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By Emil W. Ciurczak, Contributing Editor
All organic molecules are held together by covalent bonds—that is, two adjacent atoms share one, two, or three pairs of electrons in order to bond. Each bond vibrates at a set frequency, which is determined by the masses of the two atoms, the electron-withdrawing or -donating abilities of atoms adjacent to the pair, and factors such as temperature and matrix. The bonds may also move in a wagging or scissoring motion as well as rotate along their vertical axes. Each movement is excited by the proper frequency of energy impinging upon it. The strength of the bond varies according to the elements involved and the nature of adjacent groups. Thus, the chemical nature of a molecule gives a “fingerprint” when all the absorption bands are displayed.
USP Greets a New Era in Spectroscopy
The US Pharmacopeia (USP) is doing its part to aid in development of PAT/QbD programs and remains a force in the field. In order to not only give legal status to spectroscopic methods but also to allow pharma Quality Assurance departments to more readily accept PAT/QbD, the USP expert committees are reviewing and revising all chapters related to spectroscopy—a good sign for process analysts.
The following new General Chapters for spectroscopy are to appear in the September- October issue of Pharmacopeial Forum:
Future revisions are also slated for the following chapters:
Work is ongoing on these chapters:
Both of the above should appear at the end of 2008 or beginning of 2009 in the PF. Already completed and appearing in the PF are:
Since the chapters for NIR and Raman are to be mentioned in <197>, there is a possibility that they will receive new numeric designations. Chapters above <1000> are considered “for reference,” while those under <1000> have the force of law, being “official” methods and appearing in monographs within the USP.
Some influence is also exerted by “nearby” atoms and bonds both internal and external to the molecule in question. This causes shifts in what would be a “pure” spectrum of the chemical. These shifts may be used to determine environmental factors, such as degree of crystallization, polymorphic form, and solvation effects. The intramolecular influences on the mid-infrared (MIR) spectral region are indirectly affected (crystal structure, hydrogen bonding, etc.). The same forces affect nearinfrared (NIR) and are accentuated by the fact that the overtones in NIR are mainly hydrogen atoms, strongly influenced by hydrogen bonding. In the case of farinfrared, the influences are more intermolecular and are mostly only important at interfaces and boundaries between phases.
Because, in a typical organic molecular spectrum, there are more potential “unique” modes of vibration (and stretching and rotation) than found in electronic signatures, it is easy to understand why it has become a staple in almost every laboratory in the world. Vibrational spectroscopy became popular during World War II. While the near-infrared spectral range was discovered first (circa 1800), mid-range infrared came to the fore because it was extensively used in the synthetic rubber industry. Because of its long service, it tops the list of equipment/methodologies:
Originally done with a salt prism, the MIR technique moved almost entirely to gratings by the 1960s. In the early 1980s, interferometric or Fourier Transform (FT-IR) instruments became the new standard in industry. Fast, quiet and simple to operate, the latest models are beginning to appear in process applications. The spectral bands arise from non-symmetric bonds (i.e., separation of electron density) and, while dominated by vibrational bands, the spectra also contain bending and rotational bands.
MIR is excellent for speciation and is found in every synthetic organic laboratory. That is, the structure of molecules is easily determined in a pure material from the distinctive spectrum of each molecule. In mixtures, the resolution available to IR allows specification of analytes within the mix. One minor difficulty is that MIR radiation is strongly absorbed by the analytes and solvents. So, in order to use MIR in situ, sample viewing is usually performed by devices based on attenuated total reflection, or ATR. ATR is essentially a surface technique where the IR radiation is guided along a crystal and “sees” a thin layer of the sample (either powder or liquid).
MIR is used in liquid chemical reaction vessels and more and more in biological processes. The ability to follow reactions such as fermentation allows biopharmaceutical operations to respond more quickly in either batch-fed operations or simply to quench a reaction in a timely fashion and not rely merely on timeconsuming, biological assays.
Developed by the US Department of Agriculture in the late 1950s, NIR has a history of being used for samples where the matrix is left intact—to determine, for example, protein content of wheat, starch in corn, or oil in soy. Since the most common mode of operation was diffuse reflection, it seemed ideal for the powders, granules and tablets in pharmaceutical manufacturing. While work was done on apples and melons decades ago (USDA), new, sensitive detectors allow for quality transmission spectra through solid-dosage forms.
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