Miniaturized FTIR for Maximized Productivity

In today’s fast-paced business environment, many companies are under pressure to improve their productivity. This is especially true in the pharmaceutical industry, where reducing time-to-market for new drug products and late-stage attrition of drug candidates are major productivity-related (as well as cost-related) issues.

In the organic synthesis laboratory, one way to improve productivity is to ease the bottlenecks associated with analyzing samples and interpreting data. This allows chemists to determine the results of their experiments more quickly. The faster chemists can obtain these results, the faster they can make judgments about the next experiments, and the more productive they become.

Infrared spectroscopy is a proven tool for organic synthesis-related applications. The relatively rapid analysis time of an FTIR instrument, coupled with the ability of infrared spectroscopy to provide functional group information, makes it effective for material identification, reaction monitoring, polymorph characterization, and formulation verification. However, due to historically tedious sample preparation and data interpretation, plus the fact that a synthesis laboratory environment is not normally conducive to the operation of a sensitive spectrometer, IR has given way to other techniques such as HPLC for most routine analyses.

Miniaturized FTIR customized for organic chemistry applications

Figure 1 - ChemID analysis system customized for organic chemistry applications.

The ChemID system (Smiths Detection Scientific, Danbury, CT) (Figure 1) is a rugged, compact, and lightweight FTIR (less than 25 lb with a footprint of only 7 × 15 in.) that can be easily used outside of the traditional analytical laboratory setting, wherever it is needed, even in a chemical fumehood. Using a diamond attenuated total reflection (ATR) sample interface, the analysis of liquid or solid samples can be performed without any sample preparation. The integrated 90× video microscope permits the operator to view (and record an image of) exactly what is being analyzed.

ChemAssist software (Smiths Detection Scientific), which operates the ChemID system, has been customized specifically for synthetic chemistry tasks such as reaction monitoring, solid form characterization, and material identification. Featuring a simplified user interface, the software contains powerful algorithms that make it easy for a nonspectroscopy expert to extract the desired information from the IR spectra collected with the system.

Diamond ATR operation

Figure 2 - Diagram of diamond ATR sample interface.

The principle of operation for the diamond ATR optics is depicted in Figure 2. Because of its superior chemical resistance and hardness, use of a diamond sample surface allows the analysis of the broadest range of samples, including caustic, corrosive, and abrasive materials. Even gritty solids cannot harm the surface. Because the surface can be cleaned quickly with a solvent-wetted laboratory tissue, analyses can be performed at short intervals—typically less than 1 min.

To perform an analysis, a sample is placed on the diamond internal reflection element. Sample viewing is aided by using the built-in darkfield (DF) or brightfield (BF) illumination. The infrared beam from the miniature interferometer and the optical light for darkfield illumination arrive at the center of the element from below. The brightfield illumination path is through the tip of a specially designed force applicator that contains a sapphire insert. The operator can see exactly what he or she is analyzing on the integrated monitor so that, for example, crystal shape can be confirmed. For solid samples, the force applicator is moved into position to contact the sample; a digital readout displays the force applied. The force applicator is not used with liquid samples. Both IR spectra and video images can be collected using ChemAssist software’s infrared and image capturing features.

Convenient and simplified reaction analysis

Figure 3 - ChemID operating in a fumehood.

Unlike traditional laboratory FTIR systems, ChemID is small and rugged enough to be placed in a chemical fumehood (Figure 3) or on a nearby bench in a synthesis laboratory, where space for such equipment is usually limited, and where the environment for spectrometers is not ideal. This makes it much more convenient for the chemist to take advantage of infrared spectroscopy for monitoring the progress of chemical reactions. In addition, the powerful ChemAssist software helps nonspectroscopists identify spectral bands for monitoring the functional groups involved in the reaction. Even for the IR spectroscopy expert, this software makes reaction analysis faster and easier to perform than with traditional methods. As an option, the software can include libraries of more than 25,000 individual spectra, and can be customized for users to add their own proprietary library of compounds.

Figure 4 - QuickTrakIR confirms that changes in the spectra at 1745 cm–1 are due to the formation of an aliphatic acetate.

For many reactions, the user may simply want to know if a reaction has initiated and if the desired product or intermediate is being formed. For these situations, the ChemAssist software’s QuickTrakIR feature allows the user to easily recall and display the spectral signature information for the functional groups of interest to see if the required peaks are present and changing (see Figure 4). This feature makes it easy for the user to make judgments in seconds regarding the progress of the reaction, thus permitting him or her to move on to the next activity more quickly than with techniques that require longer analysis times.

ChemID is especially effective for react ion analysis in situations where HPLC analysis may be difficult. A common example is when the target analyte does not contain a chromophore, which is needed for detection when using the most common HPLC detectors. Other examples include analyte compounds that are not stable with respect to HPLC solvents, air- and moisture-sensitive materials, and reagents and catalysts that may be harmful to the HPLC column.

Reaction profiling

In other situations, especially when trying to optimize a specific reaction, it is helpful to have a better understanding of the reaction kinetics. This is usually accomplished by creating a time-based profile for all reaction components: reactants, intermediates, and products. To set up a method for time-based profiling of a reaction, the analyst first inputs the chemical structures and IR spectra for all components of the reaction using standard chemical-drawing tools for structures. The spectra for the reaction components may be recalled from a directory of spectrum files or may be easily collected in just a few seconds using ChemID.

In the next step, which requires only a single click by the user, the software uses a sophisticated algorithm to examine each of the chemical structures and break them down into a list of the functional groups present. It then compares the lists and, along with the spectra entered, presents the user with a number of suggested bands, with their corresponding functional groups, to monitor for the reaction.

While the chemical reaction is taking place, the analyst pulls samples periodically from the reaction vessel and analyzes them. As the samples are analyzed, the software automatically builds a time-dependent profile of the reaction progress.

Figure 5 - Reaction profiles generated using ChemID with ChemAssist software.

Figure 5 shows reaction profiles built by tracking a C–O out-of-phase stretch band for the reactant and a C–O stretch band for the product. These bands were suggested by the software based on the structures entered by the user. In the case of the reactant, each sample point shows a decrease in the intensity of the tracked band until, finally, the band disappears, indicating that the compound containing it has been consumed and the reaction is complete. Likewise, the increasing profile for the product indicates that the product is formed on the same time scale. Armed with this easily obtained information about the reaction, the user can quickly move on to the next steps for optimizing the reaction.

Solid form characterization

In this example, ChemID was used to characterize furosemide crystals. Furosemide crystallizes into different polymorphic forms depending on the temperature and solvent used. Each form has a unique IR spectrum and crystal habit. The preferred form in this example consists of needle-like structures.

Figure 6 - a) Spectrum and 90× video image for furosemide recrystallized from n-butanol, compared with reference spectrum for preferred form. b) Library search results indicating match with preferred form.

Various approaches were used to make the preferred form without co-crystallizing other forms or solvates. Figure 6a shows IR data obtained on recrystallization of furosemide from n-butanol along with a 90× video image collected for the sample. A reference spectrum for the prefer red form is shown as the lower IR trace. A comparison of the actual and reference IR data and the appearance of needle-like crystals in the image suggest the preferred form. Verification is done by a single mouse click, which initiates a search of known forms and selects the closest match (Figure 6b).

Summary

The ChemID FTIR is an easy-to-use, fast, and versatile tool customized for organic chemistry applications. It can accept samples with little or no preparation—solids, liquids, powders, gels, and pastes—right from the reaction vessel if needed. Combined with ChemAssist software, it is a useful tool for reaction analysis, polymorph screening, and other material identification applications. It offers a new model for chemical detection, identification, and measurement, one in which the confines of the traditional laboratory are eliminated, where IR expertise is contained within the instrument, and where results are immediate.

Dr. Fredeen is Senior Product Manager, Dr. Seelenbinder is Microscope Product Manager, and Dr. Norman is Application Scientist, Smiths Detection Scientific, 14 Commerce Dr., Danbury, CT 06810, U.S.A.; tel.: 203-207-9700; fax: 203-207-9780; e-mail: ken.fredeen@smithsdetection.com.

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