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Applied Spectroscopy Reviews

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Application of Fourier Transform Infrared Spectrophotometry in Pharmaceutical Drugs Analysis

Andrei A. Bunaciua; Hassan Y. Aboul-Eneinbc; Serban Fleschind a CROMATEC_PLUS SRL, Analytical Research Department, Bucharest, Romania b Pharmaceutical and Medicinal Chemistry Department, Pharmaceutical and Drug Industries Research Division, Dokki, Cairo, Egypt c Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia d Department of Organic Chemistry, Faculty of Chemistry, University of Bucharest, Panduri, Bucharest, Romania Accepted uncorrected manuscript posted online: 09 February 2010 Online publication date: 09 February 2010 To cite this Article Bunaciu, Andrei A. , Aboul-Enein, Hassan Y. and Fleschin, Serban(2010) 'Application of Fourier

Transform Infrared Spectrophotometry in Pharmaceutical Drugs Analysis', Applied Spectroscopy Reviews, 45: 3, 206 219, doi: 10.1080/00387011003601044, First posted on: 09 February 2010 (iFirst) To link to this Article: DOI: 10.1080/00387011003601044 URL: http://dx.doi.org/10.1080/00387011003601044

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Applied Spectroscopy Reviews, 45:206219, 2010 Copyright Taylor & Francis Group, LLC ISSN: 0570-4928 print / 1520-569X online DOI: 10.1080/00387011003601044

Application of Fourier Transform Infrared Spectrophotometry in Pharmaceutical Drugs Analysis


ANDREI A. BUNACIU,1 HASSAN Y. ABOUL-ENEIN,2,3 AND SERBAN FLESCHIN4
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CROMATEC PLUS SRL, Analytical Research Department, Bucharest, Romania 2 Pharmaceutical and Medicinal Chemistry Department, Pharmaceutical and Drug Industries Research Division, Dokki, Cairo, Egypt 3 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia 4 Department of Organic Chemistry, Faculty of Chemistry, University of Bucharest, Panduri, Bucharest, Romania
Abstract: This review provides some background to infrared spectroscopy including Fourier transform infrared spectroscopy. It is not meant to be complete or exhaustive but to provide the reader with sufcient background for selected applications in pharmaceutical analysis. Fourier transform infrared spectroscopy (FTIR) is a fast and nondestructive analytical method. Associated with chemometrics, it can become a powerful tool for the pharmaceutical industry. Indeed, it is suitable for analysis of solid, liquid, and biotechnological pharmaceutical forms. This review focuses on pharmaceutical FTIR applications used for qualitative and quantitative analysis. Moreover, it can be implemented during pharmaceutical development, in production for process monitoring, and in quality control laboratories. Keywords: FTIR analysis, drug analysis, quality control

INTRODUCTION
Infrared (IR) spectroscopy is one of the most important analytical techniques available to scientists. One of the great advantages of IR spectroscopy is that any sample in virtually any state may be studied. As a consequence of improved instrumentation, a variety of new sensitive techniques have now been developed in order to examine formerly intractable or difcult samples (1, 2). The infrared region starts immediately after the visible region at 700 nm. The classical infrared region extends from 2,500 to 50,000 nm. This spectral region encompasses three

Address correspondence to Professor Hassan Y. Aboul-Enein, Pharmaceutical and Medicinal Chemistry Department, Pharmaceutical and Drug Industries Research Division, Dokki, Cairo 12311, Egypt. E-mail: enein@gawab.com

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subdivisions: the far-infrared (FIR: 40010 cm1 or 261,000 m), mid-infrared (MIR: 4,000400 cm1 or 2.626 m), and near-infrared (NIR: 13,0004,000 cm1 or 0.76 2.6 m), named in relation to the visible region. Infrared spectroscopists often use wavenumbers to describe the infrared spectral region. The energies of infrared radiation range from 48 kJ mol1 at 2,500 nm to 2.4 kJ mol1 at 50,000 nm. These low energies are not sufcient to cause electron transitions but they are sufcient to cause vibrational changes within molecules. Two units are used in vibrational spectroscopy: cm1 (wavenumbers) or nm. The choice of one of the units depends either on the type of spectrometer (dispersive vs. Fourier transform [FT]) or to avoid too large numbers in the NIR range where nm is more often used. The relationship between the two units is given by Eq. (1): [cm1 ] = 1 [nm] 107 (1)

The basic principle of IR spectroscopy is the measurement of the amount of IR radiation, which is absorbed (or emitted) by a sample as a function of the wavelength (3). The IR measurement can be carried out in the modality of transmission or reectance. The rst one is the most popular. Infrared spectroscopy is often called vibrational spectroscopy. An IR spectrum is obtained by passing infrared radiation through a sample and determining what fraction of the incident radiation is absorbed at a particular frequency. Therefore, IR spectroscopy is based on the absorption of electromagnetic radiation by a molecular system. IR spectra provide images of vibrations of the atoms of a compound. IR spectroscopy has a high potential for the elucidation of molecular structures. The IR spectrum of a poly-atomic molecule is based on molecular vibrations, each specically dependent on atomic masses, bond strengths, and intra- and intermolecular interactions. As a consequence, the entire IR spectra of an organic compound provide a unique ngerprint, which can be readily distinguished from the IR absorption pattern of other compounds including isomers. In other words, when reference spectra are available, most compounds can be unambiguously identied on the basis of their IR spectra. The vast majority of molecules exhibit infrared bands in the mid-infrared region between 400 and 4,000 cm1. The position and intensity of a vibrational band are characteristic of the underlying molecular motion and consequently of the atoms participating in the chemical bond, their conformation, and their immediate environment. Thus, a certain submolecular group produces bands in a characteristic spectral region. These characteristic bands form the empirical basis for the interpretation of vibrational spectra. The reader interested in details of the basic principles of vibrational spectroscopy and the interpretation of vibrational spectra is referred to relevant books (47). Moreover, characteristic absorption bands can be used for compound-specic detection. Finally, IR spectroscopy obeys a law, similar to that described by Beer-Lamberts law, and can thus be used for quantitative purposes. The major advantage of IR over other spectroscopic techniques is that practically all compounds show absorption (emission) and can thus be analyzed both qualitatively and quantitatively. Besides, IR spectroscopy is nondestructive and allows in situ and remote measurements of almost any sample, irrespective of the physical state and without elaborate sample preparation (8, 9). The introduction of Fourier transform infrared (FTIR) instrumentation generated a true revolution in IR spectrometry; due to the great advantages it provides (1014). FTIR spectrometry is a fast analytical technique that provides very interesting qualitative and quantitative information from solid, liquid, and gaseous samples. At this point it is important

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to point out that the use of IR for quantitative purposes has grown dramatically in recent years. FTIR was originally a spectroscopic technique to identify the functional groups of chemical constituents but has been widely used and applied in recent years for the identication, quality control, and manufacturing process supervision of pharmaceutical drugs. The objective of this article is to review new developments in applications of FTIR spectroscopy in pharmaceutical or drug analysis, covering the period between 2005 and 2009. Prior to a review on this subject, it is useful to give a short introduction to the concept of the FTIR technique and to briey explain the principles of attenuated total reection (ATR) as well as diffuse reectance infrared spectroscopy (DRIFTS) methods. In the major section quantitative and qualitative determination of active principle ingredient (API) content in different dosage forms will be presented in alphabetic order of the API.

FOURIER TRANSFORM INFRARED TECHNIQUE


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FTIR spectrometers have almost entirely replaced dispersive instruments because of their improved performance in nearly all respects. The application of this technique has improved the acquisition of IR spectra dramatically. The heart of the optical hardware in such FT spectrometers is the interferometer. The classic two-beam Michelson interferometer is shown schematically in Figure 1 and consists of two mutually perpendicular plane mirrors: a xed mirror and a movable one. A semi-reecting mirror, the beam splitter, bisects the planes of these two mirrors. A beam emitted by a source is split in two by the beam splitter. The reected part of the beam travels to the xed mirror, is reected there, and hits the beam splitter again. The same happens to the transmitted radiation. Because the two split beams are spatially coherent, they interfere on recombination. The beam, modulated by the movement of the mirror, leaves the interferometer and is nally focused on the detector as shown in Figure 2. The signal actually registered by the detector, the interferogram, is thus

Figure 1. Schematic of a Michelson interferometer.

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Figure 2. Schematic of an FTIR spectrometer.


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the radiation intensity of the combined beams as a function of the position of the movable mirror. The mathematics of the conversion of an interferogram into a spectrum is the Fourier transformation. Based on fully developed software, a computer performs this transformation. The essential steps for obtaining an FTIR spectrum are to produce an interferogram with and without a sample in the beam and then to transform these interferograms into spectra of the source with sample absorption and the source without sample absorption. The ratio of the former to the latter is the IR transmission spectrum of the sample. In the case of FTIR spectroscopy, the sample is usually placed between the interferometer and the detector. In transmission measurement, the source illuminates the sample and the detector is placed behind the sample (Figure 3) to acquire the fraction of light transmitted through the sample. Transmission analysis requires the sample to be partly transparent. In most cases, in the MIR range, samples must be diluted in nonabsorbing matrix; otherwise, no light might be transmitted to the detector. Liquid can be prepared as a dilute solution in a cell. Solid samples are dispersed usually in a potassium bromide (KBr) disk or mull. Moreover, the powder particle size must be smaller than the radiation wavelength to avoid the Christiansen scattering effect, which appears as band distortion in the spectra (4). Transmission has been extensively used to analyze thin samples such as lms (15) or tissues (16). It is not possible with thick samples such as tablets.

Source

Sample

Detector

Figure 3. Schematic representation of transmission measurements.

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Figure 4. Schematic representation of ATR crystal.

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In reection measurement, the detector is placed on the same side of the sample as the source to record the signal reected by the sample. The sample is presumed innitely thick and incapable of transmission. The two types of reection measurement commonly used in CI analysis of pharmaceutical forms are attenuated total reection (ATR) and diffuse reection (DRIFTS). In attenuated total reection, the sample is placed in optical contact against a special crystal, termed the ATR crystal, which is composed of a material with a high index of refraction (e.g., usually made of zinc selenide [ZnSe], diamond, silicon [Si], or germanium [Ge]). The IR beam from the spectrometer is focused onto the beveled edge of the ATR element by a set of mirrors, reected through the crystal, and then directed to the detector by another set of mirrors. The use of ATR in spectroscopy is based upon the fact that although completed internal reection occurs at the samplecrystal interface, radiation does in fact penetrate a short distance into the sample (see Figure 4). The penetration depth, dp , is given (17) by Eq. (2): dp = i 2 n1 sin2 n2 21
1/2

(2)

where is the wavelength; n1 and n2 are the refractive indices of the ATR crystal and the sample, respectively; and is the angle of incidence. Obviously, the penetration depth of the beam depends on the wavelength. Furthermore, Eq. (1) shows that total reection occurs when the angle of incidence is larger than the critical angle = sin1(n2 /n1 ). Samples examined by FTIR-ATR generally require minimal or no sample preparation, but an intimate optical contact between the sample and the ATR crystal is crucial. Unfortunately, the crystal will degrade with surface scratching and cracking.

Figure 5. Schematic representation of DRIFTS measurements.

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In diffuse reection, DRIFTS, incoming radiation interacts with the sample and is scattered by interaction with the particles. A fraction of this light is reected by the sample and recorded by the detector (Figure 5). In the MIR range, DRIFTS requires the sample to be diluted between 10 and 100 times to avoid saturation and band distortion (18). For this reason, MIR-DRIFTS is rarely used for imaging; its use has not been reported in the literature. On the other hand, because samples need no dilution at all in the NIR range (the bands are weak), NIR-DRIFTS is widely used for the image analysis of thick, nontransparent samples in various noninvasive applications such as pharmaceutics (19, 20); e.g., tablets.

SELECTED PHARMACEUTICAL APPLICATIONS


The literature studied shows a great number of papers dedicated to pharmaceutical drug analysis using FTIR. Most of the papers are related to qualitative assay of an active compound, but there are also many papers dedicated to quantitative methods, even though pharmacopoeia had introduced (omologated) FTIR spectroscopy for such determinations. Ampicilline and nitrofurantoin, in both anhydrous and hydrate forms, were characterized by powder DRIFTS, X-ray diffractometry (XRD), and thermogravimetric and differential thermal analyses (TG/DTA) (21). Of all the analytical tools applied, only DRIFTS was able to indicate the formation of hydrogen bonds between the molecules of the anhydrous drug substance and crystalline water uptaken from atmospheric moisture as evidenced by the signicant absorption at 3,5003,700 cm1 corresponding to crystal water. Signicant differences were observed in the DRIFTS patterns between the anhydrous and hydrate forms of ampicilline. The FTIR spectral patterns of the anhydrous and hydrate forms of nitrofurantoin also exhibited signicant differences. A Fourier transform infrared spectrometric method was developed for the rapid and direct measurement of acetylsalicylic acid (ASA) in different pharmaceutical products (22). Conventional KBr spectra were compared for the best determination of the active substance in drug preparations. Beer-Lamberts law and two chemometric approaches, partial least squares (PLS) and principal components regression (PCR+) methods, were used in data processing. The authors studied the possibility of using the Beer-Lambert law for the quantitative determination of ASA in pharmaceutical products at 1,605.49 cm1. The results are very similar, and the authors suggest the use of the PCR+ method because of the smaller value of relative standard devaiaition (RSD; <3.0%). FTIR spectrometry was used for the rapid, direct measurement of ascorbic acid (vitamin C) and biotin (vitamin H) in different pharmaceutical products. Conventional KBr spectra were compared for the best determination of active substances in drug preparations. The Beer-Lambert law and chemometric approaches were applied in data processing (23). Vitamin C is an essential nutrient for a large number of higher primate species (24), representing 20% of all mammalian species, and a small number of other species such as the guinea pig and a few species of birds and sh. Vitamin H or B7 is a water-soluble B-complex vitamin composed of a ureido (tetrahydroimidizalone) ring fused with a tetrahydrothiophene ring. A Fourier transform infrared spectrometric method was developed for the rapid, direct measurement of bucillamine (25). Bucillamine, N-(2-mercapto-2-methylpropionyl)-lcysteine, is a novel disease-modifying antirheumatic drug. Conventional KBr-spectra and DRIFTS spectra were compared for best determination of active substance in drug preparations. A good similarity between the spectra in the ngerprint region (1,500750 cm1) was

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obtained using the two methods proposed by Bunaciu et al. (25) (DRIFTS and KBr-disk). Two chemometric approaches, PLS and PCR+ methods, were used in data processing. Similar results were obtained with both chemometric methods, but the authors suggest the use of the PCR+ method because of the smaller value of RSD (<2.0%). Carbamazepine is a poorly soluble drug, with known bioavailability problems related to its polymorphism, and a form (C-monoclinic or form IV) less soluble than the pharmaceutically acceptable (P-monoclinic or form III) can be formed under various conditions during drug formulation. Therefore, quantitative analysis of form IV in form III is important to the drug formulators. A fast and simple nondestructive method was developed for quantication of form IV in form III, by using DRIFTS spectral data subjected to the standard normal variate transformation (row centering and scaling) and to the lazy learning algorithm (26). Diffuse reectance FTIR spectroscopy coupled with modern multivariate calibration methods, namely, articial neural networks (ANNs) in two versions (ANNraw and ANN-pca), support vector machines (SVMs), lazy learning (LL), and partial least squares (PLS) regression, in this study for the quantication of carbamazepine crystal forms in ternary powder mixtures (I, III, and IV) (27). Two spectral regions (6751,180 and 3,400 3,600 cm1) were selected and the data were partitioned into training and test subsets applying the Kennard-Stone design. It was found that all the selected algorithms perform better than the PLS regression (root mean squared error of prediction [RMSEP]) from 3.0 to 8.2%). An FTIR spectrometric method was developed for the rapid, direct measurement of chromium (tris) picolinate [Cr(pic)3 ] in different pharmaceutical products. Conventional KBr spectra were compared for best determination of active substance in drug preparations. Beer-Lamberts law and two chemometric approaches, PLS and PCR+ methods, were used in data processing (28). The data interval was expanded and parts of the spectra were eliminated to reduce the size of the data matrix required by the calibration modeling. The rst range used was between 4,000 and 400 cm1 and the second range was 2,000 400 cm1. In both cases no blanks were rst selected, but after calibration was performed, the computer itself selects ranges of blanks due to the thresholds. The results are very similar, and the authors suggest the use of the method that demands a blank with the principal excipient because of the smaller value of RSD (about 2.0%). A spectrometric method was developed for the rapid, direct measurement of coenzyme Q10 (CoQ10) in different pharmaceutical products. Conventional KBr spectra were compared for the best determination of active substance in drug preparations. Beer-Lamberts law and the two chemometric approaches, PLS and PCR+ methods, were used in data processing (29). The results obtained using chemometric approaches are much higher than the expected values, taking into account that the determination was made possible using Beer-Lamberts law. A study in the development of a quantication method to detect the amount of amorphous cyclosporine (cyclosporine A) using FTIR was performed (30). The mixing of different percentages of crystalline cyclosporine with amorphous cyclosporine was used to obtain a set of standards, composed of cyclosporine samples characterized by different percentages of amorphous cyclosporine. Calibration models were generated by PLS method over the wavelength ranges of 4501,125 cm1 and 1,5153,200 cm1, with the exclusion of the spectral regions from 1,125 to 1,515 cm1 and from 3,200 to 4,000 cm1, to which a blank function has been applied. The regions where crystalline and amorphous cyclosporine spectra are essentially similar, and consequently are not indicative of signicative differences between the two forms, were subjected to the blank function.

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Diclofenac sodium (DS) is a nonsteroidal antiinammatory drug widely used in painful and inammatory diseases. In standard conditions, by exposure to relative humidity even below 60% at 25 C, the anhydrous form DS gives rise to a hydrate species DSH, a tetrahydrate form different from that obtained by crystallization from water and previously described. Data from FTIR spectroscopy, XRD, and thermal analysis were used for the identication and the characterization of DSH. DS and DSH were easily differentiated by their FTIR spectra, X-ray patterns, and thermal behavior (31). The methods of preparation of the trihydrate form (named DSH3) were described and its physicochemical properties were investigated (32). Data from FTIR spectroscopy, XRD, and thermal analysis were used for identication and characterization of DSH3 in comparison with the anhydrous form (DS, the commercial form) and the hydrate form DSH (obtained by exposure of DS to relative humidity even below 60%). FTIR spectroscopy was a useful tool to distinguish the new form from DS and DSH: DSH3 exhibited signicant differences in the observed vibrational transitions in the 3,6002,000 cm1 range of frequencies. An FTIR spectrometric method was developed for the rapid, direct measurement of dehydroepiandrosterone (DHEA) in drugs (33). Conventional KBr spectra and KBr + 2.0 mg MCC (microcrystalline cellulose) spectra were compared for best determination of the active substance in drug preparations. Two chemometric approaches, PLS and PCR+ methods, were used in data processing. The best results were obtained with PCR+ method. It is of interest to mention that there are no signicant changes between the two spectra in the ngerprint region (under 2,000 cm1). The peaks in the DHEA-MCC spectra are a little more evident than in the DHEA-KBr one. The authors suggest the use of the PCR+ method because the peak to peak error value must be a maximum of ve times greater than the RMS error value. Plus the concentration values of DHEA/tablet are a little higher in DHEA-MCC than in DHEA-KBr because of possible interfering signals in spectra. Diffuse reectance infrared Fourier transform spectroscopy coupled with PLS data analysis has been used to determine the minor component in a mixture of structurally similar solid-state compounds. There are a number of situations when there is a need to determine the concentrations of components in solid-state mixtures without dissolving the sample, in this case mixtures of ephedrine and pseudoephedrine (34). These spectral data were converted to log(R/R0 ) and KubelkaMunk units, assembled into data les, and subjected to PLS analysis. The differences in the IR spectra of ephedrine and pseudoephedrine are due to differences in the intermolecular interactions between the molecules in the solid-state forms; hence, they have properties similar to that of polymorphs. There is, for example, a difference in the frequency of the O-H stretching vibration in the two forms. A novel analytical procedure has been developed for quantitative determination of levodopa and carbidopa in aqueous binary solutions acidied by HCl and without any other sample pretreatment. The method is based partially on least squares treatment of data obtained by ATR-FTIR spectrometry in 1,2111,315 cm1 and 1,4881,550 cm1 spectral regions. The simple, rapid, and accurate proposed method was applied to determine levodopa and carbidopa in Levodopa-C R tablets (Alborz Daruou Pharmaceutical Company, Tehran, Iran) (35). A new method is presented for quantitative determination of naltrexone in aqueous solutions based up on the wavelength selection in mid-FTIR spectra using PLS technique. The main aim is to nd wavelengths that produce signicant improvements in PLS prediction. PLS wavelength selection treatment is performed on the data obtained by ATR-FTIR spectrometry in 8301,800 cm1 wavenumber range (36). A simple, rapid, and convenient analytical method without sample handling procedures is proposed for the determination of niumic acid in a pharmaceutical gel with ATR/FTIR

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(37). A PLS calibration model for the prediction of niumic acid contents was developed using 81 and 27 spectra of standard gels as training and validation sets, respectively. The used spectral range of niumic acid for the establishment of this model was 2,300 1,100 cm1. All spectra were obtained in the transmittance mode, then normalized and rst derivative transformed. A quantitative IR and Raman spectroscopic approach for determination of phenacetin (Phen) and salophen (Salo) in binary solid mixtures with caffeine:phenacetin/caffeine (system 1) and salophen/caffeine (system 2) is presented (38). Absorbance ratios of 746 or 721 cm1 peaks (characteristic for each of determined compounds in the Systems 1 and 2) to 1,509 and 1.616 cm1 (attributed to Phen and Salo, respectively) were used. The IR spectroscopy gives condence of 98.9% (system 1) and 98.3% (system 2), whereas the Raman spectroscopic data are with slightly higher condence of 99.1% for both systems. The IR measurements gave a standard deviation of 0.013 and 0.013 at p = 0.0513 and 0.0507 for both systems. An analytical reectometric method that has an objective not only of industrial quality control but detecting possible falsications and/or adulterations of propranolol in pharmaceutical formulations was proposed (39). The method is based on the diffuse reectance measurements of the colored product (III) of the spot test reaction between propranolol hydrochloride (I) and 2,6-dichloroquinone-4-chloroimide (II) using lter paper as solid support. The methodology involving the combination spot testdiffuse reectance spectroscopy offers advantages, such as simplicity and extremely low consumption of reagents. A PLS procedure in combination with infrared spectroscopy has been developed for simultaneous determination of sulphamethoxazole (SMZ) and trimethoprim (TMP) in raw material powder mixtures used for manufacturing commercial pharmaceutical products (39). Spectral data were recorded between 650 and 4,000 cm1 with a 4 cm1 resolution by FTIR spectroscopy coupled with an ATR accessory (40). FTIR spectroscopy can be interesting in stability studying of cosmetic or pharmaceutical oil-in-water (O/W) emulsions. During the aging process, modications of chemical functions are measured by FTIR (using spectrometric indices); such modications included a decrease of unsaturation index, an increase of carbonyl index, and a broadening of the carbonyl band (41). The amounts of drug and excipient were predicted from ATR-FTIR spectra using two multiway modeling techniques, parallel factor analysis (PARAFAC) and multilinear partial least squares (N-PLS) (42). Data matrices consisted of dissolved and undissolved parallel samples having different drug content and spectra, which were collected at axially cut surfaces of the at-faced matrix tablets. Spectra were recorded comprehensively at different points on the axially cut surface of the tablet. Chemical images of compacted pharmaceutical tablets were obtained in situ using a miniature compaction cell and a diamond ATR accessory (43). Combining this in situ ATR approach with FTIR imaging yielded chemical images based on the spatial distribution of the absorbance of the spectral bands for corresponding excipients in the tablets. Model excipients and drug used in these experiments were avicel, hydroxypropylmethylcellulose (HPMC), lactose, magnesium stearate, and paracetamol. Water-soluble polymers are often used in tablet compaction for their desirable compaction and dissolution properties (44). ATR-FTIR spectroscopic imaging has been used to analyze in situ the spatial distribution of different components in tablets with different compositions. Caffeine tablets made of three different polymer matrices, microcrystalline cellulose, HPMC, and lactose, were investigated. Counterfeit drugs are becoming a serious problem because they can damage health by supplying inappropriate substances or products devoid of API. FTIR is a useful weapon in

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rapid counterfeit detection. The counterfeiting of pharmaceuticals has been detected since about 1990 and, recently, the problem has escalated. Many more cases are being discovered not only in the developing world but, increasingly, in developed countries. The World Health Organization (WHO) has dened counterfeit drugs as those that are deliberately mislabeled with respect to identity and/or source. Counterfeiting can apply to both branded and generic products with counterfeit products including drugs with the correct ingredients or with the wrong ingredients; without active ingredients, with insufcient active ingredient or with fake packaging. (45) Some papers related to counterfeit detection using FTIR spectrometry will be briey discussed as most of the investigations reported were performed using NIR spectrometry. A scientic and systemic method for differentiation and quality estimation of a wellknown Chinese traditional medicine, Cordyceps, has not been established (46). But FTIR and two-dimensional correlation infrared spectroscopy (2D-IR) are employed to propose a method for its analysis. The different ngerprints display different chemical constitutes such as fatty acids, nucleotides, sterols, mannitol and polysaccharides. It has presented that IR spectra of real Cordyceps of different origins and counterfeits have their own macroscopic ngerprints, with discriminated shapes, positions, and intensities. Through the three steps, different Cordyceps and their counterfeits can be discriminated effectively and their qualities distinctly displayed. In support of the efforts to combat the illegal sale and distribution of counterfeit antimalarial drugs, a new analytical approach for the characterization and fast screening of fake and genuine artesunate tablets (47) using a combination of Raman spectroscopy, spatially offset Raman spectroscopy (SORS), and ATR-FTIR imaging. Vibrational spectroscopy provided chemically specic information on the composition of the tablets; the complementary nature of Raman scattering and FTIR imaging allowed the characterization of both the overall and surface composition of the tablets. The advantages provided by a combination of SORS and ATR-FTIR imaging in this context conrm its potential for inclusion in the analytical protocol for forensic investigation of counterfeit medicines. The quality of pharmaceutical products such as ginseng is important for ensuring consumer safety and efcacy (48, 49). Ginseng is an expensive herb, and adulteration with other cheaper products may occur. Quality assurance of ginseng is needed because many of its commercial products now come in various formulations such as capsules, powder, softgels, and tea (48). The herbal materials of Asian ginseng (the root of Panax ginseng), American ginseng (the root of Panax quinquefolius), and Notoginseng (the root of Panax notoginseng) were differentiated by conventional Fourier transform infrared spectroscopy (1D-FTIR) and two-dimensional (2D) correlation FTIR applying a thermal perturbation (49). However, variation in peak intensity was observed at about 1,640, 1,416, 1,372, and 1,048 cm1 in the FTIR spectra among these species for their ease differentiation. During the last 510 years, the molecular solid state has gained recognition by the pharmaceutical industry for its role in drug manufacturing, stability, and activity. In addition, denition of the crystalline phase has become as important as molecular composition in patent protection. Numerous methods have been used to measure the solid-state composition of pharmaceuticals; these include X-ray diffraction, optical microscopy, thermal analysis, dissolution testing, particle size analysis, NMR, and IR and Raman spectroscopy. Changes in polymorphic form and purity often inuence physical properties and pharmaceutical performance of a product (50, 51).

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Crystalline product should exist in optimal polymorphic form. Robust and reliable methods for polymorph characterization are of great importance. Several authors (5257) studied polymorphic forms. Two polymorphic and a pseudopolymorphic crystal form of the local anesthetic drug hydroxyprocaine hydrochloride are characterized by spectroscopy (FTIR, FT-Raman, SSNMR spectroscopy), thermal analysis (hot stage microscopy, differential scanning calorimetry, and thermogravimetry), powder X-ray diffractometry, and water vapor sorption analysis (52). The quality assurance of the sulfathiazole product during the whole development and manufacturing cycle of pharmaceuticals through increased level of process understanding is the main aspect to be considered within process analytical technology (PAT). multivariate statistical process control (MSPC), soft independent modeling of class analogy (SIMCA), and PLS together with orthogonal signal correction (OSC) techniques were utilized to characterize the polymorphic composition of bulk samples from DRIFT data (53). Sulfathiazole crystallization from ve different mixtures of water and 1-propanol using four different constant cooling rates was studied (54). ATR-FTIR was applied for in situ concentration measurement to be able to evaluate concentration level effects to outcome of product. Estimations of polymorphic composition were carried out by correlating calculated X-ray powder diffraction (XRPD) diffractograms from Cambridge Crystallographic Data Center (CCDC) to the XRPD measurements from samples. Five polymorphic forms of tranilast were characterized by thermal, diffractometric, and spectroscopic techniques. From a pharmaceutical development perspective, it is shown that although the anhydrous forms of tranilast have similar thermal properties, they can be reliably distinguished by spectroscopic methods (55). Because FTIR can be performed more rapidly and for less cost than most other techniques, an IR method was used during process development and manufacturing of tranilast to check for phase purity in Form I (the desired form). The presence of Form II was detectable at ca. 5% levels by observation of a band at 843 cm1. Form III could be detected at similar levels by use of a signal at 1,378 cm1. Nevirapine is a lipophilic drug of low aqueous solubility used in AIDS treatment. Three different crystal forms of this non-nucleoside reverse transcriptase inhibitor were obtained after recrystallization procedures (56). Two new pseudopolymorphs have been characterized, too: nevirapine hemihydrate and nevirapine hemiethyl acetate. Polymorphs and pseudopolymorphs of a drug may exhibit different chemical and physical properties, which can affect dissolution, besides manufacturing, stability, and bioavailability. For this reason, an investigation on the behavior of the two nevirapine pseudopolymorphs through the dissolution test has been described. Identication of the crystal phase of an active pharmaceutical ingredient in a pharmaceutical tablet is of outmost importance because different polymorphs exhibit different physicochemical properties. Furthermore, some of the crystal phases are protected by patents. Identication of risperidone polymorph A in lm coated commercial tablets was attempted using IR spectroscopy, Raman spectroscopy, and XRPD (57). The stability of this polymorph through time and during the manufacturing process was also examined.

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CONCLUSION
The recent analytical methods in quality control of API were reviewed. It is obvious that FTIR spectrometry is capable of the analytical quantication of pharmaceutical products.

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With the commercial software involving chemometric approaches, the methods proposed are simple, precise, and not time consuming compared to other methods that are avaialble in literature. Quantication can be done in about 1015 min, including sample preparation and spectral acquisition.

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