Music is nature’s gift to humans. Irrespective of nationality, we all like to hum melodies, tap rhythms and sway to pleasing tunes. Even children just learning to stand enjoy wiggling to good music. In all cultures, the notes that comprise musical scales are used in varying sequences and different combinations to compose music. These notes can be thought of as the the physical properties of music. Just as composers use notes to create music, designers of chemical processes use scientific and engineering principles to assemble processes. And just as creating the most enjoyable music takes time, skill, hard work and imagination, creating elegant, cost-effective chemical processes requires exploiting the physical properties of chemicals (the musical “notes” of chemicals) in imaginative ways to craft excellent chemical manufacturing and formulation processes.
Whether an architect envisioning a building, an automotive engineer building cars or a metallurgist producing metal ingots, all use the principles of science and engineering, along with the physical characteristics of the materials and their own creativity and imagination to create a product via a process that is sustainable, cost-competitive and has the desired quality for the price. Similar factors are at play when simplifying and improving existing chemical processes.
Key Properties Review
The following list represents several of the critical physical properties that should be examined in process design and process optimization:
1. Physical state of a material at room temperature, along with its melting, boiling or freezing point
2. Solubility
3. Density
4. Viscosity
5. Specific heat
6. Heat of formation
7. Azeotropic behavior
In addition to those listed above, other physical properties may have to be considered for specific processes and applications, but those above are the most commonly used in process development, scaleup and process design. Molecular weight is also important, but is excluded from the list because every developer has to know the formula and molecular weight of every chemical they deal with.
Although chemists and chemical engineers are familiar with the properties mentioned in the list, it is worth discussing the value of each individually, as well as how each interacts with others and how they can be exploited in process development, scaleup and commercialization of products.
Physical state
A chemical’s physical state at room temperature, its melting, boiling or freezing point, along with solubility, tells process developers a great deal about how the product can be handled during process development and in a commercial operation. It is advisable to handle every chemical with respect, even if the product literature suggests low or no toxicity. Chemical quantities used in the laboratory are small, so handling them in a safe manner is generally easier. However, the quantities required for scale-up experiments and commercial-scale operations are higher and different methods are used to handle and feed materials. Care needs to be exercised for each chemical.
Solid chemicals, when used in a scale-up or commercial operation, will require proper equipment to feed at the desired rate while controlling dust emissions. Additional precautions might be necessary when handling toxic materials. Another way to handle solid materials can be by dissolving or slurrying them in appropriate solvent, preferably the one that is being used in the process. When slurries are used in a process, it is important that the slurry be uniform. If feed to the reactor or the formulation vessel is not uniform, the product quality would vary for a continuous process and could result in potential financial loss. Variable feed rate can influence batch-process product quality also. Each situation has to be considered on an individual basis.
Since we do not handle molten materials in the laboratory, we do not consider melt addition on a larger scale. This can be due to our lack of experience in handling molten materials or lack of availability of bulk molten material. Melt feed addition might be economical for high volume or selective products as molten liquid metering systems are commercially available. We should consider melt use as it can reduce solvent need, which in turn can improve process productivity and sustainability. Lower product cost and higher profits are additional incentives.
When a gas is needed for a reaction, we end up bubbling the gas using a weight-loss system or, in the case of ammonia, using its solution. This works well for the laboratory, but on a commercial scale, the large volume of water required to dissolve ammonia takes up reactor volume. This can lower productivity significantly. Weight-loss systems work well for batch operations, but are not very efficient for continuous processes. If the volume is justified, liquefied gas addition is safer because, in its liquid state, it can be metered more effectively. Gas would be evaporated and mixed in the reaction mass.
Solubility
Solubility is not an exotic property but is an important and valuable property. Mutual solubility or the lack thereof, can be very useful in reactive chemical processing and formulations. If the reactants and reaction product dissolve in the same solvent, the reaction rate can improve through improved mass transfer. Solubility of materials in the solvents used in the formulated products improves mixing and results in a uniform product. Solubility characteristics of chemicals are also critical for product crystallization, purification and separation of products.
Generally, higher solubility is considered to be more valuable, but low solubility can also be useful, especially for separating chemicals. In reactive processes, low solubility can be effectively used to separate phases and reaction products to improve process yield. Creative use of solubility in reaction systems to improve conversion will be discussed more later.
Density
Density is defined as mass per unit volume, and shows mass relative to other chemicals. In a thoroughly mixed system, density might not have value, but it is one of the unique properties that can be effectively used for separation of two immiscible liquids. I think of density as mother nature’s gift — imagine the challenge involved with separating petroleum and water if their densities were same. Density differences can be effectively used for product separation, and also for creating a mix that is beneficial in the reaction and formulation process.
Viscosity
The importance of viscosity is different in chemical reactions versus formulated products. By itself, viscosity may not be considered a very important property, but engineers must be aware of it, especially when the chemicals in the process mixtures are in liquid form. Viscosity is important while feeding, mixing and pumping liquids. It is best to reduce the viscosity to its lowest levels to facilitate addition, pumping and mixing. This can be accomplished either by dissolving in suitable solvents, or by heating the liquids, although the stability of the liquid has to be carefully considered. Preferred solvents should be the ones that are being used in the process. In certain formulated products, viscosity control is necessary for product performance and their applications.
Specific heat
Specific heat of a chemical is an important property and is of value in chemical reactions. For chemical reactions, it is important to control the heat of reaction, and specific heat determines how much heat needs to be removed. Specific heat values impact capital investment because it affects the size of the heat-transfer equipment required.
Heat of formation
Process reactions are either endothermic or exothermic. In general, most reactive processes are exothermic. How we control the heat of reaction can significantly impact the rate of reaction as well as the size of the equipment necessary. In addition, it is critical to control the heat of reaction, as a runaway reaction can rapidly raise the process temperature and result in explosions and other hazardous situations. Effective control of the heat of formation can reduce the reaction residence time, which in turn, reduces the size of the equipment (that is, investment). Heat of formation is also influenced and controlled by the method and sequence used for raw material addition.
Azeotropic behavior
To many chemists or chemical engineers, the azeotropic behavior of chemicals might appear to be of limited value — it does not have much value in formulations. However, the azeotropic behavior of chemicals can be used very creatively in manipulating reaction processes. Imagine a reaction process where the liquid mix has an azeotrope and the chemicals are immiscible. Combination of these two properties can be very effectively used not only to control a reaction exotherm but also used to improve yield.
Examples
Physical properties are valuable tools for the process creator and manipulator, and he or she can take advantage of them when creating and simplifying a process. Exploiting several different physical properties in a process is an exhilarating challenge with moments of success and failure. However, failures should be viewed as learning experiences that will help in future applications.
When developing processes, engineers should look to incorporate anything and everything they can imagine. Imagination and creativity can lead to unconventional ways of exploiting unique chemical properties and their interactions to arrive at excellent processes. In the end, how the simplified process is executed in a commercial scenario matters a great deal. This is very similar to creation of an excellent musical composition. Some of the examples of how physical properties can be manipulated for process simplification are included here:
Use of molten raw materials
Traditional approach: A primary raw material “A” is solid at room temperature. Its melting point is about 65oC. It reacts with chemical “B”, a liquid, in presence of a solid catalyst. The reaction is carried out at about 75oC. The resulting product “C” is a liquid at room temperature. The product-solvent mix is reacted further. Traditionally, “A” would be dissolved in a solvent and added to the reactor. Catalyst would be added using appropriate methods. Concentration of “A” in the solvent is about 25% to have a soluble solution.
Alternate approach: Since the melting point of the raw material “A” is low and to achieve a reasonable reaction rate requires the reaction mass to be heated to a temperature higher than the melting point of “A,” it may be efficient and productive to feed the raw material “A” as a melt. Melt addition raises the temperature of the reaction mass faster than heating the reaction mass from room temperature. This will reduce the cycle time of the batch process. Reaction temperature can be controlled using conventional process-control strategies.
If the process is continuous, maintaining the reaction temperature at the desired temperature can control the reaction rate. Because the solvent is replaced with a melt, the process productivity improves considerably. Since product “C” is a liquid at room temperature, using a melt also raises process productivity. Reduced solvent use also lowers the solvent recovery load and improves process sustainability.
To be viable, the alternate method has some built-in caveats, including that the raw material “A” has to be available in melt form, and the production volume has to be large enough to warrant the melt material handling investment.
There are numerous cases where molten raw materials can be used with very tight stoichiometric control. Each situation has to be evaluated. The resulting product can be purified using different unit operations and crystallized to produce products with the desired quality. Such processes are environmentally more sustainable, productive and highly profitable compared to solvent-based processes.
Use of phase separation
Case A: In some reactions, a byproduct, such as water, must be removed. If the solvent is insoluble in water, and if their densities are sufficiently different, then the solubility and density differences can be used to separate the two and the solvent can be recycled back to the process.
In processes where water forms an azeotrope with the solvent, water is evaporated out with the solvent and the mix is condensed. Use of chilled water in the overhead condenser can not only improve the condensation of the azeotropic mix, but since the solvent temperature will be lower compared to that of condensation using cooling-tower water, the reaction rate can be improved. This will lower the batch cycle time and improve profitability.
Case B: Phase separation can be effectively used to enhance process yield. In the following reaction, intermediates “C” and “D” are produced. Intermediate “C” is soluble in water and “D” is soluble in an organic solvent. In the subsequent reaction, these two intermediates are reacted to produce product “E.” However, intermediate “D” hydrolyzes to produce an unwanted product if left in contact with water, and process yield is significantly lowered.
A + B —> C + D > E
To preserve the yield, it is best to separate the two phases and mix them just before the production of “E” begins.
U.S. patent no. 7,078,524 discusses a chemical reaction where two isomers are produced. One is a desired pharmaceutical product and the other cannot be converted to a saleable product. However, the overall process yield is improved if the undesired isomer is isolated and recycled after separation. The process suggested in the patent can be significantly simplified through creative solvent selection. Were the described process to be commercialized as indicated in the patent, it would be cumbersome and would extend the batch cycle time significantly.
However, through proper solvent selection, the “undesired” isomer can be recycled in situ, the process could be not only simplified, but process yield would be improved. This is an example of how human creativity, along with the ability to finesse physical characteristics, could generate a better process — a possible “Eureka” moment.
For any reactive chemical process, solvent selection is extremely important, especially where phase separation is involved. Greater difference in densities facilitates and accelerates phase separation. Recognize that solution density increases as more solid is dissolved in a solvent. If the densities of the solutions to be separated approach each other, separation can become a challenge, and will take longer. Thus it is important to choose solvents such that there is a noticeable density difference under the process conditions. This difference can hasten the separation, lowering the processing time. From a manufacturing standpoint reduced process time through a faster separation is important.
Capitalizing on exotherm
Due to equipment capability limitations during process development in the laboratory, the exotherm is controlled either by lowering the reaction temperature with ice or chilled water, or by slowing the raw-material addition rate. When such processes are scaled-up, the same practice continues. These methods work, but they extend the reaction time and reduce the process productivity.
It is well known that raising the reaction temperature speeds the reaction rate and can improve yield. A reaction exotherm can be very effectively controlled by the efficient use of heat exchangers. Commercial technologies exist for doing this. What variables can be manipulated (such as, feed method, flow, flowrate, temperature control, and so on) and how they are controlled, will improve profits through the development of a simpler and more sustainable process.
Controlling exotherms effectively, and as soon as they happen, using heat exchangers can not only improve the process yield, but makes the process safer and prevents formation of color bodies that can occur due to localized heat generation. Inline heat exchangers in a pump-around system represent one of the methods. Other methods are situation dependent.
Creating excellent processes
Engineers are routinely educated about the physical and chemical properties of common reactants, solvents and products. However, they generally are not taught how to creatively exploit them to develop processes that are simple, sustainable and economical. Finding methodology to finesse these properties into simplified processes comes from a firm understanding of the properties, and from previous experience. Chemical properties must be integrated with the correct unit operations and proper stoichiometry control to produce a quality product. Such processes will be more robust, economical and will require minimal in-process testing of intermediates. Products will have consistent and repeatable quality, and therefore, lower cost. Incomplete understanding and poor manipulation of the physical properties of the chemicals in a process and their interactions can lead to quality issues. It would be like composing a musical piece where the notes are poorly placed and required fine tuning each time the composition is performed.
Working with creative people who are “masters in manipulation” of chemical properties helps a great deal. Additional examples and methods to those discussed in this article can be found in [1].
Establishing processes that yield the desired quality and that require minimal (or no) testing of process intermediates should be the goal of chemists and engineers involved with both chemicals and pharmaceuticals. Most existing chemical processes can be simplified and improved as part of a “continuous improvement” exercise by fine tuning, using design of experiments and other similar tools. However, changes to processes and products requiring regulatory approval (such as pharmaceuticals) pose a cost and time challenge in this area, since process adjustments to a product that has been approved would require re-approval, and that can be an expensive undertaking.
A key challenge for chemists and process engineers in both the chemical and pharmaceutical arenas is to gain a comprehensive understanding of the nuances of the physical properties of the chemicals they work with, and to think carefully — from the earliest stages of process design and development — about how to leverage those properties to create a simple process.
Edited by Scott Jenkins
References
1. Malhotra, G. “Chemical Process Simplification: Improving Productivity and Sustainability,” John Wiley & Sons, Hoboken, N.J., 2011.
Author
Girish Malhotra is president and founder of EPCOT International (29150 Bryce Road, Pepper Pike, OH 44124; Email: [email protected]; Phone: 216-292-0626). He has more than 43 years of industrial experience in pharmaceuticals, specialty, custom and fine chemicals, coatings, resins and polymers, additives in manufacturing, process and technology development and business development. Malhotra enhances profitability by simplifying technology and manufacturing practices using engineering and science principles. Malhotra focuses on process technology development; process simplification and quality improvement; lowering manufacturing costs; process improvements; and waste reduction. He has an M.S.Ch.E. from Clarkson University and a B.S.Ch.E from H. B. Technological University, India. Malhotra is a Member of AIChE and is a licensed professional engineer in the states of Illinois and Ohio.