G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
analysis from one single measurement. However, if
photometers or light-emitting diode (LED)-based
not the analytical target, scatter effects in NIR spectra,
instruments provide selected frequencies, thus, cover-
resulting from physical sample variations, may also
ing only a narrow spectral range of 50–100 nm.
pose more or less severe analytical problems. In these
Diffraction grating, interferometer, diode-array or
situations, they have to be considered in the calibra-
acousto-optic tunable filter (AOTF)-based instruments
tion process as dinterfering parametersT, as will be
provide full spectral coverage. Selection of the
discussed in Section 3. More detailed information on
appropriate technology is usually based upon the
the theory of absorption and scatter effects in diffuse
required analyte sensitivity, reliability, ease of use,
reflectance and transmittance NIR spectroscopy can
calibration transferability and implementation needs.
be found elsewhere
The latter aspect requires laboratory and processanalyzers to be differentiated.
2.2. Instrumentation and sample presentation
Laboratory analyzers are intended for off-line or
at-line measurements in quality control, research and
A NIR spectrometer is generally composed of a
plant laboratories, i.e. high analyte sensitivity and
light source, a monochromator, a sample holder or a
reliability are required, while speed is of lower
sample presentation interface, and a detector, allowing
importance. Optimum sample presentation to the
for transmittance or reflectance measurements (
instrument, high signal-to-noise ratio, instrument
The light source is usually a tungsten halogen
stability, and sufficient resolution are the most
lamp, since it is small and rugged Detector types
important aspects for analysis. Presently, grating and
include silicon, lead sulfide (PbS) and indium gallium
interferometer-based instruments are mainly in use for
arsenide (InGaAs) Silicon detectors are fast, low-
this purpose. The appropriate NIR measuring mode
noise, small and highly sensitive from the visible
will be dictated by the optical properties of the
region to 1100 nm. PbS detectors are slower, but very
samples (Transparent materials are usually
popular since they are sensitive from 1100 to 2500 nm
measured in transmittance (Turbid liquids or
and provide good signal-to-noise properties. The most
semi-solids and solids may be measured in diffuse
expensive InGaAs detector combines the speed and
transmittance (diffuse reflectance (
size characteristics of the silicon detector with the
or transflectance (E), depending on their
wavelength range of the PbS detector.
absorption and scattering characteristics. In any case,
A number of optical configurations exist that can
absorbance (A) values relative to a standard reference
be used to separate the polychromatic NIR spectral
material are measured, with A corresponding to log 1/
region into dmonochromaticT frequencies. A detailed
R and log 1/T for reflectance and transmittance
description of the different principles can be found in
various textbooks Here the basic principles and
To measure good NIR spectra, the proper sample
main differences will be shortly discussed from a
presentation is of utmost importance, especially when
practical point of view. Broadband, discrete filter
measuring solid samples, since scatter effects and
Diffuse Reflectance
Fig. 1. Basic NIR spectrometer configurations.
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
opaque liquids and solids is typically carried out bycontact transmission and reflectance probes, whilenon-contact reflectance measurements are performedon materials transported in hoppers or conveyor belts.
3. Theory and practice of chemometric dataprocessing
Since NIR spectra are typically composed of broad
overlapping and, thus, ill-defined absorption bandscontaining chemical and physical information of allsample components, the analytical information is
multivariate in nature and, therefore, hardly selective.
To perform qualitative or quantitative NIR analysis,i.e. to relate spectral variables to properties of theanalyte, mathematical and statistical methods (i.e.
chemometrics) are required that extract brelevantQ
Fig. 2. NIR measuring modes—(A/B) transmittance, (C) diffuse
information and reduce birrelevantQ information, i.e.
reflectance and (D/E) transflectance.
In the following sections, the most frequently used
mathematical data pretreatments and their specific
stray light induced by variations in packing density of
purpose (Section 3.1), reduction of variables with
powders or sample positioning of tablets or capsules
principal component analysis (Section 3.2), multi-
may cause large sources of error in the spectra
variate calibration methods for quantitative analysis
Therefore, several types of sample cells, such as
(Section 3.3), and multivariate classification techni-
quartz cuvettes with defined optical path length for
ques for qualitative analysis (Section 3.4) will be
liquids, specifically designed sample cells with quartz
discussed. Different methods for calibration transfer
windows for semi-solids and powders, and adjusted
between instruments, an important economic and
sample holders for tablets and capsules have been
regulatory issue for qualitative and quantitative
developed Temperature control and sample
pharmaceutical NIR analysis, have recently been
movement are other options that have been realized.
commented on by Blanco et al. and will, thus,
Process analyzers are intended for in-line or on-
not be considered here in detail.
line measurements to provide real-time processinformation while operating in harsh conditions. This
3.1. Data pretreatments
requires fast and rugged instruments with no movingparts, such as AOTF-based instruments, allowing for
Interfering spectral parameters, such as light
numerous readings per second without being sensitive
scattering, path length variations and random noise,
to vibrations. AOTF-based instruments choose wave-
resulting from variable physical sample properties or
lengths by using radio-frequency signals to alter the
instrumental effects, call for mathematical corrections,
refractive index of a birefringent crystal (usually
so-called data pretreatments, prior to multivariate
TeO2). Wavelength scans can, thus, be performed
modeling in order to reduce, eliminate or standardize
much more rapidly than with other configurations.
their impact on the spectra. Since careful selection of
Since process analyzers are dedicated to performing a
data pretreatments can significantly improve the
particular analysis on a specific sample type, the
robustness of a calibration model, the most commonly
process sample interface depends on the sample type
used methods are briefly discussed with respect to the
and the process conditions, with NIR light being
effect they are able to correct. A detailed description
transferred via fiber optics. In-line analysis of clear to
of the techniques can be found elsewhere
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
Mathematical treatments used to compensate for
method is principal component analysis (PCA). PCA
scatter-induced baseline offsets include multiplica-
is a mathematical procedure that resolves the spectral
tive scatter correction (MSC) and standard normal
data into orthogonal components whose linear combi-
variate (SNV). Both methods have originally been
nations approximate the original data. The new
developed to process reflectance spectra, but they
variables, called principal components (PC), eigen-
are also applied to transmittance spectra. Baseline
vectors or factors, correspond to the largest eigenval-
shifts and intensity differences resulting from vari-
ues of the covariance matrix, thus, accounting for the
able positioning or path length variations may be
largest possible variance in the data set. The first PC
reduced or eliminated by normalization algorithms.
represents maximum variance amongst all linear
Derivatives can be applied to improve the resolution
combinations and each successive variable accounts
of overlapping bands. In addition, they are able to
for as much of the remaining variability as possible.
reduce baseline offsets. Since spectral noise is also
The transformation procedure is visualized schemati-
amplified by derivation, derivatives are usually
cally in on the basis of three original variables,
combined with Taylor or Savitzky Golay smoothing
i.e. three wavelengths per spectrum. For real spectra
with p wavelengths the transformation leads to a p-dimensional space.
3.2. Reduction of variables by principal component
In pharmaceutical NIR analysis, it is often possible
to compress most of the spectral variability to only afew principal components, i.e. factors with only a
Since multivariate NIR spectral data contain a huge
rather small loss of information. A number of multi-
number of correlated variables (= collinearity), there is
variate calibration and classification methods, there-
a need for reduction of variables, i.e. to describe data
fore, rely on PCA data (see Sections 3.3 and 3.4). For
variability by a few uncorrelated variables containing
further details on PCA, interested readers are referred
the relevant information for calibration modeling. The
to the excellent and comprehensive treatise of Howard
best known and most widely used variable-reduction
Fig. 3. Transformation of a spectrum with three variables, i.e. wavelengths (a) to a new coordinate system with one axis for each wavelengththereby 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).
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
3.3. Multivariate calibration for quantitative analysis
3.4. Multivariate classification for qualitative analysis
Before a NIR spectrometer can do any quantitative
In qualitative analysis, sample properties that have
analysis, it has to be trained, i.e. calibrated using
to be related to spectral variations have discrete values
multivariate methods. The calibration process basi-
that represent a product identity or a product quality,
cally involves the following steps:
for example bgoodQ or bbadQ. To solve the selectivityand interference problems of NIR spectra, multivariate
1. Selection of a representative calibration sample set.
classification methods are used for grouping samples
2. Spectra acquisition and determination of reference
with similar characteristics. Multivariate classification
methods, also known as pattern-recognition methods,
3. Multivariate modeling to relate the bspectral var-
are subdivided in bsupervisedQ and bnon-supervisedQ
iationsQ to the breference valuesQ of the analytical
learning algorithms, depending on whether or not the
target property.
class to which the samples belong is known.
4. Validation of the model by cross validation, set
bNon-supervisedQ methods, also known as cluster
validation or external validation.
analysis, do not require any a priori knowledgeabout the group structure in the data, but instead
The multivariate regression methods most fre-
produces the grouping, i.e. clustering, itself. This
quently used in quantitative NIR analysis are principal
type of analysis is often very useful at an early stage
component regression (PCR) and partial least-squares
of an investigation to explore subpopulations in a
(PLS) regression PCR uses the principal compo-
data set, for instance different physical grades of a
nents provided by PCA (see Section 3.2) to perform
material. Cluster analysis can be performed with
regression on the sample property to be predicted.
simple visual techniques, such as PCA (see Section
PLS finds the directions of greatest variability by
3.2) or some hierarchical methods leading to so-called
comparing both spectral and target property informa-
tion with the new axes, called PLS components or
bSupervised classificationQ methods, also known as
PLS factors. Thus, the main difference between the
discriminant analysis, are used to build classification
two methods is that the first principal component or
rules for a number of pre-specified subgroups, i.e. the
factor in PCR represents the largest variations in the
group structure of the training set is known. The
spectrum, whereas in PLS it represents the most
classification rules are later used for allocating new or
relevant variations showing the best correlation with
unknown samples to the most probable subgroup.
the target property values. In both cases, the optimum
Identity or good/bad quality are, thus, defined as
number of factors used to build the calibration model
belonging to a group with known properties. Algo-
depends on the sample properties and the analytical
rithms of this type such as LDA (= linear discriminant
target. Too many factors may lead to an boverfittedQ
analysis), QDA (= quadratic discriminant analysis),
model with a high regression coefficient and a low
SIMCA (= Soft Independent Modelling of Class
standard error of calibration (SEC), but a large
Analogies) or KNN (= K nearest neighbours) are
standard error of prediction (SEP). Such a model is
typically used for constructing spectral libraries.
not very robust and may fail when tested with an
Most of the classification methods can operate
independent validation set.
either in wavelength space or in a dimension-reduced
In some cases, the spectral data and the target
factor space. In any case, their ultimate goal is to
property may not be linearly related as a result of
establish mathematical criteria for parametrizing
physical sample properties or instrumental effects.
spectral similarity, thus, allowing similarity between
These cases can only be addressed by non-linear
samples or a sample and a class to be expressed
calibration methods, such as PLS-2, locally weighted
quantitatively. For this purpose, comprehensive libra-
regression (LWR) or artificial neural networks
ries of spectra that represent the natural variation of
(ANNs). For details on these methods interested
each product have to be constructed in a bcalibrationQ
readers are referred to the corresponding chapters in
process, with similarity being expressed by either a
a recent textbook on multivariate calibration
correlation coefficient, such as the spectral match
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
value (SMV) or a distance measure, such as
dress the suitability of NIR instrumentation for use in
Euclidian or Mahalanobis distance.
pharmaceutical analysis focussing mainly on opera-
A detailed description of the different classification
tional qualification and performance verification com-
procedures is certainly beyond the scope of this paper.
prising wavelength scale and repeatibility, response
Interested readers are, therefore, referred to a recent
repeatibility, photometric linearity, and photometric
textbook on the topic Worth mentioning here are
noise. Only some limited guidance is provided in terms
the following practical aspects:
of developing and validating an application.
The general legal requirements for instrumentation
! The correlation coefficient, being defined as the
qualification procedures, namely design qualification
cosine of the angle between vectors for the sample
(DQ), installation qualification (IQ), operational qual-
spectrum and the average spectrum for each
ification (OQ), and performance qualification (PQ),
product in the library, is a rather robust parameter
are described in the cGMP guideline title 21 CFR part
that can be favorably used for chemical identity
211. For practical realization of these requirements,
testing (see Section 5.1), since it relies on second
the American Society for Testing and Materials
derivative spectra and is, thus, not influenced by
(ASTM) has provided NIR specific directions regard-
spectral offsets and globalintensity variations
ing appropriate methodology for establishing spec-
resulting from physical differences or concentra-
trophotometer performance tests including suitable
tion changes.
standards and multivariate calibration Further
! Distance-based methods, on the other hand, also
guidance for evaluation of a NIR spectrophotometer
allow for product qualification. The conformity
has been provided in a special report of the Analytical
index (CI), based on the wavelength distance
Methods Committee of the British Royal Society of
method, is one such parameter that has been used
successfully to pinpoint quality differences in raw
Many pharmaceutical companies have success-
materials and products by using a so-called C-plot,
fully implemented NIR spectrometers in their
i.e. a plot of the absolute distance at each wave-
quality control laboratories for routine use in raw
length as a function of the wavelength (see
material identification and qualification. This is
also Section 5.1).
based on the fact that major pharmacopoeias allowmanufacturers to use analytical methods other thancompendial ones for compliance testing, provided
4. Regulatory aspects
they are validated according to parameters, such asspecificity, linearity, range, accuracy, precision,
4.1. Actual status of pharmaceutical NIR analysis
repeatibility, reproducibility, detection limit, quanti-fication limit, and robustness, as is detailed in the
NIR spectroscopy has a large number of advan-
U.S.P. Chapter 1225 on Validation of Compendial
tages over other analytical techniques, and, thus,
Methods and the general ICH Guidelines Q2A
offers many interesting perspectives in pharmaceutical
and Q2B on Validation of Analytical Procedures
analysis. The scientific rationale of this technology
has been established for many different applications
Interestingly, only few quantitative NIR methods
and justified by a huge number of publications from
have gained regulatory approval as yet. The main
academia and industry (see Section 5). However, in
reason for this is that bnon-separativeQ multivariate
the highly regulated pharmaceutical world, an ana-
NIR methods differ markedly from bseparativeQ uni-
lytical method is only valuable for routine implemen-
variate chromatographic methods for which U.S.P.
tation if it is approved by regulatory authorities.
Chapter 1225 and the general ICH Guidelines Q2A
Actually, the major pharmacopoeias have generally
and Q2B were written. Moffat et al. discussed
adopted NIR techniques. The European and
these aspects extensively in an excellent paper
United States Pharmacopoeia both contain a
published in 2000. Based on the example of a
general chapter on near-infrared spectrometry and
quantitative NIR method for the analysis of para-
spectrophotometry, respectively. These chapters ad-
cetamol in tablets, the authors made suggestions on
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
how NIR assays can best meet the ICH Guidelines on
According to a recently published U.S.F.D.A.
Validation. The recently published Guidelines for the
Guidance for Industry PATs are defined as
Development and Validation of Near-Infrared Spectro-
systems for real-time monitoring and control of
scopic Methods in the Pharmaceutical Industry
critical process parameters and material performance
established by the NIR sub-group of the UK Pharma-
attributes, thus, helping to improve process under-
ceutical Analytical Sciences Group (PASG), cover the
standing, manufacturing cycle time, and final prod-
unique and specific NIR requirements whilst remain-
uct quality. NIR spectroscopy and imaging may be
ing complementary to ICH Q2A and Q2B, which
one of the major PAT tools, since these techniques
address traditional method validation requirements. It
are well-suited for at-line, in-line and on-line
might be expected that the PASG guidelines, compris-
measurements. They can provide a wealth of
ing hardware as well as software aspects, can help both
chemical and physical information important for
pharmaceutical industry and regulatory agencies in
measuring process performance and open up oppor-
evaluating future submissions of qualitative and
tunities to move forward from traditional quality
quantitative NIR methods. For details of the PASG
control concepts to process qualification and product
conformity testing. Although a number of challengesconcerning hardware design and regulatory approval
4.2. NIR spectroscopy in view of the U.S.F.D.A.
must be overcome to realize the full potential of NIR
initiative on PAT
spectroscopy and imaging as PAT tools, it may beexpected that parametric or even real-time release
The production of pharmaceutical dosage forms is
concepts may be well assisted by the use of NIR
usually a multistage operation, consisting of several
techniques (see Sections 5.3 and 6.3).
validated processes managed by standard operatingprocedures (SOPs). Quality assurance, includingdecisions concerning the satisfactory completion of
5. Pharmaceutical applications
each unit operation, is actually based on off-linetesting to document quality of a small, nominally
NIR spectroscopy combined with multivariate
random product sample. This approach is often very
data analysis opens many interesting perspectives
time consuming and adds significantly to the manu-
in pharmaceutical analysis, both qualitatively and
facturing cycle time, since it requires the process to be
quantitatively. Fast and nondestructive NIR measure-
stopped during sample removal, data generation and
ments without any sample pre-treatments may
documentation. In addition, it does not assure zero
increase the analytical throughput tremendously.
defect product quality, since risk assessment and risk
The use of fiber optic probes offers the opportunity
management are not included, e.g. critical process
for in-line and on-line process monitoring. The
parameters and material performance attributes may
special feature of combined chemical and physical
not be identified.
information allows for the assessment of a bspectral
In view of this undesirable situation for industry
signatureQ of raw materials, intermediates and final
and public health, it has been recognized that new
dosage forms, which in turn offers the possibility of
testing paradigms are required to succeed in both, an
a simultaneous determination of several sample
increase in manufacturing efficiency and product
safety. The Process Analytical Technology (PAT)
Notwithstanding these advantages, pharmaceutical
initiative, driven by the United States Food and
industry and regulatory bodies have been slow to
Drug Administration (U.S.F.D.A.) and major phar-
adopt the NIR technique, most probably since it
maceutical companies, is a challenging approach
lacks the ability of mid-IR to identify samples by
intended to assist the progression of real-time or
mere inspection of spectra and involves calibration
parametric release and quality-by-design concepts
by sophisticated mathematical techniques (see Sec-
by providing an opportunity to move from the
tion 3). Although the earliest publications on phar-
laboratory-based btesting to document quality para-
maceutical NIR applications date back to the late
digmQ to a bcontinuous quality assurance paradigmQ.
1960s, it was not until the last 20 years that NIR
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
spectroscopy has gained increasing interest in the
The methods are time-consuming, as they are usually
pharmaceutical industry with the real breakthrough in
performed in an off-line laboratory, are often wet-
the 1990s as a result of hardware and software
chemical in nature, and are, therefore, not appropriate
improvements. Within the last 10 years a growing
to handle the enormous number of analyses of modern
number of research and review articles have reported
industrial material identification and qualification
on the great potential of NIR spectroscopy in
pharmaceutical research, production, and quality
With the pharmacopoeial-based authorization to
control focussing on various banalytical targetsQ, such
use methods other than the compendial ones for
as identity, content uniformity, moisture content,
compliance testing and the GMP-based opportunity
particle size, polymorphic and pseudopolymorphic
of using bany appropriate procedure or measure to
forms, hardness, thermal and biopharmaceutical prop-
assure the identity of the contents of each container
erties. These different aspects, resulting from the dual
of starting materialsQ, it has been possible to take
dependence of the NIR signal on chemical and
advantage of multi-sensing NIR techniques based on
physical sample characteristics, will be discussed in
fiber optic probes for fast and nondestructive
the context of raw material and intermediate identi-
pharmaceutical raw material identification and qual-
fication and qualification (Section 5.1), analysis of
ification. Many papers have reported on the feasi-
intact dosage forms (Section 5.2), and process
bility of NIR identification and qualification of both
monitoring (Section 5.3), with a main focus on solid
active ingredients and excipients and most
dosage forms.
companies have adopted some form of NIR materialtesting in their supply chain, either in the warehouse
5.1. Identification and qualification of raw materials
only and/or elsewhere in a manufacturing operation,
and intermediates
i.e. wherever rapid assessment of identity and qualityis needed. In combination with bar-code readers,
Raw materials intended for use in pharmaceutical
weighing stations, and electronic batch documenta-
products, i.e. active ingredients and excipients, are
tion a bsmartQ system can be developed that
subject to pharmaceutical quality requirements as
guarantees successful manufacturing operations by
prescribed by Good Manufacturing Practice (GMP)
ensuring that the correct materials of the appropriate
Guidelines for Medicinal Products, and pharmaco-
quality are used in the manufacturing process (see
poeial monographs. To guarantee maximal product
also Sections 4.2 and 5.3).
safety, the GMP guidelines require special testing
Using NIR techniques, the chemical identity of a
procedures within the material supply chain (Directive
particular material is usually confirmed with a spectral
91/355/EEC, Chapter 5.30). In addition to the routine
library approach. If an appropriate library has been
release testing of the substance, single container
constructed, the combined chemical and physical
identification has to be performed for any lot of raw
information in the spectra can also be used for material
material at any time of dispensal.
qualification. Moreover, with an appropriate calibra-
Since modern pharmaceutical processes rely heav-
tion setup, simultaneous quantitative measurements,
ily on a reproducible source and grade of raw
such as moisture content and particle size determi-
materials to ensure consistent finished product quality,
nations, can be performed or bconformityQ approaches
material qualification is another analytical require-
can be used to predict material performance in
ment in the supply chain that has to be fulfilled.
manufacturing processes. The different approaches
Qualification is supposed to confirm the grade and/or
will be discussed in the following paragraphs.
source of materials including physical properties, suchas particle size, density, morphology etc., which may
5.1.1. Library approach
in turn indicate its suitability for the intended use.
Chemical identification usually does not involve
Traditionally, pharmaceutical raw material identifica-
any conceptual problems with respect to spectral
tion and qualification, known as compliance testing,
library development However, exten-
has been based on compendial methods and/or
sion of the identification concept to material qual-
alternative validated in-house testing procedures.
ification is usually more complex. The key parameters
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
for constructing a robust spectral library may, there-
derivative data. For qualification of different grades of
fore, be defined as follows:
excipients, more sophisticated algorithms, such asSIMCA are recommended (see Section 3.4). Only
1. Definition of library scope and purpose.
recently, Kemper and Luchetta have published a
2. Selection of authentic sample spectra for calibra-
comprehensive paper giving practical guidelines for
tion, internal and external validation.
construction, validation and maintenance of spectral
3. Rationale of data pretreatments.
libraries for raw material identification and qualifica-
4. Selection of classification algorithm(s).
5. Determination of thresholds.
6. Maintenance and updating.
5.1.2. Conformity approach
In the early 1990s, van der Vlies and co-workers
The library structure may depend on the software
developed a discriminating method, which
limitations and the user's requirements. In the
they called the bconformityQ approach, and introduced
simplest case, all materials are incorporated into
a new quality parameter, the Conformity Index (CI),
one library . Alternatively, they may be split into
to replace compendial methods for identification,
sub-libraries to ensure the required level of specific-
assay, and moisture content determination of ampi-
ity, as for discrimination of chemically similar
cillin trihydrate. It is worth mentioning that this was
substances, such as close members of a homologous
the first NIR method for release testing of a bulk
series or different grades of microcrystalline cellulose
pharmaceutical product for human consumption
approved by the U.S.F.D.A.
The selection of samples is critical to the success of
The CI is the largest value obtained by dividing the
the application. Two sets of samples are required: one
absolute difference in absorption between sample and
for the construction of the library and an independent
reference spectrum (first or second derivative) for
one for external validation purposes to verify the
each data point by the standard deviation of the
performance of the data base. The number of batches
absorbance of the reference spectrum at that particular
required to train the system depends on the intended
data point. The authors defined the bstandard qualityQ,
scope, i.e. the required discriminatory power of the
i.e. the specification of their material at CI of 5 or
method. The training set must collectively describe
lower, and achieved a high sensitivity of CI for
the typical variation of the substance being analyzed.
chemical and physical deviations. With the so-called
As a rule of thumb, identification normally requires a
Conformity Plot (C-Plot: CI versus wavelength plot) it
much smaller number of different batches (usually 3)
was possible to pinpoint the sources of even very
than qualification (usually 20 or more).
slight variations in chemical and physical properties,
Data pretreatments (see also Section 3.1) strongly
including crystallinity. The conformity approach is
depend on the application. For identification purposes,
well suited for industrial raw material and intermedi-
second derivative and scatter correction are often used
ate qualification, since it gives qualitative answers to
to reduce offsets, due to variable physical material
quantitative questions without the need of exhaustive
characteristics. The rationale of transforms in qual-
calibration work.
ification methods strongly depends on the parameterof interest and is a case by case decision. The effect of
5.1.3. Quantitative calibration models
NIR data pre-processing on the pattern recognition of
Quantitative calibration models in raw material
pharmaceutical excipients has been discussed by
qualification have been described for analytical
targets, such as moisture content particle
The classification model (see also Section 3.4) is
size specific surface area polymor-
the heart of the library. The proper choice of the
phic and pseudopolymorphic forms amor-
algorithm depends on the scope of the library. For
phous/crystalline ratios viscosity and
identification purposes, where physical parameters are
gel strength Moisture content, particle size and
not determined, it is usually sufficient to use a match
polymorphism, also relevant to pharmaceutical inter-
by wavelength correlation method based on second
mediates, will be discussed in more detail.
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
Since chemical, physical, technological and bio-
potential of NIR spectroscopy for particle size
pharmaceutical properties of active ingredients and
determination has been alluded to in many review
excipients may be largely affected by their water
articles, only a few research papers have been
content and the type of water present, evaluation of
dedicated to this subject. Mean particle size
batch-to-batch variability or storage effects on water
or particle size distribution measurements
content and water binding is usually an integral part of
with NIR spectroscopy have been reported, using
material qualification. NIRS is an effective alternative
lactose monohydrate microcrystalline cel-
to traditional methods, such as thermogravimetry and
lulose NaCl, and sorbitol aspirin,
Karl Fischer titration for both water content and water
caffeine and paracetamol and piracetam as
binding determinations. This is due to the fact that
model excipients and active ingredients, respectively.
O–H bands of water are very intensive in the NIR
Various chemometric approaches have been sug-
region, exhibiting five absorption maxima (at 760,
gested for correlating particle size with NIR spectral
970, 1190, 1450, 1940 nm), the positioning of which
information and the literature data clearly reveal that
depends on the hydrogen bonding intensity. The
there is more than one way to model mean particle
specific band to be used for water determinations
size data with NIR spectra, depending on the particle
depends on the desired sensitivity and selectivity level.
size range, shape of the particle size distribution,
NIR quantification of moisture content is usually an
materials refractive index, and absorption properties.
easy task with respect to data processing, i.e. MLR and
Ciurczak et al. found an inverse relationship
PLSR models have been reported. Moreover, reference
between absorbance at each wavelength and mean
data provided by Karl Fischer titration are reliable. It
particle size, with two distinct segments below and
is, therefore, not surprising that NIR moisture content
above 85 Am, indicating the complicating effect of
determinations in both transmittance and reflectance
small particles for quantitative NIR mean particle size
mode have been described extensively in the literature.
measurements. Burger and coworkers have investi-
Most of the early work has been summarized and
gated this aspect in detail and the interested reader is
discussed by Blanco Two papers are worth
referred to some excellent papers of the group dealing
mentioning here, since they demonstrate the potential
with radiative transfer investigations to quantify
of NIRS to distinguish different states of water in raw
absorption and scattering coefficients of pharmaceut-
materials and intermediates. Ciurczak and coworkers
ical powders From a more practical point of
were among the first who demonstrated the
view, Blanco et al. revealed that spectral
opportunity of NIRS to differentiate between total,
reproducibility was affected by sample compactness
bound, and surface bulk water in pharmaceutical raw
and varied in an exponential manner with particle size
materials, thus, demonstrating the advantage of NIRS
(in the range 175–325 Am), thus, pointing to the
over traditional methods, such as KFT and LOD. Dziki
importance of sample presentation for quantitative
et al. detected differences in the location or
particle size measurements.
orientation of the water molecules within the crystal
Pharmaceutical raw materials may exist in amor-
lattice of sarafloxacin with NIRS and used this
phous or crystalline form, with polymorphism and
approach to distinguish between acceptable and
pseudopolymorphism being widely observed in crys-
unacceptable batches for formulation purposes.
talline compounds. The impact of a certain poly-
Mean particle size and particle size distribution of
morphic or pseudopolymorphic form or the degree of
solid raw materials and intermediates are key issues in
crystallinity on the physicochemical and biopharma-
the formulation of many pharmaceutical products,
ceutical material characteristics is well known. NIR
since they have a profound effect on bulk physical
spectroscopy has been reported to be an alternative to
properties, which in turn influence blending and flow
traditional techniques, such as DSC and X-ray powder
characteristics, density, compressibility, and dissolu-
diffraction, for qualification and quantification of the
tion rate. Particle size measurements with NIRS in
crystallinity of miokamycin, lactose mono-
diffuse reflectance mode rely on the particle size-
hydrate, mannitol, sucrose and raffinose; of polymor-
dependent scatter effect of powders resulting in non-
phic or pseudopolymorphic forms of sulfathiazol,
linearly sloping baselines Although the
caffeine and theophylline in bulk and of
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
crystallinity upon hydration during granulation pro-
ing mode is not as critical as with quantitative
cesses The rationale behind this approach is
applications, except for very thick, highly absorbing
the sensitivity of NIR spectra to intermolecular
tablets and sugar-coated tablets, for which the
bondings. The magnitude of spectral differences
reflectance mode is recommended to overcome
between the different forms is, therefore, the key
problems of low analyte signal intensity or even total
issue for quantitative determinations. Patel et al.
absorption in transmittance. Challenges associated
demonstrated in a recent paper that NIRS can be used
with the identification of placebo and verum tablets
to determine polymorphs of sulfathiazol in binary
of different dosage levels (2, 5, 10 and 20% w/w)
mixtures in the range of 0.3% w/w. For amorphous/
within the blister packaging have been reported by
crystalline mixtures of lactose monohydrate, the
Dempster et al. The results of this study clearly
amorphous content was accurately determined to
revealed a higher discriminating ability of direct
within 1% w/w. The literature data clearly reveal that
measurements compared to measurements through
NIR results are comparable with other techniques,
the blister packaging, thus, emphasizing that the effect
thus, reflecting the potential of the method for the
of the packaging material on the accuracy of NIR
assessment of different physical forms in bulk
identification approaches may not be neglected.
materials and intermediates.
Quantitative NIR analysis of active ingredients in
tablets has been widely reported and reviewed in the
5.2. Analysis of intact dosage forms
literature. However, in the earliest NIR assays, tabletswere not analysed intact. The active was extracted
The nondestructive and multivariate nature of NIR
from the matrix or the tablets were at least pulverized
techniques opens new perspectives in the pharma-
prior to NIR measurements. The opportunity to
ceutical analysis of intact dosage forms, including
accurately measure active contents in whole tablets
chemical, physical and related biopharmaceutical
started in the late 1980s with the development and
aspects. This section will discuss NIR applications
subsequent commercialization of appropriate sample
for the characterization of solid dosage forms, namely
holders that allow for a proper fit of even curved
tablets, capsules, lyophilized products and implants.
tablets, thereby reducing variable positioning andstray light effects. Within the last 10 years, the number
of publications describing quantitative NIR measure-
Most of the literature data available on NIR
ments of active ingredients in intact tablets has
applications for intact dosage forms focus on tablets,
increased tremendously Various aspects
ranging from identification and assay to physical and
have been addressed, two of which will be discussed
biopharmaceutical parameters, such as hardness, coat-
in more detail, namely the rationale for selecting the
ing thickness and dissolution rate. It is certainly
appropriate measuring mode, and the practical and
beyond the scope of this paper to review all the
regulatory aspects to be considered in choosing the
published data in these fields. This section is rather
appropriate chemometric approach, including calibra-
intended to provide an update of and comment on
tion sample selection and data pretreatments.
some specific aspects that have not been reviewed in
Selecting the measuring mode for NIR tablet
detail yet. Special attention will be paid to the
analysis strongly depends on tablet thickness, compo-
importance of sample selection, sample presentation
sition and target parameter. Considering quantitative
and collection of reliable reference data for develop-
analysis of active ingredients in tablets, the reflectance
ing robust calibration models. Readers interested in a
mode, mainly used in early work, may have some
more comprehensive coverage of the topics including
limitations, since it covers only a certain part of the
earlier data are referred to selected review articles
tablet This, in turn, can cause false results, if
and a recent book chapter
homogeneity within the tablet cannot be assured or is
Fast and nondestructive identification of active
part of the delivery concept, such as in multilayer
ingredients and exipients in whole tablets, even
tablets. Moreover, the assay of coated tablets may be
through the blister packaging, is certainly a domain
complicated in cases where the majority of spectral
of NIR spectroscopy Generally, the measur-
information is coming from the coating polymer. In
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
view of this, regulators have expressed their concerns
it is surprising that stability issues, i.e. identification
regarding reflectance measurements for content uni-
and quantification of degradation products in tablets,
formity testing. Transmittance spectra, representing a
have only rarely been addressed. There is merely one
larger volume of the scanned tablet, certainly provide
early paper by Drennen and Lodder that reports
a better description of a tablet matrix in bulk.
the use of NIR diffuse reflectance spectroscopy for
Improved accuracy, precision, and sensitivity of
monitoring the hydrolysis of acetylsalicylic acid to
transmittance measurements in various tablet assays
salicylic acid in tablets upon water absorption. Due to
have been demonstrated in the literature
the combined spectral information on water and
However, it should not be neglected that a signifi-
salicylic acid, the authors were able to predict both
cantly narrower wavelength range is available in
parameters from one single measurement, thus,
bdiffuseQ transmittance mode, and limitations are
emphasizing the great potential of NIRS for tablet
observed with very thick tablets Recent papers
stability testing. In addition to chemical stability,
dealing with NIR tablet assays for content uniformity
polymorphic transitions might be another target
testing, therefore, clearly reveal that selection of the
parameter that could be addressed in tablets
appropriate measuring mode is a case by case decision
The mechanical performance of tablets is of
importance for bulk handling, coating, packaging,
As a non-separative method, quantitative NIR
removal from blister, and disintegration. Current
measurements on tablets rely heavily on chemometric
methods of hardness testing are destructive in nature
procedures for data modelling, with sample selection
and often subject to operator error. NIR spectroscopy,
and data pretreatments being the most critical issues
on the other hand, offers the opportunity for fast and
regarding calibration development. Since process-
nondestructive hardness measurements, and provides
related natural variations in tablet mass and hardness
additional information on structural features of the
affect the optical properties and, thus, the baseline of
tablet matrix. Several groups have described the
the recorded spectra, derivative transformation and/or
application of NIRS as an alternative method for
normalization are usually required for accurate NIR
tablet hardness testing Since the approaches
content uniformity measurements. Sample selection
are different with respect to the measuring mode, the
for calibration modelling strongly depends on the
range of hardness levels included in the model, and
chemometric approach. For bconformityQ testing, the
the chemometric data processing, they will be
calibration samples should bsimplyQ cover the normal
discussed in more detail.
range of tablet variability, including intra-batch and
Drennen and co-workers were among the
batch-to-batch variability. Out-of-specification sam-
first who applied NIR spectroscopy to tablet hardness
ples should be considered in the validation step. For
testing. The authors used diffuse reflectance spectro-
quantitative modelling, additional requirements have
scopy and realized that an increase in tablet hardness
to be fulfilled, namely the use of tablets with an
causes a bprimaryQ effect of wavelength-dependent
extended range of active concentrations in the
nonlinear baseline shifting to higher absorbance
calibration step. This is not an easy task in industrial
values, which can be attributed to a decrease in
practice since normal tablet production batches
multiplicative light scattering. Various tablet formula-
are manufactured with tight tolerances. In an excellent
tions, including coated tablets, were investigated at
and comprehensive paper, Moffat and co-workers
hardness levels ranging from 1 to 7 kp and from 6
have discussed this issue and given various options
to 12 kp respectively. A pressure-dependent
for proper calibration sample selection In the
bsecondaryQ spectral effect, namely a peak shifting at
same paper, the authors provided suggestions on how
higher hardness levels arising from changes in
to meet the ICH Guidelines on Validation for NIR
intermolecular bonding, could be observed for some
quantitative analysis of active ingredients in tablets
materials. In view of these observations, the authors
(also see Section 4.1). Validation of quantitative NIR
used different approaches for different hardness
methods has also been addressed by Blanco
levels to correlate spectral data with hardness values.
Considering the huge amount of literature data on
For hardness values in the range of 6 to 12 kp, they
NIR assays for active qualification and quantification,
used PCA/PCR based models, considering mainly
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
bsecondaryQ spectral effects, while removing baseline
Prediction of drug dissolution rates from whole
shifts also resulting from tablet positioning variability
tablet NIR spectra is another application that has been
The SEP values obtained were as precise as the
alluded to in many review articles. However, only a
laboratory hardness test. For hardness values in the
few research papers are really concerned with this
range of 1 to 7 kp, where the bprimaryQ spectral effect
topic, probably due to the challenge of providing
was mainly observed, the authors developed a spectral
tablet samples that cover the appropriate range of
best-fit algorithm based on traditional statistical
variability required to develop robust calibration
methods The proposed approach exploits the
models. The first papers, dating back to the early
baseline shift and involves the determination of a best-
1990s deal with the prediction of the
fit line through each spectrum, thereby reducing the
dissolution rate of carbamazepine tablets following
spectrum to slope and intercept values, e.g. de-
exposure to high humidity. NIR diffuse reflectance
weighting individual absorbance peaks and valleys.
spectra were collected periodically from whole tablets
The method was found to be insensitive to slight
stored in a hydrator. Dissolution rates were correlated
formulation changes (1–10% w/w cimetidine) and
with the spectral data using PCR and the bootstrap
compared favorably to the multivariate PCA/PCR
(BEST) algorithm for modelling. Although this
method with SEP values of around 0.5 kp.
example clearly indicates the potential of NIRS for
Morisseau and Rhodes revealed SEP values in
nondestructive dissolution testing, its citation in
the same range (0.3–0.6 kg) for different tablet
review articles is somewhat misleading, since in this
formulations, namely hydrochlorothiazide (15 and
special example the most prominent parameter affect-
20% w/w) and chlorpheniramine (2 and 6% w/w) in
ing dissolution rate was the moisture content. Quanti-
a matrix of microcrystalline cellulose and magnesium
tative modelling of drug dissolution rates of
stearate, at six hardness levels ranging between 2 and
commercialized tablets stored under normal condi-
12 kg. The authors used MLR and PLS to model the
tions is certainly a greater challenge and requires
diffuse reflectance spectra. Obviously, due to the wide
exhaustive calibration work based on a priori knowl-
range of hardness levels included in the calibration
edge of the formulation- and process-dependent tablet
model, it was not possible to develop acceptable
variables, as well as their effect on both the drug
bmixedQ calibrations by combining data from two
dissolution profile and the spectra. A qualitative
concentrations of the same drug. In a recent paper,
bconformityQ approach (see Section 3.4) might be a
Chen et al. described the favorable use of
more practical option for modelling drug dissolution
artificial neural networks (ANN) to predict tablet
from fast dissolving tablets.
hardness from diffuse reflectance NIR spectral data.
Some authors have examined the
Interestingly, there is only one paper that describes
opportunity of predicting the drug dissolution profile
the use of NIR transmittance measurements for tablet
of tablets with a rate-controlling film coat from whole
hardness determinations Based on the fact that
tablet NIR spectra. Kirsch and Drennen used
compaction of pharmaceutical powders results in
theophylline tablets coated with various amounts of
density variations in different directions and regions
ethylcellulose and collected the spectra in diffuse
of the tablet the author suggests a better
reflectance mode. Reich and co-workers
predictability of whole tablet hardness values from
used a transmittance configuration to collect spectra
transmittance than from reflectance measurements
from Eudragit RL-coated theophylline tablets. In both
Indeed, the data revealed a strong correlation
cases, reliable quantitative calibration models could
between tablet hardness and transmission spectra over
be developed to predict the time required for 50% of
a wide range of hardness levels (10–180 N). In
the theophylline to be released. The rationale behind
addition, material specific bprimaryQ and bsecondaryQ
these approaches is the effect of film coat thickness
spectral effects were used to study the consolidation
and film coat uniformity on both drug dissolution rate
characteristics of different pharmaceutical excipients
and NIR spectra. It is, therefore, not surprising that the
and active ingredients indicating the potential of
same authors used NIR diffuse reflectance and trans-
NIR transmittance applications in tablet formulation
mission spectroscopy to predict film coat thickness
and even film coat uniformity on
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
tablets. SEP values for the determination of film coat
monitoring, for NIR measurements on intact hard
thickness were comparable for transmission and
capsules. The sources of variance in NIR measure-
diffuse reflectance mode. However, reliable reference
ments on hard capsules, being more pronounced than
data were difficult to achieve and were, thus, the
with tablets, has been stressed in detail by Candolfi et
major source of error in the quantitative models.
al. Positioning and time of measurement were
Prediction of film coat uniformity and related gastro-
found to be the most important sources of variance.
resistance with a conformity approach provided much
Positioning effects were attributed to the loose and
better results and required less calibration work
movable filling and the round, smooth, and brilliant
This indeed emphasizes again that bnon-calibratingQ
shell, which affected the reflection angles. The time
qualitative chemometric techniques combined with
factor expresses the effect of surrounding conditions,
NIRS are valuable tools to answer quantitative
such as temperature and relative humidity, on the
sample properties, by inducing small changes in thewater content of the gelatin shell.
Taking these aspects into consideration, it is not
Besides tablets, capsules are among the most
surprising that only a few papers mainly focussing on
prominent solid dosage forms. Since hard and soft
empty capsule shell properties have been published.
capsules differ with respect to manufacturing technol-
Buice et al. and Berntsson et al. described
ogy and formulation, i.e. shell and fill composition,
NIR moisture determinations of empty capsule shells
which in turn may affect analytical target parameters
using reflectance measurements with a filter and a
and NIR measurements, they will be discussed
grating-based instrument, respectively. Buice et al.
used the time-dependent weight gain upon water
Hard capsules are a rather versatile dosage form
uptake of the transparent capsule shells in a hydrator
that can be filled with a variety of formulations, such
at 100% relative humidity as reference data for the
as powders, granules, pellets, microtablets, and even
PCR model, and observed an inaccuracy of the NIR
liquids or semi-solids. The empty shell, usually
method at high humidities. Several possible explan-
composed of gelatin and 12–16% residual moisture
ations were given. However, the most obvious one,
acting as a plasticizer, is purchased from a contract
namely structural changes of the gelatin shell induced
manufacturer and filled on automatic high speed
at high moisture levels was not considered and
filling machines. Identity, assay, moisture content
certainly omitted in the PCR model simply based on
and drug dissolution are the key parameters in hard
the first PC. Berntsson et al. used loss on drying
capsule quality control. At first glance, NIR spectro-
reference data in the moisture range of 5.6–18% w/w
scopy is actually an ideal method to simultaneously
and obtained best results using MLR based on three
determine these parameters from one single measure-
wavelength regions for water and the gelatin back-
ment, thus, replacing time-consuming compendial
bone, respectively.
methods. Moreover, stability testing, aiming at the
Since gelatin is susceptible to cross-linking when
effect of storage conditions and shell/fill interactions,
traces of aldehydes are present in the fill, non-
might be facilitated. The reality is, however, some-
destructive monitoring of this reaction is highly
what more difficult, as will be discussed below.
valuable, since it affects the in vitro dissolution rate
In 1987, Lodder and co-workers published a
of the capsules. Gold et al. published a paper
paper describing the use of NIR spectroscopy and a
on NIR reflectance monitoring of formaldehyde-
quantile-BEAST bootstrap algorithm for discriminat-
induced crosslinking of hard gelatin capsules.
ing adulterated and unadulterated capsules. It is worth
Although the measurements were performed with
mentioning that this was the first report of NIRS
empty capsules, the target parameter for the calibra-
applied to the analysis of intact dosage forms
tion model was the dissolution rate of amoxicillin
following the deaths caused by cyanide-laced capsules
used as a model drug in the fill. The NIR spectra of
in the early and mid-1980s. The authors reported the
stressed versus unstressed capsule shells revealed
significance of shell color, which induced light
changes reflecting new chemical bonds and water
scattering, and sample positioning, which affected fill
loss upon cross-linking.
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
Within the last few years, Reich and co-workers
composed of gelatin, water and one or two polyol
have presented a large body of data
plasticizers Analysis of soft gelatin capsu-
demonstrating the potential of NIR transmittance
les, i.e. identity, assay, hardness, moisture content,
and reflectance spectroscopy in hard capsule shell
dissolution, and stability testing, is usually a very
qualification focussing on identification of the gelatin
time-consuming procedure, due to the more or less
type, manufacturing and storage-induced structural or
complex composition of shell and fill. A non-
moisture changes, and related performance problems,
separative, multi-sensing method, such as NIR spec-
such as brittleness. The studies revealed that the
troscopy, providing combined chemical and physical
spectral range between 1800 and 2500 nm is favorable
information of shell and fill, would certainly be
for hard gelatin capsule shell identification and
desirable. However, only a few papers have been
qualification purposes. Different batches of chemi-
published dealing with the application of NIR to soft
cally identical transparent and opaque capsules with
gelatine capsule analysis Several
different mechanical performance upon filling, result-
reasons might be responsible for this: (1) The thick,
ing from manufacturing-induced structural changes,
often colored gelatin shell strongly absorbs in the NIR
could be distinguished by characteristic band shifts in
region, thus, more or less complicating NIR measure-
this region (Moisture content evaluation was
ments of target parameters in the fill. (2) Positioning
found to depend strongly on the type of colorant
for spectra collection can be an important source of
present in the shell. Strong correlations of NIR
variance, due to shape effects, e.g. variable shell
spectral data with DSC and DMTA test parameters,
thickness within the capsule, seam effects, and bi-
e.g. differences in gelatin physical state (Tg), struc-
coloring (3) Room conditioning is required
tural order (enthalpy), and viscoelastic properties (EV,
during NIRS measurements to reduce undesired
EW) were feasible In summary, these data
effects of moisture changes in the shell
clearly reveal that NIR spectroscopy is a powerful tool
Considering these challenges, it is not surprising
for predicting hard capsule shell performance upon
that NIR feasibility studies focussing on shell cross-
filling, thus allowing for at-line or even on-line
linking shell moisture content plasticizer
control of these parameters at capsule filling machines
content and related physical shell perform-
(see Section 5.3.5).
ance have been performed with transparent,
Soft capsules consist of a lipophilic, hydrophilic or
emptied capsules and/or film formulations. Gold et al.
amphiphilic liquid or semi-solid fill enveloped by a
used NIR reflectance measurements to study the
one-piece, hermetically sealed outer shell. Contrary to
migration of formaldehyde from a polyethylene glycol
hard capsules, they are formed, filled, and sealed in
(PEG) fill into the shell and its reaction with gelatin.
one continuous operation. Their shell, having a
The authors used clear capsules and extracted the fill
thickness in the range of about 500 Am, is usually
before data collection. The spectral changes clearlyrevealed the formation of new chemical bonds and adepletion of water in the shell with increasingconcentration of formaldehyde in the PEG fill. Only
Empty Hard Gelatin Capsules -3D- Loading Plot
recently, Reich and co-workers presented a series ofconference proceedings demonstrating the potential ofNIRS for assessing the chemical and physical proper-ties of soft gelatine capsule shells immediately afterprocessing and upon storage Toreduce the variance associated with positioning andinterferences with the fill, the authors used transparentfilm formulations instead of soft capsules in their
feasibility studies, which were performed in trans-
flectance mode. The spectral data revealed that thecomplex dynamic gelatin/water/plasticizer system of a
Fig. 4. NIR discrimination of elastic and brittle hard gelatin capsuleshells.
soft capsule shell that has been reported in the
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
literature requires careful selection of data
Interestingly, very little data is available on the use
pretreatments and data processing for modelling
of NIRS for quality control of lyophilized proteins
moisture and plasticizer content determinations
Lin and Hsu used five different
Moreover, the type of gelatin was found
proteins to evaluate the accuracy of NIR moisture
to be an important issue that should not be neglected.
content determinations using different chemometric
However, with the appropriate chemometric approach,
approaches. The results revealed differences between
robust calibration models were able to reliably
the proteins with respect to calibration modelling.
quantify moisture (range: 6–12% w/w; SEP = 0.3%;
Reich and co-workers reported the use of
Karl Fischer reference data) and plasticizer content
NIR spectroscopy to evaluate stress-induced structural
(range: 0–50% w/w relative to gelatin; SEP = 1.3%) in
changes of proteins and stabilization effects of sugars
different formulations with respect to gelatin and
upon lyophilization, storage, and rehydration. Spectra
plasticizer type These results clearly indicate
of stressed and unstressed proteins revealed changes
that understanding the NIR spectral changes of soft
associated with the primary, secondary, and tertiary
gelatin capsule shells associated with water and
structure of the proteins. Sensitive amide I, II and III
plasticizer changes is a prerequisite for future appli-
bands and the water absorption band could be used for
cations of NIR spectroscopy in soft capsule quality
the assessment of protein structural changes and
control and stability testing.
aggregation, moisture content changes, and even thephysical state (Tg) of the lyophilized product. Based
5.2.3. Lyophilized products
on MIR reference data, reliable calibration models for
Lyophilization is usually performed to increase the
the determination of changes in the a-helical structure
storage stability of hydrolytically unstable drugs that
were achieved In addition, feasibility of NIR
are intended to be used as injectables or to achieve an
qualification and quantification of amorphous to
instantly soluble oral dosage form. High cake poros-
crystalline transitions as a function of storage con-
ity, low residual moisture, and, in the case of proteins,
ditions were shown.
an amorphous, glassy state are the most prominent
Although there are still a number of challenges to
quality criteria of lyophilized products.
overcome, it can be expected that in the near future
Traditionally, the moisture content of lyophilized
noninvasive NIR measurements will at least partly
products is determined by time-consuming methods,
replace mid-IR measurements for stability testing of
such as Karl Fischer titration. In addition, the
lyophilized proteins. Moreover, this approach is
procedure requires the vial to be opened for analysis.
interesting for on-line and in-line process monitoring
Moisture determination with NIR diffuse reflectance
(see Section 5.3.2).
techniques can be performed in a fast and non-invasive manner through the glass vials. Due to these
5.2.4. Polymeric implants and microspheres
advantages, the NIR technique has been well-
Within the last 20 years, polymeric implants and
adopted in the pharmaceutical industry for efficient
microspheres have gained increasing interest as
moisture content determination of lyophilized prod-
parenteral drug delivery systems to provide sustained
ucts. Early and recent scientific papers in this field
release profiles. The matrix of such systems usually
have focussed on the investigation of
consists of a hydrophobic, non-degradable polymer
parameters affecting measurement accuracy, such as
and optionally a water-soluble pore-forming additive,
cake dimensions particle size
or a biodegradable polymer, such as polylactide-co-
porosity and formulation changes
glycolide (PLGA). Quantitative analysis of active
Derksen et al. used the NIR approach for
ingredients and/or release-controlling excipients
stability testing and correlated moisture content data
within these dosage forms usually involves destruc-
with the concentration of the active ingredient to
tive extraction procedures. Moreover, release testing
calculate product shelf-lives. Only recently, Sukow-
is time-consuming and often requires huge amounts of
ski and Ulmschneider described high speed
test samples, since these dosage forms are sometimes
AOTF-based NIR measurements of lyophilized vials
formulated to release the active component over
for moisture compliance, i.e. release testing.
weeks or months.
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
The application of NIRS as a fast and non-
133,135]. The studies revealed that release monitoring
destructive alternative method for quantification of
of drugs from PLGA matrices is a great challenge,
excipients and actives within polymeric drug delivery
since upon incubation in buffer solution the polymer
systems, such as implants, films and microspheres has
hydrates and slowly hydrolyses, and the matrix
been reported in the literature by two different groups.
erodes. Spectral changes recorded from tablets, films
Brashear et al. investigated the use of NIR
or microspheres, therefore, comprise not only the
reflectance measurements for quantification of an
information of the decreasing drug content, but also
active compound, namely lomefloxacin HCl, and a
the information of the changing structure of the
pore-forming excipient, namely polyethylene glycol
polymer matrix. Anyhow, reliable calibration models
(PEG) 600, in poly(e-caprolactone) microspheres and
could be obtained for both dried and hydrated
implants fabricated by a melt-mold technique. Analyte
samples, thus, indicating the potential of NIRS even
specific wavelength selection and second derivative
for the analysis of complex matrix systems (
transformation followed by PLS modelling allowedfor excellent correlations with UV results for the
5.3. Process monitoring and process control
active and weight-based theoretical values for PEG,respectively. Reich and co-workers used
Noninvasive monitoring of all relevant process
NIR transmittance and reflectance spectroscopy
steps leading to a pharmaceutical drug product is an
together with analyte specific wavelength selection,
integral part of the PAT paradigm of real-time or
second derivative transformation, and PLS data
parametric release and quality by design (see Section
processing to determine theophylline and quinine
4.2). Ideally, the pharmaceutical survey chain should
content (0–20% w/w) within PLGA microparticles
include raw material income (see Section 5.1), all unit
and tablets and lyophilized protein/sugar
operations leading to intermediates and final products,
mixtures (absolute protein content: 0–2.5% w/w) in
and packaging.
The noninvasive and multivariate character of NIR
The same group described the application of NIR
techniques provides an interesting platform for
transmittance and reflectance measurements for mon-
pharmaceutical process monitoring and control.
itoring matrix hydration, matrix degradation, and drug
Although most of the reported applications of NIR
release (theophylline and lysozyme) from biodegrad-
spectroscopy in the pharmaceutical industry are off-
able PLGA tablets, films and microspheres
line or at-line, there are also some on-line and in-line
Lysozym release from PLGA
Validation Spectra f(x)=0.9601x+0.2566 r=0.974755
Calibration Spectra f(x)=0.9777x+0.0964 r=0.988771
- NIR measurement
Lysozym in tablet after incubation [mg]
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 pH7.4/37 8C).
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
applications. In this section, the current state and
also evenly distributed. The role of the excipients,
future potential of NIR techniques in pharmaceutical
which not only improves dosage form compliance, but
at-line, on-line, and in-line process monitoring and
also affects the technological and biopharmaceutical
process control will be reviewed and discussed, with
performance of the formulation, is simply neglected.
the main focus on technological unit operations that
Considering these disadvantages of traditional
are critical for the manufacture of solid dosage forms.
powder blend monitoring procedures, the potential
A discussion on chemical reactions, crystallization
value of a noninvasive NIR on-line or in-line approach
and fermentation processes, or extraction and purifi-
is evident. NIR monitoring of powder blending can be
cation procedures, all relevant operations in the
performed with fiber-optic reflectance probes, thus,
production of pharmaceutical raw materials, is
minimizing assay time and sampling error. Moreover,
beyond the scope of this paper and will not be
since most pharmaceutical active ingredients and
considered. For these topics, the interested reader is
excipients absorb NIR radiation, NIR measurements
referred to an excellent textbook chapter dealing with
can provide homogeneity information regarding all
chemical reaction monitoring and some inter-
mixture components. The multi-sensing property of
esting papers containing a comprehensive discussion
NIR diffuse reflectance spectra, resulting from absorp-
of chemical reaction polymorph conver-
tion and scattering, provides a bmultivariate finger-
sion and bioprocess monitoring
printQ of both chemical and physical sample properties.
with NIR spectroscopy.
The use of NIR spectroscopic techniques for
powder blend uniformity analysis has been reported
5.3.1. Powder blending
by several authors using off-line analysis of samples
Mixing is a fundamental and critical process in the
taken from different blender locations at various
manufacturing process of solid and semisolid phar-
blending times and on-line or in-line
maceutical dosage forms. The ultimate goal of any
monitoring of powder mixing For on-line
mixing procedure is to achieve an bideal mixQ, i.e. a
and in-line monitoring, two different approaches of
situation where the components of a mixture are
spectral data acquisition have been used, namely in a
homogeneously distributed. In practice, this cannot be
bstop-startQ fashion, where the blender is kept sta-
achieved in many cases, in particular when dealing
tionary during NIR measurements, and in a bdynamicQ
with powder blends, since the nature of an boptimalQ
fashion with moving samples.
powder blend may be rather diversified depending on
Sekulic and co-workers were among the first
the material characteristics and the blender type
who reported the use of a NIR fiber-optic probe
Pharmaceutical powder blending processes are, there-
inserted in the axis of rotation of a tumble blender for
fore, optimized during development in such a way as
real on-line stop-start measurements at different times
to stop the process when the mixture homogeneity is
of the blending process. Only recently, El-Hagrasy
within a pre-defined bspecificationQ regarding active
pointed out that multiple spectral sampling
content uniformity.
points in the blender are essential for accurate and
Current approaches to assess powder blend homo-
precise estimation of mixing end points when using
geneity are time consuming and hampered by
the stop–start fashion. This result was further sub-
sampling errors since they involve the removal
stantiated by the additional use of a NIR camera that
of unit-dose samples from defined mixer locations
enabled large spectral images of the blend to be
using a sample thief, the extraction of the active drug
obtained (see also Section 6.3).
from the sample matrix, and the drug content analysis
To allow proper in situ analysis of moving powder
by either HPLC or UV spectroscopy. The distribution
blends, the effect of sample movement on the spectral
of individual excipients is typically assumed to be
response was addressed in detail by Berntsson et al.
homogeneous if the active ingredient is uniformly
The authors realized that sample move-
distributed. In the traditional pharmaceutical sense,
ment can cause unwanted spectral artefacts when
blend homogeneity obviously addresses only the
heterogeneous samples are analyzed with a dispersive,
distribution, i.e. the content uniformity of the active
mechanically scanning grating spectrometer. The
drug substance while assuming that the excipients are
performance of an FT spectrometer was found to be
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
suitable for the analysis of powders moving at
probes is a feasible option to optimize drying times.
moderate speeds (up to 1 m s1).
Several approaches, including microwave, vacuum,
Several data processing strategies for the assess-
fluid-bed and freeze drying processes, have been
ment of blend homogeneity and/or optimal blending
described in the literature.
times from NIR measurements have been evaluated in
White published a paper in 1994 reporting
the literature. Most of these reports were concerned
the use of NIR for on-line moisture endpoint detection
with qualitative assessments, such as dissimilarity
in a microwave vacuum dryer. The calibration
between the spectra of a mixture and the ideal
equation used NIR absorbances of water and the
spectrum of the mixture or a moving block
matrix measured at 1410, 1930 and 1630 nm,
standard deviation of NIR spectra
respectively. For samples containing less than 6%
These approaches generally revealed acceptable
moisture, NIR values were within 1% of the Karl
results, although Wargo and Drennen suggested
Fischer reference data with a SEP of 0.6%. At
that bootstrap techniques provided a greater sensitiv-
moisture levels above 6%, a bias was observed,
ity for blend homogeneity assessment than chi-square
which was attributed to sampling limitations and the
calculations. Some recent papers are also
broad range of moisture contents (0.7–25.7%) con-
concerned with quantitative analysis, pointing out that
sidered in the calibration. Changes in drug content of
quantitative analysis is a prerequisite for a complete
the granules did not affect the prediction of moisture
resolution of the chemical and physical properties of
content, thus, demonstrating the robustness of the
the mixture. Non-linearity, which was found to be a
calibration model.
feature of powder blends containing coarse and fine
The work of Harris and Walker involved
particles, was not a problem when using a cubic PLS
real-time quantification of organic solvents, water and
mixtures thereof, evaporating from a vacuum dryer. A
To summarize, it can be concluded that on- and in-
fiber-optic coupled AOTF-NIR spectrometer was used
line powder blend monitoring with NIR spectroscopy
for data collection from the vapor stream and a
is not an easy task, but feasible and in line with the
balance was placed in the dryer to record the reference
PAT paradigm of real-time release, focussing on
data. PLS calibration models were built for on-line
continuous process understanding and quality control
prediction of optimal drying times. Morris et al.
of all production steps, rather than a final product
and Wildfong et al. used NIR in-line monitoring
control only.
to visualize the different stages during a fluid-beddrying process and to accurately determine the
endpoint of accelerated fluid-bed drying processes.
The manufacturing process of a solid pharmaceut-
Only recently, Zhou et al. described the
ical dosage form usually involves several steps, often
advantage of NIRS for in-line monitoring of a drying
including at least one blengthyQ drying process,
process with concomitant distinction between bound
resulting from the time required to dry the material
and free water of a drug substance forming different
plus the time to analytically verify the drying
hydrates. The study revealed that NIRS can serve as a
endpoint. Fluid-bed drying and tray drying in a large
tool to ensure that the desired hydrate form is
oven are the most frequently used methods for wet
achieved at the end of a drying process.
granules. Microwave vacuum drying is another
An interesting paper on the in situ monitoring of a
option, although less popular. Freeze- and spray-
freeze-drying process has recently been published by
drying are the methods of choice for temperature- and
Brqlls et al. A NIR fiber-optic probe fitted to a
moisture-sensitive drug substances. Current methods
FT spectrometer was placed in the center of a vial 1
to determine drying endpoints include indirect in-line
mm above the bottom. An aqueous PVP solution was
methods, such as temperature measurements, and
used as a model formulation. NIR monitoring of the
direct off-line moisture analysis of samples taken
different stages of the process, namely freezing,
from the dryer. Since O–H vibrations of water exhibit
primary, and secondary drying, was able to detect
a large absorption in the NIR region, on-line
the freezing point, completion of ice formation, and
monitoring of moisture levels using NIR fiber-optic
transition from the frozen solution to an ice-free
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
material. Moreover, NIR spectra provided new infor-
ments. The authors observed a significant effect of the
mation about the drying process, such as the
liquid flow rate and the process air temperature
desorption rate and the steady-state value at which
Frake et al. reported the use of in-line NIR to
drying was complete. These results clearly indicate
investigate granule water uptake and particle size
that the application of an in situ NIR configuration
changes during aqueous top-spray fluid-bed granula-
offers the possibility of studying product character-
tion. During the process, spectra were obtained every
istics during freeze-drying, thus, increasing our
2.5 min with a mounted fiber-optic probe fitted to a
understanding of important parameters in the formu-
grating-based spectrometer ranging from 1100 to
lation development of lyophilized products.
2500 nm. To determine moisture content quantita-tively, and, thus, allowing for exact endpoint deter-
5.3.3. Granulation
mination, the second derivative absorbance changes at
The production of tablets often requires a gran-
1932 nm were calibrated against LOD and Karl
ulation step to improve powder flow and compaction
Fischer reference data. A linear relationship was
characteristics, as well as to achieve content uniform-
obtained with SEC values in the order of 0.5% for
ity. Wet granulation is usually performed in a high
both models ranging from 1.5 to 11% w/w of
speed mixer or a fluid-bed granulator and comprises
moisture. For particle growth monitoring, the authors
the following critical steps: wetting, granule formation
tried to develop another calibration model, again
and drying. At-line or in-line monitoring and endpoint
based on one single wavelength only, namely 2282
determination of wet granulation processes with NIR
nm. However, considering the complex full range
spectroscopy offers the possibility of simultaneously
spectral effects of particle size changes (see also
determining particle size and moisture content. More-
Section 5.1), it is not surprising that the authors failed
over, water/excipient interactions, hydrate formation,
to develop an acceptable quantitative calibration
and/or blend segregation may be assessed easily. The
model for particle size determination.
following examples taken from the literature will
Goebel and Steffens presented successful
illustrate the potential and limitations of granulation
data for a simultaneous on-line determination of
process monitoring with NIR spectroscopy in both
particle size and moisture content of samples in a
formulation development and in routine production.
fluid-bed granulation process using a FT spectrometer.
In 1996, List and Steffens published a paper
The robustness of the PLS calibration models, based
on NIR in-line monitoring of a wet granulation
on Karl Fischer and laser diffraction reference data,
process in a mixer granulator. The process was
was evaluated by applying them to development and
stopped after certain time intervals and a NIR sensor
pilot-scale plants. The results clearly revealed that
probe within the mixer recorded the spectra. A reliable
particle size measurements are a greater challenge for
quantitative PLS calibration model for moisture
NIR on-line monitoring configurations than moisture
determination of a placebo mixture ranging between
content determination, a fact that was attributed to
6 and 15% w/w was developed and validated using
sample presentation, e.g. density effects and certain
Karl Fischer reference data. Best results were obtained
variables of the fiber-optic probes.
with the following spectral pretreatments: wavelength
Rantanen and co-workers published a series of
selection (5000–5500 cm1), normalization, and first
papers dealing with the evaluation of a
derivative. The authors discussed the limitations of
NIR sensor of only a few wavelengths for in-line
transferring placebo calibrations to active products
moisture monitoring of fluid-bed granulation. In one
and demonstrated the feasibility of qualitative NIR
of the papers the authors investigated the effect
particle size monitoring during granulation.
of particle size, particle composition and binder type
Watano and co-workers were among the
on NIR moisture monitoring using a full range off-line
first who reported the use of a NIR sensor for moisture
FT spectrometer. The study revealed that wetting and
monitoring and process automation of an agitation
particle growth changes the reflection and refraction
fluid-bed granulation process. A fixed-wavelength
properties of the granules in a complex manner,
NIR filter instrument was used to study the effects
depending not only on the wavelength, but also on the
of operational variables on the NIR moisture measure-
absorption properties of the powder matrix and the
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
binder type. Calibration of in-line NIR moisture
the hydrate formation of anhydrous theophylline and
measurements, even with a fixed-wavelength setup,
caffeine during wet granulation.
therefore, requires understanding and consideration ofthese factors affecting NIR signals.
5.3.4. Pelletization
The use of spectral changes of solid powders and
Interestingly, only little literature data is available
granules associated with moisture uptake and/or
on NIR monitoring of pelletization. In 1996, Wargo
moisture loss is not limited to moisture content
and Drennen developed an at-line NIR method
determinations. They can help to understand the
to monitor the layering of non-pareil seeds with an
chemical and physical performance of active com-
aqueous suspension containing diltiazem HCl, poly-
pounds and excipients in wet granulation processes.
vinyl pyrrolidone, and micronized talcum. Three
Buckton et al. used NIR to study the effect of
independent calibration models were developed to
granulation on the structure of microcrystalline
determine endpoint pellet potency of 15, 30 and 55%
(MCC) and silicified (SMCC) microcrystalline cellu-
w/w diltiazem beads. The models were successfully
lose and to explain the compressibility changes of
transferred from a laboratory scale to pilot scale.
MCC after wet granulation. It was found that MCC,
Radtke et al. described in- and at-line NIR
SMCC and wet granulated SMCC had essentially
configurations for moisture monitoring during matrix
identical physical structures, while wet granulated
pellet production in a rotary fluidized bed. The authors
MCC exhibited structural changes in the NIR spec-
found out that sample presentation is as critical in this
trum related to C–H bonding. With the NIR assess-
case as in granulation process monitoring.
ment of the altered physical structure, it was possibleto explain the change in compressibility of MCC after
5.3.5. Tabletting and capsule-filling
wet granulation.
High speed automatic capsule filling and tabletting
Derbyshire et al. used NIR together with
machines require non-segregating powder blends or
other analytical techniques, namely DSC, NMR, and
granule mixtures with good flow characteristics to
TDS, to study the molecular properties of water in
work properly, and ensure content uniformity and
hydrated mannitol. In accordance with the results
consistent dissolution profiles of the final product. In
obtained from the other methods, NIR spectral data at
practice, segregation of free-flowing particulate mix-
5172 cm1 (O–H bond of water) and 5930 cm1
tures with differences in particle size and/or density is
(C–H stretching peak) clearly indicated two transition
likely to occur through inherent vibrations during
points for the coordination between water molecules
blender discharge, batch transfer to the filling or
and mannitol molecules, namely at 0.11 and 0.25 g/g,
compression area, and even within the equipment.
respectively. The authors speculate that the transitions
Since NIR techniques are able to recognize
are associated with different stages of microdissolu-
chemical and physical changes of particulate blends
tion of the solid, thereby changing the hydrogen-
whole tablets and filled capsules, noninvasive
bonded network between water and mannitol, e.g. the
NIR monitoring of tabletting and capsule filling, from
molecular response of water and mannitol in the
the very beginning to the very end of the process,
spectra. This result argues for the potential of NIR in-
would be valuable to increase production speed and
line measurements in predicting the quantity of water
improve product quality. A NIR sensor on the feed
required for the successful formation of granules
hopper of a capsule-filling machine or a tablet press
could effectively identify the powder mixture and
With the opportunity to monitor solid/water inter-
detect segregation problems of particulate matter upon
actions, i.e. to detect different states of water
feeding the equipment. The final product could be
molecules in a solid, it is not surprising that NIR
further assessed for content uniformity, dissolution
spectra may also provide information on pseudopoly-
properties, and, in the case of tablets, for hardness (see
morphic transitions during wet granulation. In two
also Section 5.2). Indeed, there are some industrial
subsequent papers, R7sanen et al. and Jorgensen
approaches leaning in this direction, although they
et al. demonstrated the efficiency of NIR
have not yet been fully exploited, due to limitations in
spectroscopy to study the state of water and, thus,
spectra collection of tablets or capsules produced at
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
high speed. However, it might be expected that
method provided predictions of applied polymer films
progress in process instrumentation and chemometric
with SEP values of 1.07% or less, depending on the
data processing will speed up the development of NIR
coating formulation. For pigment-free coating formu-
process monitoring in tabletting and capsule filling in
lations, the calibration model was based mainly on
the near future.
distinct absorption peaks of the coating polymer. Informulations containing high concentrations of water-
5.3.6. Film coating
insoluble dyes and opacifying agents, such as titanium
Film coating is a process commonly employed in
dioxide, baseline shifts were the primary spectral
the pharmaceutical industry to either improve the taste
change caused by an increase in film thickness.
or swallowing of tablets, or to control drug dissolution
Subsequent papers on this topic were published by
rate from the solid dosage forms. Regardless of the
Andersson et al. who described an indus-
intended use, the functionality of a film coat is closely
trial in-line approach for film coat monitoring of
related to its thickness and uniformity around the solid
pharmaceutical pellets with fiber-optic probes. Cali-
core. In most production settings, the endpoint of a
bration models for the determination of film coat
coating process is determined by in-process sample
thickness were based on reference data obtained from
acquisition, the weighing of a known sample size and
the determination of the theoretical amount of applied
Despite these interesting and excellent papers
polymer. Correct film coat thickness and uniformity
clearly reflecting the great value of NIR techniques
are evaluated indirectly by disintegration and/or
for at-line or in-line monitoring of a coating process,
dissolution testing. In the PAT sense, this analytical
the multivariate potential of NIR spectroscopic meth-
procedure has two major disadvantages: first, deter-
ods has not been fully exploited in this field. As
mination of mass increase does not account for mass
indicated by Reich and Frickel in a series of conference
loss of core material, thus, reducing the accuracy of
proceedings NIRS could be implemented as
the method; and secondly, disintegration and/or
a useful at-line or in-line tool to survey and determine
dissolution testing are only indirect, rather time-
the effect of process conditions on film coat uniformity
consuming methods for the measurement of coating
(and related biopharmaceutical properties (see
levels and uniformity.
also Section 5.2.1). As will be discussed in section
NIR techniques, on the other hand, allow for a
6.3, imaging techniques might be an additional tool to
rapid, noninvasive at-line and in-line monitoring and
improve product quality and the production speed of
control of film coating processes prior to biopharma-
film-coated dosage forms
ceutical testing. Kirsch and Drennen and Wargoand Drennen were among the first to describethe use of NIR for at-line monitoring of film coatingprocesses on tablets and pellets. A Wurster columnwas retrofitted with a sample thief, allowing with-drawal of 10-tablet samples during coating. Sampleswere collected after different time intervals andmeasured on a grating-based NIR spectrometer inreflectance mode. In the case of pellets coatingsamples were classified by a bootstrap patternrecognition technique. The bootstrap standard devia-tion plot made a qualitative identification of coatingendpoints possible. In the case of tablets quantitative calibration models for the determinationof applied polymer solids, namely ethylcellulose andhydroxypropylmethyl cellulose formulations, were
Fig. 6. NIR discrimination of Eudragit L film coats on tablets; effect
developed based on mass increase reference data (0–
of spraying temperature before ageing (20bT: 20 8C, 30bT: 30 8C)
30% w/w) corrected for core attrition. The NIR
and after ageing (20aT, 30aT).
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
Packaging is the last step in the production line of
a pharmaceutical product. To ensure the product
6.1. Basic principles and instrumentation
safety of pharmaceuticals, a last identity check of theproduct on the packaging line would be highly
NIR imaging is a combination of NIR spectroscopy
desirable. Such an inspection system based on the
with digital image processing. A NIR imaging system
combination of a conventional high resolution camera
is basically composed of an illumination source, an
with an on-line diode NIR spectrometer ranging from
imaging optic, a spectral encoder selecting the wave-
900 to 1700 nm at 6 nm resolution has been
lengths, and a focal plane array (FPA) as indicated in
developed recently. The system is supposed to
NIR light from an illumination system is
perform a 100% identity check at full line speed
focussed upon the sample. The diffuse reflectance
(i.e. 12,000 tablets per minute) before closing the
image of the sample is collected by an imaging optic,
blister. The potential of this type of equipment has
the configuration of which depends on the sample size
been evaluated in a feasibility study Using
and type. For macroscopic or microscopic images a
hard gelatin capsules of different shell and fill
focusing lens or a microscope objective are used,
compositions, the authors could demonstrate that the
respectively. Data collection proceeds by recording a
real-time algorithms used in this system work as
series of images on the near-infrared (i.e. InSb or
reliably and accurately as a PCA-based data evalua-
InGaAs) FPA at each wavelength position selected by
tion of spectra collected on an off-line lab spectro-
a spectral encoder, such as a liquid crystal tunable
meter to ensure the identification of flawed products.
filter element (LCTF) or an interferometer. The result
It may, therefore, be expected that other configu-
is a three-dimensional data set, known as a spectral
rations based on high speed NIR spectrometer or NIR
hypercube with the x and y axis representing spatial
imaging techniques will be developed in the near
information and the z axis representing the spectral
future for identity check on packaging lines.
False Colour Image
Fig. 7. Basic configuration of a near-infrared imaging system.
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
Regarding instrumentation there are basically two
because the spectral data are collected in parallel
different approaches. The first approach is the wave-
and, thus, are not hampered by a dilution effect in
length scanning method, also known as the bstaring
the same way as NIR bulk measurements are. This
imager methodQ. Sample and camera are kept sta-
is a great advantage over conventional NIRS when
tionary and single images are recorded for each
analyzing low dose actives or excipients in a
wavelength. The spectral information is provided
either by a number of discreet filters, by tuneable
! Moreover, NIR imaging enables quantitative infor-
filters, or by combination with an imaging Fourier-
mation to be obtained without running separate
transform spectrometer. The images recorded for the
calibration samples, since pure component spectra
different wavelengths are combined by the software
are directly available from the spectral imaging
and the spectra calculated. The second approach, also
data cube of heterogeneously mixed samples. This
known as bpush-broom scanningQ method, requires a
approach can help to save time and money when
relative movement between camera and sample to
building a quantitative calibration model for
scan over the surface. The imaging system records the
pharmaceutical applications, in particular for
spatial information linewise and provides the spectral
expensive peptide or protein drug formulations.
information for each pixel along the line by projectionalong the second axis of the two-dimensional camera-
NIR spectroscopic imaging has only a short
chip. The spectral encoding is provided by either
history when compared with MIR and Raman
linear variable filters, a digital micro-mirror array in
imaging techniques. This is due to the fact that its
combination with a grating, or dispersive optics. The
advantages over Raman and MIR imaging techni-
computer software combines the slices, derives the
ques, such as adaption to a wide variety of fields-
second axis and, thus, reconstructs the full image.
of-view (FOV) and extreme tolerance to variations
Experimental setups based on the staring imager
in sample geometry, have only recently been fully
method are mainly used in research and quality
exploited With the use of simple quartz–
control laboratories with data acquisition times of
tungsten halogen sources and an image filtering,
typically 2 min or less. The second approach is used
instead of a source filtering approach, NIR imaging
for conveyor belt survey with data acquisition times
techniques enable wide-field illumination for a
depending on the spectral encoder. A detailed
variety of magnifications and imaging modes,
description of the different principles can be found
ranging from around 0.2 to 125 mm. In addition,
in some recent textbooks
flatness of the sample is not a prerequisite as inRaman and MIR imaging. On the contrary, NIR
6.2. Analytical targets and strengths
imaging systems allow experiments to be performedon very irregular samples, since NIR imaging
Conventional, i.e. non-imaging NIR spectroscopy,
systems perform well in the reflectance mode with
analyzes the sample in bulk and determines an
large depths-of-field and an excellent signal-to-noise
average composition across the entire sample. NIR
ratio of the arrays.
imaging, on the other hand, provides informationabout the spatial distribution of the components
6.3. Pharmaceutical applications
comprising the sample. It is, therefore, a powerfulbline extensionb of conventional NIR analysis in a
With the addition of spatial information and
number of different ways
parallel data collection, NIR imaging certainly meetsthe challenging analytical needs of pharmaceutical
! The opportunity to visualize the spatial distribution
quality and process control, and may serve as a
of a chemical species throughout the sample enables
versatile adjunct to conventional, non-imaging NIR
the degree of chemical and/or physical heteroge-
spectroscopy in many fields. Despite the obvious
neity within a given sample to be determined.
strengths of NIR imaging techniques, the number of
! The array-based spectral sensing of a NIR imaging
scientific papers and technical notes describing their
system also allows for trace sample measurements,
practical use is limited and mainly in other fields,
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
e.g. plastic sorting high-throughput screening
NIR imaging to identify mixing problems as being
of biological material on conveyor belts,
responsible for bad and good flow characteristics of
remnant analysis of works of art and
powder blends, as well as tablet sticking and tablet
identification of atherosclerotique plaques by means
fracture. The results clearly reveal that NIR imaging is
of an intra-arterial catheter imaging system recently
a powerful tool for matrix characterization not only in
developed at the University of Kentucky. Pharma-
final product control, but also in research, develop-
ceutical papers, as discussed in more detail in the
ment and scale-up of solid pharmaceutical dosage
following paragraphs, focus on three different
forms, i.e. for process and formulation optimization
aspects, namely blend uniformity analysis in pow-
ders and tablets, composition and morphological
The same group pointed out that matrix character-
features of coated tablets and multi-layer granules,
ization of complex solid dosage forms requires an
and spatial changes in biodegradable PLGA matrix
understanding of the spatial relationship and inter-
systems upon matrix hydration, degradation and
action of drug formulation components. NIR imaging
active release.
was, therefore, used to examine the internal structure
El-Hagrasy et al. used an InSb imaging
of time-release granules The chemical image of
camera with discrete bandpass filters encompassing
a bisected granule (0.9 mm2) was obtained at 10-nm
absorption bands of the blend components, in
intervals from 1000 to 1700 nm through a 10
addition to a conventional NIR fiber-optic probe in
microscope objective with a total acquisition time of
six sapphire windows mounted at different locations
approximately 2 min. In contrast to the visible image,
in a V-blender, to monitor powder blend homoge-
the NIR chemical image clearly revealed that the
neity of salicylic acid/lactose mixtures and compare
distinct layers and boundaries were consistent with the
the potential of the two techniques. Data analysis
expected physical structure and composition of this
indicated the necessity of using multiple sampling
points for mixing endpoint determination by tradi-
Another interesting application of NIR imaging is
tional NIRS and clearly revealed that coupling both
the chemical visualization of coating layers on
techniques might provide a very robust tool for
tablets. In a technical note published at the AAPS
monitoring powder blending, since the volume of
Annual Meeting in 2001, Lewis and co-workers
powder captured by the imaging technique is much
showed the chemical image of a sectioned
multilayer-coated tablet. The macroscopic chemical
Koehler et al. demonstrated the use of NIR
image depicted the tablet core and two distinct
imaging to visualize and quantify the spatial dis-
coating layers of different thickness. Due to the large
tribution of the active ingredient in a tablet. The
field-of-view (FOV), a detailed examination of the
authors used an unsupervised PCA score plot to
film coat uniformity on the tablet core was not
qualitatively visualise the degree of chemical hetero-
feasible. Moreover, sectioning of the tablet was
geneity of the formulation showing the active in
necessary to achieve the multilayer chemical image
unevenly distributed clumps. An alternate least
of the tablet. However, considering that formulation-
square regression method, based on pure component
and/or process-induced microheterogeneities in film
spectra isolated from the spectral data cube of the
coats on tablets or pellets might have rather
tablet, was used to build a quantitative concentration
important implications on their biopharmaceutical
distribution estimate of the active in the tablet.
properties, the necessity of spectroscopic imaging
Although in this special case, the active concen-
techniques for film coat uniformity analysis is
tration was 20% by weight, the example clearly
obvious. Interestingly, the application of microscopic
demonstrates the strength of NIR imaging for the
ATR-FTIR imaging rather than NIR imaging has
analysis of low dose drugs.
been reported for this purpose Nondestructive
Correlation of physical properties and technolog-
chemical images (250 Am 250 Am) of Eudragit FS
ical functionality of powder blends with their chem-
30 D film coats were obtained from different areas
ical heterogeneity is the approach described by
(i.e. at the center part and at the edges) of the tablets
Hammond and Clarke The group has used
to visualize and relate different coating levels,
G. Reich / Advanced Drug Delivery Reviews 57 (2005) 1109–1143
process and/or curing conditions to film coat
phase protein adsorption on the PLGA matrix
uniformity. The study revealed that, due to its low
certainly occurs (
penetration depth, ATR-FTIR imaging may provide
In conclusion, the literature data discussed in this
interesting new insights in the processes involved in
section clearly reveal that spectroscopic imaging
film coating and, thus, a better understanding and
approaches, with NIR imaging in particular, have a
control of manufacturing defects resulting in func-
huge potential for gaining rapid information about the
tionally important microheterogeneities. Although
chemical structure and related physical or biopharma-
using the mid-IR, this example again indicates the
ceutical properties of all types of pharmaceutical
overall great potential of spectroscopic imaging
dosage forms, thus improving product quality and
techniques in research, development, scale-up and
enhancing production speed.
production control of pharmaceutical dosage forms.
Structurally even more complex than film-coated
oral tablets or granules are biodegradable poly(d,l-
7. Concluding Remarks
lactide-co-glycolide) (PLGA) matrix systems forparenteral use. As discussed in Section 5.2.4,
This review has covered some of the recent
hydration, degradation and drug release kinetics can
methods and pharmaceutical applications of NIR
be successfully monitored by classical NIR spectro-
spectroscopy and imaging. As a fast and noninvasive
scopy, however, without any information on the
multivariate technique, conventional NIR spectro-
spatial changes. In an attempt to fill this gap, NIR
scopy has already gained wide industrial acceptance
imaging was used (1) to investigate the time-depend-
for raw material identification and/or qualification,
ent spatial microenvironmental changes within bio-
and nondestructive chemical analysis of intact dosage
degradable PLGA films upon in vitro hydration and
forms. Considering the continuing improvements in
degradation in different media and (2) to
hardware and software design, and the analytical
chemically visualize the distribution and relative
requirements of the most recent concepts of quality by
abundance of a model protein, namely lysozyme, in
design and real-time or parametric release, it is
PLGA matrix tablets, immediately after processing
anticipated that in the near future both NIR spectro-
and during the release phase Within these
scopy and imaging may progressively become routine
studies it could be demonstrated for the first time
methods for pharmaceutical process monitoring and
without fluorescence-labeling that during the release
process control.
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).
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Source: http://www.odin.life.ku.dk/news_letters/Q2_Q3_2005/news001.pdf
The RCPA(NZ) News In this issue - Professor Peter Browett, Haematologist, University of Auckland, discusses a case of Polymyositis provides an update on Non-Hodgkin's Lymphoma. Non-Hodgkin's Lymphoma Update Key Points • lymphomas are a heterogeneous group of malignancies with variable clinical presenta-tion, response to therapy and prognosis.
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