FINE CHEMICALS
Pilot Plant Studies C. R. BARTELS, G. KLEIMAN,
D. B. IRISH,
AND
T. M. ROSENBLATT
Chemicol Development Division, The Squibb lnsfifufe for Medico1 Research, N e w Brunswick, N . 1.
Since the fine %chemicalindustry is characterized by rapidly changing market conditions, it is imperative that new products and process improvements get into production as rapidly as possible. As a result, pilot plant studies generally must be carried out in a limited time and often with bench scale equipment that will duplicate the operation of equipment available in the plant or that can be readily obtained from the vendor. Whenever possible, simple, small scale tests are performed to determine the applicability of various types of equipment for the particular processing problem under study. A number of tests, experimental techniques, and types of small scale equipment are described in this paper which have proved of great value in obtaining process data rapidly and accurately in solvent extraction, filtration, centrifugation, and ion exchange. Successful pilot plant engineering in the final chemical industry depends more on careful planning, close observation, and decisive action than on the precise determination of all the details in a process study.
HE fine chemical field includes the manufacture of chemicals, organic or inorganic, that require appreciable processing and that are made in amounts of less than a ton a day-such as most pharmaceuticals, intermediates, perfumes and flavors, photographic chemicals, some surface active agents, and chemical specialties. The industry is characterized by rapid changes in market conditions. The initial demand is often so high that no workable process step for producing a high priced material is precluded. Then, a~ competition becomes intense, the market price drops rapidly, making a low cost process a necessity. As an example of this price fluctuation, the present market prices for penicillin and streptomycin are less than 1% of the initial market price. Large numbers of products are studied compared with the few that reach commercial production. I n finding new antibiotics, it has been necessary to investigate tens of thousands of soil samples from which the antibiotics have to be isolated, purified, and tested. Products of the fine chemical industry must often meet extreme requirements in regard to purity, appearance, or physical form. One dye lot may be chemically indistinguishable from another, but if the shade does not meet control standards, it must be rejected or reworked. A pharmaceutical that is to be administered by injection may be rejected if it contains minute quantities of pyrogenes-substances that cause a temperature rise on injection. The production rate on individual products is low and often subject to wide fluctuations. I n these cases production must be fitted into multipurpose plants. An important characteristic of this industry is that management must rely heavily on pilot plant data, since there are often no competitors against whom process economics ran be judged. If competition does exist, comparisons may be rendered worthless by the existence of special economic circumstances. Therefore, in many cases, limited pilot plant data must provide the sole basis for management decisions. The primary objective of pilot plant engineering must be to get into production as soon as possible. Pilot plant work begins as soon as an identifiable product has been synthesized or isolated in the laboratory and sometimes even before that. Basic data are usually incomplete. Analytical and assay methods are sometimes so inexact that the chemical engineer must forego the use of such important working data as the material balance.
August 1954
The tentative process must be selected with care in order to avoid any limitations to ultimate cost; reduction. For example, in the isolation of a natural product there may be a choice between the use of solvent extraction and ion exchange. The cost of a liquid-liquid solvent extraction process is proportional to the volume processed, while the cost of an ion exchange process is proportional to the amount of material absorbed and elutcd because of the stoichiometric characteristic of the operation. There is a greater possibility of cost reduction by increasing the input concentration in the solvent extraction process than in the ion exchange process. Preproduction pilot plant operation is held t o a bare minimum in order that the process may be put into production as soon as possible. Very often the ability to market a product rveeks before a competitor, establishes a reputation that is a great boon to future sales. Therefore, in contrast to the detailed pilot plant studies carried out in the heavy chemical industry, pilot plant studies in the fine chemical industry may be allotted days or weeks rather than months or years. Three or four runs that produce a satisfactory product may serve as the basis for starting production. These runs are carried out in any standard pilot plant equipment that approximates the same physical and chemical environment as the production equipment that probably will be used. Design factors are then estimated or determined by separate experiments on an appropriate scale. This limited experimental work cannot include detailed studies on a factor such as recycle of side fractions. The decision t o start production, therefore may be made on the basis of discarding side fractions with the thought that their recovery in the process at a later date will serve as a final step in cost reduction. Tribute must be paid to the long-suffering design engineer, who must plan, purchase, and install equipment on the basis of minimal information, knowing full well that the equipment, when it is ready, may be used on a process two or three times removed from that for which it was planned. This emphasizes the need for the utmost cooperation between the pilot plant and design groups. To avoid delay caused by special orders, the designer uses standard equipment as much as possible. The pilot plant engineer must be fully aware of the various types of equipment, their advantages, and limitations. The testing of a new type of equipment should be done preferably before the need for it
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ENGINEERING, DESIGN, AND PROCESS DEVELOPMENT arises. If production must start in a month, there is little use in considering a new type of drier or centrifuge unless none of the familiar types can possibly do the job.
Small Scale Tests The equipment vendor who has readily available test units can expect favored treatment from both the pilot plant and design engineer. Use of suitable, vendor-supplied pilot plant units makes possible the consideration of equipment that might otherwise be eliminated because of suspected but unproved operational problems. Equally welcome is the equipment vendor who can tell by simple laboratory or bench scale tests whether further consideration of his equipment is warranted.
Figure 2. coat Filter
Figure 1 .
PreLeaf
Simple Filter Leaf
For example, a vendor’s t8est ( 1 ) of liquid-solid centrifuges determines whether a slurry can be handled in a liquid-solid, scroll discharge centrifuge. A sample is spun in a 15-cc. laboratory test tube centrifuge for about I minute a t the centrifugal force equivalent to that in the machine being considered. If the solids in the bottom of the tube will support. the weight of a 6-inch length of 6- or 8-mm. glass rod, they probably will be moved satisfactorily by the scroll conveyor. I n the field of liquid-liquid solvent extraction the development of compact and efficient units such as the Podbielniak extractor and the Scheibel column (4)has led to t,he use of this technique on a scale hitherto thought impracticable. Fortunately, the development of experimental techniques has kept pace with the development of this new equipment.. While working on the fractionation of biologically active materials, Craig and his associates developed a number of devices for t,he study of solvent fractionation processes ( 8 ) . The Craig apparatus is a compact laboratory apparatus in xhich more than 100 simultanous equilibrations of two liquid phases may be conducted. Each ptage consists of a tube in which the phases are mixed and provisions are made for separating and transferring the phases in opposite directions. 4 pure substance is distributed in a pattern that can be calculated from its distribution coefficient and a binominal expansion; alternatively, the distribution coefficient can be calculated from the pattern. If a mixed solute is fed to the system in one of the phases, its separation will depend on the relative distribution coefficients of the components. These data indicate the feasibility of the solvent extraction process. A test is then made to determine the applicability of specific equipment. Podbielniak’s test is relied on when the use of a centrifugal countercurrent extractor for liquid-liquid extraction is considered. Solvent and aqueous phases are mixed in the desired proportions by shaking in a laboratory centrifuge tube. The tube is centrifuged for a short period and the interference is examined. A clean interface indicates the probability of successful handling in a centrifugal countercurrent extractor, while emulsions or solids a t the interface indicate possible difficulty. This simple test permits the study of demulsifying agents, residence time, and centrifugal force with a minimum of test solution.
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9 similar test probably could be devised to determine t,he applicability of the liquid-liquid extraction column developed by Scheibel, although in t8hiscase it would be preferablc to use the laboratory unit that has been described in the lit’erature ( 4 ) . Filtration. Filtration is another field in which the experimental approach has been greatly simplified. Porcelain or stone\+-are vacuum filt’ers, filter presses, and small tank filters arc typical pilot plant equipment, and they are used for pilot operation. On a production scale, more specialized equipment is sometimes justified. Almost all vendors of filtration equipment have available for test’ purposes pilot models of their full scale units, but, when time and material are a t a premium, it is often better to use leaf tests t’o obtain design data. In fact, in the case of rotary filters such tests mag be perferred, since in different sizes equal filtration cyclcs result in different peripheral speeds. Filter test, leaves are readily available commercially or they can be fabricated by the average shop with little difficulty. The simple filter leaf coiisists of a metal or plastic frame over which the filtering medium is stretched, and an internal drainage chamber through which filtrate is removed by vacuum. The general technique for using these units is described in the “Chemical Engineers’ Handbook.,’ These tests are versatile, adaptable to special circumstances, and they afford the careful M orlrer the opportunity for obt,aiiiing more iriformat,ion on this scale of operation than on a larger scale. I n simulating a continuous filt,er, the same cycle of immersion, drying, washing, and discharge is used on the leaf that is to be used on the production unit. By averaging the results of from 5 to 10 operational cycles, fairly consistent rates are obtained. Differences between the individual cycles are real and oft’en give the careful observer clues to operational problems that are lost in studies on model equipment. Another advantage of leaf tests is that since they require only a few gallons of slurry they can be run a t a very early stage in process development.
Figure 3.
Filter Leaf Setup
On the simple filter leaf a precoat,, particularly if it is applied in the same thickness as in plant operation and peeled with a hand-held knife, does not give reproducible results. To overcome this difficulty, a unit which fits like a piston within a cylinder has been built. The filtration collection tube is threaded through a bushing a t the bottom of the cylinder. I n use, the leaf is withdrawn from 1 to 3 inches into the cylinder and precoated by immersion in a thin slurry of filter aid. When a sufficient cake is built up, it is pulled dry and then advanced above the edge of the cylicder by rotating the leaf stem in the bushing. 4 scale calibrated in terms of precoat advance, a8 determined by the pitch of the thread, is provided to obtain a cut of any desired thickness. The lop edge of the cylinder acts as a guide for the knife blade which, though hand held, can remove cleanly a few thousandths of an inch of precoat, on each cycle. This unit has been very valuable in comparing filtcr aids
I N D U S T R I A L A N D E N G I N E E R I N G CHEMISTRY
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FINE CHEMICALS for use as precoats and admix. The same type of unit installed within a body made of glasg fittings can be used to simulate operation of a pressure precoat filter. A simple filter leaf is shown in Figure 1. Figure 2 shows the precoat filter leaf. The setup is shown in Figure 3. Data obtained on such a leaf, as compared with data on the same slurry on a plant filter with 1300 times the area, are shown in Table I. The pressure precoat leaf is shown in Figure 4. The filter contains the following primary elements:
thicknesses by recycling mother liquor a t a rate sufficient to keep the interior surface of the cake wet but without an appreciable liquid layer. When the data are plotted on log-log graph paper as rate versus cake thickness, a straight line is obtained. The average centrifugation rate for the entire cake is equal t o the instantaneous rate for one third of the final cake thickness.
1. U-shaped agitator is operated by hand crank on top of unit
to keep the precoat and test slurries in suspension.
2. Adjustable piston-type filter element with screw-type adjustment is operated by knob a t bottom of unit. 3. Knife blade is operated by handle a t right to cut off cake built up during the test.
Table I. Prediction of Plant Production Continuous Filter Performance by Filter Leaf AV.
Filtrate brea, S q . Ft.
(Fermentation broth; 0.1-sq. ft. filter leaf) Production Filtrate Filtration Filter Leaf Filtration Rate, Gal./ Rate, Gal./ Time, Volume, (Sq. Ft.)(Hr.) ( S q . Ft.)(Hr.) Hr. Gal.
hfanufacturers of string discharge filters have recognized the utility of the filter leaf. A commercially available, rectangular leaf with a string holder is used in this laboratory to study the operation of such filters and the discharging characteristics of various filter cakes.
Purification of Product In many cases, extreme requirements in regard to purity, form, and color of the product lead to multiple purification steps. Since each of these raises cost and lowers yield, the number of steps is held to a minimum by getting the utmost purification from each step. Centrifugation. The use of a perforate basket centrifuge in place of a filter press to separate a granular product from its mother liquor is a good example of a way t o reduce materials handling problems. Although any material processed in such a unit could probably be recovered by filtration, there are a number of advantages which often make this more expensive equipment worth while: 1. The liquid holdup in the cake is considerably reduced with a corresponding reduction of the dryer capacity required. 2. With standard mechanical unloading equipment, the time required to unload the cake is shortened to a few minutes and the actual physical handling of the product is eliminated. Careful pilot plant studies are necessary to ensure proper scaleup data and a good full scale operation. Publications comparing filtration data with perforate basket centrifugation data ( 3 ) are of interest. While it would be very helpful to scale up one from the other, all the factors involved are not well enough understood. Laboratory units with baskets about 5 inches in diameter are availabIe and are helpful if only very small quantities of slurry are available. However, the effective diameter of these small baskets changes rapidly as the cake builds up. Therefore, it is better, if possible, to run tests on a 12-inch basket. A full scale unit is selected tentatively, and tests on the pilot unit are carried out a t equivalent centrifugal force. The procedure described by Smith (6) is reliable. It requires that in each run the filtration rate be determined a t three different cake
August 1954
Figure 4.
Pressure Precoat Leaf
If the wash liquid is the same as the mother liquor, the wash rate is equal to the instantaneous rate for the final cake thickness, If it is substantially different, direct determinations of wash rate should be made a t several cake thicknesses. The time for “wringing out” the cake can be assumed to be proportional to the cake thickness. The unloading time varies with equipment and location and must be estimated on the basis of experience. In the case of compressible cakes, considerable work is required to determine optimum conditions for feeding and washing, since basket speed and operating cycle are important variables. The aim is to find the highest speed that will not squeeze down the cake and thereby interfere with the washing procedure. Ion Exchange. The demand for high purity materials that are comparatively unstable water-soluble compounds has led to the rapid rise in recent years of ion exchange as a process tool. In the pilot plant, ion exchange studies are carried out readily in equipment assembled from standard glass pipe in sizes from 2 to 6 inches in diameter. Optimum operation is usually achieved in pilot plant rather than laboratory or plant equipment. Scaling up is done on the basis of equivalent hydraulic rates that are usually well within the allow-able chemical rates. In process work, the recovery of product from the interstices of the bed a t maximum concentration would require lengthy studies were it not that a plot on log-log paper of concentration versus displacement volumes of washout liquid is a straight or nearly straight line. Only one or two points are needed for a washout curve.
Conclusions These techniques give a general picture of pilot plant operation in the fine chemical industry. Once a process is in production, both large and small scale pilot operations are continued to achieve the necessary cost reduction. Statistical analysis of production data is particularly helpful.
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ENGINEERING, DESIGN, AND PROCESS DEVELOPMENT The unduly rash pilot plant engineer may overlook factors that preclude ultimate commercial success in his eagerness to start production. ~i~ shortcomings are apparent. The Overly engineer is less Often uncovered' He may turn down one process after another or spend so much time in development that competitive advantage is lost. Successful pilot plant engineering in the fine chemical industry depends more on careful planning, close observation, and decisive action than on the precise determinat,ion of all the details of a process study.
ERIC R. BLEU
AND
Literatwre Cited (1)
Bird Centrifuge Co., private comrllunication.
( 2 ) Craig, L. C., J . B i d . Chem.. 155, 519 (1944). (3) Haruni, M. &I,, and Storrow, J, -i,, IxD,ENC,CHEM,,44, 2751 (1952). (4) Scheibel, E. G., them. piogr,,44, 681 (1948). (5) Smith, J , c., IND.ESG. CHEY.,39, 474 (1947). RECEIVED for review November 12. i 3 5 3 .
ACCEPTEDMay 19,1954.
WILBERT L. KLEIBER
Genesee Research Corp., 967 lye11 Ave., Rochester 6, N. Y.
The process engineer in a small plant i s limited to designs that balance end result, time, available capital, and manpower. Equipment must b e chosen not only for maximum efficiency for the individual process but also for maximum flexibility and versatility. Materials of construction for handling noxious organics are selected from the available standard materials that are adaptable to the process. Materials of unproved acceptability but easy adaptability for process requirements may be tested readily for corrosion resistance and physical properties to determine their possible use in the process. A design of vacuum trains for small plant distillations of halogen acid-forming organics, as well as the design and operation modifications of forepumps, cold traps, diffusion pumps, leak detection, and vacuwm measurement are discussed.
T
HE process development engineer in the small fine chemicals plant is faced with problems that are unique. His
function is in contrast to process development in the petroleum and heavv chemical industries where the Fise of processing operations warrants the use of teams of technical personnel to do costing of products and processing, pilot planting, projecting pilot plants, and making initial plant trial runs. The small plant engineer must perform all of these functions. .4n analogy could undoubtedly be drawn between the country doctor and the small plant process development engineer. This paper deals with three aspects of fine chemical processing in the small plant. First there will be a general approach t o process design. Second, materials of construction for corrosion resistant processing equipment will be discussed. Finally, some aspects of a dependable vacuum soul ce for the distillation of fatty acid chlorides will be presented. Approach to Processing Problems
The small fine organic chemicals plant is a multiple usc plant. At the Symposium on Multiple Use Plants presented a t the 121st ACS Meeting in Milwaukee, Cooper and RIcIntire ( 1 ) stated: In general it has been found that there is no universal continuous reactor and that it is not possible to obtain the same degree of flexibility with continuous operation as with batch operation Economics as vi-ell as flexibility ordinarily dictate batch operation. Therc is not much question in rhoice between continuous opcration and batch operation for a specific process in thc small plant. Completely automatic versus manual control also falls in the same category. The small plant usually favors manual control. The total production cycle of a specific fine organic chemical is often a matter of weeks or months. Deliveries are made in
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small lots. Small quantities of high cost products are kept under close laboratory inspect'ion in all manufacturing steps. This t'ype of processing operation is contrasted with relat'ively low cost, large volume items n-here changes in basic processing rcquirements are sinall. Figure 1 shows a continuous flow sheet of the multiple reactor type. Process B is a three-step synthesis, involving saponification, filtration, acidification, condensation wit'h a second raw material, recovery, and drying of a precipitate. There are actually six parts in this process representing four separate unit operations-mixing, filtration, centrifugation, and drying. Saponification is carried out alternately in reactors 1 and 2. The saponified material is clarified in plate and frame presses 1 and 2. Two presses would be necessary to keep t'he flow truly continuous. The clarified material is transferred alternately to reactors 3 and 4. Two reactors are necessary for performing the acidification and condensation steps resulting in a precipitate. The slurry formed in reactors 3 and 4 passes to a continuous-type centrifuge, the product being a crystalline solid. This solid is conveyed to the continuous dryer-the final processing step. The completely continuous process operated from a master control panel would involve automatic cycling and automatic sequence valving. This is an example of attempting t'o make a continuous process out of one involving batch unit operations. Major equipment items are four batch-type reactors, two filter presses, one cont,inuous autoniat'ic cycle centrifuge, and one continuous dryer-eight major units in all. Add to these eight itcme an automat,ic cycle master controller, motorized valves, and automatic material movement control, and a rough picture of capital expenditure for continuous Process A i j obtained. Figure 2 shows a flow sheet for performing Process A batchwise. The batch iiow sheet indicates the obvious difference
INDUSTRIAL A N D E N G I N E E R I N G CHEMISTRY
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