THOMAS D. WAUGH Coordination of sales, development, and production managementfunctions is the key to modern methodology f o r new chemical product development, particularly f o r the small-scale and specialty chemicals producer the past few years some doubt has been During expressed about the real utility of research and development in the pursuit of corporate goals. Small chemical companies have certainly experienced difficulties in underwriting research and development; yet small chemical companies are even more dependent than large companies on continuing development of new products, because obsolescence and competitive attrition take a heavy toll of their product lists. Furthermore, as the scale of production is generally modest, it takes a good many new products each year to maintain a steady rate of growth. Even if a small company depends on outside suggestions for new products, it must still develop efficient processes for their production. Processes given by an outside source are usually inadequately developed, and experience shows that the potential profit return depends almost entirely on the amount of technical contribution made to the process. Therefore, research and development for the small chemical company is at worst a painful necessity and a t best, a golden opportunity. Arapahoe Chemicals is a small, fine chemicals manufacturing company, whose efforts over the years have been directed toward the custom manufacturing of drugs, intermediates, and agricultural chemicals. In addition, Arapahoe manufactures a line of reagents and intermediates for captive use in the synthesis of a wide variety of organic compounds. Its product line embraces about 100 compounds, and its research and development program has been directed almost entirely to the development of new products rather than to contract research. Accordingly, this program is underwritten with the expectation of profits over an extended period of years, rather than a restricted profit in any one year. To carry out this product development program Arapahoe Chemicals has a staff of five organic chemists engaged in process development work. These chemists are backed up by an analytical staff of four chemists who also provide production quality control. The pilot plant is equipped with small-scale steel and glass-lined vessels that serve as models for plant equipment. Little or no flask operation is carried out in the pilot plant. I t is staffed by a chemical engineer and two operators. Each development chemist works for the most part by himself on his own project, without assistance from technicians or junior chemists. Experience shows that limited facilities can best be utilized by highly trained
people making their own observations and directing their own work. Many of the critical observations that are required for high-quality process development are of a subtle nature and require the accurate inference of the professional. Project Selection
Perhaps the most difficult problem that faces any director of research and development is the choice of projects to be studied. The small company, with its limited operating capital, is generally forced to select projects that lead to products for which an immediate demand exists. Long-term or fundamental research projects can seldom be justified. It is, therefore, most important that close liaison be maintained with the sales department so that accurate market information precedes the choice of projects. At Arapahoe Chemicals most suggestions for products are generated by the sales department, based on customer requests for development of a particular product for their use either on a custom basis or on open sale. Because Arapahoe’s manufacturing operation is limited to small-scale batch processing, it must avoid taking on the development of very large volume products. Large volume, low-priced products are made, as a rule by continuous processes that require large amounts of capital to set up and hence are the proper province of the larger chemical companies. On the other hand, we have found it impractical to attempt to develop processes for very. small-scale products, even though their prices may be quite high. Experience has shown that in this context economic production of quantities smaller than a few hundred pounds is not possible. Thus, our search for new products is limited to those compounds which have markets in the range of several hundred pounds to several hundred thousand pounds. Arapahoe directs its development effects toward new compounds or compounds with new uses. Here is where imaginative process development can pay off best. Established products for established uses usually have all the profit margin squeezed out of them; a new use may, however, expand the market sufficiently to justify the exploration of new routes. Many new products are generated by the fund of technology which is built up over the years. For example, Arapahoe’s long experience with Grignard reagents and more recently with organosodium compounds has brought in most of our requests for custom VOL. 5 7
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Many new products are generated through tapping the inventory manufacture. This technology, with its associated equipment, has naturally led to other organometallic fields such as the metallocenes. This latter group of compounds required a cyclopentadiene cracker which naturally led to other projects that utilized cyclopentadiene as the raw material. Thus Arapahoe’s choice of projects is based on demand, scale of operation, novelty, and utilization of captive technology. Reseorch Phosm
Once a project has been selected, it is assigned to a research chemist, usually on the basis of his particular background. The man who has already developed three Friedel-Crafts processes is likely to turn out a fourth in record time. Each chemist reports directly to the research director and thus has complete responsibility for each of his own projects. He not only develops the process in the laboratory, but carries it through to the pilot plant, and ultimately to production where he acts as pmess consultant and troubleshooter as long as production continues. Basic to the attitudes applied in research is the premise that all chemical processes are temporary expedients. The best way to make any product depends on the scale of operation. Furthermore, the development program is limited by the expected level of sales. If the product volume grows to another level of production, further development is undertaken to reduce unit production costs and, therefore, to maintain a competitive price. Experience shows that it occasionally pays to take on a project for the sole p u r p e of expanding captive technology or to look for new and unusual approaches to basic problems. A distrust of projects that are too simple is important; if anybody can do the job in an old tub in his garage, hewill have a lot of competition, and the profit margin will be thin. Work on more complicated projects for which the technical contribution can be greater is therefore more rewarding. These basic attitudes suggest, as an initial research approach, a study of the literature relating to the particular project. After a thorough study of the pertinent literature, the project is presented to a weekly seminar for criticism, ideas, and new approaches from the rest of the staff. Before actual laboratory work is started, the alternative paper processes are subjected to cost comparison to avoid spending laboratory time on an intrinsically uneconomical process. This general ap-
AUTHOR
Thomas D . Waugh is Vice R e d d for Research
of Arapahoe Chemicals, Division of Syntex Corporation. He is apimem in the application of advanced technology to deuelop mmt and production of& chemicals. He presmted this paper at the September ACS National Meeting in Atlantic City. 64
proach narrows the field to two or three possible processes to be studied in the laboratory. In the usual case, none will be taken directly from the literature, but more often each will involve combinations of steps from a variety of sources. One step may have been applied to the target compound, another may have been arrived at by analogy, a third may be entirely new. The laboratory job then is to piece these steps together to make a finished, workable plant process. F i t laboratory experiments are generally carried out in test tube scale, not to determine accurate yields, times, temperatures, or the l i e , but to learn whether the various steps of a process actually proceed in the direction that we had hoped they would. A great deal of laboratory time can be saved by making this superficial test tube check. Alternative steps can be eliminated and completely new ideas tried until the process emerges as a whole, in blurred, outliie form. The task is then to bring this blurred outline into clear focus. To accomplish this, the chemist must first visualize the operation of the process in the plant and strive to utilize in the laboratory only those procedures that can be duplicated in the plant. Therefore, Arapahoe provides steam-heated drying ovens in each of its laboratories, thus avoiding the drying of solids in vacuum desiccators or in electrically heated ovens. Laboratory hydrogenation equipment is also internally agitated to approximate plant conditions rather than being shaken, as many laboratory hydrcgenators are. Also avoided are operations such as evaporation to dryness under vacuum, vacuum distillations at pressures below 5 mm., and, in general, all reactions that cannot be run in standard steel or glasslined vessels at pressures between 5 mm. and about 50
INDUSTRIAL AND ENGINEERING C U E M I S T R Y
Pilot NN of the laboratory procedure promde the data for scale-up and for anticipation of theproblenu that are likcry to dewlop whm a plocess reochcr production rcale. The pilot plant ir also utiliud for small-scale production of chemical products that are only in small demad or thnl require special pwi~?cotion
of technology which is developed over a long period o f years p.8.i. Of course, if a very profitable looking project comes along that requires conditions outside those presently available in our plant, the capability of the plant will be extended. Process ScalcUp
Four major factors are pertinent to process design for the plant. They are raw materials, plant tie-up, quality, and safety. Once a process has been decided upon in principle, the primary raw material cost will be proportional to yield; therefore, yield is of utmost importance and a great deal of effort goes into increasing and stabilizing the yield. Nonetheless, major economies can often be made by minimizing solvent cost. With careful choice of solvents, it is often possible to convert a doubtful process into a real winner. In many complex processes involving several steps, the dominant factor is often plant tie-up. To exceed our break-even point, plant capacity must be fully utilized. F’rcduction in each kettle must reach as much dollar value of product as possible in as short a time as possible. Batch size must be held at the maximum and time of occupancy at the minimum. Letting reactions go overnight is a fallacy because on three-shift operation, there is no “night” for plant equipment. Batch sizes are brought to maximum by several techniques in the laboratory. Slow filtrations are avoided by growing better crystals through the use of appropriate wetting agents, tailored solvent mixtures, or differential precipitations. Removal of solvents by distillation, particularly by vacuum distillation, is avoided where possible. Long reaction times can frequently be shortened by the simple expedient of raising the temperature. It is surprising how many literature processes are written up to be run at very’ low temperature when elevated temperatw is no real problem. The problem that causes the most difficulty in process development is that of phase heterogeneity. Even when it might be possible to run a reaction in a homogeneous system by proper choice of solvent and concentration, the economics of fine chemicals operation forces us into a heterogeneous system to reach an economical batch size and to reduce solvent costs to a minimum. The problem with heterogeneous reactions is that they do not scale up readily. In a homogeneous system, if it takes 1 hour to run a reaction in the laboratory, it will take about 1 hour to run it in the plant. Much longer times are usually required in the plant with heterogeneous reaction. Consequently, reaction time in the laboratory is generally extended when dealing with heterogeneous reactions to be sure that adverse side reactions are not promoted by the long time to be expected in the plant. In many c a m thii requires reversal of the order of addition, 80 that sensitive, unreacted products are not subjected to strenuous conditions for long periods. Dis-
tillation, removal of solvents, drying of final products must all be checked out for the long times involved in plant operation of these heterogeneous processes. A few grams of solid product can generally be dried in about an hour in the laboratory. Several tons of the same product may require a day or more in the tray dryers in the plant. Therefore, every effort is made to produce the final product in form that is easily dried. High boiling solvents may be washed off with lower boiling solvents, or the bulk of the water wetting a final cake may be substantially removed by washing the cake with an immiscible organic solvent before drying. Most of the problems of heterogeneity can theoretically be anticipated and solved in the laboratory before the process ever gets to the plant. This however is not always achieved in practice and much of the troubleshooting we do for the plant stems from heterogeneity. The purification of final plant products is an art all in itself. Each plant has its own special techniques. At Arapahoe great use has been made of the saltingout technique-that is, an organic acid or base is converted to a convenient and not very soluble salt which can then be salted out of solution by the addition of an appropriate inorganic salt, such as sodium chloride or ammonium sulfate. This is often more convenient and effectivefor removing colors than decolorization or precipitation by neutralization. Avoidance of or removal of iron contamination is another prevalent problem, routinely solved through use of Vexsene or some other chelating agent in the final purifications. Thii program of studying and restudying a process to improve its efficiency demands a very high order of analytical backup. It starts in the very first test tube experiments where identication of the desired intermediates in the process is required and continues through the entire process development program. Byproducts must also be identified and methods for their estimation must be developed. As much information can often be obtained from one laboratory preparation by suitable sampling and analysis as can be obtained from half a dozen experiments run through to the end and judged only on the basis of final yield. Constant use of vapor phase chromatography and infrared spectrw copy to follow the c o m e of reactions has proved invaluable as have thin-layer and paper chromatography. Not infrequently, analytical support is the most hportant factor in the development of a process. Therefore, a great deal of time is spent on the development of analytical methods to monitor processes and to judge final products. Plant troubleshooting, of course, is primarily a matter of analytical work. Ultimately, the reputation of our whole product line rests on careful and critical analytical control. A strong analytical department is a major asset to any small chemical company. Considerations of safety must always be foremost in the V O L 5 7 NO. 1 1
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minds of development chemists. Laboratory work should be conducted with special attention to the safety of the processes we send to the plant. We avoid separation of solids from toxic solvents, such as benzene or methanol, unless there is no satisfactory alternative. I n those cases, it is best to provide in the process a final wash of the cake with some less noxious solvent; water, toluene, or paraffin hydrocarbon is preferred. Carbon tetrachloride and carbon bisulfide are also avoided for safety reasons. Ethyl ether is not used except in closed systems. The research and development department is ultimately responsible for the safety of its processes.
INDUSTRIAL A N D ENGINEERING CHEMISTRY
Pilot Plant Test
The final step in laboratory development of a process is the preparation of the laboratory procedure. This is written up in precisely the same form we use for the finished plant process. As a result, the pilot plant is able to make rapid transition from the laboratory procedure by simply multiplying weights and volumes to scale up to larger equipment. Similarly, the cost group can easily estimate the cost of the process from the same procedure, although it is not good policy to make bids on the basis of laboratory work alone. Before a bid is made, it is best to subject processes to pilot plant study to assure that the product can be made to specification and to provide a sound basis for calculating costs. During several runs in the pilot plant, scale-up problems are uncovered, recovery of solvents is studied, and sample materials are produced. Exceptional care is taken to record volumes at each step, to estimate heating and cooling requirements, to determine the time required for each step, and to make material balances. A pilot plant procedure is finally prepared for submission to the plant. A minor use of the pilot plant is made for production of small amounts of either old or new products that have not grown to economic plant scale. Development does not stop at the end of pilot plant work, however. Early plant runs are followed with great care by our plant superintendent, a Ph.D. chemical engineer. Voluminous records are kept of these early runs, and a great deal of feedback of information to the laboratory takes place. Generally, a number of laboratory check runs are made at this stage and much analytical work is done to iron out minor difficulties that show u p in plant operation. Ultimately a revised plant process is prepared and used, sometimes for years, with only minor variations. A certain number of products, however, continue to develop larger and larger markets until pressure begins to be exerted for lower prices. This generally requires a restudy of the whole process in the laboratory. On a number of occasions this has led to the development of entirely new processes, because the scale of operations now makes it economical to install new equipment, because new technology has come along, or simply because the scale of operations now justifies the additional development work necessary to try out a new process.
