Reaction monitoring and control

The majority of APIs are produced by conventional synthetic organic chemistry, though there are a significant number of therapeutic agents produced through biosynthetic 

In addition, there is a need for maximizing process understanding while consuming the minimum amount of material due to the value (and frequently limited supply) of the materials themselves. Many of the synthetic processes involve numerous reaction steps and numerous manipulations, so it is common for the supply of material to be the limiting factor to the number of experiments that can be performed, making the information content of each experiment of paramount importance. 

Automation of experiments in process development groups, particularly in combination with design of experiments (DOE), have been the focus of extensive work, including a special section in the journal Organic Product Research and Development,16 but a preponderance of the published work in this field still cites near-line or off-line HPLC for analysis. A number of application notes and technical reports that describe on-line spectroscopic measurements can be found at some of the automation vendors sites, such as Mettler Autochem and Argonaut.17 

Frequently, however, the lack of specificity in an analytical technique can be compensated for with sophisticated data processing, as described in the chemometrics chapter of this text (Chapter 8). Quinn and associates provide a demonstration of this approach, using fiber-optic UV-vis spectroscopy in combination with chemometrics to provide realtime determination of reactant and product concentrations.23 Automatic window factor analysis was used to evaluate the spectra. This technique was able to detect evidence of a reactive intermediate that was not discernable by off-line HPLC, and control charting of residuals was shown to be diagnostic of process upsets. Similarly, fiber-optic NIR was demonstrated by some of the same authors to predict reaction endpoint with suitable precision using a single PLS factor.24 

One way to circumvent issues with generating and maintaining multivariate calibrations is to use first-principle kinetic models that are fit to robust experimental data. This 

---

Process analytical chemistry is being expanded for use in areas beyond that of monitoring chemical reactions, monitoring and controlling driers, or other processes that may not be... 

Schoenmakers P. Analysis of polymer molecules Reaction monitoring and control. In van Herk A, editor. Chemistry and Technology of Emulsion Polymerisation. Oxford Black-well Publishing 2005. p 160. 

Alb AM, Reed WF. Fundamental measurements in online polymerization reaction monitoring and control with a focus on ACOMP. Macromol React Eng 2010 4 470-485. 

Analysis of Polymer Molecules Reaction Monitoring and Control... 

A number of composition analyzers used for process monitoring and control require chemical conversion of one or more sample components preceding quantitative measurement. These reactions include... 

Overheating can result in overpressure due to reduction of allowable stress. Therefore, flie design must include monitoring and control features to prevent the occurrence of decompositions and runaway reactions, since conventional pressure reheving devices cannot normally provide protection against these contingencies. 

These methods will be applied by chemical engineers to monitor and control reaction and recovery systems. 

Biotransformation with flasks can be used to make gram quantities of a desired product, as shown for the 21 -hydroxylation of epothilone B [75]. In cases when greater quantities of a metabolite are needed, microbial biotransformations can be carried out in a fermentor, which will allow better monitoring and control of fermentation conditions (such as pH, oxygen and glucose levels, etc.) for reaction optimization [76]. 

Area 300 is controlled using a distributed control system (DCS). The DCS monitors and controls all aspects of the SCWO process, including the ignition system, the reactor pressure, the pressure drop across the transpiring wall, the reactor axial temperature profile, the effluent system, and the evaporation/crystallization system. Each of these control functions is accomplished using a network of pressure, flow, temperature, and analytical sensors linked to control valves through DCS control loops. The measurements of reactor pressure and the pressure differential across the reactor liner are especially important since they determine when shutdowns are needed. Reactor pressure and temperature measurements are important because they can indicate unstable operation that causes incomplete reaction. 

Production of the API begins with the selection of a synthetic route, as determined in the development program. Raw materials are added into a reaction vessel. These raw materials as reactants are heated or cooled in the reaction vessel (normal range is from -15 to 140 °C purpose-built vessels are needed for extreme reactions that require lower or higher temperature controls or pressurization of reaction processes). The chemical synthesis reactions are monitored and controlled via sensor probes (pH, temperature, and pressure) with in-process feedback controls for adjustments and alarms when necessary. Samples are withdrawn at dehned intervals for analysis to determine the reaction progress. Catalysts, including enzymes, may be added to speed up and direct the reaction along a certain pathway. 

Process monitoring and control of API production, sans the regulatory environment, is analogous to that within the chemical industry. Since the early 1990s, numerous papers have been published noting on-line specnoscopic techniques as applied to API reaction monitoring. A representation of some of these on-line specnoscopic reaction monitoring techniques will be provided herein with additional information discussed in Chapter 15. 

Figure 4.11. a so liter bench fermenter that can be scaled for production of recombinant proteins. The bench-top scale configuration contains all the control valves and ports necessary to monitor and control cell cultivation while maintaining sterility of the culture. The stainless steal reaction vessel allows easy cleaning and permits heat and pressure sterilization in place by connecting the vessel to a steam supply. (New Brunswick Bioflo-4500, adapted from the manufacturer s literature with permission)... 

When it is important to control the water activity in a reactor, a water activity sensor is quite useful. The sensor should ideally measure the water activity in the liquid reaction medium. However, the sensors available are designed for gas phase measurements, and, provided there is effective enough equilibration between the liquid and gaseous phases, they can be used to control the water activity in the reactor. If the measured water activity is above the set point, drying is initiated, for example, by passing dry air through the reactor. On the other hand, if the water activity is too low, water can be added, either as liquid water or as humid air. Automatically controlled systems of this kind have been successfully used to monitor and control enzymatic reactions in organic media [13, 14]. 

ATR-IR spectroscopy can be used as a spy inside a reactor for on-line monitoring and control of a reaction. The emphasis in this kind of application of ATR spectroscopy is on the detection of reactants and products in the bulk fluid phase. Such applications benefit from the excellent time resolution of FTIR instruments compared to other analytical tools, such as chromatographs. The method can be used in investigations of kinetics of reactions in batch reactors instrumentation has been developed and even commercialized that allows measurements at elevated temperatures and pressures. 

A number of composition analyzers used for process monitoring and control require chemical conversion of one or more sample components preceding quantitative measurement. These reactions include formation of suspended solids for turbidimetric measurement, formation of colored materials for colorimetric detection, selective oxidation or reduction for electrochemical measurement, and formation of electrolytes for measurement by electrical conductance. Some nonvolatile materials may be separated and measured by gas chromatography after conversion to volatile derivatives. 

MAT 311A instrument operating at 70 eV [electron impact (El) mode] and reported as m/z and relative intensity (%). Field desorption (FD) mass measurements were carried out on a ZAB 2-SE-FDP instrument. Microwave-assisted synthesis was performed using a CEM-Discovery monomode microwave system utilizing an IR temperature sensor and magnetic stirrer in sealed 10 -mL glass vials with aluminum caps and a septum. All reactions were monitored and controlled using a personal computer. 

For reproducible processing it is necessary to monitor and control conditions used for the reaction and work-up. In-process monitoring will be addressed in Chapter 7. All observations and relevant data should be recorded, such as reaction temperature, pH, equivalents of reagents charged, reaction pressure profile, and duration of reaction. 

---