Chapter 4 Chemical Processing of Industrial Technology
Batch, Semi-continuous, and Continuous Processing
In pharmaceutical and fine chemicals industries, most processes are developed for batch or semi-continuous operations. In a batch process all the reaction components are combined and held under controlled conditions until the desired process end point has been reached. Reactions are typically slow, taking hours, and the product is isolated at the end of the process cycle. Chapter operations, such as fermentation and crystallization, can be carried out on the entire batch with fine control. Because the product output, typically no more than hundreds of kilos, can be readily correlated with input materials, batch operations are suited for c GMP considerations and commonly used in the pharmaceutical and fine chemicals industries.
Semi-continuous operations, also known as semi-batch, batch-flow, or (in the biotechnology industry) fed-batch processes, combine aspects of both batch and continuous operations. For example, a reactor may be gradually filled with process streams, with none of the mixture being displaced. After a suitable time the product is isolated. An example of this is the controlled crystallization of a product by slow p H adjustment or addition of a non-solvent. The output from continuous operations can also be combined and treated as a batch, for example, recrystallized; such processing is also considered semi-continuous. The distinction between batch and semi-continuous operation is often blurred, and strictly speaking many processes used in pharmaceutical and fine chemicals industries are semi- continuous processes.
Continuous processing is typically used to prepare commodity chemicals on a tonnage basis. There are two primary types, continuously stirred tank reactors (CSTR) and plug flow reactors (PFR), along with the recently developed microreactors.In CSTR processing, process streams are continuously mixed in reactors and continuously harvested; after a vessel is filled the output streams overflow into another reactor at the same rate as the input streams are added, thus maintaining a constant volume under steady-state conditions. On a microscopic scale there is a range of residence times for molecules as they enter and leave such a mixed vessel, and as more mixed vessels are added in series the reactor train becomes more characteristic of a batch system. The continuous, controlled movement of the process streams through equipment increases the product throughput on a space-time basis, allowing more material to be made from a smaller plant with smaller capital investment than would be possible under batch conditions. Typically continuous processes are used for fast reactions, requiring minutes or less. For the preparation of high-quality material it is essential that the process be conducted with little variation from optimal conditions; such steady-state conditions should be reached quickly upon start-up of the processing for optimal yields.
PFRs are tubes commonly constructed of metal or plastic. As narrow-bore tubes, the high surface area-to-volume ratio allows for rapid heat transfer and control of reaction temperature. Mixing in PFRs occurs radially, not axially, making PFRs useful for minimizing side reactions in which reagents react with the product. PFRs that are run at elevated temperatures are sometimes called hot tube reactors, and they have many uses in industry. Other PFRs are static mixers, inexpensive tubes with stationary internal elements that split and sometimes rotate the stream flow, producing intimate mixing. Static mixers are powerful tools, with diverse applications ranging from mixing solutions in low-viscosity solvents to blending peanut butter. Most PFRs are relatively inexpensive, portable, and useful for the laboratory, pilot plant, and manufacturing.
Microreactors, miniaturized systems produced by microtechnology and precision engineering, have fluid channels in the range of submicrometers to submillimeters, and reactors at the higher end of this range are sometimes referred to as minireactors. The structural elements of microreactors include static mixers, reactors, microseparators, heat exchangers, pumps, and other components, and the primary focus is to intensify mass transport and heat exchange. Microreactors have been used for peptide synthesis and PCR amplification, and hold promise for commercial applications. As the microreactor field is an emerging technology, few devices are commercially available. This review examines continuous processing with equipment more commonly available for the laboratory, and does not include microreactors.
Power and Productivity of Continuous Processing
Financial considerations have led to the development of large-scale continuous processing. High-volume solvents such as methyl tert-butyl ether (MTBE) and ethyl acetate (Et OAc) have been produced by continuous contact of starting materials with an immobilized acidic catalyst. Simulated moving bed chromatography (SMB) is a powerful technique for cost-effective, continuous purification. Continuous processing has been used in the manufacture of silanes and siloxanes. In the manufacture of cyclopropylamine by Hofmann rearrangement of cyclopropylcarboxamide, CSTR processing has been developed to control the exothermic hydrolysis of the intermediate isocyanate, and PFR technology is claimed to increase productivity. Highly reactive compounds such as diazomethane and phosgene are generated continuously in small volumes due to safety considerations. Polyacrylate resins have been made by PFR technology with improved productivity. A continuous photochemical process is used to manufacture cyclohexanone oxime, a precursor to caprolactam. In the solid-phase manufacture of oligonucleotides, continuous processing using axial-flow packed bed reactors is markedly more efficient than processing using stirred-bed reactors. An excellent review on industrial and laboratory applications of continuous processing was published in 1992.
Continuous processes have been used for scale-up in the laboratory and pilot plant. The feasibility of continuous processing can often be assessed with a modicum of effort, and sometimes batch processing cannot effectively scale up some processes (vide infra). For initial laboratory work and scale-up to the pilot plant, reactors are smaller than those used in manufacturing settings. Despite of their small size, continuous flow reactors can lead to large productivity due to rapid flow rates. M. A. Poliakoff, in describing his 5-m L reactor used for continuous hydrogenation in supercritical fluids, was quoted:“With our 5-m L reactor, we have achieved a throughput that is larger than that required by most synthetic organic laboratories.”Examples below describe the power and productivity of continuous processing applied in the laboratory, using equipment that is readily available.
Continuous Processing That Has Been Applied to Laboratory Operations
CSTR and Semi-continuous Operations
The chlorination of the furfuryl alcohol 1 provides one of the most powerful examples of how continuous processing can be readily applied in the laboratory. The chloride 2 was an intermediate in the preparation of the nitrile 3. When the chlorination was scaled up to more than 100 g in a batch mode, unacceptable yields of 3 were obtained. The poor stability of 2 (t1/2at room temperature of only 20 min) was the cause of poor yields upon scale-up of the batch process. A CSTR process was set up to convert 2 to 3 soon after 2 had been generated, using two 10-m L round-bottomed flasks with magnetic stirrers. Separate solutions of 1 and SOCl2were charged to a flask by ganged syringe pumps, and the reaction stream overflowed into a second flask and then into a reactor charged with an excess of Na CN. PTC conditions rapidly converted 2 to 3. Continuous operations for one week produced 10 kg of 3 using this train of two 10-m L reactors!
Plug Flow Reactors
Safety studies showed that nitration of the pyrimidine 4 was highly exothermic and generated a large amount of gases upon decomposition at a relatively low temperature. Due to safety considerations this reaction was run on scales no larger than 22 L in a batch mode. The nitration was found to be rapid and was adapted for PFR processing. Using a translucent Teflon tube, at 45℃ a solution of 4 in H2SO4 was combined with 90% HNO3. Residence time in the reactor was about 2.5 min, and the use of the open-ended tube decreased concerns of any gas build-up. The reaction was quenched into cold H2O, and the salt 5 was isolated in 86% yield from 45 kg of 4.
Reactors Involving Immobilized Catalysts
Immobilized catalysts allow for ready recovery and recycle of valuable reagents, with decreased contamination of product. The use of immobilized TADDOLate catalysts contained in “tea bags” has been described for the addition of dialkyl zinc reagents to aldehydes. Operationally simple is the process of passing a reaction stream through a catalyst contained in a column. Resin-mediated epimerization has been studied in detail. Recirculating an aqueous DMSO solution of fructose (6) through a bed of strongly acidic ion-exchange resin led to isomerization and dehydration, producing the aldehyde 7. Passing a solution of 8 in i-Pr OH-heptane through a chromatography column containing a rhodium catalyst and chiral amine adsorbed to silica gel produced the chiral alcohol 9.
Immobilized catalysts have been developed and used in continuous reactors, often termed “bioreactors” when enzymes or cells are used. Enzymes have been immobilized to increase enzymatic stability, ease workup, and allow for convenient continuous processing. Cell cultures attached to porous materials have been claimed to continuously produce metabolites. Workers at Degussa have developed soluble polymer-bound catalysts contained by membranes, with the smaller product molecules permeating the membranes. Crosslinked enzyme crystals (CLECs) have been used in the hydrolytic kinetic resolution of sec-phenethyl acetate, with recycle of the CLECs affording a semi-continuous process. A continuous bioreactor was used for the enzymatic transformation of glucose and fructose to gluconic acid (10) and sorbitol. Under the latter conditions a portion of the process stream was continuously withdrawn and passed into a reactor fitted with tangential ultrafiltration; the products permeated the membrane, and the larger enzyme was returned to the reactor. Nanofiltration similarly retained the enzymes used in the reduction of the R-ketoester 12. The alcohol 13 was obtained in 90% yield on a 10-kg basis, using equipment in two adjacent walk-in hoods.
Scale-up of Continuous Microwave Processes
Microwaves are known to markedly accelerate reactions, and recently the value of microwaves in developing discovery libraries has been discussed. Due to the shortened reaction times, larger amounts of material can be prepared by running successive batches in a conventional microwave reactor. Batch processing has been scaled up under neat conditions, producing as much as 620 g of an ester by PTC alkylation and 269 g of a dithioketal by ketal exchange. Microwave processes can produce localized high temperatures and pressures, and any scale-up operations must consider these potential dangers and limitations.
Photochemical Processes
Conventional multipurpose reactors are not prepared for immersion of a light source or transmission of light through the vessel walls. Continuous operations permit the effective scale-up of some photochemical processes, with process streams being circulated within close proximity to light sources in specially designed transparent cells. Many of these cells are made of glass or Teflon, and can be fabricated by local craftsmen. Continuous photolytic reactors have been described for the photochemical degradation of wastewater containing dichloromethane or inorganic salts and photochemical iodide/bromide exchange.
Continuous photobromination was used to convert the olefin 14 to the ally lie bromide 15. l,3-Dibromo-5,5-dimethyl hydantoin (DBH) was used as the bromine source, and Perkadox 16N was the radical initiator. The reaction mixture was pumped through a helical Teflon.
Coil winding upward around the light source. In one pass 14 was converted to 15 in a yield of 89.9% (28-kg scale). In the radical-induced telomerization of 16, vapor-phase photobromination reactions were carried out in cylindrical glass tubes, glass desiccators, or 100-dm3 stainless steel vessels. The key feature is that under irradiation from a low-pressure Hg lamp tetrafluoroethylene reacted with volatilized 16 to form 17, while the heavier oligomers (such as 18) were held as liquids and not subjected to irradiation. Vapor-phase irradiation decreased the formation of oligomers.
Electrochemical Processes
Electrochemical reactions have wide applications for the commercial preparation of commodity chemicals, such as the reductive dimerization of acrylonitrile to produce the nylon-6 precursor adiponitrile. Reactions, especially oxidations, can be readily carried out in the laboratory and scaled up. An intriguingexample is the electrochemical formation of the epoxide 19 using catalytic amounts of Na Br. Continuous equipment is available for laboratory scale-up of electrochemical processes.
Summary
Continuous processing, long established as cost-effective in the commodity chemicals sector, has been shown to be useful in the laboratory and pilot-plant scale-up of pharmaceuticals and fine chemicals. The benefits of continuous processing include greater process control, enhanced margins of safety, increased productivity, and improved quality and yields. Many processes that cannot be scaled up using batch operations can be readily scaled up in the laboratory and pilot plant through continuous operations. Continuous processing will be more commonly used in the future for scale-up in the lab and pilot plant.