B RIEFING
854Mid-Infrared Spectroscopy. A new chapter on mid-infrared spectroscopy is presented. As part of the General Chapters Expert Committee workplan, the general test chapter Spectrophotometry and Light-Scattering 851 will be replaced by a family of chapters pertaining to atomic absorption, UV-Vis, infrared, and fluorescence spectroscopy. Each of these chapters will be presented in pairs (a general test chapter numbered sub-1000 and a general information chapter numbered greater than 1000). This chapter focuses on the performance of the test for compendial purposes. Its sections are: Introduction; Qualification of IR Spectrophotometers; Procedure; and Validation and Verification.
Mid-Infrared Spectroscopy—Theory and Practice 1854describes the theory, instrumentation, and sampling techniques in some detail, and also includes analytical considerations that could help in method development. The chapter sections are: Principles of Mid-Infrared Spectroscopy; Sampling Techniques; Instrumentation; and Analytical Considerations.
(GCCA: H. Pappa.)
Correspondence Number—C102380
Comment deadline:  November 30, 2011
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854 MID-INFRARED SPECTROSCOPY
INTRODUCTION
Mid-infrared (mid-IR) spectroscopy is an instrumental method used in monograph procedures. The method involves measurement of the absorption of electromagnetic radiation with wavelengths between 4000 and 400 cm-1 (2.5 and 25 µm) caused by the promotion of molecules from the ground state of their vibrational modes to an excited vibrational state. Unless otherwise specified in a monograph, the region from 3800 to 650 cm-1 (2.6 to 15 µm) should be used to ensure compliance with monograph specifications for IR absorption.
Vibrational modes involve the motion of all atoms of the molecule. When molecules contain a certain functional group, the transitions often occur in narrow spectral ranges. In this case, the wavenumbers at which these transitions occur are known as group frequencies. When a vibrational mode involves atomic motions of more than just a few atoms, the frequencies occur over wider spectral ranges and are not characteristic of a particular functional group but are more characteristic of the molecules as a whole. Such bands are known as fingerprint bands. All strong bands that absorb at wavenumbers
above 1500 cm-1 are group frequencies. Strong bands that absorb below 1500 cm-1 can be either group frequencies or fingerprint bands.
For discussion of the theory and principles of measurements, see Mid-Infrared Spectroscopy—Theory and Practice 1854.
QUALIFICATION OF IR SPECTROPHOTOMETERS
Qualification of mid-IR spectrometers is divided into three components: Installation Qualification (IQ); Operational Qualification (OQ); and Performance Qualification (PQ). For further discussion, see the general information chapter Analytical Instrument Qualification 1058 .
Installation Qualification
The IQ requirements provide evidence that the hardware and software are properly installed in the desired location.
Operational Qualification
Because essentially all mid-IR spectra are measured with Fourier-transform IR (FT-IR) spectrometers,
only these instruments will be discussed. [ NOTE— No recommended values for signal-to-noise ratio or 100% line stability are included in this chapter because these vary with manufacturer, model, and age of the instrument. ]
WAVENUMBER ACCURACY
The most commonly used wavenumber standard for IR spectrometry is an approximately 35-µm-thick, matte polystyrene film. The spectrum of such a film has several sharp bands of which the most frequently used is located at 1601.4 cm-1. The wavenumber of maximum response of the chosen band can be measured using the center-of-gravity, polynomial spline procedure, or other peak-picking algorithms. The acceptable tolerance for the measured wavenumber is ±1.0 cm-1.
PHOTOMETRIC ACCURACY
There is no good way of measuring the absolute photometric accuracy of an FT-IR spectrometer. A good way to test the accuracy of the instrument’s zero-energy level is to check the region of the single-beam spectrum below the detector cut-off between 200 and 300 cm-1 when a deuterated triglycine sulfate (DTGS) detector is used and between 400 and 300 cm-1 when a mercury cadmium telluride (MCT) detector is used. The average value of the single-beam spectrum in this region should be less t
han 1000 times the
maximum value of the signal in the single-beam spectrum. This criterion is usually met when a DTGS detector is used but is rarely met with an MCT detector.
SENSITIVITY
The sensitivity of the instrument can be determined by measuring two single-beam spectra under exactly the same conditions and calculating their ratio to produce what is commonly known as a 100% line. The noise level in different spectral regions can be estimated either as the peak-to-peak noise, i.e., the difference between the maximum and minimum values of the percent transmission in the selected spectral region(s), or the root-mean-square (RMS) noise, i.e., the standard deviation of the spectrum in that region. The RMS noise level is the preferred metric because this calculation involves all the data in the selected region rather than just the two most deviant points. Typical measurement conditions to test the sensitivity of an FT-IR spectrometer equipped with a DTGS detector are 16 co-added scans, a resolution of 2 cm-1, and Norton-Beer medium apodization. The most commonly used spectral region is 2200–2000 cm-1 because (a) this is where the performance of most mid-IR spectrometers is highest and (b) no common atmospheric
interferent such as H
2O or CO
2
absorbs strongly in this region. However, other regions
should be tested close to the ends of the spectrum, such as 650–450 cm-1 and 4000–3800 cm-1. The signal-to-noise ratio (SNR) of the spectrometer operating with certain parameters in a given spectral region is estimated as 100/(RMS noise level in percent transmission).
STABILITY
The short- and long-term stability of the instrument also can be estimated from the deviation of the 100% line from 100% T (where T stands for transmittance) at the short wavelength (high wavenumber) end of the spectrum. Short-term stability is estimated by measuring the two single-beam spectra a few minutes apart and calculating the 100% line. The long-term stability is measured by increasing the time between the two measurements to several hours.
SIGNAL AVERAGING
The SNR should increase with the square root of the number of co-added scans. To test the signal-averaging capability, measure the SNR with the following numbers of scans: N = 1, 4, 16, 64, 256, 1024, and 4096. A plot of SNR vs. N is linear if the instrument is correctly averaging signals. An alternative means of testing this is to plot log SNR vs. log N. This plot should be linear with a slope of 2.00.
Performance Qualification
The purpose of performance qualification (PQ) is to determine that the instrument is capable of meeting the user’s requirements for all the parameters that may affect the quality of the measurement.
PROCEDURE
Mid-IR spectra can be measured by transmission, external reflection, internal reflection (often called attenuated total reflection), diffuse reflection, and photoacoustic spectroscopy. Different sample preparation techniques are available for these options. The most common sample preparation techniques are presented below.
validation verification
KBr Discs
Certain powdered alkali halides such as KBr, KCl, and Csl coalesce under high pressure and can be formed into self-supporting disks that are transparent to mid-IR radiation. The alkali halide most commonly used is powdered, dry, highly pure KBr, which is transparent to mid-IR radiation to about 400 cm-1.
Commercial presses and dies in a range of diameters are available for the preparation of alkali-halide and similar disks.
Mineral Oil Mulls
A typical procedure to prepare a mull is to place 10–20 mg of the sample into an agate or mullite mortar and then to grind the sample to a fine particle size powder using a vigorous rotary motion of the pestle. A small drop of the mulling agent is added to the mortar. Rotary motion of the pestle is used to mix the components into a uniform paste, which is transferred to the center of a clean IR-transparent window (e.g., KBr, NaCl, AgBr, or Csl).
A second matching window is placed on top of the mull, and the mull is squeezed to form a thin translucent film that is free from bubbles.
The most widely used mulling agent for the mid-IR region is a saturated hydrocarbon mineral oil (liquid paraffin, Nujol).
Compression Cells
A compression cell is useful when measuring a small or limited-quantity solid sample such as a single particle of an active pharmaceutical ingredient (API) or excipient, a contaminant such as a short length of fiber, or a small fragment from a packaging material. This is particularly the case for investigations using an IR microscope system.  When using a compression cell, the sample is placed between the windows of the cell, the cell is then tightened, and the sample thickness is reduced to an optimum for a
transmission measurement. Because of the high strength of diamond, it is commonly used as the window material of compression cells.
Self-Supported Polymer Films
The mid-IR transmission spectrum of many polymers used as packaging materials is at times recorded from samples prepared as thin self-supporting films using hot compression molding or microtoming.
Capillary Films
Nonvolatile liquids can be examined neat in the form of a thin layer sandwiched between two matching windows that are transparent to mid-IR radiation. The liquid layer must be free of bubbles and must completely cover the diameter of the IR beam focused on the sample.
Liquids and Solutions in Transmission Cells
For the examination of liquid and solution samples, transmission cell assemblies that comprise a window pair, spacer, filling ports, and a holder are available commercially in both macro- and micro-sample configurations.
For laboratory applications, spacers typically are formed from lead, poly (tetrafluoroethylene), or poly(ethylene terephthalate) and can be supplied, depending on spacer materials, in standard thickness path lengths from approximately 6 µm to 1 mm or larger.
Gases
Mid-IR transmission cells for static or flow-through gas and vapor sampling are available in a wide range of materials to suit the application, from laboratory to process scale. In the laboratory, the traditional gas cell has been a 10 cm long cylinder made from borosilicate glass or stainless steel with
an approximately 40-mm aperture at each end. Each open end is covered with an end cap that contains one of a pair of mid-IR–transparent windows constructed from, e.g., KBr, ZnSe, or CaF
.
2
Attenuated Total Reflection
Attenuated total reflectance spectroscopy relies on the optical phenomenon of radiation passing through a medium of high refractive index at a certain angle of incidence entirely reflected internally at a boundary in contact with a material of lower refractive index. The medium of high refractive index is also known as the internal reflection element (IRE).

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