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Abstract
Near-infrared (NIR) spectroscopy and imaging are fast and nondestructive analytical techniques that provide chemical and
physical information of virtually any matrix. In combination with multivariate data analysis these two methods open many
interesting perspectives for both qualitative and quantitative analysis. This review focuses on recent pharmaceutical NIR
applications and covers (1) basic principles of NIR techniques including chemometric data processing, (2) regulatory issues, (3)
raw material identification and qualification, (4) direct analysis of intact solid dosage forms, and (5) process monitoring and
process control.
D 2005 Elsevier B.V. All rights reserved.
Keywords: Noninvasive qualitative and quantitative analysis; Calibration and validation; Chemometrics; Raw material identification and
characterization; Quality control of intact dosage forms; Process analytical technologies (PAT); Process monitoring
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Basic principles of near-infrared (NIR) spectroscopy . . . . . . . . . .
2.1. Origin and characteristics of NIR absorption bands . . . . . . .
2.2. Instrumentation and sample presentation . . . . . . . . . . . .
Theory and practice of chemometric data processing. . . . . . . . . .
3.1. Data pretreatments . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Reduction of variables by principal component analysis (PCA) .
3.3. Multivariate calibration for quantitative analysis . . . . . . . .
3.4. Multivariate classification for qualitative analysis . . . . . . . .
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4.
Regulatory aspects. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Actual status of pharmaceutical NIR analysis . . . . . . . . . . .
4.2. NIR spectroscopy in view of the U.S.F.D.A. initiative on PAT . .
5. Pharmaceutical applications . . . . . . . . . . . . . . . . . . . . . . . .
5.1. Identification and qualification of raw materials and intermediates
5.1.1. Library approach . . . . . . . . . . . . . . . . . . . . .
5.1.2. Conformity approach . . . . . . . . . . . . . . . . . . .
5.1.3. Quantitative calibration models . . . . . . . . . . . . . .
5.2. Analysis of intact dosage forms . . . . . . . . . . . . . . . . . .
5.2.1. Tablets. . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.2. Capsules . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.3. Lyophilized products . . . . . . . . . . . . . . . . . . .
5.2.4. Polymeric implants and microspheres . . . . . . . . . . .
5.3. Process monitoring and process control . . . . . . . . . . . . . .
5.3.1. Powder blending . . . . . . . . . . . . . . . . . . . . .
5.3.2. Drying. . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.3. Granulation . . . . . . . . . . . . . . . . . . . . . . . .
5.3.4. Pelletization . . . . . . . . . . . . . . . . . . . . . . . .
5.3.5. Tabletting and capsule-filling . . . . . . . . . . . . . . .
5.3.6. Film coating . . . . . . . . . . . . . . . . . . . . . . . .
5.3.7. Packaging . . . . . . . . . . . . . . . . . . . . . . . . .
6. NIR imaging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1. Basic principles and instrumentation . . . . . . . . . . . . . . . .
6.2. Analytical targets and strengths . . . . . . . . . . . . . . . . . .
6.3. Pharmaceutical applications . . . . . . . . . . . . . . . . . . . .
7. Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Near-infrared spectroscopy (NIRS) is a fast and
nondestructive technique that provides multi-constituent analysis of virtually any matrix. It covers the
wavelength range adjacent to the mid infrared and
extends up to the visible region. Historically, the
discovery of the NIR region in 1800 is ascribed to
Herschel who separated the electromagnetic spectrum
with a prism and found out that the temperature
increased markedly towards and beyond the red, i.e. in
the region that is now called the near-infrared.
Although a number of NIR experiments were carried
out in the early 1920s, it was not before the mid to late
1960s that NIR spectroscopy was practically used. It
was Karl Norris from the U.S. Department of
Agriculture who recognized the potential of this
analytical technique and introduced bmodern NIRSQ
into industrial practice [1]. From then on, the breakthrough of the method as an industrial quality- and
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Detector
Diffuse Reflectance
Light Source
Monochromator
Sample
Detector
Transmittance
Transmittance
Transflectance
Diffuse
Reflectance
(A)
(D)
(C)
(B)
(E)
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Intensity
3
2
F2
3
3
2
F3
2
F1
F3
F2
F1
1
Fig. 3. Transformation of a spectrum with three variables, i.e. wavelengths (a) to a new coordinate system with one axis for each wavelength
thereby converting the spectrum to a single point in a three-dimensional space (b), cloud formation of several spectra (c), mean centering (d),
and determination of principal components F1, F2 and F3 (e).
1115
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4. Regulatory aspects
4.1. Actual status of pharmaceutical NIR analysis
NIR spectroscopy has a large number of advantages over other analytical techniques, and, thus,
offers many interesting perspectives in pharmaceutical
analysis. The scientific rationale of this technology
has been established for many different applications
and justified by a huge number of publications from
academia and industry (see Section 5). However, in
the highly regulated pharmaceutical world, an analytical method is only valuable for routine implementation if it is approved by regulatory authorities.
Actually, the major pharmacopoeias have generally
adopted NIR techniques. The European [20] and
United States Pharmacopoeia [21] both contain a
general chapter on near-infrared spectrometry and
spectrophotometry, respectively. These chapters ad-
1117
5. Pharmaceutical applications
NIR spectroscopy combined with multivariate
data analysis opens many interesting perspectives
in pharmaceutical analysis, both qualitatively and
quantitatively. Fast and nondestructive NIR measurements without any sample pre-treatments may
increase the analytical throughput tremendously.
The use of fiber optic probes offers the opportunity
for in-line and on-line process monitoring. The
special feature of combined chemical and physical
information allows for the assessment of a bspectral
signatureQ of raw materials, intermediates and final
dosage forms, which in turn offers the possibility of
a simultaneous determination of several sample
characteristics.
Notwithstanding these advantages, pharmaceutical
industry and regulatory bodies have been slow to
adopt the NIR technique, most probably since it
lacks the ability of mid-IR to identify samples by
mere inspection of spectra and involves calibration
by sophisticated mathematical techniques (see Section 3). Although the earliest publications on pharmaceutical NIR applications date back to the late
1960s, it was not until the last 20 years that NIR
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1120
Since chemical, physical, technological and biopharmaceutical properties of active ingredients and
excipients may be largely affected by their water
content and the type of water present, evaluation of
batch-to-batch variability or storage effects on water
content and water binding is usually an integral part of
material qualification. NIRS is an effective alternative
to traditional methods, such as thermogravimetry and
Karl Fischer titration for both water content and water
binding determinations. This is due to the fact that
OH bands of water are very intensive in the NIR
region, exhibiting five absorption maxima (at 760,
970, 1190, 1450, 1940 nm), the positioning of which
depends on the hydrogen bonding intensity. The
specific band to be used for water determinations
depends on the desired sensitivity and selectivity level.
NIR quantification of moisture content is usually an
easy task with respect to data processing, i.e. MLR and
PLSR models have been reported. Moreover, reference
data provided by Karl Fischer titration are reliable. It
is, therefore, not surprising that NIR moisture content
determinations in both transmittance and reflectance
mode have been described extensively in the literature.
Most of the early work has been summarized and
discussed by Blanco [12]. Two papers are worth
mentioning here, since they demonstrate the potential
of NIRS to distinguish different states of water in raw
materials and intermediates. Ciurczak and coworkers
[46] were among the first who demonstrated the
opportunity of NIRS to differentiate between total,
bound, and surface bulk water in pharmaceutical raw
materials, thus, demonstrating the advantage of NIRS
over traditional methods, such as KFT and LOD. Dziki
et al. [45] detected differences in the location or
orientation of the water molecules within the crystal
lattice of sarafloxacin with NIRS and used this
approach to distinguish between acceptable and
unacceptable batches for formulation purposes.
Mean particle size and particle size distribution of
solid raw materials and intermediates are key issues in
the formulation of many pharmaceutical products,
since they have a profound effect on bulk physical
properties, which in turn influence blending and flow
characteristics, density, compressibility, and dissolution rate. Particle size measurements with NIRS in
diffuse reflectance mode rely on the particle sizedependent scatter effect of powders resulting in nonlinearly sloping baselines [47,49]. Although the
crystallinity upon hydration during granulation processes [55,56]. The rationale behind this approach is
the sensitivity of NIR spectra to intermolecular
bondings. The magnitude of spectral differences
between the different forms is, therefore, the key
issue for quantitative determinations. Patel et al. [54]
demonstrated in a recent paper that NIRS can be used
to determine polymorphs of sulfathiazol in binary
mixtures in the range of 0.3% w/w. For amorphous/
crystalline mixtures of lactose monohydrate, the
amorphous content was accurately determined to
within 1% w/w. The literature data clearly reveal that
NIR results are comparable with other techniques,
thus, reflecting the potential of the method for the
assessment of different physical forms in bulk
materials and intermediates.
5.2. Analysis of intact dosage forms
The nondestructive and multivariate nature of NIR
techniques opens new perspectives in the pharmaceutical analysis of intact dosage forms, including
chemical, physical and related biopharmaceutical
aspects. This section will discuss NIR applications
for the characterization of solid dosage forms, namely
tablets, capsules, lyophilized products and implants.
5.2.1. Tablets
Most of the literature data available on NIR
applications for intact dosage forms focus on tablets,
ranging from identification and assay to physical and
biopharmaceutical parameters, such as hardness, coating thickness and dissolution rate. It is certainly
beyond the scope of this paper to review all the
published data in these fields. This section is rather
intended to provide an update of and comment on
some specific aspects that have not been reviewed in
detail yet. Special attention will be paid to the
importance of sample selection, sample presentation
and collection of reliable reference data for developing robust calibration models. Readers interested in a
more comprehensive coverage of the topics including
earlier data are referred to selected review articles
[12,66] and a recent book chapter [67].
Fast and nondestructive identification of active
ingredients and exipients in whole tablets, even
through the blister packaging, is certainly a domain
of NIR spectroscopy [6870]. Generally, the measur-
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B1 / elastic
B1 / brittle
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The application of NIRS as a fast and nondestructive alternative method for quantification of
excipients and actives within polymeric drug delivery
systems, such as implants, films and microspheres has
been reported in the literature by two different groups.
Brashear et al. [129,130] investigated the use of NIR
reflectance measurements for quantification of an
active compound, namely lomefloxacin HCl, and a
pore-forming excipient, namely polyethylene glycol
(PEG) 600, in poly(e-caprolactone) microspheres and
implants fabricated by a melt-mold technique. Analyte
specific wavelength selection and second derivative
transformation followed by PLS modelling allowed
for excellent correlations with UV results for the
active and weight-based theoretical values for PEG,
respectively. Reich and co-workers [131135] used
NIR transmittance and reflectance spectroscopy
together with analyte specific wavelength selection,
second derivative transformation, and PLS data
processing to determine theophylline and quinine
content (020% w/w) within PLGA microparticles
and tablets [132], and lyophilized protein/sugar
mixtures (absolute protein content: 02.5% w/w) in
lipid matrices [134].
The same group described the application of NIR
transmittance and reflectance measurements for monitoring matrix hydration, matrix degradation, and drug
release (theophylline and lysozyme) from biodegradable PLGA tablets, films and microspheres [131
1127
Transmittance
SEP = 0.42
2
4
6
8
Lysozym in tablet after incubation [mg] - Reference measurement
Fig. 5. Quantitative calibration model for NIR determination of in vitro lysozyme release from poly(d,l-lactide-co-glycolide) tablets (PBS pH
7.4/37 8C).
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material. Moreover, NIR spectra provided new information about the drying process, such as the
desorption rate and the steady-state value at which
drying was complete. These results clearly indicate
that the application of an in situ NIR configuration
offers the possibility of studying product characteristics during freeze-drying, thus, increasing our
understanding of important parameters in the formulation development of lyophilized products.
5.3.3. Granulation
The production of tablets often requires a granulation step to improve powder flow and compaction
characteristics, as well as to achieve content uniformity. Wet granulation is usually performed in a high
speed mixer or a fluid-bed granulator and comprises
the following critical steps: wetting, granule formation
and drying. At-line or in-line monitoring and endpoint
determination of wet granulation processes with NIR
spectroscopy offers the possibility of simultaneously
determining particle size and moisture content. Moreover, water/excipient interactions, hydrate formation,
and/or blend segregation may be assessed easily. The
following examples taken from the literature will
illustrate the potential and limitations of granulation
process monitoring with NIR spectroscopy in both
formulation development and in routine production.
In 1996, List and Steffens [164] published a paper
on NIR in-line monitoring of a wet granulation
process in a mixer granulator. The process was
stopped after certain time intervals and a NIR sensor
probe within the mixer recorded the spectra. A reliable
quantitative PLS calibration model for moisture
determination of a placebo mixture ranging between
6 and 15% w/w was developed and validated using
Karl Fischer reference data. Best results were obtained
with the following spectral pretreatments: wavelength
selection (50005500 cm1), normalization, and first
derivative. The authors discussed the limitations of
transferring placebo calibrations to active products
and demonstrated the feasibility of qualitative NIR
particle size monitoring during granulation.
Watano and co-workers [165,166] were among the
first who reported the use of a NIR sensor for moisture
monitoring and process automation of an agitation
fluid-bed granulation process. A fixed-wavelength
NIR filter instrument was used to study the effects
of operational variables on the NIR moisture measure-
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5.3.7. Packaging
Packaging is the last step in the production line of
a pharmaceutical product. To ensure the product
safety of pharmaceuticals, a last identity check of the
product on the packaging line would be highly
desirable. Such an inspection system based on the
combination of a conventional high resolution camera
with an on-line diode NIR spectrometer ranging from
900 to 1700 nm at 6 nm resolution has been
developed recently. The system is supposed to
perform a 100% identity check at full line speed
(i.e. 12,000 tablets per minute) before closing the
blister. The potential of this type of equipment has
been evaluated in a feasibility study [183]. Using
hard gelatin capsules of different shell and fill
compositions, the authors could demonstrate that the
real-time algorithms used in this system work as
reliably and accurately as a PCA-based data evaluation of spectra collected on an off-line lab spectrometer to ensure the identification of flawed products.
It may, therefore, be expected that other configurations based on high speed NIR spectrometer or NIR
imaging techniques will be developed in the near
future for identity check on packaging lines.
FPA
1133
6. NIR imaging
6.1. Basic principles and instrumentation
NIR imaging is a combination of NIR spectroscopy
with digital image processing. A NIR imaging system
is basically composed of an illumination source, an
imaging optic, a spectral encoder selecting the wavelengths, and a focal plane array (FPA) as indicated in
Fig. 7. NIR light from an illumination system is
focussed upon the sample. The diffuse reflectance
image of the sample is collected by an imaging optic,
the configuration of which depends on the sample size
and type. For macroscopic or microscopic images a
focusing lens or a microscope objective are used,
respectively. Data collection proceeds by recording a
series of images on the near-infrared (i.e. InSb or
InGaAs) FPA at each wavelength position selected by
a spectral encoder, such as a liquid crystal tunable
filter element (LCTF) or an interferometer. The result
is a three-dimensional data set, known as a spectral
hypercube with the x and y axis representing spatial
information and the z axis representing the spectral
information.
Signal
Processing
Filter
False Colour Image
Imaging
Optic
Sample
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7. Concluding Remarks
This review has covered some of the recent
methods and pharmaceutical applications of NIR
spectroscopy and imaging. As a fast and noninvasive
multivariate technique, conventional NIR spectroscopy has already gained wide industrial acceptance
for raw material identification and/or qualification,
and nondestructive chemical analysis of intact dosage
forms. Considering the continuing improvements in
hardware and software design, and the analytical
requirements of the most recent concepts of quality by
design and real-time or parametric release, it is
anticipated that in the near future both NIR spectroscopy and imaging may progressively become routine
methods for pharmaceutical process monitoring and
process control.
50
15
10
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5
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0
-5
25650
-10
30
Micron
Micron
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25650
20
25600
25600
10
25550
25550
0
53400
53450
53500
Micron
53550
53600
53400
53450
53500
Micron
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53600
Fig. 8. False-color near-infrared images of lysozyme distribution (10% initial loading) at the surface of a poly(d,l-lactide-co-glycolide) tablet
(A) after 4 days in PBS pH 7.4 and (B) after 14 days in PBS pH 7.4 (T = 37 8C).
References
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temperature on estimation of protein and moisture in wheat by
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[2] E.W. Ciurczak, Principles of near-infrared spectroscopy, in:
D.A. Burns, E.W. Ciurczak (Eds.), Handbook of NearInfrared Analysis, 2nd edition, Marcel Dekker Inc., New
York/Basel, 2001, pp. 7 18.
[3] L. Bokobza, Origin of near-infrared absorption bands, in:
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Infrared Spectroscopy: Principles, Instruments, Applications,
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[4] T. Burger, Radiative transfer in disperse medianew
procedures in spectroscopic infrared analysis, PhD thesis,
Wqrzburg/Germany, 1998.
[5] J.M. Olinger, P.R. Griffiths, T. Burger, Theory of diffuse
reflection in the NIR region, in: D.A. Burns, E.W. Ciurczak
(Eds.), Handbook of Near-Infrared Analysis, 2nd edition,
Marcel Dekker Inc., New York/Basel, 2001, pp. 19 51.
[6] S. Kawata, New techniques in near-infrared spectroscopy, in:
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Wiley-VCH Verlag GmbH, Weinheim, 2002, pp. 75 84.
[7] J.J. Workman Jr., D.A. Burns, Commercial NIR instrumentation, in: D.A. Burns , E.W. Ciurczak (Eds.), Handbook of
Near-Infrared Analysis, 2nd edition, Marcel Dekker Inc.,
New York/Basel, 2001, pp. 53 70.
[8] W.J. McCarthy, G.J. Kemeny, in: D.A. Burns, E.W. Ciurczak
(Eds.), Handbook of Near-Infrared Analysis, 2nd edition,
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