Pharmaceutical Chemistry Journal

Vol. 42, No. 8, 2008

STRUCTURE OF CHEMICAL COMPOUNDS, METHODS OF ANALYSIS AND PROCESS CONTROL

CURRENT STATE OF IR SPECTROSCOPY APPLIED TO PHARMACEUTICAL ANALYSIS
A. P. Arzamastsev, N. P. Sadchikova, and A. V. Titova1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 8, pp. 26 30, August, 2008.
Original article submitted July 2, 2007.

Various techniques of IR spectroscopy are considered from the standpoint of their application in pharmaceutical analysis. It is demonstrated that attenuated total reflectance in the mid-IR range and near-IR spectroscopy are promising techniques for pharmaceutical analysis.

IR spectroscopy is at present one of the leading methods in many branches of science. It is widely used in the analysis and quality control of drugs [1 3]. It is well-known that IR-radiation is by nature electromagnetic and lies in the spectral region between the red end of visible light and shortwave radio waves. GlagolevaArkadeva showed already in 1923 that there is a continuous transition from visible radiation to infrared to radio waves, i.e., there are no distinct boundaries between these ranges of radiation. Namely this explains the fact that different boundaries of the IR region are used in the scientific and educational literature. It is situated approximately between 14,000 and 20 cm 1 and is arbitrarily divided into the near or NIR (from 0.74 0.78 to 2 mm or from 13,300 to 5,000 cm 1), middle (from 2 to 25 mm or from 5,000 to 400 cm 1), and far (from 25 to 1,000 mm or from 400 to 10 cm 1) [4, 5]. Isolated reports have indicated the promise of using the far-IR region to investigate polymorphism of drugs [6, 7] and preparations of protein origin [8]. Absorption of compounds found in air (carbon oxides, nitrogen, etc.) should be avoided when working in this region of IR spectroscopy. For this reason research is performed on a vacuum-type instrument or in a stream of inert gas. Only the near- and middle-IR regions are used in modern pharmaceutical analysis of drugs. This is indicated in the corresponding pharmacopoeic articles [1 3].
1 2

Sechenov State Medical Academy, Moscow, Russia. Institute for Drug Standardization and Control, State Scientific Center for Drug Review and Control, Moscow, Russia.

These articles showed that there are also differences in the determination of the boundaries of the IR region used for pharmaceutical analysis. According to requirements of the Eur. Ph. and Br. Ph. [1, 2], IR spectra of drugs should be recorded in the region from 780 to 2,500 nm (from 12,821 to 4,000 cm 1) [1, 2] and from 4,000 to 650 cm 1 (from 2.5 to 15 mm). In certain instances, the measurement region can be expanded to 200 cm 1 (50 mm) [1, 2]. The near-IR range in the USP is defined from 780 to 3,000 nm and the simple IR range (i.e., middle), from 2.5 to 40 mm or from 4,000 to 250 cm 1 [3]. The near-IR region according to the USP includes two subranges, the short-wavelength or Hershel range (from 750 to 1,100 nm or from 13,333 to 9,000 cm 1) and the long wavelength that is traditionally considered the NIR region (from 1,100 to 2,500 nm) [3]. There are two main methods for measuring IR spectra, absorption/transmission and reflectance. Absorption spectra of a studied compound in the middle IR region is mainly used at present in pharmaceutical analysis of drugs. Samples of drugs are prepared as KBr or NaBr disks, solutions, and oil suspensions (mulls). These methods for preparing samples have their advantages and disadvantages that have been discussed in the literature [4, 9]. The main disadvantage of these methods is the distortion of the spectrum of the compound because of absorption/transmission bands of the solvent [10] or oil (nujol has absorption bands from 3,000 to 2,850 cm 1, about 1460, 1375, and 722 [9]), the presence of impurities including water in KBr or NaBr, and the reaction of solvent or matrix with the analyzed compound [4]. Despite these drawbacks, IR absorption spec466
0091-150X/08/4208-0466 2008 Springer Science+Business Media, Inc.

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Fig. 1. IR transmission spectrum in KBr disks (1) and ATIR spectrum (2) of citric acid monohdyrate dried at 105C for 2 h. Instrument: Digilab Co. Pharmalyzir (USA) single-beam IR-Fourier spectrometer with attachment for recording IR spectra in KBr disks and attachment MIRacle with single reflectance and diamond crystal at 45. Resolution, 4 cm 1; number of scans, 32; amplification, automatic; baseline, air.

troscopy in the middle region is widely used today for quality control of ingredients and drugs [1 3]. This method has been proposed for detecting falsified preparations [11]. Diffuse reflectance in the middle-IR region has not been widely used to analyze drugs most probably because of the ability to analyze only solids and the need for careful preparation of samples for measurement. The reflectance spectra of compounds depend to a large extent on the homogeneity of their particle sizes [grinding and preparation by trituration with KBr, NaBr, or other matrix (1 5%), placement and spreading of the sample in the measurement cuvette]. Attenuated total internal reflectance (ATIR, ATR, or HATR), although also viewed as a sample preparation method, is a variation of the reflectance method but differs from it. It was known long ago [4, 10] but has only recently been used for pharmaceutical analysis. This is due primarily to the serial manufacture of equipment that has made the method acceptable. The advantages of this method are the rapidity, the simplicity of the analysis, the use of the minimum amount of tested sample (several milligrams), the lack of sample preparation (a sample is placed directly on the prism face or crystal surface), the avoidance of spectral distortion by the matrix (KBr, oil, solvent, etc.) or impurities in it (water, contamination), and the ability to change samples during sample preparation. All these ensure the results are objective. Therefore, the USP proposes this method for use as an alternative to the traditional methods of obtaining IR spectra (in oil, in KBr disks) [3]. However, the ATIR spectrum is not completely identical to that obtained in KBr disks although it is very similar to it. This has been described in the literature [4, 10] and can be seen using citric acid as an example (Fig. 1).

Among the factors affecting the ATIR spectrum are the crystal and analyte index of refraction, the indicent angle of the radiation, the sample area, and the number of reflections [4]. An indisputable advantage of ATIR is the ability to use it to investigate polymorphs of compounds because transformation of native forms is avoided during sample preparation [12, 13] and to analyze liquid and solid drugs without additional sample preparation [14 20] and mixtures of compounds without their preliminary separation [21]. Although near-IR radiation was known already in 1800, it began to be used in analytical chemistry in the 1950s primarily to analyze agricultural and food products [22]. Activity with the method peaked in the 1980s-1990s when it began to be used in pharmaceutical analysis of drugs [5, 22]. Transflectance, interactance, and transmittance through scattering medium spectra can be obtained in the near-IR region in addition to diffuse reflectance and absorption/transmission spectra [5]. As a rule, transmission is measured in the short wavelength spectral region for liquid drugs; diffuse reflectance in the long wavelength spectral region, for solid drugs [23, 24]. Diffuse measurements of the reflectance of compounds in the near-IR region are made primarily using fiber-optic sensors built into a probe or tester or an integrating sphere. It should be considered that spectra in the near-IR region, on contrast with the middle region, consist as a rule of broad, weak, and overlapping bands that are difficult to interpret visually and do not always differentiate compounds with similar structures [5, 22]. This circumstance was for a long time the obstacle to development of near-IR spectroscopy as an analytical method. Only the combination of instrumental and mathematical methods for processing results enabled use of near-IR spectroscopy to expand into many branches of industry, including pharmaceuticals. This is reflected in the mod-

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ern definition of the term near-IR spectroscopy, ...modern instrumental method for quantitative and qualitative analysis of various samples that is based on the combination of spectroscopy and statistical methods of investigating multifactorial dependences [24]. Chemometry [24 28], which is described in the EU Handbook on the Use of Near-IR Spectroscopy [29], is preferred among existing mathematical methods for processing results. The procedure for identifying compounds using near-IR spectroscopy consists at present of two steps, recording of signals for the studied sample (first step) and comparison with a library of compound spectra or comparison of signals based on mathematical criteria of a parametrized spectral similarity (second step) [22]. Such an approach to the identification of samples introduced two problems. The first problem is related to the way in which the library of compound spectra is formulated. It should take into consideration possible sources of variation in spectra (manufacturer, homogeneity, different batches, method of recording spectra, operator, temperature, etc.). It is sufficient to analyze 5 10 series, producing 20 40 spectra, for manufacturers with highly reproducible production capabilities in order to characterize the scatter of compound spectra due to its production. These values should be doubled for manufacturers with poor reproducibility [22]. It is recommended to obtain three or more spectra from at least three batches of compound in the EU Handbook on the Use of Near-IR Spectroscopy in Pharmaceutical Production [29]. Samples should be analyzed beforehand by validated methods and should correspond to requirements of the specification. In general, validation of a method should show that the selectve minimum number of compound batches is acceptable so that possible variation of spectral characteristics of this compound due to various factors, primarily, its production, are fully taken into account. However, a different problem is encountered in practice. It is related to the need to establish differences in compounds produced by different manufacturers in order to identify the manufacturer. For example, such an investigation was made in 2005 2006 in China where most compound manufacturers are concentrated [30]. The second problem is related to instrument requirements. In order to avoid changes of compound spectral characteristics due to the instrument itself, it should be qualified in the appropriate manner [26 28]. This is also provided for in pharmacopoeias [1 3]. Only industrial-grade instruments satisfy these requirements. Near-IR spectroscopy is used today in pharmacy not only to identify compounds but also for qualitative or quantitative determination of acive ingredients in various drugs [22, 31 44]. Analysis of coated drugs (tablets, pellets, etc.) is the most complicated. It was shown that the NIR reflectance spectrum changed depending on the thickness of the film coating using a pellet as an example [45].

The method is especially promising for studying light sensitive compounds such as folic acid, nifedipine, etc. because of the rapidity of the analysis and the lack of sample preparation [46]. It was demonstrated at the start of the 1990s that near-IR reflectance spectroscopy can be used to identify tablets through blister packing [47]. Second derivatives of IR spectra of 165 tablets in the wavelength range from 1,600 to 2,500 nm were studied. The ability of near-IR rays to penetrate through glass and plastic container material was used to analyze lyophilized thrombin [48]. However, if libraries of spectra are used to identify compounds it should be taken into account that packing material causes changes in the reflectance or transmission spectra of the compound. This can give a false-positive result. It has been shown that the method can be used to detect falsified drugs [42, 49 53]. Near-IR spectroscopy has been used for quality control of water and other solvents in ingredients and drugs [38, 54 60], to determine particle size [61], to study polymorphism of compounds in raw material [22, 31, 62 68], and to monitor a production process for preparing drug preparations including polymorphic transformations of compounds [22, 31, 32, 38, 55, 69 82]. The method has been used to analyze the thickness [83] and hardness of tablets [31] and the viscosity of a gel [84]. A special instrument for monitoring the coating of each tablet in its preparation process has been developed based on it (USA patent 5.50.996). In our opinion, it is interesting that near-IR spectroscopy can be used to determine the rate of liberation of active ingredients from solid dosage forms [31, 85 87]. The review showed that ATIR and near-IR spectroscopy of the known and available methods of IR spectroscopy are promising for pharmaceutical analysis of ingredients and drugs. REFERENCES
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