Journal of Pharmaceutical and Biomedical Analysis 66 (2012) 1–10

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Journal of Pharmaceutical and Biomedical Analysis

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Review

Application of the near-infrared spectroscopy in the pharmaceutical technology

Marzena Jamrógiewicz ∗
Medical University of Gdansk, Faculty of Pharmacy, Department of Physical Chemistry, Hallera 107, 80-416 Gdansk, Poland

a r t i c l e i n f o a b s t r a c t

Article history: Near-infrared (NIR) spectroscopy is currently the fastest-growing and the most versatile analytical
Received 4 October 2011 method not only in the pharmaceutical sciences but also in the industry. This review focuses on recent NIR
Received in revised form 5 March 2012 applications in the pharmaceutical technology. This article covers monitoring, by NIR, of many manufac-
Accepted 7 March 2012
turing processes, such as granulation, mixing or drying, in order to determine the end-point of these
Available online 15 March 2012
processes. In this paper, apart from basic theoretical information concerning the NIR spectra, there
are included determinations of the quality and quantity of pharmaceutical compounds. Some exam-
Keywords:
ples of measurements and control of physicochemical parameters of the final medicinal products, such
Near-infrared spectroscopy
Pharmaceutical technology
as hardness, porosity, thickness size, compression strength, disintegration time and potential counter-
Quantitative feit are included. Biotechnology and plant drug analysis using NIR is also described. Moreover, some
Quality control disadvantages of this method are stressed and future perspectives are anticipated.
Multivariate analysis © 2012 Elsevier B.V. All rights reserved.
PAT

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2. Recommendations for NIR application in the pharmaceutical sciences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3. NIR in the pharmaceutical chemistry and physicochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
4. Steps of pharmaceutical technology, controlled by NIR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
5. Plant drug analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
6. Biotechnological medicinal products tested by NIR spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
7. Disadvantages of NIR spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

1. Introduction molecule causes particular bonds to vibrate in a manner which is

similar to that of a diatomic oscillator. Therefore, it is convenient to
Infrared spectral measurements have been used for a broad start from the diatomic molecule as the simplest vibrating system
range of applications – from analysis of liquids, gas compositions and then extend the concept to polyatomic molecules. Changes in
and solid substances to detailed characterization of each physi- light energy between the three regions of infrared lead to varying
cal state. One of the fundamental properties of chemical bonds is absorptions of different molecules and bonds, inducing different
that they exhibit vibrations at distinct frequencies. The vibrational types of vibrations. For instance, the least energetic far infrared
frequency of a chemical bond is intrinsic to the chemical bond of region of light (FIR) is absorbed by heavy atoms, such as some inor-
interest [1]. The electromagnetic energy of molecular vibration is ganic and organometallic substances, while the mid infrared area
defined as near-infrared (from 120 to 400 THz, from 2500 to 750 nm (MIR) is used for organic chemical analyses.
or from 12,500 to 4000 cm−1 ), infrared, or mid-infrared (from 30 Near-infrared (NIR) spectroscopy was not a popular technique
to 120 THz, from 2500 to 25,000 nm or from 4000 to 40 cm−1 ) and until 1960s. The current triumph of this method is owed to Karl
far-infrared between 300 GHz and 30 THz (that is from 25,000 nm Norris who recognized the potential of the use of NIR in industrial
to 1,000,000 nm). Infrared radiation absorbed by an individual practice for measurements of certain types of food, agricultural
components [2] and product quality control. This method gained
wide acceptance within the pharmaceutical industry, particularly
∗ Tel.: +48 58 349 16 56; fax: +48 58 349 16 52.
for the analysis of intact dosage forms and process monitoring [3],
and it could be applied for liquid, slurry, powdered or solid samples.
E-mail address: majam@gumed.edu.pl

0731-7085/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.jpba.2012.03.009
2 M. Jamrógiewicz / Journal of Pharmaceutical and Biomedical Analysis 66 (2012) 1–10

A potential molecule, intended to be analyzed by NIR spec-

troscopy, should possess the change of dipole moment and also a
large mechanical anharmonicity of the vibrating atoms [4]. There-
fore, a large variety of compounds is appropriate for analysis in the
range of near-infrared. Characteristic features of the NIR spectrum
are overtones and combination bands of CH, OH and NH function-
alities which dominate the spectrum, whereas the corresponding
overtones resulting from the fundamental absorption values of
the most intense MIR area are rarely represented [5]. Overtones
(electron excitations to higher energy levels) are similar to octaves
in a musical scale, like harmonics of the fundamental vibrational
frequencies [6]. Combination bands are the sum of two different
vibrations corresponding to different chemical bonds. Although
the absorbance values of combination bands and overtones are
smaller than transitions ones, in bulk materials (for example phar-
maceuticals) this feature is an advantage because of the material’s
properties, which allow obtaining high absorbance values.
Unfortunately, because of the overlapping of overtones and
combination of vibrations NIR spectra are much more complicated
for interpretation [7]. The total NIR spectrum contains up to four
overtones from the absorptions of methyl (C H), methylene (C H),
methoxy (C H), aromatic (C H), carbonyl associated (C H) groups,
N H from primary and secondary amides, N H from amines (pri-
mary, secondary, and tertiary), N H of amine salts, O H (alcohols
and water), S H, or C O groups [8]. In some papers clarification
of spectroscopic signals and wavenumber ranges characteristic for
each vibration–harmonics could be found [9].
Over the last few years near-infrared spectroscopy has devel-
oped into indispensable tool for academic research and industrial
quality control in a wide field of applications, from the synthetic
chemistry to the agriculture and from some life sciences to the Fig. 1. Critical stages of pharmaceutical manufacturing process of medicinal prod-
environmental analysis. It is the crucial method also in the pharma- ucts with the usage of NIR spectroscopy.
ceutical area, mainly in such branches as technology, microbiology,
toxicology, counterfeit detection, determination of physicochem-
spectroscopic studies were performed for a group of newly devel-
ical properties, stability testing and also quality control of a final
oped synthetic biopolymers. In this case, NIR spectra result mainly
product. Pharmaceutical technology needs NIR spectroscopy for
from these vibrational regions which could be divided into:
implementation of in- and on-line processes control in many phases
of manufacturing process (Fig. 1) [10–13].
- the first overtone of the hydroxyl stretching region;
The identification of specific wavelength regions is needed when
- the second overtone of the C H stretching mode, which could
changes in the signal obtained from the near-infrared spectrometer
be found in the high wavenumber region between 9000 and
indicate the changes which are proportional to the concentration of
6500 cm−1 ;
chemical components of pharmaceuticals, or represent the physi-
- the first overtone of the C H stretching vibrations, which could
cal characteristics of samples under analysis. Generally, qualitative
be found in the 5900–5350 cm−1 region;
and quantitative analysis performed by near-infrared spectroscopic
- the combination of O H stretching (mode) and second overtone
methods requires the application of multivariate calibration algo-
of the C O stretching mode, arising in the lower wavenumber
rithms (MCA), and, eventually, the usage of some chemometric
region between 5300 and 4800 cm−1 [17].
methods essential for model spectral response to chemical or phys-
ical properties of a calibration or learning model set. It is possible
and also quite recommended to create the spectral library of stan- The assignment of NIR absorption bands is important for simple
dard pharmaceutical materials using NIR spectroscopy as a rapid, band identification of active compound contained in a formula-
non-invasive technique for compound identification [14]. Very use- tion [18], as well as for the recognition of reaction product and
ful information about characteristic bands of active pharmaceutical also for the monitoring in the synthesis reactor. Petter et al. pre-
ingredients (APIs) or excipients is contained in recent publications sented a simple NIR spectroscopy method for monitoring of the
[15]. There is also a need for verification and identification of such peptide reaction between oxytocin and glutathione [19]. A qual-
simple compounds or residual solvents as methanol and ethanol in itative model of analysis allowed rapid identification of newly
pharmaceutical products. Two-dimensional (2D) correlation near- produced conjugates, while a quantitative method was aimed at
infrared spectroscopy sometimes is very useful for difficult and determination of the amount of oxytocin and glutathione degrada-
not typical analysis. This technique is useful for discovery of some tion products.
special vibration modes that cannot be clearly seen in the origi- A number of data and detailed spectra structure correlations
nal spectra. In example it is suited to distinguish between specific have been presented in a comprehensive handbook by Work-
bands for methanol and ethanol which are not clearly observed in man and may be helpful during interpretation of NIR spectra [10].
the combination vibration region of spectrum (5000–4500 cm−1 ) Author described the increased interest of spectroscopists, particu-
[16]. larly these involved in implementation of process of near-infrared
NIR spectroscopy is a valuable diagnostic tool which can be measurements, in this spectral region. Moreover, some examples
used for elucidation of comprehensive structural information of useful near-infrared absorption bands are presented in a book
of numerous biological samples. The comprehensive vibrational about NIR implementation by Katherine Bakeev [9].
 M. Jamrógiewicz / Journal of Pharmaceutical and Biomedical Analysis 66 (2012) 1–10
2. Recommendations for NIR application in the
pharmaceutical sciences
Advanced medicinal products require new generations of phar-
maceutical manufacture which must be ready for improved quality
control of each step in the unit process of dosage form devel-
opment [20]. In 2003, the Food and Drug Administration Agency
(FDA) announced Pharmaceutical Current Good Manufacturing
Practices (cGMPs) for the 21st century in order to modernize all
the regulations and to get a better knowledge of the production
processes. This document is recommended and respected all over
the world. Generally, it is based on a risk approach of assurance
of a pharmaceutical product quality and provides an implementa-
tion of Process Analytical Technology (PAT) in the process control
of raw-materials, intermediate and final products [21,22]. Priority
manners are focused on minimizing unwanted effects in the man-
ufacturing process and on avoiding defects in the final products
[23,24].
The reason for increasing industrial application of NIR spec-
troscopy in biomedical fields and pharmaceutical manufacture is
the possibility of non-invasive mode of analysis [25]. It may be used
in the determination of biochemicals in blood. Moreover, in spec-
trophotometric methods used for process control it is crucial to
receive signals from different points along the production line and
to obtain the information from each measuring point.
The implementation of the PAT system requires the identifica-
tion of critical parameters for each technological stage. Analytical
techniques chosen should allow the measurement of effects and
statistical analysis in a very short time. Near-infrared spectroscopy
belongs to these techniques [26] and is suitable for on-, in- and
at-line process examinations. “In-line” means that process is mon-
itored inside a reactor or a lyophilizer while “on-line” represents
continuous control up to the end point (a sample flows through the
outer tube). Spectrum registration not directly at the production
line, but close to it, is called “at-line”.
An additional advantage of NIR is the possibility to handle and
control a great number of industrial/technological variables which
must be optimized in manufacturing processes. In February 2009,
the European Medicines Agency (EMA) published the draft of a
revised guideline on the use of NIR by the pharmaceutical indus-
try and the data requirements for new submission and variations
involving this technique [27]. According to cGMP the use of NIR
spectroscopy is recommended in analytical procedure of techno-
logical production of dosage forms.
3. NIR in the pharmaceutical chemistry and
physicochemistry
Near-infrared spectroscopy provides a rapid analysis of a wide
range of materials, giving a possibility of obtaining a large num-
ber of chemical and physicochemical parameters or even chemical
composition of some formulations as well. Various pharmaceuti-
cal parameters from tablet technology, such as hardness, particle
size, compaction force, dissolution rate, or water content, can be
quantitatively analyzed by NIR spectroscopy [3,28]. Good standard
of granulation step is acquired due to such quantity and quality
tests as moisture content, particle size distribution and bulk den-
sity [29]. Tablets made of fine-grained powder are often smooth
and easy to compress. The harder is a tablet, the smoother is its
surface. Differences in properties cause reduction of light scat-
tering and consequently build an upward shift in the spectral
baselines for smooth surface (small particles powders). Similar
situation is observed during determination of coating thickness
in NIR reflectance spectra. When the coating arises on a tablet,
the absorbance values of core components decrease, because NIR
3
radiation reaching the tablet core decreases and radiation reflected
by coating components increases [30,31].
The numerous possibilities of application of the NIR spec-
troscopy and chemometric methods in the pharmaceutical area,
especially in the identification of raw materials, according to the
quality control, as well as determination of moisture, are presented
precisely in the review article written by Luypaert et al. [32].
The usage of NIR spectroscopy is very often based on a simple
identification of active compound present in a drug. Civilization
problem with counterfeit medicinal products is a plague not only
in Asia [33]. Much harm is done to the customers because of tak-
ing up such drug products. The manufacturers suffer the greatest
loss because of counterfeit drug products and therefore they have
started to develop various anti-counterfeiting practices such as dif-
ferent analytical techniques, mainly NIR spectroscopy, thin layer
chromatography (TLC) or methods based on colorimetric detection
[34].
NIR spectroscopy allows selection of some characteristic spec-
tral bands and comparison of specific spectrum of original drug
product with unknown or doubtful one (e.g. with different phar-
maceutical excipients). For example, when the spectra of Chinese
Sildenafil [35,36] and Viagra® are compared, the major variabil-
ity between 5500 cm−1 and 5000 cm−1 could be observed [37].
As another example could serve “high-quality” Metronidazole,
which counterfeit and original could be detected only by means
of chemometric NIR data [38]. NIR spectroscopy was also success-
fully applied during identification of confiscated drug blister, which
proved to be bisoprolol-hemifumarate [39]. Important analyses of
counterfeit confirmation are frequently performed on the basis of
NIR libraries created.
Special pharmaceutical excipients added to pharmaceutical
formulations create a unique composition which is difficult to
identify by means of analytical methods recommended by Phar-
macopoeias [40–42] for particular drug compound, such as infrared
spectroscopy or liquid chromatography. Excipients obtained from
different manufacturers sometimes possess dissimilar physical
properties, particle size or purity. Therefore, there is a need of
view into the structure of each ingredient of the drug product
and of determination of its quality. For example, NIR spectroscopy
may be used for recognition and confirmation of some compounds
commonly used as tablet excipients, because in the process of
manufacturing dosage forms all ingredients must be reliably iden-
tified. In the current literature some examples about the capability
of FT-NIR spectroscopy to identify such substances as potassium
sorbate, sodium starch glycolate, calcium ascorbate, calcium car-
bonate, candelilla wax, maltosextrin, monohydrated or anhydrous
lactose could be found [15]. The discrimination between anhydrous
and monohydrate form of lactose was done reliably inside USP vials.
Specific NIR band of lactose monohydrate corresponds to 1991 nm,
while the anhydrous form possesses no band in this region. Apart
from complex mixtures analysis [43], all kinds of quantity [44–46]
and quality determination are performed in case of detection [47]
and location of chemical substances in a solid dosage forms [48].
The usage of NIR spectroscopy for comparison of manufacturing
series and batches of pharmaceutical products is fast and simple
due to chemometrics [49].
In a study conducted by Bittner et al. [50], the simultaneous
identification and particle size determination of amoxicillin trihy-
drate in bulk materials was performed. NIR spectra of the observed
particle range of 7–22 ␮m showed an inverse relationship between
absorbance (baseline offset) and particle size. Similar observation
about the increase of baseline offset with decreasing particle size
of measured material was also done by Abebe et al. [51].
The use of infrared spectroscopy is suggested by a Q6A
document of ICH as a way to perform and confirm the identi-
fication of tablets and to obtain high-throughput and accurate
4 M. Jamrógiewicz / Journal of Pharmaceutical and Biomedical Analysis 66 (2012) 1–10
multiparametric data collection, as presented for a coated solid
dosage form – thiamazole tablets containing 2, 4 and 8% of active
compound [52].
4. Steps of pharmaceutical technology, controlled by NIR
There are many industrial or scientific reports about the usage of
near-infrared spectroscopy for API determination not only directly
in a formulation, but also as a raw material or during different man-
ufacturing processes [10–13]. The latter depends on homogeneity
of the formulation and compound’s stability. A non-destructive NIR
method of drug content prediction has recently been presented in
various aspects:
- determination of API in a case of powders with different parti-
cle size, which form agglomerates during blending. This research
described the problems during tablet manufacture, when the
presence of large agglomerates changes the content of API in
the direct compressive process and powder tableting [47]. The
usage of NIR-Chemical Imaging Spectroscopy method allows to
see the influence of particle size on the frequency of agglomerates
formation;
- monitoring of unstable dosage forms such as suppositories con-
taining acetylsalicylic acid [53], finding an alternative method for
nimesulide analysis in pharmaceutical formulation, which is eas-
ier and faster in comparison with potentiometric titration [44];
- quantification of low dosage pharmaceutical forms (for exam-
ple syrup with acetaminophen, containing 16–24 mg/ml of the
substance) which could be a very challenging task because of
relatively low sensibility of NIR spectroscopy methods [54],
development of a more suitable analytical method for oral solu-
tions with dipyrone than iodometric titration [55];
- usage of appropriate NIR spectroscopy models for complex phar-
maceutical matrixes, for example a hydroalcoholic gel containing
ketoprofen and two preservatives [56], examination of suitability
of a diffuse “transflection” technique for determination of diphen-
hydramine hydrochloride in pharmaceutical wafers with 2.5 cm
diameter and a thickness of about 80 ␮m [57]. Samples during
measurements are placed directly on the round window, cover-
ing the integrating sphere, and masked with a diffusely reflecting
gold plate. NIR radiation after penetration through the sample is
partially absorbed and partially reflected back into the sample,
allowing the radiation to penetrate through the wafer twice;
- development of a method that allows the simultaneous iden-
tification and quantification of ranitidine in granulates for
compression, cores (as intermediate) and coated tablets [18].
Japanese researches published some scientific reports about NIR
spectroscopic analyses of two APIs, coexisting in one tablet or form-
ing bilayer [58,59]. Due to irradiated NIR rays, penetrated through
the tablet, a method developed was non-destructive and effective.
The transmittance technique allows a simultaneous analysis of the
two layers. A highly sensitive method for determination of tablet
thickness fluctuation was also described [60].
The utility of near-infrared spectroscopy for simultaneous in-
line drug and excipients quantification in manufacturing processes
is presented in many publications (Table 1).
During the last few years, growing interest in the use of
Near-Infrared Chemical Imaging (NIR-CI) method in the field of
pharmaceutical analysis is observed. The reason for increasing
popularity of this method is its ability to provide a wealth of
information from a single sample, including the quantitative com-
position analysis and distribution of ingredients. For example,
the content and homogeneity distribution of acetylsalicylic acid
in commercial tablets were analyzed by applying quantitative
algorithm to global hyperspectral image [86]. NIR-CI system was
also used for analysis of ibuprofen location in calcium phosphate
granules [87]. It was possible to investigate the chemical compo-
sition of some granules at high magnification and to gain useful
knowledge of the spatial location of the components.
None of the authors have investigated the influence of fluc-
tuations of environmental factors or time delay during spectra
recording on the images obtained. NIR-CI allows observation of
the contrast effect of the surface containing a number of ingredi-
ents and therefore this method may be compared with microscope
techniques.
5. Plant drug analysis
In the last 40 years near-infrared spectroscopy became one of
the most useful methods for analysis not only strictly pharmaceu-
tical compounds but also proteins, dry matter of plant extracts or
carbohydrates quantity in many agriculture related products and
plant materials [3]. Some of them are intended to become medicinal
products. Recently, the use of NIR spectroscopy in determination
of some minor compounds such as alkaloids, tocopherols, phenolic
and glycoside compounds, glucosinolates, or essential oils in plant
materials has been reported [88,89]. In most cases authors claimed
that the biggest challenge in the wider use of NIR spectroscopy
is the interpretation of complex spectra obtained. Despite many
multivariate analyses or chemometrics models used for the inter-
pretation of spectra, the knowledge of the principles of molecular
spectroscopy in natural products analysis is still the main barrier in
understanding the basis and functionality of the models developed.
Pharmaceutical plants are often analyzed and classified due
to the presence of some special marker compounds or medicinal
compositions. Three species of Dendrobium (Orchidaceae), used for
stomach nourishing, promotion of production of body fluid and
fever reduction, were determined by NIR [90]. It was showed that
the samples analyzed could be successfully verified on the basis
of intensities of particular patterns of spectral bands at 5180 and
4900–4800 cm−1 . This study proved to be very useful and allows
comprehensive evaluation of the different origins of Dendrobium,
as well as estimation of their clinical efficacy.
Ginkgo biloba extract could be qualified as raw material intended
for use in pharmaceutical products. Some quality specifications
of G. biloba extract, intrinsic to its natural origin, show unpre-
dicted and uncontrolled variability, which has influence on the
manufacturing process of solid dosage forms (viz. granulation and
compression). Some of these variabilities could not be determined
by conventional quality control tests, therefore NIR method was
used for qualification of the batches of Ginkgo extract, according
to their different features, and for establishment of relationship
between some of the manufacturing steps. Several approaches
were evaluated, and the NIR method developed proved to be sen-
sitive to changes in important quality specifications and therefore
adequate for qualification of incoming batches of G. biloba extract
[91]. Nowadays, medicinal plant preparations are produced with
the highest quality control measurements, and each step of their
manufacturing is also verified with PAT tools, such as NIR spec-
troscopy methods.
6. Biotechnological medicinal products tested by NIR
spectroscopy
Apart from applications in pharmaceutical technology, chem-
istry or industry, near-infrared spectroscopy has also successfully
been applied in the biotechnology field. Using near-infrared dyes,
it is possible to analyze DNA and protein molecules [92], to detect
some genetically modified organisms by comparison of their DNA
Table 1
The utility of NIR spectroscopy in the pharmaceutical technology processes.

Analyzed compound Purpose Range [cm−1 ] Description Parameters Ref.

Polymorphism
Sulphathiazole Comparison with other methods for the analysis of the solid-state 10,000–4000 Quality and quantity Heating temp. 180 ◦ C; drying temp. 105 ◦ C Time of heating [61]
forms of sulfathiazole polymorphic forms, such as DSC, XPRD, NMR, 30 min.
Raman spectroscopy
Acetaminophen Polymorphic transformation monitored during a cooling 14,000–4000 Quality, compared Cooling from 60 ◦ C (1 ◦ C/min) [62]
crystallization process with crystallographic
data, XRD and DSC
Fluconazole Determination of pure crystalline fluconazole form II in a binary 12,500–4000 Samples obtained by A set of 12 samples covering a concentration range from [63]
polymorphic mixtures containing forms I and II comparing with XPRD mixing known 37.5 to 87.5% (37.5, 50, 62.5, 87.5% (w/w) was used to test
quantities of pure
polymorphic forms II
and III

M. Jamrógiewicz / Journal of Pharmaceutical and Biomedical Analysis 66 (2012) 1–10

Crystallization
Ibuprofen Comparative study of attenuated total reflectance (ATR), Fourier 12,000–4000 Quality and quantity Cooling (0.5 ◦ C/min) [64]
transform infrared (FTIR), and Fourier transform (FT) near-infrared
(NIR) spectroscopy for batch cooling crystallization of four different
crystallization systems
Cephalexin The crystallinity of cephalexin in microcrystalline cellulose was 8500–8300 Quality and quantity 6 types of standard material with various degrees of [65]
determined with the molecular interaction of a ground amorphous crystallinity were prepared by the physical mixing
solid investigation. X-ray powder diffraction profiles were
determinated
Trehalose The phase behavior of sugars in ice and lyophilized solids was 10,000–4000 Quality and quantity Amorphous trehalose was prepared using aqueous [66]
investigated for quantitate trehalose crystallization comparing with trehalose solutions frozen at −70 ◦ C and freeze-dried at
Raman spectroscopy −40 ◦ C with pressure of approximately 100 mbar for 72 h
Particle size
Dibasic calcium phosphate Quantification of the median particle size of dry powders 9100–4550 Quality and quantity Diameter of fractions: 53, 75, 106, 150, 180, 212, 250, [67]
300 ␮m time of mixing 10 min
Particle size distribution
Acetaminophen Quantitative determination of acetaminophen in granulates, 9000–4000 Quality and quantity Temp. 60 ◦ C, compacting pressure 195–215 Mpa, time [68]
establishment of the particle size distribution and examination of 180 min
average particle size was performed. The granulate samples were used
to obtain laboratory tablets examined in the study. Particle size
distribution was determined by using a PLS2 model allowing
correlation between the spectral data matrix and more than one
variable and prediction of various particle sizes with a single
calibration model
Humidity/water content
Unknown API In-line measurement of water content during the fluid bed drying 8500–4800 Quality and quantity Time: 30 min, temp. 60 ◦ C, air volume 1400–2300 m3 /h [69]
process of a drug product. This method is currently being applied on
the commercial scale to control the drying end point
Unknown API Determination of moisture content ranging from 1% to 8%. The 12,500–3600 Quantity Heating temp.: 105 ◦ C, time: 90 min [70]
calibration protocol covered 6 different moisture levels: 0.5%, 1%, 2%,
4%, 8% and 10%. The entire calibration was performed within 2 days.
Batches belonging to three different production campaigns were
chosen. Each sample was measured with the NIR spectrometer in
triplicate under two different temperature conditions: 5 and 25 ◦ C.
Lyophilized allergen The small amount of samples (10 mg/vial), despite of low moisture 14,300–4000 Quality – [71]
vaccine products content it was possible to use the NIR spectroscopy method
Blending
Acetaminophen Distribution of mixture components and simulated chemical 7140–6000 Quality and quantity Time: 0.5, 1, 2, 5, 10, 15, 20, 24, 30, 40 min; Rotation: [72]
concentrations of samples in a small scale with the usage of chemical 25 rpm
imaging
Acetaminophen Determination of blending end-point by the usage of a high rate of 11,000–6000 Variation of Time: 90 min, 200 spectra [73]
spectra collection (sensors positioned at the top and rotational axis of concentration
a bin-blender)

5

Table 1 (Continued)
Analyzed compound
Unknown API
Acetaminophen
Unknown API
Tobramycin base
Tabletting
Micronized
chlorphenira-mine maleate
Compacts of lactose
monohydrate with
lubricant
Compression
Metoprolol tartrate
Production process of a
new potent drug
Coating/film thickness
Sulfanilamide-based
tablets coated with HPMC,
PEG mixture
MCC, lactose monohydrate,
PVP, PEG 400, HPMC,
fluorescein sodium salt
MCC, lactose, PVP, starch
PE and 0.1% Aerosil 200
Porosity
Folic acid, microcrystalline
cellulose, crosscarmellose
sodium, magnesium
stearate
Stability testing
Metoprolol tartrate tablets
6
Purpose Range [cm−1 ] Description Parameters Ref.
A real-time noninvasive NIR quantitative method was developed for 7400–6600; Quantity Rotation: 25 and 10 rpm; Time: 8, 20 min [74]
on-line blend uniformity analysis and transfer of the calibration model 6600–5500
from laboratory to industrial scale
Monitoring of the concentration of acetaminophen blends during the 8800–6000 Quantity Rotation 1.000 rpm; Time: 2 min [75]
real time of the mixing process
Based on a powder blend study, it was shown that the current practice 8300–4200 Quantity Rpm = 12; Time: 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, [76]
of calculating the % standard deviation for a given component within a 29, 60 min
specimen was not enough sensitive to assess blend uniformity
Assessing blend uniformity in the context of the specific constraints of 10,000–4000 Quantity Rotation: 67 rpm; Time: 19 min [77]
complex seven-component blends and small batches
In-line quantification enabled the content analysis of individual tablets 10,200–5200 Quality and quantity 5 kg powder batch; Time: 30 min; Rotary tabletting [45]
M. Jamrógiewicz / Journal of Pharmaceutical and Biomedical Analysis 66 (2012) 1–10
in the production batch and detection of problems with content machine with 10 mm flat faced punches, operated at a
uniformity towards the end of the tabletting process. Furthermore, it speed of 10 rpm. Tablet weight: 530 mg
provided the assurance of in-process monitoring of content uniformity
of the particular excipients during the tabletting process
Monitoring of the physical quality of tablets, control of tableting 7100–4000 Quality and quantity Lactose monohydrate was blended with 0%, 0.25%, or 1.0% [78]
process and final ejection and production of density profiles by the MgSt for 30 s or 30 min. Compacts were prepared of each
usage of NIR-Chemical Imaging method blend, with compaction forces monitored by load cell
Demonstration of physical changes due to compression differences 7000–4000 Quality and quantity Tablets prepared by direct compression and wet [79]
(porosity, hardness) granulation. Time 10 s, pressure: 6.9–31 MPa
Blend homogeneity, content uniformity, tablet coating thickness. A 12,500–5800 and Quality and quantity Duration of each mixing step: 25 min, rpm = 15, [31]
total of 720 tablets from five batches were used as calibration set. 12,500–3600 compression forces 100–400 MPa
Target value was 2.98% (w/w). The validation set – 15 cores each
compacted at 100–400 MPa
In-line control of the coating thickness (3% deviation from the actual 7500–4800 Quality and quantity Time: 160 min, number of tablets: 1.300, turnplate: [80]
thickness), end-point determination for the fluid-bed coating process 200 rpm, fan flow: 125 m3 /h, temp. 238 ◦ C, humidity 40%,
spraying rate 1.1 mL/min, shaking bag interval: 60 s
Correlation between in-line NIR spectra from a fluid-bed pellet coating 7500–5000 Quality and quantity Inlet air temp. 50 ◦ C, air flow: 60 m3 /h, spray rate of [81]
process and two separate methods for determination of coating coating solution: 1 mL/min, atomization pressure 5 psi
thickness; laser diffraction particle size analysis and image analysis
Quantification of coat thickness for tablets coated at different process 9100–4000 Quality and quantity Tablets (6 mm diameter), 15% (w/w) solids coating [82]
conditions with the use of optical microscopy, micrometer, X-ray dispersion composed of 12% (w/w) hypromellose, 2% (w/w)
fluorescence, Raman and NIR spectroscopy. Tablet weight, thickness polyethylene glycol, and 1% (w/w) iron oxide in water
and diameter, hardness, surface roughness and color were determined
A novel small-scale coating system as a method of preparation a 9100–4500 Quality and quantity Tablets diameter between 7 and 11 mm, rotation speed [83]
calibration model used to predict the coating layer thickness. In-line 1 rpm, Six experiments with different rotations: 5, 10, 12,
coating analysis useful during the early stage of formulation studies 15, 20, 25 resulting in thickness from 25 to 400 ␮m
when the amount of drug is limited and formulations are being tested
on a small scale. Determination the coating thickness of tablets in a
drum coating process was performed. High-density polyethylene used
a strong NIR absorber to enable the detection of a core signal.
Assessment of the effects of compaction variability in the tableting 11,520–6000 Quality and quantity Time of mixing: 12 min, tablet mass: 200.46 mg, diameter [84]
process on the performance of content prediction using NIR diffuse 10 mm, thickness 2.39 mm, resistance to crushing 95.33 N,
transmission mode. Examination of the effects of tablet thickness porosity 30.79%, dwell time 118.30 ms, upper compaction
variation and/or porosity on the spectra. Elucidation of the force 3.90 kN
proportional contribution of various areas of a tablet to the final NIR
spectrum in diffuse transmission mode
Presentation of differences in spectra obtained from metoprolol 7000–4000 Quality and quantity 1. Temp. 25 ◦ C, humidity: 60% [85]
tartrate tablets packed in the original high density polyethylene 2. Temp. 40 ◦ C, humidity 75%; Time: 13 and 52 weeks
containers or in USP Class A unit-dose blister packs
 M. Jamrógiewicz / Journal of Pharmaceutical and Biomedical Analysis 66 (2012) 1–10
fragments [93], and above all, to examine the activities and roles of a
particular gene expression in some seed phenotypes with regard to
their physiochemical composition [94]. Near-infrared spectroscopy
characteristics have also been used for localization of some oxida-
tive DNA damages [95].
The development of some new analytical tools, including spec-
troscopic sensors and data analysis, still continues. Miniaturized
tools for remote environmental monitoring, based on integrated
circuit technology, have recently been developed, leading to the
marriage of biosensors and the lab-on-a-chip [23]. Near-infrared
spectroscopy has many applications as a process monitoring and
process supervision technique, also in the context of bioman-
ufacturing. An industrial pilot-plant process of mammalian cell
cultivation presented the use of on-line in situ NIR application by
means of an immersion transflectance [96]. For animal cell culture
processes, important recommendations for improving efficiency
and for ensuring the quality of the final product were defined
by PAT. An analytical procedure, using FT-NIR spectroscopy and
chemometrics with multivariate techniques, was developed for
the determination of the fruit authenticity and for the quantifica-
tion of the fruit content [97]. Spectral information was correlated
with the fruit content and gravimetric data obtained from sequen-
tial fractionation of the alcohol-insoluble residue. The contents
of rhamnose, fucose, arabinose, xylose, mannose, galactose, and
glucose in the hemicellulose fraction of apricots, peaches, and
pumpkins were correlated and determined.
NIR is also an improved method for evaluation of the amount
of physiologically acceptable polymer moieties (PEG) conjugated
to a protein. None of the existing analytical methods (colorimetry,
HPLC, phase-partitioning) are reliable enough for the quantitative
determination of the amount of polymer molecules bound to a pro-
tein. This patented method [98] involves contact of the sample with
a light source in the near-infrared spectrum and then measurement
of relative absorbance levels. Inventors of the method claimed to
determine over a range of the near-infrared wavelengths the num-
ber of polymer molecules, conjugated to the protein or protein
complex. The essence and important advantage of the near-infrared
spectroscopy is that this technique is useful in studies in which
other methods are inadequate or ineffective.
A large number of biomolecules with potential pharmaceutical
application are produced just as all medicinal products on the basis
of Quality-by-Design (QbD) initiative [99]. Desired biological prop-
erties of the molecules are achieved during development of such
factors as serum half-life, formulation, aggregation propensity, and
immunogenicity, which are important for the production of the
biologically active molecule.
7. Disadvantages of NIR spectroscopy
Near-infrared spectroscopy possesses several advantages over
other analytical techniques used in the pharmaceutical technology
but there are also some disadvantages of this method (Table 2).
One of the main disadvantages of NIR spectroscopy used in phar-
maceutical technology is a problem with aqueous environment
(solutions of medicinal products or active pharmaceutical ingre-
dients alone) for direct quantity determinations. High absorbance
of water, which leads to a broad peak on a spectrum, creates a limit
of detection for other compounds that are present in the sample
analyzed in smaller quantities. In situ NIR spectroscopy technique
allows monitoring an activated sludge reactor by estimation of the
nitrate and oxygen concentration (N NO3 − ) and the amount of
total suspended solids [100]. Characteristic spectra were collected
with the use of immersion probes on the settler. This alternative
method, both with UV–Vis spectroscopy, presents clear advan-
tages during monitoring and controlling of wastewater treatment
7
processes as well as provides a way of qualification. Such quantita-
tive studies are very important also in toxicological measurements
of wastes from pharmaceutical manufactures.
During work with samples which may suffer any kind of peri-
odic or seasonal change, NIR operators should be aware of any
changes in the reference method which may negatively impact the
calibration process. Keeping the sample calibration pool updated
by adding new samples when required and using standards for
periodic examinations should be an obligatory practice by NIR cal-
ibrations, which means that standardization tasks are periodically
unavoidable [101].
Scientific and academic groups of pharmacists and chemists are
not especially involved in the applications of NIR method. This may
be due to the fact that during academic work smaller amounts of
samples are prepared in comparison with industrial conditions.
Routine in work with reference methods is accepted and suffi-
cient when a great number of samples are analyzed. Therefore, NIR
spectroscopy is the most popular method used by people working
or connected with industry, where PAT, FDA or Pharmacopoeias
recommendations play a primary role.
A proper interpretation of results obtained after application
of NIR spectroscopy in quality as well as quantity determina-
tion, which usually are numerous, chemometric data, is a difficult
task. A person who operates NIR device must be well prepared to
choose the best from many spectra obtained by pre-treatments
steps, calibration and validation processes for further calculation.
Apart from software developed for a method planning and setting
for special analysis (establishment of API concentration, end-point
determination or identification) NIR operator needs a harder view
to manipulate spectra obtained in order to create good fitted
mathematic results. Good analytical practice requires collabora-
tion between analyst, chemist, technologist and also well-educated
mathematician or statistician for proper calculation of all data.
NIR spectroscopy provides an alternative for validated con-
ventional methods. Although, it is important to keep in mind
restrictions about sensitivity and equipment or environmental
specificity of this method. It cannot be repeated easily in official
control laboratories, so the reference method needs to remain the
important part of the official specifications. Current software allows
development of NIR spectroscopy methods with minimal under-
standing of the relevant chemometrics, which creates a high risk
of obtaining invalid results due to some unknown hidden variables
[102].
Choice of proper parameters during pre-treatments operations
or spectral pre-processing methods, which are needed during
the near-infrared spectroscopy application, is regulated by a set
of mathematical procedures before development of a calibration
model. Mathematical pre-treatment of spectrum reduces noise
or background information (smoothing techniques) and increases
signal from the chemical compound analyzed (differentiation pro-
cess). Any pre-treatment technique should succeed in a robust
model with good predictive ability. In general, pre-processing
methods can be defined as baseline correction–normalization,
enhancement, and statistical filtering of the signal obtained. The
effects of several pre-processing methods used on absorbance spec-
tra obtained by reflectance mode instrument are presented by
Agelet and Hurburgh [8]. The offset baseline correction could be
observed when pre-processing method with SNV (standard nor-
mal variation) is used. With the usage of MSC (multiple scatter
correction) and first and second Savitzky–Golay derivatives pre-
processing methods, after elimination of scatter effects, the spectra
obtained are more grouped together. In each case, the NIR operator
is forced to choose a proper way to achieve satisfactory results. This
step of analysis may cause some difficulties.
According to Lambert–Beer’s law, in the case of calibration of
spectroscopy method, the linear correlation between analyte or
8 M. Jamrógiewicz / Journal of Pharmaceutical and Biomedical Analysis 66 (2012) 1–10
Table 2
Several advantages and disadvantages of NIR spectroscopy application in the pharmaceutical technology and manufacturing.
Advantages
Non-destructive and non-invasive method
Rapid spectral measurements (<1 min)
Low-cost of analysis – no chemical reagents needed, single operator can analyze a
large number of samples
A possibility of scanning several spectra on the same object permits obtaining
more representative sample composition and more accurate result of analysis
Sample requires minimal (drying and grinding) or no preparation
Several constituents of the same sample can be measured at the same time
Easily applicable in different environments such as industry or laboratory
Measurements can be carried out on/in/at line
The possibility of using optical probes allows analysis of the sample in situ
The availability of portable instruments permits obtaining spectra directly in the
field, which is useful for following some active processes
Ability to penetrate glass containers
Can also be used for particulate level (e.g., particle size) and bulk level (e.g., water
content) measurements with proper calibration
property measured and its absorbance should be the first assump-
tion. NIR calibration models correlate either raw or pre-processed
spectra with one or more chemical-physical properties of a set of
samples. As complicated as it may sound, there are several well-
developed calibration methods which are proved to work with
most of NIR applications and also are included in all chemometric
software packages.
Unfortunately, NIR spectroscopy has received some bad public-
ity as a “black box” technique. Something is introduced into the
black box and something out of this box is replaced without the
knowledge of a mechanism or detailed calculation. Testing of a
method is combined with verification and validation, while veri-
fication means checking the components of the system in terms of
their compliance with the attached specifications. Moreover, it is
often said that chemometric correlation requires a lot of faith in
numbers that many spectroscopists do not possess [103]. Making a
lot of analyses on a modern instrument without advanced courses
about proper usage of complicated software may be in fact a totally
bad experience.
NIR spectroscopy has increasingly been adopted as an analytical
tool (PAT) in pharmaceutical industry, mainly on the step of pre-
formulation and quality control of manufacturing process. The fast
and harmless analysis performed and samples characterization as
well as this method flexibility is the main reasons for popularity
and particular usage of NIR.
8. Conclusions
There are many applications of near-infrared spectroscopy in
the pharmaceutical technology. In addition, many difficult techno-
logical problems in the scientific or industrial field may be solved
due to this popular PAT tool. NIR spectra band depends on the phys-
ical or chemical nature of the sample and allows its identification
as well as determination of physical or chemical parameters of the
sample. The advantages of NIR spectroscopy method are numer-
ous: non-invasive and non-destructive techniques, no preparation
of sample, high frequency of spectrum acquisition, as well as large
number of molecules which could be quantified. NIR method is
crucial not only in scientific, but also in practical sense. It requires
cooperation between good chemists, pharmaceutical technologists
and mathematics for chemometric calculations and results descrip-
tion, and this trend corresponds to the interdisciplinary of science
also in other fields of manufacturing practice. NIR spectroscopy will
certainly play a key role in the analysis of many industrial pro-
cesses after implementation this method into the real-time process
monitoring during continuous pharmaceutical production.
Disadvantages
Low sensitivity of the signal limit by the determination of substances with
concentration below 0.1% (w/w)
The initial high financial investment for the instrumentation
Development of calibration models requires high trained personnel
Accurate and robust calibration requires a large data set incorporated with
large variation, which is often difficult to obtain
Requires a continuous maintenance of the calibration data set
It is difficult to transfer calibration between instruments of the same
manufacture or between different manufactures
It requires an accurate chemical and physical analysis of reference samples
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