By Jennifer Hicks, contributing editor R & D Magazine
Any process that results in heat being generated by or exchanged with the environment is a candidate for a calorimetric study. Since all chemical, physical and biological processes are accompanied by heat flow, calorimetry clearly has a broad range of applicability, ranging from drug design to quality control of process streams in the chemical industry.
While a variety of calorimeters and calorimetric techniques such as temperature rise, heat flow, and power compensation exist.
Heat Flow operates under isothermal conditions; the reactor chamber remains constant while the surrounding temperature is varied. As the reaction starts, an exotherm occurs and power is removed by reducing the external temperature.
The greater the intensity of the process, the more heat produced and a greater temperature difference results.
With power compensation calorimetry, the reactor temperature is maintained by a calibrated heater and the surroundings are set about 20° C lower than the required reaction temperature. When equilibrium is reached, the reactor inputs a steady power into the mixture. A reaction begins, an exotherm is generated, the internal temperature rises. As the temperature rises, the control system, in an effort to maintain isothermal conditions, reduces the power input by the same amount as was generated by the reaction. Using power compensation drastically reduces the time needed for an experiment, minimizes the need to determine the heat transfer coefficient and surface area. This format is often used when dealing with process optimization.
However, it is reaction calorimetry (RC) that supplies "precious information to hasten the development process of any chemical operation in an efficient and safe way", says Urs Groth, chemical engineer HTL and manager of market support for RC and ALR at Mettler-Toledo GmbH in Switzerland. RC enables scientists to control each element of the process to simulate actual conditions. As a rule, reaction calorimetry (RC), is used to study reaction when they are under control, such as screening for the most applicable catalyst, the most efficient, cost-effective temperature to run at, or the best feed rate for optimal yield. It provides the foundations for optimization of the process with regard to profitability, quality, ecology and safety.
"The isothermal operation of reactions allows to investigate the reactions - heat flow, heat transfer coefficient, thermal conversion, specific heat, kinetics, and more - at constant reaction conditions in depth," says Groth.
And, when RC is run in adiabatic mode, simulation of disasters can be performed to study thermal hazards and the consequences of operations gone wrong such as a loss of cooling or misfeeds.
In adiabatic calorimetry, heat within the sample is maintained and higher pressures are used. For instance, the HEL GroupÕs PHI-TEC II reactor uses a pressure tracking system and high volume (100-120 ml) sample cells with very thin walls and low thermal mass (Phi = 1.05).
Electric heaters surrounding the sample cell heat the container and the observed adiabatic temperature falls. The temperature of the heaters around the sample is maintained slightly above the sample temperature to minimize heat flow between the sample and the container. As Gary Etherington, a product specialist with the HEL Group in the UK and on assignment in the US points out, "when a reaction runaway is initiated, the thermal mass of the sample cell is high when compared to the sample itself. A high degree of the energy released is absorbed by the container, thus limiting the adiabatic temperature rise."
A drawback to this experimental process comes from the fact that the maximum temperature rise is limited so reactions that begin with high temperatures will not be seen.
Exothermic chemical reactions are performed throughout the world as part of the normal manufacturing of products and their intermediates. When these reactions use thermally unstable materials, they carry built-in risks including loss-of-control, human injury or fatality, and loss of plant.
The most important information provided by hazard evaluation according to Etherington, is that which lets the researchers know exactly how much cooling power is needed. For instance, experiments with both RC and adiabatic calorimetry furnish data about fixed feed reactions so researchers can know exactly how much the longer a reaction will occur after the power has been disconnected.
Hazard evaluation typically returns data that includes:
- reaction enthalpy
- the heat of crystallization
- the heat transfer coefficient
- the temperature at which the hazard begins and the temperature of no return
- the self-heating rate for each temperature evaluated, along with the maximum self-heating rate
- the time of the explosion
- the pressure measurements
Thus, reaction calorimetry provides information important to control the process (or regain control of it) and maximize its yields. It can also help determine at what temperature to set the alarms and detail the time available for corrective action or evacuation. In the developmental stages, RC provides heater exchange information, reactor and process designs and relief vent sizing.
As Etherington explains, "youÕve got to know the cooling duty required when you scale up. From that, you can begin to calculate some kinetics and, at this stage, know exactly how much heat may be generated if you loose control the reaction by knowing that youÕve added x kilos of reagent and knowing that the reaction produce y kjoules per kilo."
But, as he points out, RC goes beyond this. "You also can determine if your reaction is feed rate limited, which is the ideal, and if it is not, then you can determine how much accumulation you will have during your process. This can tell you that you may need to perform more work on catalysts, stirrers, etc."
And this is what B. Wayne Bequette, associate professor of chemical engineering at Rensselaer Polytechnic Institute in New York, is doing with his work with Merck. They are trying to gain a better understanding of how the scale-up of a chemical reactor affects overall operability of reactors in the pharmaceutical and specialty chemical industries, particularly in regards to safety and process and on-line monitoring.
To maintain desired operating conditions and be sensitive to changes in operating conditions, Bequette uses various sized reactors as the process proceeds through various stages of development. Beginning with the 1-litre laboratory-scale reactor, such as the Mettler RC1, they move to the 200 ø 1000 liter small-scale pilot plant to the 1000 ø 2500 liter large-scale pilot plant and finally the 5000 ø 40000 liter large-scale manufacturing one. As the reactors increase in size, the heat transfer capability tends to decrease. By moving through the various sizes in the process, they can learn whether the temperature and feed rate profiles that were easily controlled in a small-scale reactor can be feasibly handled in the larger-scale reactor.
MettlerÕs RC1 lab-scale reactor, which uses heat flow calorimetry, is a commonly-used, computer-controlled batch reactor that allows for the monitoring of chemical or physical reactions under process-like conditions. Complete with composition sensors, it incorporates a powerful high-speed thermostat for fast heating and cooling and quick reactions on exotherms and endotherms, according to Groth. The PC software in combination with the integrated intelligence ensures a precise and safe control of the unit including temperature and stirrer control, automatic dosings, pH and pressure control.
But, according to Bequette, one of the problems of moving up to pilot scale reactions is the inability to tightly control the temperature. Part of the problem stems from the thermal lags and constraints inherent in the larger reactors. In addition, the larger reactors donÕt have the precision heating probe available in the lab-scale reactors. "The use of this probe," he says, "allows accurate characterization of the heat capacity of the fluid and inert components in the reactor ø the agitator and sensors - and of the heat transfer coefficient. A heat transfer fluid circulates at a high rate in a jacket around the reactor, allowing tight control of the reactor temperature." But because the pilot-scale reactors donÕt have these probes, "a series of transient tests, ramping jacket temperatures up and down, for example, must be performed."
In an effort to minimize the number of tests that need to be performed BequetteÕs group is developing techniques to minimize the number of experiments required to achieve a desired accuracy of mathematical models used to describe reactor behavior. They hope to be able to create the model from "past measurement data to improve estimates of variables or parameters not directly measured, and to predict future behavior and change current control actions accordingly", says Bequette.
The group has recently developed a small-scale calibration heat exchanger system, which can rapidly characterize pilot-scale reactors. This allows for better tracking of the process which can determine, for instance, if an overfeed occurs. Development of better monitoring and control strategies would prevent reactor runaway where a rapid increase in temperature leads to secondary decomposition reactions.
When isothermal instead of adiabatic techniques are used, in-depth investigations can be performed of the chemical reaction under constant conditions which allows scientists to predict stability, storage life, and mechanisms of decomposition for both organic and inorganic materials.
To assess the status of living systems, often an array of methods is used to determine the effects of activators or inhibitors. Providing definitive information then comes from analyzing all results and combining them into useful information. With microcalorimetry, a single measure can depict the metabolic activity for most cellular systems, offering the potential of detailed information regarding the effect of pharmaceuticals on changes in growth rate and basal metabolism.
For instance, calorimetric reactions can determines the action of drugs and antibiotics on living cells or organ parts such muscle tissue. It can provide information about the thermal activity of tumor cells to help characterize certain metabolic diseases such as diabetes. Perhaps more interestingly given the potential applications, it can show how well a pharmaceutical drug binds to receptor sites.
Isothermal titration calorimetry uses thermodynamics to define how substances interact with one another. When substances bind and generate or absorb heat, the heat can be measured to ascertain binding constants, reaction stoichiometry, enthalpy, and entropy.
Microcal Inc., in North Adams, Massachusetts, manufactures ultra-sensitive calorimeters and specializes in isothermal titration calorimetry (ITC). According to Mohan Chellani, their technical services manager and a molecular biologist, traditional analytic methods for antibody product quality consist of electrophoresis or chromatography, which characterize the molecular structure cannot tell researchers much about binding activity. Using ITC overcomes this problem.
According to Chellani, ITC can be used for any drug screening application that involve questions about molecular binding. The calorimeter cell holds about 1.3 mL of solution and is surrounded by an adiabatic chamber. To begin the process, a ligand solution is titrated against a binding solution under constant temperature conditions. Samples are delivered into the top of the cell via syringe, which typically introduces 2 ø 5 m L of the drug into the cell which begins the reaction process. Successive equal volumes of the ligand solution are added about every 2 ø 3 minutes and the process is completed in about an hour.
The computerized system collects and analyzes the results. This calorimetric method can be used to measure a broad range of attributes including antibody affinity, the heat of antigen binding, and the apparent number of active binding sites. The resulting information can help determine antibody lot-to-lot variation, antibody characterization, and quality control parameters.
Chellini sees the integration of combinatorial chemistry methodologies and ITC technology as becoming a strong force in future drug discovery. "This technology gives such precise values," he says, "that in the long run, weÕll see effective therapeutic drugs being discovered. But, in the short-term, thereÕs much to do. As more molecules are discovered, ITC can be used to provide needed information about their binding properties ø and this will spur the long-term development of many new drugs. It could be that as more proteins are targeted for therapeutic drugs, ITC might be able to predict their potential by looking at their binding characteristics."