Wakeman, R. J. Understanding Flux Decline in Crossflow Microfiltration: Part IIIsEffects of Membrane Morphology. Chem. Eng. Res. Des. 1994b, 72, 441-50. Wakeman, T. J. Visualization of Cake Formation in Crossflow Microfiltration. Chem. Eng. Res. Des. 1994, 72, 530-540.
Received for review August 23, 1995 Revised manuscript received December 27, 1995 Accepted January 13, 1996X IE950529I
X Abstract published in Advance ACS Abstracts, March 1, 1996.
