Feature Report

A Bit of Extra Lab Effort Can Prevent Grief During Scaleup

The key is persuading the chemist to undertake a little extra data collection
Francis X. McConville, Impact Technology Consultants
ts an old saw, but Ive long held that process development is very much a team effort. Developing safe, robust and scaleable chemical processes calls for close collaboration between synthesis chemists, process development engineers and pilot plant personnel. But experience shows that, particularly in many fine chemical and pharmaceutical organizations, researchers fail to put this principle into practice until its too late. Finding out in the process Hazop that the environmental permits prohibit the use of your chosen extraction solvent in your companys pilot plant is no laughing matter. Nor is arriving at the contract manufacturers site for the project only to learn that the designated equipment is not set up for vacuum distillation (it happened to me!). Attention to just such mundane details is, unfortunately, still an important part of process technology transfer and scaleup. Clearly, good communication is the key ingredient to minimizing such painful experiences. However, the more glamorous role of process development, at least on paper, is the collection of quantitative data on process performance to help streamline the scaleup effort. This is where experienced engineers and their colleagues can really shine. Its unfortunate that some synthesis chemists, their minds focused on the latest asymmetric catalysis breakthrough or planning their next ligand screening study, show little interest in thinking about collecting scaleup data.
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Francis X. McConville

FIGURE 1. Filtration time typically behaves quadratically (left). Such plots can be linearized by factoring out the filtrate volume, V. The slope and intercept are related to the cake resistance and the intrinsic filter cloth resistance (see text)

Admittedly, so many projects die in the early stages that chemists can ill afford to conduct detailed engineering studies, nor do they get paid to do so. But most do not realize how little effort they would have to expend to collect a few valuable data points along the way while they work. A little data, correctly interpreted, can stave off scaleup disasters down the road. Might I suggest that such individuals only need a good engineering mentor to help them see the light? Many examples come to mind. Even things as simple as recording densities of the various process streams, or partition coefficients of key compounds, can prove invaluable in closing mass balances, calculating volumetric productivity and developing a cost model. Recording pot temperature and operating pressure during batch distillations can help establish important operating parameters for scaleup, rather than just leaving them to chance. In this article, I consider two examples of simple laboratory-scale studies that can help head off potential problems in that first pilot run. Both involve solid-liquid separation processes

isolation of a crystalline solid from a slurry by batch filtration or centrifugation, and the drying of said solid in a batch contact dryer. Both examples also illustrate that in this age of advanced instrumentation and online analysis, simple low-cost test methods still have great value. It certainly is true that many serious problems are encountered for the first time only in the pilot plant, but there are usually quantifiable physical reasons for this. Sometimes, the reasons involve poor reaction selectivity due to the very different mixing environment found in large processing vessels, or extended processing times at large scale. But often, problems arise simply due to inexperience or the failure to quantify some basic physical properties of the process streams involved. Such problems can create significant delays in the program, and can even kill an otherwise promising project with a tight timeline. Anyone who has ever transferred a process from the laboratory to the pilot plant can vouch for the fact that

Solids isolation

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TABLE 1. RESULTS OF A FILTRATION EXPERIMENT

AND ASSOCIATED CALCULATIONS

Total volume, m3 0 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 Average volume, m3 0.00005 0.00015 0.00025 0.00035 0.00045 0.00055 0.00065

Filtration data: Total vol- Time, s ume, mL 0 0 100 5 200 25 300 55 400 93 500 140 600 198 700 266

t/V, s/m3 50,000 200,000 300,000 380,000 470,000 580,000 680,000

Experimental Conditions: Filter diameter: 7.0 cm Filter area: 0.00385 m2 Slurry concentration: 12.0 g/L = 12.0 kg/m3 Filtrate viscosity (est.): 20 cP = 0.020 kg/(m)(s) Filtration pressure: -8.0 psivac = 551 mbar = 55,144 Pa = 55,144 kg/(m)(s)2

Calculation results: Slope, a = 9.51E+08 s/m6 Intercept, b = 5.44E+04 s/m3 Specific cake resistance, = 6.47E+09 m/kg Filter medium resistance, RM = 5.77E+08 m1

FIGURE 2. Shown here is a linearized plot of the filtration data from Table 1. It is often necessary to ignore the first data point in the calculation of slope and intercept

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everything in the plant takes longer often much, much longer. Product isolation is a perfect example. Many pharmaceutical and fine chemical intermediates and products are crystalline materials isolated by centrifugation or vacuum or pressure filtration. Equipment limitations being what they are, it is often necessary to isolate a crystallization batch in a centrifuge or filter in multiple loads. I have personally experienced what was a 5-minute filtration in the laboratory taking nearly 24 hours to complete at the 2,000-gallon scale. If ours had been a more poorly-filtering product, that time might have been 48 hours or longer. What might be happening to the slurry in the crystallizer during all that time? Without the proper studies, its anyones guess. Thats why it can be critical to quantify solids filterability, which is typically accomplished in a couple of different ways. The very first thing to do is a slurry settling test, which is just what it says turn off the mixing and allow a sample of the slurry to settle on the bottom of the vessel. If the solids settle readily leaving a clear supernatant phase, that is a good sign that the material may filter well. Another method is to conduct a simple cake-permeability test. Prepare a filter cake about 5 cm (2 in.) deep in a Bchner funnel using vacuum, collect the mother liquors, then pour those clear mother liquors back through the cake and measure their flowrate. A common rule of thumb states that a flowrate of at least 40 L/min/m2 under vacuum is desired. Anything slower

than that indicates a potentially problematic filtration on scaleup. A more formal approach is to determine the specific filter-cake resistance, usually designated by and expressed in units of kg/m. Filtration under constant driving force, such as vacuum filtration, generally fits a parabolic profile, which looks something like the first plot in Figure 1. The behavior is described by this relationship: t = aV2 + bV (1) where V is the filtrate volume (m3) and t is the time (s). This quadradic behavior reflects the fact that as the cake depth increases, the flowrate of mother liquors decreases. Equation (1) can be linearized by factoring out V: t/V = aV + b (2) which, when plotted, gives a straight line with slope a and y-intercept b as shown in the second plot of Figure 1. The slope and intercept, which are determined by linear regression, are related to the cake resistance, , and the intrinsic filter cloth resistance, RM, according to the following classical definitions of the constants: a = c/2A2P b = RM/AP (3) (4)

Here is the specific cake resistance (m/kg), is the mother liquor viscosity [kg/(m)(s)], c is the concentration of solids in the slurry (kg/m3), A is the filter area (m2), P is the pressure differential driving the filtration (Pa or N/m2), and finally RM is the specific filter cloth, or filter medium, resis-

tance (m1). It should be pointed out here that these relationships must be applied to the instantaneous volumetric flowrate t/V versus V, extrapolated from the raw data (see Table 1). Of course, it is critical that all quantities be expressed in the proper units. The data collection itself is fairly straightforward; all that is required is a stopwatch and a properly graduated filtrate receiver, or if using positive filtration pressure, a filtrate receiver on a balance. Good technique is required to obtain meaningful numbers, and it may be necessary to throw out the first data point if the system hasnt stabilized. If the filtration rate is too rapid, the pressure can be reduced using a vacuum controller or pressure regulator as necessary. Table 1 and Figure 2 show some typical data for a filtration using a controlled vacuum of 55,200 Pa (551 mbar, 414 mmHg vac), the derived instantaneous rate data, and the results of the regression to determine both and RM (busy chemists may wish to leave the data manipulation to their engineering colleagues, but the important point here is to collect the data). Typical ranges of are ~108 m/kg for fast filtering materials to ~1012 m/kg for more poorly behaved solids. Testing several filter media is also a worthwhile idea if it appears that the cloth is a rate limiting factor. A wide variety of woven and non-woven cloths in a variety of materials, pore sizes and structures are available, and some are more prone to blinding in some situations than others. We are now equipped to predict filtration performance at large scale,
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Feature Report
since specific cake resistance is an intensive property of the slurry and not scale-dependent, assuming of course that the large-scale crystallization has successfully generated the same particle size distribution (psd) and crystal habit as the laboratory operation (a topic beyond our scope here). At any rate, bench scale values in the range of 10111012 should be a cause for concern. The good news is that you now have an excellent yardstick by which to gauge the success of the crystallization studies that you may subsequently undertake to improve filtration performance. The goals of such work should be to narrow the particle-size distribution, reduce the number of fines and generate a larger mean particle size. Various techniques, such as cooling profile manipulation, temperature cycling and slurry aging, to name just a few, are at your disposal for achieving this goal. For further reading on crystallization process design see References [14]. Couple this with a photomicrographic record of the results of various crystallization experiments, perhaps throw in a bit of particle size analysis, and youve got yourself a nice little crystallization study. But more importantly, you have taken a major step toward preventing a painfully slow and troublesome filtration in the plant, and the many consequences thereof, such as particle attrition, product degradation and unwanted polymorph interconversion, among others. There are, of course, many more advanced techniques available for studying crystallizations, such as on-line particle size analysis via FBRM (laser diffraction), PVM (visual microscopy), and pressure filtration studies, which can be important for identifying filter cakes that are highly compressible, and therefore poor candidates for centrifugation, and for selecting the best filter media for the process. But I think weve demonstrated that one simple laboratory measurement can generate a lot of information. Further reading on these techniques can be found in References [511].

FIGURE 3. An example of a theoretical drying curve is shown on the left. The various stages of drying can be made much more evident by plotting the rate of drying versus time (right)

Product drying

Lets turn our attention to another type of laboratory study that requires
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little effort but can be invaluable in identifying potential scaleup issues in product drying. As weve said, everything takes longer in the plant, and drying is no exception, especially in the ubiquitous vacuumtray dryer. Deeper cakes, in contact with the heated surfaces of contact dryers for extended periods, and longer heat-up and cool down times, can spell trouble. Batches subjected to prolonged drying cycles at elevated temperatures are prone to all manner of undesired behavior from polymorph interconversion in the wet cake, agglomeration and product degradation to runaway exothermic decomposition. Solids drying is characterized by a series of internal and external resistances to solvent removal. By performing a simple drying study, we can identify which of these various resistances is the controlling factor in our particular product. This type of study fits our profile perfectly you were going to dry the material anyway; why not collect a few data points along the way? In a nutshell, we need to monitor the progress of the drying operation by collecting some data on the wet cake weight versus time. This can be accomplished in a variety of ways. Some have reported success conducting the drying study in a flask on a rotary evaporator (rotovap). Personally I think the ideal approach is to dry in a vacuum-tray dryer on a balance installed right in the oven, eliminating the need to break the vacuum to remove the cake and weigh it. However the data are collected, one should expect the cake to lose weight rapidly early on and more slowly toward the end of the drying cycle. By plotting the data, as discussed below, one can identify the various stages of drying and the resistances associated with each of those stages. Lets assume, by the way, that prior to this work weve already established a specification for our final moisture content. Do not assign this specification arbitrarily. Time is money, and drying can be a real process bottleneck.

Do not target extremely low moisture content when some higher value may be perfectly acceptable, particularly in the case of intermediates (do they need to be dried at all?). As in the above filtration case, it is the instantaneous drying rate data that will be of most use to us in identifying the drying stages. Therefore the wet cake weight versus time must be reduced to change in solvent content versus time. By plotting the instantaneous rate data, we can readily identify several key stages in the drying process. Initially, the moisture being removed from the cake is surface moisture residing on or between the crystal particles. This unbound moisture has essentially the same enthalpy of vaporization and boiling point as the free liquid would at the given operating pressure. Except for perhaps a brief warm-up period, the evaporation rate at this stage is essentially constant, limited by the rate of heat transfer to the wet cake. This constant rate period, not always apparent from the raw data, is evident in a plot of drying rate versus time, as shown in Figure 3. The drying rate during this period is not particularly product-dependent, especially for crystalline materials. The moisture content at the end of the constant rate period is called the critical moisture content, or sometimes the transition moisture content. This point in the drying curve represents a transition from surface solvent removal to a stage of drying that is very much dependent on the characteristics of the product itself. For instance, in a highly porous material, a significant amount of solvent can be trapped within the crystals. But this solvent has an effective boiling point much higher than the free liquid, due to attractive capillary forces and slowing rates of evaporation as the liquid in the pores changes from a continuous liquid phase filling the pores into non-contiguous droplets of liquid in the pores. This stage of drying is called, appropriately enough, the fall-

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TABLE 2. DATA SHOWING THE PROGRESS OF DRYING A WET-CAKE SOLID IN A VACUUM-TRAY DRYER
Time, min 0 60 120 151 240 360 480 1,020 1,260 1,360 1,462 1,656 Gross weight, kg 5.766 5.702 5.669 5.578 5.520 5.480 5.385 5.351 5.342 5.335 5.325 Net weight, kg* 5.830 2.716 2.652 2.619 2.528 2.470 2.430 2.335 2.301 2.292 2.285 2.275 Wt.% solvent** 27.80 20.2 17.3 15.9 11.8 9.3 7.5 3.3 1.8 1.4 1.1 0.6 Drying rate, g/min 23.0 1.07 1.08 1.05 1.03 0.48 0.33 0.18 0.14 0.09 0.06 0.05

*Tare weight of the tray = 3.050 kg **Calculated based on a final dry-cake weight of 2.260 kg

FIGURE 4. This plot of drying rate versus moisture content (data from Table 2) is particularly useful for identifying the various drying stages

ing rate period, reflecting the fact that the more and more tenacious solvent remains in the later stages. Moisture trapped in occlusions within the crystal body would be the next to evaporate. Removal of this solvent is likely to be diffusion limited, and one might detect this in a secondary critical moisture content in the drying curve and a transition to a second falling rate stage. The final stages of drying may include stripping solvent from a crystal solvate or hydrate sometimes not the desired result of drying, and so understanding where this stage occurs and the conditions that bring it about can be most important. Table 2 provides some typical data from a vacuum-tray-dryer experiment. The data are plotted in Figure 4, which illustrates that one can obtain greater differentiation between the drying stages by plotting drying rate versus solvent content, as shown. But, again, the take-home message is that we can learn a great deal about drying behavior by conducting a relatively simple drying study if the data are gathered and we do the study. Lets consider some possible scenarios. If the majority of the drying time occurs in the constant rate period, we may interpret this to mean that there is little

moisture within the crystals, and we are simply limited by evaporation of the free moisture. In such a case, we may be able to significantly speed drying if we can obtain a larger mean-particle size at the crystallization step, or perhaps attempt to reduce wet cake solvent content by using centrifugation with a long deliquoring spin cycle, instead of vacuum filtration. Other options might include conducting a final cake wash with a lower-boiling solvent or even a minimum-boiling azeotropic solvent mixture to speed solvent removal in the dryer. If, however, the constant rate period is relatively short, and the majority of the drying cycle is taken up removing solvent trapped within the crystals, then the above techniques would have little effect on the total drying time. Instead, you may need to do more work on the crystallization step to achieve purer crystals with less entrapped solvent. Maintaining better control over the nucleation and crystal growth steps using a well-designed seeding protocol and manipulating the cooling or antisolvent addition profile to maintain constant supersaturation throughout the crystallization are common ways of approaching this. For further reading on this topic, see References [5, 6, 12].
7. Wakeman, R.J., and Tarleton, S., Solid/Liquid Separation, 1st ed. Principles of Industrial Filtration, Elsevier, N.Y., 2005. 8. Purchas, D. Industrial Filtration of Liquids, 2nd ed., Leonard Hill Pub., London, 1967. 9. Svarovsky, L., Solid-Liquid Separation, 2nd ed., Butterworth, London, 1981. 10. Purchas, D. and Sutherland, K., Handbook of Filter Media, 2nd ed., Elsevier, N.Y., 2001. 11. Strauss, H. and Kaufman, M., Handbook for Chemical Technicians, McGraw-Hill, N.Y., 1976. 12. Perry, R.H. and Green, D.W., ed., Perrys Chemical Engineering Handbook, 7th ed., McGrawHill, N.Y., 1997.

I have tried to show in this article that quantitative information on the filtration and drying behavior of solid chemical products can be very helpful in predicting process performance at large scale. But more importantly, collecting such data at laboratory scale is often neither difficult nor particularly time consuming. Much has been written about controlling crystallizations and many advanced techniques exist for studying and characterizing the materials so produced. But utilizing these tools effectively means establishing a baseline for performance to help set the goals for further development. Naturally, the value of gathering lab data and establishing a baseline for performance can apply to other chemical process operations besides filtration, drying and crystallization. Very often, simple laboratory studies that require little time or effort can provide valuable insight into the physical and chemical mechanisms at work in your process. Edited by Gerald Ondrey

Final remarks

Author
Francis McConville is a senior consultant for Impact Technology Consultants (9 Tabor Hill Road, Lincoln Mass. Phone: (508) 951-2436; Fax: (718)-240-7688; Email: fran@fxmtech.com) and has a private consulting business, FXM Engineering & Design (Worcester, Mass.). He is the author of The Pilot Plant Real Book A Unique Handbook for the Chemical Process Industry, and is an instructor for the Scientific Update professional training course, Secrets of Batch Process Scale-Up. He has over 25 years experience in the process industries, including 14 years as a pharmaceutical processdevelopment engineer at Sepracor, Inc. (Marlborough, Mass.). McConville holds a B.S. degree in chemistry and M.S. degrees in biotechnology and chemical engineering from Worcester Polytechnic Institute. He is a member of the ACS, ISPE and a lifetime member of AIChE.

References
1. Botsaris, G. and Toyokura, K., Separation and Purification by Crystallization, ACS, N.Y., 1997. 2. Mullin, J. W., Crystallization, 4th ed., Butterworth-Heinemann, Oxford, 2001. 3. Mersmann, A., ed, Crystallization Technology Handbook, Marcel-Dekker, N.Y., 1995. 4. Davey, R.J. and Garside, J., From Molecules to Crystallizers, An Introduction to Crystallization, Oxford Science, N.Y., 2000. 5. Chopey, N. P., ed, Handbook of Chemical Engineering Calculations, 3rd ed., McGraw-Hill, N.Y., 2003. 6. McCabe, W., Smith, J. and Harriott, P., Unit Operations of Chemical Engineering, McGraw-Hill, N.Y., 2004.

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