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Advanced Drug Delivery Revi

Near-infrared spectroscopy and imaging Basic principles

and pharmaceutical applications

Gabriele ReichT

Institute for Pharmacy and Molecular Biotechnology Department of Pharmaceutical Technology and Pharmacology

University of Heidelberg Im Neuenheimer Feld 366 D-69120 Heidelberg Germany

Received 17 December 2003 accepted 19 January 2005

Abstract

Near-infrared (NIR) spectroscopy and imaging are fast and nondestructive analytical techniques that provide chemical and

physical information of virtually any matrix In combination with multivariate data analysis these two methods open many

interesting perspectives for both qualitative and quantitative analysis This review focuses on recent pharmaceutical NIR

applications and covers (1) basic principles of NIR techniques including chemometric data processing (2) regulatory issues (3)

raw material identification and qualification (4) direct analysis of intact solid dosage forms and (5) process monitoring and

process control

D 2005 Elsevier BV All rights reserved

Keywords Noninvasive qualitative and quantitative analysis Calibration and validation Chemometrics Raw material identification and

characterization Quality control of intact dosage forms Process analytical technologies (PAT) Process monitoring

Contents

1 Introduction 1110

2 Basic principles of near-infrared (NIR) spectroscopy 1111

21 Origin and characteristics of NIR absorption bands 1111

22 Instrumentation and sample presentation 1112

3 Theory and practice of chemometric data processing 1113

31 Data pretreatments 1113

32 Reduction of variables by principal component analysis (PCA) 1114

33 Multivariate calibration for quantitative analysis 1115

34 Multivariate classification for qualitative analysis 1115

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G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash11431110

4 Regulatory aspects 1116

41 Actual status of pharmaceutical NIR analysis 1116

42 NIR spectroscopy in view of the USFDA initiative on PAT 1117

5 Pharmaceutical applications 1117

51 Identification and qualification of raw materials and intermediates 1118

511 Library approach 1118

512 Conformity approach 1119

513 Quantitative calibration models 1119

52 Analysis of intact dosage forms 1121

521 Tablets 1121

522 Capsules 1124

523 Lyophilized products 1126

524 Polymeric implants and microspheres 1126

53 Process monitoring and process control 1127

531 Powder blending 1128

532 Drying 1129

533 Granulation 1130

534 Pelletization 1131

535 Tabletting and capsule-filling 1131

536 Film coating 1132

537 Packaging 1133

6 NIR imaging 1133

61 Basic principles and instrumentation 1133

62 Analytical targets and strengths 1134


7 Concluding Remarks 1136

References 1137

1 Introduction

Near-infrared spectroscopy (NIRS) is a fast and

nondestructive technique that provides multi-constit-

uent analysis of virtually any matrix It covers the

wavelength range adjacent to the mid infrared and

extends up to the visible region Historically the

discovery of the NIR region in 1800 is ascribed to

Herschel who separated the electromagnetic spectrum

with a prism and found out that the temperature

increased markedly towards and beyond the red ie in

the region that is now called the near-infrared

Although a number of NIR experiments were carried

out in the early 1920s it was not before the mid to late

1960s that NIR spectroscopy was practically used It

was Karl Norris from the US Department of

Agriculture who recognized the potential of this

analytical technique and introduced bmodern NIRSQinto industrial practice [1] From then on the break-

through of the method as an industrial quality- and

process-control tool proceeded in jumps coinciding

with the introduction of efficient chemometric data

processing techniques and the development of novel

spectrometer configurations based on fiber optic

probes

In recent years NIR spectroscopy has gained wide

acceptance within the pharmaceutical industry for raw

material testing product quality control and process

monitoring The growing pharmaceutical interest in

NIR spectroscopy is probably a direct result of its

major advantages over other analytical techniques

namely an easy sample preparation without any

pretreatments the possibility of separating the sample

measurement position and spectrometer by use of

fiber optic probes and the prediction of chemical and

physical sample parameters from one single spectrum

This paper is dedicated to pharmaceutical applica-

tions of NIR spectroscopy To fully appreciate the

analytical versatility of this spectroscopic technique a

short introduction into the principles of the method is

G Reich Advanced Drug Delivery Reviews 57 (2005) 1109ndash1143 1111

helpful To this end the author provides the reader

with a short introduction into the theoretical funda-

mentals of the technique (Section 21) the equipment

it uses (Section 22) and the mathematical and

statistical tools that are needed to process recorded

signals and extract the relevant information for

qualitative or quantitative analysis (Section 3) Sec-

tion 4 focuses on regulatory aspects that are critical

for pharmaceutical NIR analyses Important current

and possible future pharmaceutical applications of

NIR spectroscopy including raw material identifica-

tion and characterization analysis of intact dosage

forms and process monitoring are discussed in

Section 5 Section 6 briefly emphasizes the pharma-

ceutical potential of NIR imaging techniques

2 Basic principles of near-infrared (NIR)

spectroscopy

21 Origin and characteristics of NIR absorption

bands

The American Society of Testing and Materials

(ASTM) defines the NIR region of the electro-

magnetic spectrum as the wavelength range of 780ndash

2526 nm corresponding to the wave number range

12820ndash3959 cm1 The most prominent absorption

bands occurring in the NIR region are related to

overtones and combinations of fundamental vibra-

tions of ndashCH ndashNH ndashOH (and ndashSH) functional

groups The key issues which determine the occur-

rence and spectral properties ie frequency and

intensity of NIR absorption bands are anharmonicity

and Fermi resonance the physical basis of which will

be briefly described in this section For a more

comprehensive treatise the reader is referred to some

excellent textbook chapters on the subject matter [23]

Since the energy curve of an oscillating molecule is

affected by intramolecular interactions vibrations

around the equilibrium position are non-symmetric

and the spacings between energy levels that the

molecule can attain are not identical but rather

decrease with increasing energy This situation

resembles the quantum mechanical model of an

anharmonic oscillator Since quantum mechanical

selection rules do not rigorously exclude transitions

with Dt N1 for anharmonic systems transitions

between vibrational states of Dt =2 or 3 are possible

although their probability decreases with an increase

in the vibrational quantum number t These multi-

level energy transitions are the origin of NIR overtone

bands that occur at multiples of the fundamental

vibrational frequency For most chemical bonds the

wave numbers of overtones can be estimated from

their fundamental vibrations with an anharmonicity

constant v of 001ndash005 by the following equation

mx frac14 Dy m0 1 Dyveth THORN eth1THORN

where mx =wave number of x overtone m0=wavenumber of fundamental vibration v =anharmonicity

constant

Combination bands appearing between 1900 nm

and 2500 nm are the result of vibrational interactions

ie their frequencies are the sums of multiples of each

interacting frequency A special type of configuration

interaction called Fermi resonance leads to the

feature that two NIR absorption bands of a polyatomic

molecule with the same frequency do not simply

overlay and sum up but split in two peaks of

somewhat higher and lower frequencies than the

expected unperturbed position Furthermore intermo-

lecular hydrogen bondings and dipole interactions

have to be considered since they alter vibrational

energy states thus shifting existing absorption bands

andor giving rise to new ones This effect allows

crystal forms for instance to be determined by NIR

spectroscopy

In conclusion NIR absorption bands are typically

broad overlapping and 10ndash100 times weaker than

their corresponding fundamental mid-IR absorption

bands These characteristics severely restrict sensitiv-

ity in the classical spectroscopic sense and call for

chemometric data processing to relate spectral infor-

mation to sample properties (see Section 3) The low

absorption coefficient however permits high pene-

tration depth and thus an adjustment of sample

thickness This aspect is actually an analytical

advantage since it allows direct analysis of strongly

absorbing and even highly scattering samples such as

turbid liquids or solids in either transmittance or

reflectance mode without further pretreatments

The dual dependence of the analytical signal on the

chemical and physical properties of the sample

resulting from absorption and scatter effects can be

favorably used to perform chemical and physical


analysis from one single measurement However if

not the analytical target scatter effects in NIR spectra

resulting from physical sample variations may also

pose more or less severe analytical problems In these

situations they have to be considered in the calibra-

tion process as dinterfering parametersT as will be

discussed in Section 3 More detailed information on

the theory of absorption and scatter effects in diffuse

reflectance and transmittance NIR spectroscopy can

be found elsewhere [45]

22 Instrumentation and sample presentation

A NIR spectrometer is generally composed of a

light source a monochromator a sample holder or a

sample presentation interface and a detector allowing

for transmittance or reflectance measurements (Fig 1)

The light source is usually a tungsten halogen

lamp since it is small and rugged [6] Detector types

include silicon lead sulfide (PbS) and indium gallium

arsenide (InGaAs) [6] Silicon detectors are fast low-

noise small and highly sensitive from the visible

region to 1100 nm PbS detectors are slower but very

popular since they are sensitive from 1100 to 2500 nm

and provide good signal-to-noise properties The most

expensive InGaAs detector combines the speed and

size characteristics of the silicon detector with the

wavelength range of the PbS detector

A number of optical configurations exist that can

be used to separate the polychromatic NIR spectral

region into dmonochromaticT frequencies A detailed

description of the different principles can be found in

various textbooks [7ndash9] Here the basic principles and

main differences will be shortly discussed from a

practical point of view Broadband discrete filter

Light Source Monochromator

DetDiffuse R

Fig 1 Basic NIR spectrom

photometers or light-emitting diode (LED)-based

instruments provide selected frequencies thus cover-

ing only a narrow spectral range of 50ndash100 nm

Diffraction grating interferometer diode-array or

acousto-optic tunable filter (AOTF)-based instruments

provide full spectral coverage Selection of the

appropriate technology is usually based upon the

required analyte sensitivity reliability ease of use

calibration transferability and implementation needs

The latter aspect requires laboratory and process

analyzers to be differentiated

Laboratory analyzers are intended for off-line or

at-line measurements in quality control research and

plant laboratories ie high analyte sensitivity and

reliability are required while speed is of lower

importance Optimum sample presentation to the

instrument high signal-to-noise ratio instrument

stability and sufficient resolution are the most

important aspects for analysis Presently grating and

interferometer-based instruments are mainly in use for

this purpose The appropriate NIR measuring mode

will be dictated by the optical properties of the

samples (Fig 2) Transparent materials are usually

measured in transmittance (Fig 2A) Turbid liquids or

semi-solids and solids may be measured in diffuse

transmittance (Fig 2B) diffuse reflectance (Fig 2C)

or transflectance (Figs 2DE) depending on their

absorption and scattering characteristics In any case

absorbance (A) values relative to a standard reference

material are measured with A corresponding to log 1

R and log 1T for reflectance and transmittance

spectra respectively

To measure good NIR spectra the proper sample

presentation is of utmost importance especially when

measuring solid samples since scatter effects and

ectoreflectance

DetectorTransmittance

Sample

eter configurations

Transmittance

DiffuseReflectance

Transflectance

(A)

(B)

(C)

(D)

(E)

Fig 2 NIR measuring modesmdash(AB) transmittance (C) diffuse

reflectance and (DE) transflectance


stray light induced by variations in packing density of

powders or sample positioning of tablets or capsules

may cause large sources of error in the spectra [10]

Therefore several types of sample cells such as

quartz cuvettes with defined optical path length for

liquids specifically designed sample cells with quartz

windows for semi-solids and powders and adjusted

sample holders for tablets and capsules have been

developed [11] Temperature control and sample

movement are other options that have been realized

Process analyzers are intended for in-line or on-

line measurements to provide real-time process

information while operating in harsh conditions This

requires fast and rugged instruments with no moving

parts such as AOTF-based instruments allowing for

numerous readings per second without being sensitive

to vibrations AOTF-based instruments choose wave-

lengths by using radio-frequency signals to alter the

refractive index of a birefringent crystal (usually

TeO2) Wavelength scans can thus be performed

much more rapidly than with other configurations

Since process analyzers are dedicated to performing a

particular analysis on a specific sample type the

process sample interface depends on the sample type

and the process conditions with NIR light being

transferred via fiber optics In-line analysis of clear to

opaque liquids and solids is typically carried out by

contact transmission and reflectance probes while

non-contact reflectance measurements are performed

on materials transported in hoppers or conveyor belts

3 Theory and practice of chemometric data

processing

Since NIR spectra are typically composed of broad

overlapping and thus ill-defined absorption bands

containing chemical and physical information of all

sample components the analytical information is

multivariate in nature and therefore hardly selective

To perform qualitative or quantitative NIR analysis

ie to relate spectral variables to properties of the

analyte mathematical and statistical methods (ie

chemometrics) are required that extract brelevantQinformation and reduce birrelevantQ information ie

interfering parameters

In the following sections the most frequently used

mathematical data pretreatments and their specific

purpose (Section 31) reduction of variables with

principal component analysis (Section 32) multi-

variate calibration methods for quantitative analysis

(Section 33) and multivariate classification techni-

ques for qualitative analysis (Section 34) will be

discussed Different methods for calibration transfer

between instruments an important economic and

regulatory issue for qualitative and quantitative

pharmaceutical NIR analysis have recently been

commented on by Blanco et al [12] and will thus

not be considered here in detail

31 Data pretreatments

Interfering spectral parameters such as light

scattering path length variations and random noise

resulting from variable physical sample properties or

instrumental effects call for mathematical corrections

so-called data pretreatments prior to multivariate

modeling in order to reduce eliminate or standardize

their impact on the spectra Since careful selection of

data pretreatments can significantly improve the

robustness of a calibration model the most commonly

used methods are briefly discussed with respect to the

effect they are able to correct A detailed description

of the techniques can be found elsewhere [13]


Mathematical treatments used to compensate for

scatter-induced baseline offsets include multiplica-

tive scatter correction (MSC) and standard normal

variate (SNV) Both methods have originally been

developed to process reflectance spectra but they

are also applied to transmittance spectra Baseline

shifts and intensity differences resulting from vari-

able positioning or path length variations may be

reduced or eliminated by normalization algorithms

Derivatives can be applied to improve the resolution

of overlapping bands In addition they are able to

reduce baseline offsets Since spectral noise is also

amplified by derivation derivatives are usually

combined with Taylor or Savitzky Golay smoothing

algorithms

32 Reduction of variables by principal component

analysis (PCA)

Since multivariate NIR spectral data contain a huge

number of correlated variables (= collinearity) there is

a need for reduction of variables ie to describe data

variability by a few uncorrelated variables containing

the relevant information for calibration modeling The

best known and most widely used variable-reduction

Inte

nsity

λ1 λ2 λ3

λ1

λ2

λ3

λ2

λ3 F3

Fig 3 Transformation of a spectrum with three variables ie wavelength

thereby converting the spectrum to a single point in a three-dimensional s

and determination of principal components F1 F2 and F3 (e)

method is principal component analysis (PCA) PCA

is a mathematical procedure that resolves the spectral

data into orthogonal components whose linear combi-

nations approximate the original data The new

variables called principal components (PC) eigen-

vectors or factors correspond to the largest eigenval-

ues of the covariance matrix thus accounting for the

largest possible variance in the data set The first PC

represents maximum variance amongst all linear

combinations and each successive variable accounts

for as much of the remaining variability as possible

The transformation procedure is visualized schemati-

cally in Fig 3 on the basis of three original variables

ie three wavelengths per spectrum For real spectra

with p wavelengths the transformation leads to a p-

dimensional space

In pharmaceutical NIR analysis it is often possible

to compress most of the spectral variability to only a

few principal components ie factors with only a

rather small loss of information A number of multi-

variate calibration and classification methods there-

fore rely on PCA data (see Sections 33 and 34) For

further details on PCA interested readers are referred

to the excellent and comprehensive treatise of Howard

Mark [14]

λ1

λ2

λ3

λ1

F1F2

F2F3

F1

s (a) to a new coordinate system with one axis for each wavelength

pace (b) cloud formation of several spectra (c) mean centering (d)


33 Multivariate calibration for quantitative analysis

Before a NIR spectrometer can do any quantitative

analysis it has to be trained ie calibrated using

multivariate methods The calibration process basi-

cally involves the following steps

1 Selection of a representative calibration sample set

2 Spectra acquisition and determination of reference

values

3 Multivariate modeling to relate the bspectral var-iationsQ to the breference valuesQ of the analytical

target property

4 Validation of the model by cross validation set

validation or external validation

The multivariate regression methods most fre-

quently used in quantitative NIR analysis are principal

component regression (PCR) and partial least-squares

(PLS) regression [15] PCR uses the principal compo-

nents provided by PCA (see Section 32) to perform

regression on the sample property to be predicted

PLS finds the directions of greatest variability by

comparing both spectral and target property informa-

tion with the new axes called PLS components or

PLS factors Thus the main difference between the

two methods is that the first principal component or

factor in PCR represents the largest variations in the

spectrum whereas in PLS it represents the most

relevant variations showing the best correlation with

the target property values In both cases the optimum

number of factors used to build the calibration model

depends on the sample properties and the analytical

target Too many factors may lead to an boverfittedQmodel with a high regression coefficient and a low

standard error of calibration (SEC) but a large

standard error of prediction (SEP) Such a model is

not very robust and may fail when tested with an

independent validation set

In some cases the spectral data and the target

property may not be linearly related as a result of

physical sample properties or instrumental effects

These cases can only be addressed by non-linear

calibration methods such as PLS-2 locally weighted

regression (LWR) or artificial neural networks

(ANNs) For details on these methods interested

readers are referred to the corresponding chapters in

a recent textbook on multivariate calibration [16]

34 Multivariate classification for qualitative analysis

In qualitative analysis sample properties that have

to be related to spectral variations have discrete values

that represent a product identity or a product quality

for example bgoodQ or bbadQ To solve the selectivity

and interference problems of NIR spectra multivariate

classification methods are used for grouping samples

with similar characteristics Multivariate classification

methods also known as pattern-recognition methods

are subdivided in bsupervisedQ and bnon-supervisedQlearning algorithms depending on whether or not the

class to which the samples belong is known

bNon-supervisedQ methods also known as cluster

analysis do not require any a priori knowledge

about the group structure in the data but instead

produces the grouping ie clustering itself This

type of analysis is often very useful at an early stage

of an investigation to explore subpopulations in a

data set for instance different physical grades of a

material Cluster analysis can be performed with

simple visual techniques such as PCA (see Section

32) or some hierarchical methods leading to so-called

dendrograms

bSupervised classificationQ methods also known as

discriminant analysis are used to build classification

rules for a number of pre-specified subgroups ie the

group structure of the training set is known The

classification rules are later used for allocating new or

unknown samples to the most probable subgroup

Identity or goodbad quality are thus defined as

belonging to a group with known properties Algo-

rithms of this type such as LDA (= linear discriminant

analysis) QDA (= quadratic discriminant analysis)

SIMCA (= Soft Independent Modelling of Class

Analogies) or KNN (= K nearest neighbours) are

typically used for constructing spectral libraries

Most of the classification methods can operate

either in wavelength space or in a dimension-reduced

factor space In any case their ultimate goal is to

establish mathematical criteria for parametrizing

spectral similarity thus allowing similarity between

samples or a sample and a class to be expressed

quantitatively For this purpose comprehensive libra-

ries of spectra that represent the natural variation of

each product have to be constructed in a bcalibrationQprocess with similarity being expressed by either a

correlation coefficient such as the spectral match


value (SMV) [17] or a distance measure such as

Euclidian or Mahalanobis distance

A detailed description of the different classification

procedures is certainly beyond the scope of this paper

Interested readers are therefore referred to a recent

textbook on the topic [18] Worth mentioning here are

the following practical aspects

The correlation coefficient being defined as the

cosine of the angle between vectors for the sample

spectrum and the average spectrum for each

product in the library is a rather robust parameter

that can be favorably used for chemical identity

testing (see Section 51) since it relies on second

derivative spectra and is thus not influenced by

spectral offsets and globalintensity variations

resulting from physical differences or concentra-

tion changes

Distance-based methods on the other hand also

allow for product qualification The conformity

index (CI) based on the wavelength distance

method is one such parameter that has been used

successfully to pinpoint quality differences in raw

materials and products by using a so-called C-plot

ie a plot of the absolute distance at each wave-

length as a function of the wavelength [19] (see

also Section 51)

4 Regulatory aspects

41 Actual status of pharmaceutical NIR analysis

NIR spectroscopy has a large number of advan-

tages over other analytical techniques and thus

offers many interesting perspectives in pharmaceutical

analysis The scientific rationale of this technology

has been established for many different applications

and justified by a huge number of publications from

academia and industry (see Section 5) However in

the highly regulated pharmaceutical world an ana-

lytical method is only valuable for routine implemen-

tation if it is approved by regulatory authorities

Actually the major pharmacopoeias have generally

adopted NIR techniques The European [20] and

United States Pharmacopoeia [21] both contain a

general chapter on near-infrared spectrometry and

spectrophotometry respectively These chapters ad-

dress the suitability of NIR instrumentation for use in

pharmaceutical analysis focussing mainly on opera-

tional qualification and performance verification com-

prising wavelength scale and repeatibility response

repeatibility photometric linearity and photometric

noise Only some limited guidance is provided in terms

of developing and validating an application

The general legal requirements for instrumentation

qualification procedures namely design qualification

(DQ) installation qualification (IQ) operational qual-

ification (OQ) and performance qualification (PQ)

are described in the cGMP guideline title 21 CFR part

211 For practical realization of these requirements

the American Society for Testing and Materials

(ASTM) has provided NIR specific directions regard-

ing appropriate methodology for establishing spec-

trophotometer performance tests including suitable

standards and multivariate calibration [22] Further

guidance for evaluation of a NIR spectrophotometer

has been provided in a special report of the Analytical

Methods Committee of the British Royal Society of

Chemistry [23]

Many pharmaceutical companies have success-

fully implemented NIR spectrometers in their

quality control laboratories for routine use in raw

material identification and qualification This is

based on the fact that major pharmacopoeias allow

manufacturers to use analytical methods other than

compendial ones for compliance testing provided

they are validated according to parameters such as

specificity linearity range accuracy precision

repeatibility reproducibility detection limit quanti-

fication limit and robustness as is detailed in the

USP Chapter 1225 on Validation of Compendial

Methods [24] and the general ICH Guidelines Q2A

and Q2B on Validation of Analytical Procedures

[25]

Interestingly only few quantitative NIR methods

have gained regulatory approval as yet The main

reason for this is that bnon-separativeQ multivariate

NIR methods differ markedly from bseparativeQ uni-variate chromatographic methods for which USP

Chapter 1225 and the general ICH Guidelines Q2A

and Q2B were written Moffat et al [26] discussed

these aspects extensively in an excellent paper

published in 2000 Based on the example of a

quantitative NIR method for the analysis of para-

cetamol in tablets the authors made suggestions on


how NIR assays can best meet the ICH Guidelines on

Validation The recently published Guidelines for the

Development and Validation of Near-Infrared Spectro-

scopic Methods in the Pharmaceutical Industry [27]

established by the NIR sub-group of the UK Pharma-

ceutical Analytical Sciences Group (PASG) cover the

unique and specific NIR requirements whilst remain-

ing complementary to ICH Q2A and Q2B which

address traditional method validation requirements It

might be expected that the PASG guidelines compris-

ing hardware as well as software aspects can help both

pharmaceutical industry and regulatory agencies in

evaluating future submissions of qualitative and

quantitative NIR methods For details of the PASG

guidelines see wwwpasgorgukNIRmay01pdf

42 NIR spectroscopy in view of the USFDA

initiative on PAT

The production of pharmaceutical dosage forms is

usually a multistage operation consisting of several

validated processes managed by standard operating

procedures (SOPs) Quality assurance including

decisions concerning the satisfactory completion of

each unit operation is actually based on off-line

testing to document quality of a small nominally

random product sample This approach is often very

time consuming and adds significantly to the manu-

facturing cycle time since it requires the process to be

stopped during sample removal data generation and

documentation In addition it does not assure zero

defect product quality since risk assessment and risk

management are not included eg critical process

parameters and material performance attributes may

not be identified

In view of this undesirable situation for industry

and public health it has been recognized that new

testing paradigms are required to succeed in both an

increase in manufacturing efficiency and product

safety The Process Analytical Technology (PAT)

initiative driven by the United States Food and

Drug Administration (USFDA) and major phar-

maceutical companies is a challenging approach

intended to assist the progression of real-time or

parametric release and quality-by-design concepts

by providing an opportunity to move from the

laboratory-based btesting to document quality para-

digmQ to a bcontinuous quality assurance paradigmQ

According to a recently published USFDA

Guidance for Industry [28] PATs are defined as

systems for real-time monitoring and control of

critical process parameters and material performance

attributes thus helping to improve process under-

standing manufacturing cycle time and final prod-

uct quality NIR spectroscopy and imaging may be

one of the major PAT tools since these techniques

are well-suited for at-line in-line and on-line

measurements They can provide a wealth of

chemical and physical information important for

measuring process performance and open up oppor-

tunities to move forward from traditional quality

control concepts to process qualification and product

conformity testing Although a number of challenges

concerning hardware design and regulatory approval

must be overcome to realize the full potential of NIR

spectroscopy and imaging as PAT tools it may be

expected that parametric or even real-time release

concepts may be well assisted by the use of NIR

techniques (see Sections 53 and 63)

5 Pharmaceutical applications

NIR spectroscopy combined with multivariate

data analysis opens many interesting perspectives

in pharmaceutical analysis both qualitatively and

quantitatively Fast and nondestructive NIR measure-

ments without any sample pre-treatments may

increase the analytical throughput tremendously

The use of fiber optic probes offers the opportunity

for in-line and on-line process monitoring The

special feature of combined chemical and physical

information allows for the assessment of a bspectralsignatureQ of raw materials intermediates and final

dosage forms which in turn offers the possibility of

a simultaneous determination of several sample

characteristics

Notwithstanding these advantages pharmaceutical

industry and regulatory bodies have been slow to

adopt the NIR technique most probably since it

lacks the ability of mid-IR to identify samples by

mere inspection of spectra and involves calibration

by sophisticated mathematical techniques (see Sec-

tion 3) Although the earliest publications on phar-

maceutical NIR applications date back to the late

1960s it was not until the last 20 years that NIR


spectroscopy has gained increasing interest in the

pharmaceutical industry with the real breakthrough in

the 1990s as a result of hardware and software

improvements Within the last 10 years a growing

number of research and review articles have reported

on the great potential of NIR spectroscopy in

pharmaceutical research production and quality

control focussing on various banalytical targetsQ suchas identity content uniformity moisture content

particle size polymorphic and pseudopolymorphic

forms hardness thermal and biopharmaceutical prop-

erties These different aspects resulting from the dual

dependence of the NIR signal on chemical and

physical sample characteristics will be discussed in

the context of raw material and intermediate identi-

fication and qualification (Section 51) analysis of

intact dosage forms (Section 52) and process

monitoring (Section 53) with a main focus on solid

dosage forms

51 Identification and qualification of raw materials

and intermediates

Raw materials intended for use in pharmaceutical

products ie active ingredients and excipients are

subject to pharmaceutical quality requirements as

prescribed by Good Manufacturing Practice (GMP)

Guidelines for Medicinal Products and pharmaco-

poeial monographs To guarantee maximal product

safety the GMP guidelines require special testing

procedures within the material supply chain (Directive

91355EEC Chapter 530) In addition to the routine

release testing of the substance single container

identification has to be performed for any lot of raw

material at any time of dispensal

Since modern pharmaceutical processes rely heav-

ily on a reproducible source and grade of raw

materials to ensure consistent finished product quality

material qualification is another analytical require-

ment in the supply chain that has to be fulfilled

Qualification is supposed to confirm the grade andor

source of materials including physical properties such

as particle size density morphology etc which may

in turn indicate its suitability for the intended use

Traditionally pharmaceutical raw material identifica-

tion and qualification known as compliance testing

has been based on compendial methods andor

alternative validated in-house testing procedures

The methods are time-consuming as they are usually

performed in an off-line laboratory are often wet-

chemical in nature and are therefore not appropriate

to handle the enormous number of analyses of modern

industrial material identification and qualification

economically

With the pharmacopoeial-based authorization to

use methods other than the compendial ones for

compliance testing and the GMP-based opportunity

of using bany appropriate procedure or measure to

assure the identity of the contents of each container

of starting materialsQ it has been possible to take

advantage of multi-sensing NIR techniques based on

fiber optic probes for fast and nondestructive

pharmaceutical raw material identification and qual-

ification Many papers have reported on the feasi-

bility of NIR identification and qualification of both

active ingredients and excipients [29ndash38] and most

companies have adopted some form of NIR material

testing in their supply chain either in the warehouse

only andor elsewhere in a manufacturing operation

ie wherever rapid assessment of identity and quality

is needed In combination with bar-code readers

weighing stations and electronic batch documenta-

tion a bsmartQ system can be developed that

guarantees successful manufacturing operations by

ensuring that the correct materials of the appropriate

quality are used in the manufacturing process (see

also Sections 42 and 53)

Using NIR techniques the chemical identity of a

particular material is usually confirmed with a spectral

library approach If an appropriate library has been

constructed the combined chemical and physical

information in the spectra can also be used for material

qualification Moreover with an appropriate calibra-

tion setup simultaneous quantitative measurements

such as moisture content and particle size determi-

nations can be performed or bconformityQ approachescan be used to predict material performance in

manufacturing processes The different approaches

will be discussed in the following paragraphs

511 Library approach

Chemical identification usually does not involve

any conceptual problems with respect to spectral

library development [30313940] However exten-

sion of the identification concept to material qual-

ification is usually more complex The key parameters


for constructing a robust spectral library may there-

fore be defined as follows

1 Definition of library scope and purpose

2 Selection of authentic sample spectra for calibra-

tion internal and external validation

3 Rationale of data pretreatments

4 Selection of classification algorithm(s)

5 Determination of thresholds

6 Maintenance and updating

The library structure may depend on the software

limitations and the userrsquos requirements In the

simplest case all materials are incorporated into

one library [39] Alternatively they may be split into

sub-libraries to ensure the required level of specific-

ity as for discrimination of chemically similar

substances such as close members of a homologous

series or different grades of microcrystalline cellulose

or lactose

The selection of samples is critical to the success of

the application Two sets of samples are required one

for the construction of the library and an independent

one for external validation purposes to verify the

performance of the data base The number of batches

required to train the system depends on the intended

scope ie the required discriminatory power of the

method The training set must collectively describe

the typical variation of the substance being analyzed

As a rule of thumb identification normally requires a

much smaller number of different batches (usually 3)

than qualification (usually 20 or more)

Data pretreatments (see also Section 31) strongly

depend on the application For identification purposes

second derivative and scatter correction are often used

to reduce offsets due to variable physical material

characteristics The rationale of transforms in qual-

ification methods strongly depends on the parameter

of interest and is a case by case decision The effect of

NIR data pre-processing on the pattern recognition of

pharmaceutical excipients has been discussed by

Candolfi et al [41]

The classification model (see also Section 34) is

the heart of the library The proper choice of the

algorithm depends on the scope of the library For

identification purposes where physical parameters are

not determined it is usually sufficient to use a match

by wavelength correlation method based on second

derivative data For qualification of different grades of

excipients more sophisticated algorithms such as

SIMCA are recommended (see Section 34) Only

recently Kemper and Luchetta have published a

comprehensive paper giving practical guidelines for

construction validation and maintenance of spectral

libraries for raw material identification and qualifica-

tion [42]

512 Conformity approach

In the early 1990s van der Vlies and co-workers

[1719] developed a discriminating method which

they called the bconformityQ approach and introduced

a new quality parameter the Conformity Index (CI)

to replace compendial methods for identification

assay and moisture content determination of ampi-

cillin trihydrate It is worth mentioning that this was

the first NIR method for release testing of a bulk

pharmaceutical product for human consumption

approved by the USFDA

The CI is the largest value obtained by dividing the

absolute difference in absorption between sample and

reference spectrum (first or second derivative) for

each data point by the standard deviation of the

absorbance of the reference spectrum at that particular

data point The authors defined the bstandard qualityQie the specification of their material at CI of 5 or

lower and achieved a high sensitivity of CI for

chemical and physical deviations With the so-called

Conformity Plot (C-Plot CI versus wavelength plot) it

was possible to pinpoint the sources of even very

slight variations in chemical and physical properties

including crystallinity The conformity approach is

well suited for industrial raw material and intermedi-

ate qualification since it gives qualitative answers to

quantitative questions without the need of exhaustive

calibration work

513 Quantitative calibration models

Quantitative calibration models in raw material

qualification have been described for analytical

targets such as moisture content [43ndash46] particle

size [3746ndash51] specific surface area [52] polymor-

phic and pseudopolymorphic forms [53ndash56] amor-

phouscrystalline ratios [57ndash63] viscosity [34] and

gel strength [34] Moisture content particle size and

polymorphism also relevant to pharmaceutical inter-

mediates will be discussed in more detail


Since chemical physical technological and bio-

pharmaceutical properties of active ingredients and

excipients may be largely affected by their water

content and the type of water present evaluation of

batch-to-batch variability or storage effects on water

content and water binding is usually an integral part of

material qualification NIRS is an effective alternative

to traditional methods such as thermogravimetry and

Karl Fischer titration for both water content and water

binding determinations This is due to the fact that

OndashH bands of water are very intensive in the NIR

region exhibiting five absorption maxima (at 760

970 1190 1450 1940 nm) the positioning of which

depends on the hydrogen bonding intensity The

specific band to be used for water determinations

depends on the desired sensitivity and selectivity level

NIR quantification of moisture content is usually an

easy task with respect to data processing ie MLR and

PLSR models have been reported Moreover reference

data provided by Karl Fischer titration are reliable It

is therefore not surprising that NIR moisture content

determinations in both transmittance and reflectance

mode have been described extensively in the literature

Most of the early work has been summarized and

discussed by Blanco [12] Two papers are worth

mentioning here since they demonstrate the potential

of NIRS to distinguish different states of water in raw

materials and intermediates Ciurczak and coworkers

[46] were among the first who demonstrated the

opportunity of NIRS to differentiate between total

bound and surface bulk water in pharmaceutical raw

materials thus demonstrating the advantage of NIRS

over traditional methods such as KFT and LOD Dziki

et al [45] detected differences in the location or

orientation of the water molecules within the crystal

lattice of sarafloxacin with NIRS and used this

approach to distinguish between acceptable and

unacceptable batches for formulation purposes

Mean particle size and particle size distribution of

solid raw materials and intermediates are key issues in

the formulation of many pharmaceutical products

since they have a profound effect on bulk physical

properties which in turn influence blending and flow

characteristics density compressibility and dissolu-

tion rate Particle size measurements with NIRS in

diffuse reflectance mode rely on the particle size-

dependent scatter effect of powders resulting in non-

linearly sloping baselines [4749] Although the

potential of NIR spectroscopy for particle size

determination has been alluded to in many review

articles only a few research papers have been

dedicated to this subject Mean particle size [46ndash50]

or particle size distribution [3751] measurements

with NIR spectroscopy have been reported using

lactose monohydrate [374950] microcrystalline cel-

lulose [374951] NaCl and sorbitol [47] aspirin

caffeine and paracetamol [49] and piracetam [48] as

model excipients and active ingredients respectively

Various chemometric approaches have been sug-

gested for correlating particle size with NIR spectral

information and the literature data clearly reveal that

there is more than one way to model mean particle

size data with NIR spectra depending on the particle

size range shape of the particle size distribution

materials refractive index and absorption properties

Ciurczak et al [46] found an inverse relationship

between absorbance at each wavelength and mean

particle size with two distinct segments below and

above 85 Am indicating the complicating effect of

small particles for quantitative NIR mean particle size

measurements Burger and coworkers have investi-

gated this aspect in detail and the interested reader is

referred to some excellent papers of the group dealing

with radiative transfer investigations to quantify

absorption and scattering coefficients of pharmaceut-

ical powders [46465] From a more practical point of

view Blanco et al [48] revealed that spectral

reproducibility was affected by sample compactness

and varied in an exponential manner with particle size

(in the range 175ndash325 Am) thus pointing to the

importance of sample presentation for quantitative

particle size measurements

Pharmaceutical raw materials may exist in amor-

phous or crystalline form with polymorphism and

pseudopolymorphism being widely observed in crys-

talline compounds The impact of a certain poly-

morphic or pseudopolymorphic form or the degree of

crystallinity on the physicochemical and biopharma-

ceutical material characteristics is well known NIR

spectroscopy has been reported to be an alternative to

traditional techniques such as DSC and X-ray powder

diffraction for qualification and quantification of the

crystallinity [57ndash63] of miokamycin lactose mono-

hydrate mannitol sucrose and raffinose of polymor-

phic or pseudopolymorphic forms of sulfathiazol

caffeine and theophylline in bulk [5354] and of


crystallinity upon hydration during granulation pro-

cesses [5556] The rationale behind this approach is

the sensitivity of NIR spectra to intermolecular

bondings The magnitude of spectral differences

between the different forms is therefore the key

issue for quantitative determinations Patel et al [54]

demonstrated in a recent paper that NIRS can be used

to determine polymorphs of sulfathiazol in binary

mixtures in the range of 03 ww For amorphous

crystalline mixtures of lactose monohydrate the

amorphous content was accurately determined to

within 1 ww The literature data clearly reveal that

NIR results are comparable with other techniques

thus reflecting the potential of the method for the

assessment of different physical forms in bulk

materials and intermediates

52 Analysis of intact dosage forms

The nondestructive and multivariate nature of NIR

techniques opens new perspectives in the pharma-

ceutical analysis of intact dosage forms including

chemical physical and related biopharmaceutical

aspects This section will discuss NIR applications

for the characterization of solid dosage forms namely

tablets capsules lyophilized products and implants

521 Tablets

Most of the literature data available on NIR

applications for intact dosage forms focus on tablets

ranging from identification and assay to physical and

biopharmaceutical parameters such as hardness coat-

ing thickness and dissolution rate It is certainly

beyond the scope of this paper to review all the

published data in these fields This section is rather

intended to provide an update of and comment on

some specific aspects that have not been reviewed in

detail yet Special attention will be paid to the

importance of sample selection sample presentation

and collection of reliable reference data for develop-

ing robust calibration models Readers interested in a

more comprehensive coverage of the topics including

earlier data are referred to selected review articles

[1266] and a recent book chapter [67]

Fast and nondestructive identification of active

ingredients and exipients in whole tablets even

through the blister packaging is certainly a domain

of NIR spectroscopy [68ndash70] Generally the measur-

ing mode is not as critical as with quantitative

applications except for very thick highly absorbing

tablets and sugar-coated tablets for which the

reflectance mode is recommended to overcome

problems of low analyte signal intensity or even total

absorption in transmittance Challenges associated

with the identification of placebo and verum tablets

of different dosage levels (2 5 10 and 20 ww)

within the blister packaging have been reported by

Dempster et al [68] The results of this study clearly

revealed a higher discriminating ability of direct

measurements compared to measurements through

the blister packaging thus emphasizing that the effect

of the packaging material on the accuracy of NIR

identification approaches may not be neglected

Quantitative NIR analysis of active ingredients in

tablets has been widely reported and reviewed in the

literature However in the earliest NIR assays tablets

were not analysed intact The active was extracted

from the matrix or the tablets were at least pulverized

prior to NIR measurements The opportunity to

accurately measure active contents in whole tablets

started in the late 1980s with the development and

subsequent commercialization of appropriate sample

holders that allow for a proper fit of even curved

tablets thereby reducing variable positioning [10] and

stray light effects Within the last 10 years the number

of publications describing quantitative NIR measure-

ments of active ingredients in intact tablets has

increased tremendously [2671ndash84] Various aspects

have been addressed two of which will be discussed

in more detail namely the rationale for selecting the

appropriate measuring mode and the practical and

regulatory aspects to be considered in choosing the

appropriate chemometric approach including calibra-

tion sample selection and data pretreatments

Selecting the measuring mode for NIR tablet

analysis strongly depends on tablet thickness compo-

sition and target parameter Considering quantitative

analysis of active ingredients in tablets the reflectance

mode mainly used in early work may have some

limitations since it covers only a certain part of the

tablet [76] This in turn can cause false results if

homogeneity within the tablet cannot be assured or is

part of the delivery concept such as in multilayer

tablets Moreover the assay of coated tablets may be

complicated in cases where the majority of spectral

information is coming from the coating polymer In


view of this regulators have expressed their concerns

regarding reflectance measurements for content uni-

formity testing Transmittance spectra representing a

larger volume of the scanned tablet certainly provide

a better description of a tablet matrix in bulk

Improved accuracy precision and sensitivity of

transmittance measurements in various tablet assays

have been demonstrated in the literature [7172]

However it should not be neglected that a signifi-

cantly narrower wavelength range is available in

bdiffuseQ transmittance mode and limitations are

observed with very thick tablets [73] Recent papers

dealing with NIR tablet assays for content uniformity

testing therefore clearly reveal that selection of the

appropriate measuring mode is a case by case decision

[71ndash737578ndash84]

As a non-separative method quantitative NIR

measurements on tablets rely heavily on chemometric

procedures for data modelling with sample selection

and data pretreatments being the most critical issues

regarding calibration development Since process-

related natural variations in tablet mass and hardness

affect the optical properties and thus the baseline of

the recorded spectra derivative transformation andor

normalization are usually required for accurate NIR

content uniformity measurements Sample selection

for calibration modelling strongly depends on the

chemometric approach For bconformityQ testing thecalibration samples should bsimplyQ cover the normal

range of tablet variability including intra-batch and

batch-to-batch variability Out-of-specification sam-

ples should be considered in the validation step For

quantitative modelling additional requirements have

to be fulfilled namely the use of tablets with an

extended range of active concentrations in the

calibration step This is not an easy task in industrial

practice [77] since normal tablet production batches

are manufactured with tight tolerances In an excellent

and comprehensive paper Moffat and co-workers

have discussed this issue and given various options

for proper calibration sample selection [26] In the

same paper the authors provided suggestions on how

to meet the ICH Guidelines on Validation for NIR

quantitative analysis of active ingredients in tablets

(also see Section 41) Validation of quantitative NIR

methods has also been addressed by Blanco [7475]

Considering the huge amount of literature data on

NIR assays for active qualification and quantification

it is surprising that stability issues ie identification

and quantification of degradation products in tablets

have only rarely been addressed There is merely one

early paper by Drennen and Lodder [85] that reports

the use of NIR diffuse reflectance spectroscopy for

monitoring the hydrolysis of acetylsalicylic acid to

salicylic acid in tablets upon water absorption Due to

the combined spectral information on water and

salicylic acid the authors were able to predict both

parameters from one single measurement thus

emphasizing the great potential of NIRS for tablet

stability testing In addition to chemical stability

polymorphic transitions might be another target

parameter that could be addressed in tablets [86]

The mechanical performance of tablets is of

importance for bulk handling coating packaging

removal from blister and disintegration Current

methods of hardness testing are destructive in nature

and often subject to operator error NIR spectroscopy

on the other hand offers the opportunity for fast and

nondestructive hardness measurements and provides

additional information on structural features of the

tablet matrix Several groups have described the

application of NIRS as an alternative method for

tablet hardness testing [87ndash92] Since the approaches

are different with respect to the measuring mode the

range of hardness levels included in the model and

the chemometric data processing they will be

discussed in more detail

Drennen and co-workers [8789] were among the

first who applied NIR spectroscopy to tablet hardness

testing The authors used diffuse reflectance spectro-

scopy and realized that an increase in tablet hardness

causes a bprimaryQ effect of wavelength-dependent

nonlinear baseline shifting to higher absorbance

values which can be attributed to a decrease in

multiplicative light scattering Various tablet formula-

tions including coated tablets were investigated at

hardness levels ranging from 1 to 7 kp [89] and from 6

to 12 kp [87] respectively A pressure-dependent

bsecondaryQ spectral effect namely a peak shifting at

higher hardness levels arising from changes in

intermolecular bonding could be observed for some

materials In view of these observations the authors

used different approaches for different hardness

levels to correlate spectral data with hardness values

For hardness values in the range of 6 to 12 kp they

used PCAPCR based models considering mainly


bsecondaryQ spectral effects while removing baseline

shifts also resulting from tablet positioning variability

[87] The SEP values obtained were as precise as the

laboratory hardness test For hardness values in the

range of 1 to 7 kp where the bprimaryQ spectral effectwas mainly observed the authors developed a spectral

best-fit algorithm based on traditional statistical

methods [89] The proposed approach exploits the

baseline shift and involves the determination of a best-

fit line through each spectrum thereby reducing the

spectrum to slope and intercept values eg de-

weighting individual absorbance peaks and valleys

The method was found to be insensitive to slight

formulation changes (1ndash10 ww cimetidine) and

compared favorably to the multivariate PCAPCR

method with SEP values of around 05 kp

Morisseau and Rhodes [88] revealed SEP values in

the same range (03ndash06 kg) for different tablet

formulations namely hydrochlorothiazide (15 and

20 ww) and chlorpheniramine (2 and 6 ww) in

a matrix of microcrystalline cellulose and magnesium

stearate at six hardness levels ranging between 2 and

12 kg The authors used MLR and PLS to model the

diffuse reflectance spectra Obviously due to the wide

range of hardness levels included in the calibration

model it was not possible to develop acceptable

bmixedQ calibrations by combining data from two

concentrations of the same drug In a recent paper

Chen et al [92] described the favorable use of

artificial neural networks (ANN) to predict tablet

hardness from diffuse reflectance NIR spectral data

Interestingly there is only one paper that describes

the use of NIR transmittance measurements for tablet

hardness determinations [91] Based on the fact that

compaction of pharmaceutical powders results in

density variations in different directions and regions

of the tablet [93] the author suggests a better

predictability of whole tablet hardness values from

transmittance than from reflectance measurements

[91] Indeed the data revealed a strong correlation

between tablet hardness and transmission spectra over

a wide range of hardness levels (10ndash180 N) In

addition material specific bprimaryQ and bsecondaryQspectral effects were used to study the consolidation

characteristics of different pharmaceutical excipients

and active ingredients [94] indicating the potential of

NIR transmittance applications in tablet formulation

development

Prediction of drug dissolution rates from whole

tablet NIR spectra is another application that has been

alluded to in many review articles However only a

few research papers are really concerned with this

topic probably due to the challenge of providing

tablet samples that cover the appropriate range of

variability required to develop robust calibration

models The first papers dating back to the early

1990s [9596] deal with the prediction of the

dissolution rate of carbamazepine tablets following

exposure to high humidity NIR diffuse reflectance

spectra were collected periodically from whole tablets

stored in a hydrator Dissolution rates were correlated

with the spectral data using PCR and the bootstrap

(BEST) algorithm for modelling Although this

example clearly indicates the potential of NIRS for

nondestructive dissolution testing its citation in

review articles is somewhat misleading since in this

special example the most prominent parameter affect-

ing dissolution rate was the moisture content Quanti-

tative modelling of drug dissolution rates of

commercialized tablets stored under normal condi-

tions is certainly a greater challenge and requires

exhaustive calibration work based on a priori knowl-

edge of the formulation- and process-dependent tablet

variables as well as their effect on both the drug

dissolution profile and the spectra A qualitative

bconformityQ approach (see Section 34) might be a

more practical option for modelling drug dissolution

from fast dissolving tablets

Some authors [8797ndash101] have examined the

opportunity of predicting the drug dissolution profile

of tablets with a rate-controlling film coat from whole

tablet NIR spectra Kirsch and Drennen [87] used

theophylline tablets coated with various amounts of

ethylcellulose and collected the spectra in diffuse

reflectance mode Reich and co-workers [97ndash101]

used a transmittance configuration to collect spectra

from Eudragit RL-coated theophylline tablets In both

cases reliable quantitative calibration models could

be developed to predict the time required for 50 of

the theophylline to be released The rationale behind

these approaches is the effect of film coat thickness

and film coat uniformity on both drug dissolution rate

and NIR spectra It is therefore not surprising that the

same authors used NIR diffuse reflectance and trans-

mission spectroscopy to predict film coat thickness

[87102] and even film coat uniformity [97ndash99] on


tablets SEP values for the determination of film coat

thickness [102] were comparable for transmission and

diffuse reflectance mode However reliable reference

data were difficult to achieve and were thus the

major source of error in the quantitative models

Prediction of film coat uniformity and related gastro-

resistance with a conformity approach provided much

better results and required less calibration work [98]

This indeed emphasizes again that bnon-calibratingQqualitative chemometric techniques combined with

NIRS are valuable tools to answer quantitative

questions

522 Capsules

Besides tablets capsules are among the most

prominent solid dosage forms Since hard and soft

capsules differ with respect to manufacturing technol-

ogy and formulation ie shell and fill composition

which in turn may affect analytical target parameters

and NIR measurements they will be discussed

separately

Hard capsules are a rather versatile dosage form

that can be filled with a variety of formulations such

as powders granules pellets microtablets and even

liquids or semi-solids The empty shell usually

composed of gelatin and 12ndash16 residual moisture

acting as a plasticizer is purchased from a contract

manufacturer and filled on automatic high speed

filling machines Identity assay moisture content

and drug dissolution are the key parameters in hard

capsule quality control At first glance NIR spectro-

scopy is actually an ideal method to simultaneously

determine these parameters from one single measure-

ment thus replacing time-consuming compendial

methods Moreover stability testing aiming at the

effect of storage conditions and shellfill interactions

might be facilitated The reality is however some-

what more difficult as will be discussed below

In 1987 Lodder and co-workers [103] published a

paper describing the use of NIR spectroscopy and a

quantile-BEAST bootstrap algorithm for discriminat-

ing adulterated and unadulterated capsules It is worth

mentioning that this was the first report of NIRS

applied to the analysis of intact dosage forms

following the deaths caused by cyanide-laced capsules

in the early and mid-1980s The authors reported the

significance of shell color which induced light

scattering and sample positioning which affected fill

monitoring for NIR measurements on intact hard

capsules The sources of variance in NIR measure-

ments on hard capsules being more pronounced than

with tablets has been stressed in detail by Candolfi et

al [10] Positioning and time of measurement were

found to be the most important sources of variance

Positioning effects were attributed to the loose and

movable filling and the round smooth and brilliant

shell which affected the reflection angles The time

factor expresses the effect of surrounding conditions

such as temperature and relative humidity on the

sample properties by inducing small changes in the

water content of the gelatin shell

Taking these aspects into consideration it is not

surprising that only a few papers mainly focussing on

empty capsule shell properties have been published

Buice et al [104] and Berntsson et al [105] described

NIR moisture determinations of empty capsule shells

using reflectance measurements with a filter and a

grating-based instrument respectively Buice et al

used the time-dependent weight gain upon water

uptake of the transparent capsule shells in a hydrator

at 100 relative humidity as reference data for the

PCR model and observed an inaccuracy of the NIR

method at high humidities Several possible explan-

ations were given However the most obvious one

namely structural changes of the gelatin shell induced

at high moisture levels [106] was not considered and

certainly omitted in the PCR model simply based on

the first PC Berntsson et al used loss on drying

reference data in the moisture range of 56ndash18 ww

and obtained best results using MLR based on three

wavelength regions for water and the gelatin back-

bone respectively

Since gelatin is susceptible to cross-linking when

traces of aldehydes are present in the fill non-

destructive monitoring of this reaction is highly

valuable since it affects the in vitro dissolution rate

of the capsules Gold et al [107] published a paper

on NIR reflectance monitoring of formaldehyde-

induced crosslinking of hard gelatin capsules

Although the measurements were performed with

empty capsules the target parameter for the calibra-

tion model was the dissolution rate of amoxicillin

used as a model drug in the fill The NIR spectra of

stressed versus unstressed capsule shells revealed

changes reflecting new chemical bonds and water

loss upon cross-linking


Within the last few years Reich and co-workers

[108ndash112] have presented a large body of data

demonstrating the potential of NIR transmittance

and reflectance spectroscopy in hard capsule shell

qualification focussing on identification of the gelatin

type manufacturing and storage-induced structural or

moisture changes and related performance problems

such as brittleness The studies revealed that the

spectral range between 1800 and 2500 nm is favorable

for hard gelatin capsule shell identification and

qualification purposes Different batches of chemi-

cally identical transparent and opaque capsules with

different mechanical performance upon filling result-

ing from manufacturing-induced structural changes

could be distinguished by characteristic band shifts in

this region (Fig 4) Moisture content evaluation was

found to depend strongly on the type of colorant

present in the shell Strong correlations of NIR

spectral data with DSC and DMTA test parameters

eg differences in gelatin physical state (Tg) struc-

tural order (enthalpy) and viscoelastic properties (EVEW) were feasible [108] In summary these data

clearly reveal that NIR spectroscopy is a powerful tool

for predicting hard capsule shell performance upon

filling thus allowing for at-line or even on-line

control of these parameters at capsule filling machines

(see Section 535)

Soft capsules consist of a lipophilic hydrophilic or

amphiphilic liquid or semi-solid fill enveloped by a

one-piece hermetically sealed outer shell Contrary to

hard capsules they are formed filled and sealed in

one continuous operation Their shell having a

thickness in the range of about 500 Am is usually

Empty Hard Gelatin Capsules -3D- Loading Plot

B1 elasticB1 brittle

Fig 4 NIR discrimination of elastic and brittle hard gelatin capsule

shells

composed of gelatin water and one or two polyol

plasticizers [113114] Analysis of soft gelatin capsu-

les ie identity assay hardness moisture content

dissolution and stability testing is usually a very

time-consuming procedure due to the more or less

complex composition of shell and fill A non-

separative multi-sensing method such as NIR spec-

troscopy providing combined chemical and physical

information of shell and fill would certainly be

desirable However only a few papers have been

published dealing with the application of NIR to soft

gelatine capsule analysis [111115ndash119] Several

reasons might be responsible for this (1) The thick

often colored gelatin shell strongly absorbs in the NIR

region thus more or less complicating NIR measure-

ments of target parameters in the fill (2) Positioning

for spectra collection can be an important source of

variance due to shape effects eg variable shell

thickness within the capsule seam effects and bi-

coloring [10] (3) Room conditioning is required

during NIRS measurements to reduce undesired

effects of moisture changes in the shell [10]

Considering these challenges it is not surprising

that NIR feasibility studies focussing on shell cross-

linking [115] shell moisture content [116] plasticizer

content [116ndash119] and related physical shell perform-

ance [111] have been performed with transparent

emptied capsules andor film formulations Gold et al

[115] used NIR reflectance measurements to study the

migration of formaldehyde from a polyethylene glycol

(PEG) fill into the shell and its reaction with gelatin

The authors used clear capsules and extracted the fill

before data collection The spectral changes clearly

revealed the formation of new chemical bonds and a

depletion of water in the shell with increasing

concentration of formaldehyde in the PEG fill Only

recently Reich and co-workers presented a series of

conference proceedings demonstrating the potential of

NIRS for assessing the chemical and physical proper-

ties of soft gelatine capsule shells immediately after

processing and upon storage [111116ndash119] To

reduce the variance associated with positioning and

interferences with the fill the authors used transparent

film formulations instead of soft capsules in their

feasibility studies which were performed in trans-

flectance mode The spectral data revealed that the

complex dynamic gelatinwaterplasticizer system of a

soft capsule shell that has been reported in the


literature [113114] requires careful selection of data

pretreatments and data processing for modelling

moisture and plasticizer content determinations

[116ndash119] Moreover the type of gelatin was found

to be an important issue that should not be neglected

However with the appropriate chemometric approach

robust calibration models were able to reliably

quantify moisture (range 6ndash12 ww SEP=03

Karl Fischer reference data) and plasticizer content

(range 0ndash50 ww relative to gelatin SEP=13) in

different formulations with respect to gelatin and

plasticizer type [116] These results clearly indicate

that understanding the NIR spectral changes of soft

gelatin capsule shells associated with water and

plasticizer changes is a prerequisite for future appli-

cations of NIR spectroscopy in soft capsule quality

control and stability testing

523 Lyophilized products

Lyophilization is usually performed to increase the

storage stability of hydrolytically unstable drugs that

are intended to be used as injectables or to achieve an

instantly soluble oral dosage form High cake poros-

ity low residual moisture and in the case of proteins

an amorphous glassy state are the most prominent

quality criteria of lyophilized products

Traditionally the moisture content of lyophilized

products is determined by time-consuming methods

such as Karl Fischer titration In addition the

procedure requires the vial to be opened for analysis

Moisture determination with NIR diffuse reflectance

techniques can be performed in a fast and non-

invasive manner through the glass vials Due to these

advantages the NIR technique has been well-

adopted in the pharmaceutical industry for efficient

moisture content determination of lyophilized prod-

ucts Early and recent scientific papers in this field

[120ndash128] have focussed on the investigation of

parameters affecting measurement accuracy such as

cake dimensions [120125] particle size [123]

porosity [123124] and formulation changes [124]

Derksen et al [123] used the NIR approach for

stability testing and correlated moisture content data

with the concentration of the active ingredient to

calculate product shelf-lives Only recently Sukow-

ski and Ulmschneider [125] described high speed

AOTF-based NIR measurements of lyophilized vials

for moisture compliance ie release testing

Interestingly very little data is available on the use

of NIRS for quality control of lyophilized proteins

[124126ndash128] Lin and Hsu [124] used five different

proteins to evaluate the accuracy of NIR moisture

content determinations using different chemometric

approaches The results revealed differences between

the proteins with respect to calibration modelling

Reich and co-workers [126127] reported the use of

NIR spectroscopy to evaluate stress-induced structural

changes of proteins and stabilization effects of sugars

upon lyophilization storage and rehydration Spectra

of stressed and unstressed proteins revealed changes

associated with the primary secondary and tertiary

structure of the proteins Sensitive amide I II and III

bands and the water absorption band could be used for

the assessment of protein structural changes and

aggregation moisture content changes and even the

physical state (Tg) of the lyophilized product Based

on MIR reference data reliable calibration models for

the determination of changes in the a-helical structure

were achieved [126] In addition feasibility of NIR

qualification and quantification of amorphous to

crystalline transitions as a function of storage con-

ditions were shown

Although there are still a number of challenges to

overcome it can be expected that in the near future

noninvasive NIR measurements will at least partly

replace mid-IR measurements for stability testing of

lyophilized proteins Moreover this approach is

interesting for on-line and in-line process monitoring

(see Section 532)

524 Polymeric implants and microspheres

Within the last 20 years polymeric implants and

microspheres have gained increasing interest as

parenteral drug delivery systems to provide sustained

release profiles The matrix of such systems usually

consists of a hydrophobic non-degradable polymer

and optionally a water-soluble pore-forming additive

or a biodegradable polymer such as polylactide-co-

glycolide (PLGA) Quantitative analysis of active

ingredients andor release-controlling excipients

within these dosage forms usually involves destruc-

tive extraction procedures Moreover release testing

is time-consuming and often requires huge amounts of

test samples since these dosage forms are sometimes

formulated to release the active component over

weeks or months


The application of NIRS as a fast and non-

destructive alternative method for quantification of

excipients and actives within polymeric drug delivery

systems such as implants films and microspheres has

been reported in the literature by two different groups

Brashear et al [129130] investigated the use of NIR

reflectance measurements for quantification of an

active compound namely lomefloxacin HCl and a

pore-forming excipient namely polyethylene glycol

(PEG) 600 in poly(e-caprolactone) microspheres and

implants fabricated by a melt-mold technique Analyte

specific wavelength selection and second derivative

transformation followed by PLS modelling allowed

for excellent correlations with UV results for the

active and weight-based theoretical values for PEG

respectively Reich and co-workers [131ndash135] used

NIR transmittance and reflectance spectroscopy

together with analyte specific wavelength selection

second derivative transformation and PLS data

processing to determine theophylline and quinine

content (0ndash20 ww) within PLGA microparticles

and tablets [132] and lyophilized proteinsugar

mixtures (absolute protein content 0ndash25 ww) in

lipid matrices [134]

The same group described the application of NIR

transmittance and reflectance measurements for mon-

itoring matrix hydration matrix degradation and drug

release (theophylline and lysozyme) from biodegrad-

able PLGA tablets films and microspheres [131ndash

Lysozym rele

Lysozym in tablet after incubati2 4

2

4

6

8Validation Spectra f(x)=09601x+02566 r=

Calibration Spectra f(x)=09777x+00964 r

Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t

Fig 5 Quantitative calibration model for NIR determination of in vitro lys

7437 8C)

133135] The studies revealed that release monitoring

of drugs from PLGA matrices is a great challenge

since upon incubation in buffer solution the polymer

hydrates and slowly hydrolyses and the matrix

erodes Spectral changes recorded from tablets films

or microspheres therefore comprise not only the

information of the decreasing drug content but also

the information of the changing structure of the

polymer matrix Anyhow reliable calibration models

could be obtained for both dried and hydrated

samples thus indicating the potential of NIRS even

for the analysis of complex matrix systems (Fig 5)

53 Process monitoring and process control

Noninvasive monitoring of all relevant process

steps leading to a pharmaceutical drug product is an

integral part of the PAT paradigm of real-time or

parametric release and quality by design (see Section

42) Ideally the pharmaceutical survey chain should

include raw material income (see Section 51) all unit

operations leading to intermediates and final products

and packaging

The noninvasive and multivariate character of NIR

techniques provides an interesting platform for

pharmaceutical process monitoring and control

Although most of the reported applications of NIR

spectroscopy in the pharmaceutical industry are off-

line or at-line there are also some on-line and in-line

ase from PLGA

on [mg] - Reference measurement6 8

0974755

=0988771

TransmittanceSEP = 042

ozyme release from poly(dl-lactide-co-glycolide) tablets (PBS pH


applications In this section the current state and

future potential of NIR techniques in pharmaceutical

at-line on-line and in-line process monitoring and

process control will be reviewed and discussed with

the main focus on technological unit operations that

are critical for the manufacture of solid dosage forms

A discussion on chemical reactions crystallization

and fermentation processes or extraction and purifi-

cation procedures all relevant operations in the

production of pharmaceutical raw materials is

beyond the scope of this paper and will not be

considered For these topics the interested reader is

referred to an excellent textbook chapter dealing with

chemical reaction monitoring [136] and some inter-

esting papers containing a comprehensive discussion

of chemical reaction [137138] polymorph conver-

sion [139140] and bioprocess [141ndash143] monitoring

with NIR spectroscopy

531 Powder blending

Mixing is a fundamental and critical process in the

manufacturing process of solid and semisolid phar-

maceutical dosage forms The ultimate goal of any

mixing procedure is to achieve an bideal mixQ ie asituation where the components of a mixture are

homogeneously distributed In practice this cannot be

achieved in many cases in particular when dealing

with powder blends since the nature of an boptimalQpowder blend may be rather diversified depending on

the material characteristics and the blender type [144]

Pharmaceutical powder blending processes are there-

fore optimized during development in such a way as

to stop the process when the mixture homogeneity is

within a pre-defined bspecificationQ regarding active

content uniformity

Current approaches to assess powder blend homo-

geneity are time consuming and hampered by

sampling errors [144] since they involve the removal

of unit-dose samples from defined mixer locations

using a sample thief the extraction of the active drug

from the sample matrix and the drug content analysis

by either HPLC or UV spectroscopy The distribution

of individual excipients is typically assumed to be

homogeneous if the active ingredient is uniformly

distributed In the traditional pharmaceutical sense

blend homogeneity obviously addresses only the

distribution ie the content uniformity of the active

drug substance while assuming that the excipients are

also evenly distributed The role of the excipients

which not only improves dosage form compliance but

also affects the technological and biopharmaceutical

performance of the formulation is simply neglected

Considering these disadvantages of traditional

powder blend monitoring procedures the potential

value of a noninvasive NIR on-line or in-line approach

is evident NIR monitoring of powder blending can be

performed with fiber-optic reflectance probes thus

minimizing assay time and sampling error Moreover

since most pharmaceutical active ingredients and

excipients absorb NIR radiation NIR measurements

can provide homogeneity information regarding all

mixture components The multi-sensing property of

NIR diffuse reflectance spectra resulting from absorp-

tion and scattering provides a bmultivariate finger-

printQ of both chemical and physical sample properties

The use of NIR spectroscopic techniques for

powder blend uniformity analysis has been reported

by several authors using off-line analysis of samples

taken from different blender locations at various

blending times [145ndash147] and on-line or in-line

monitoring of powder mixing [148ndash153] For on-line

and in-line monitoring two different approaches of

spectral data acquisition have been used namely in a

bstop-startQ fashion where the blender is kept sta-

tionary during NIR measurements and in a bdynamicQfashion with moving samples

Sekulic and co-workers [148] were among the first

who reported the use of a NIR fiber-optic probe

inserted in the axis of rotation of a tumble blender for

real on-line stop-start measurements at different times

of the blending process Only recently El-Hagrasy

[154] pointed out that multiple spectral sampling

points in the blender are essential for accurate and

precise estimation of mixing end points when using

the stopndashstart fashion This result was further sub-

stantiated by the additional use of a NIR camera that

enabled large spectral images of the blend to be

obtained (see also Section 63)

To allow proper in situ analysis of moving powder

blends the effect of sample movement on the spectral

response was addressed in detail by Berntsson et al

[155156] The authors realized that sample move-

ment can cause unwanted spectral artefacts when

heterogeneous samples are analyzed with a dispersive

mechanically scanning grating spectrometer The

performance of an FT spectrometer was found to be


suitable for the analysis of powders moving at

moderate speeds (up to 1 m s1)

Several data processing strategies for the assess-

ment of blend homogeneity andor optimal blending

times from NIR measurements have been evaluated in

the literature Most of these reports were concerned

with qualitative assessments such as dissimilarity

between the spectra of a mixture and the ideal

spectrum of the mixture [146151] or a moving block

standard deviation of NIR spectra [146148150]

These approaches generally revealed acceptable

results although Wargo and Drennen [147] suggested

that bootstrap techniques provided a greater sensitiv-

ity for blend homogeneity assessment than chi-square

calculations Some recent papers [156157] are also

concerned with quantitative analysis pointing out that

quantitative analysis is a prerequisite for a complete

resolution of the chemical and physical properties of

the mixture Non-linearity which was found to be a

feature of powder blends containing coarse and fine

particles was not a problem when using a cubic PLS

calibration

To summarize it can be concluded that on- and in-

line powder blend monitoring with NIR spectroscopy

is not an easy task but feasible and in line with the

PAT paradigm of real-time release focussing on

continuous process understanding and quality control

of all production steps rather than a final product

control only

532 Drying

The manufacturing process of a solid pharmaceut-

ical dosage form usually involves several steps often

including at least one blengthyQ drying process

resulting from the time required to dry the material

plus the time to analytically verify the drying

endpoint Fluid-bed drying and tray drying in a large

oven are the most frequently used methods for wet

granules Microwave vacuum drying is another

option although less popular Freeze- and spray-

drying are the methods of choice for temperature- and

moisture-sensitive drug substances Current methods

to determine drying endpoints include indirect in-line

methods such as temperature measurements and

direct off-line moisture analysis of samples taken

from the dryer Since OndashH vibrations of water exhibit

a large absorption in the NIR region on-line

monitoring of moisture levels using NIR fiber-optic

probes is a feasible option to optimize drying times

Several approaches including microwave vacuum

fluid-bed and freeze drying processes have been

described in the literature

White [158] published a paper in 1994 reporting

the use of NIR for on-line moisture endpoint detection

in a microwave vacuum dryer The calibration

equation used NIR absorbances of water and the

matrix measured at 1410 1930 and 1630 nm

respectively For samples containing less than 6

moisture NIR values were within 1 of the Karl

Fischer reference data with a SEP of 06 At

moisture levels above 6 a bias was observed

which was attributed to sampling limitations and the

broad range of moisture contents (07ndash257) con-

sidered in the calibration Changes in drug content of

the granules did not affect the prediction of moisture

content thus demonstrating the robustness of the

calibration model

The work of Harris and Walker [159] involved

real-time quantification of organic solvents water and

mixtures thereof evaporating from a vacuum dryer A

fiber-optic coupled AOTF-NIR spectrometer was used

for data collection from the vapor stream and a

balance was placed in the dryer to record the reference

data PLS calibration models were built for on-line

prediction of optimal drying times Morris et al [160]

and Wildfong et al [161] used NIR in-line monitoring

to visualize the different stages during a fluid-bed

drying process and to accurately determine the

endpoint of accelerated fluid-bed drying processes

Only recently Zhou et al [162] described the

advantage of NIRS for in-line monitoring of a drying

process with concomitant distinction between bound

and free water of a drug substance forming different

hydrates The study revealed that NIRS can serve as a

tool to ensure that the desired hydrate form is

achieved at the end of a drying process

An interesting paper on the in situ monitoring of a

freeze-drying process has recently been published by

Brqlls et al [163] A NIR fiber-optic probe fitted to a

FT spectrometer was placed in the center of a vial 1

mm above the bottom An aqueous PVP solution was

used as a model formulation NIR monitoring of the

different stages of the process namely freezing

primary and secondary drying was able to detect

the freezing point completion of ice formation and

transition from the frozen solution to an ice-free


material Moreover NIR spectra provided new infor-

mation about the drying process such as the

desorption rate and the steady-state value at which

drying was complete These results clearly indicate

that the application of an in situ NIR configuration

offers the possibility of studying product character-

istics during freeze-drying thus increasing our

understanding of important parameters in the formu-

lation development of lyophilized products

533 Granulation

The production of tablets often requires a gran-

ulation step to improve powder flow and compaction

characteristics as well as to achieve content uniform-

ity Wet granulation is usually performed in a high

speed mixer or a fluid-bed granulator and comprises

the following critical steps wetting granule formation

and drying At-line or in-line monitoring and endpoint

determination of wet granulation processes with NIR

spectroscopy offers the possibility of simultaneously

determining particle size and moisture content More-

over waterexcipient interactions hydrate formation

andor blend segregation may be assessed easily The

following examples taken from the literature will

illustrate the potential and limitations of granulation

process monitoring with NIR spectroscopy in both

formulation development and in routine production

In 1996 List and Steffens [164] published a paper

on NIR in-line monitoring of a wet granulation

process in a mixer granulator The process was

stopped after certain time intervals and a NIR sensor

probe within the mixer recorded the spectra A reliable

quantitative PLS calibration model for moisture

determination of a placebo mixture ranging between

6 and 15 ww was developed and validated using

Karl Fischer reference data Best results were obtained

with the following spectral pretreatments wavelength

selection (5000ndash5500 cm1) normalization and first

derivative The authors discussed the limitations of

transferring placebo calibrations to active products

and demonstrated the feasibility of qualitative NIR

particle size monitoring during granulation

Watano and co-workers [165166] were among the

first who reported the use of a NIR sensor for moisture

monitoring and process automation of an agitation

fluid-bed granulation process A fixed-wavelength

NIR filter instrument was used to study the effects

of operational variables on the NIR moisture measure-

ments The authors observed a significant effect of the

liquid flow rate and the process air temperature [166]

Frake et al [167] reported the use of in-line NIR to

investigate granule water uptake and particle size

changes during aqueous top-spray fluid-bed granula-

tion During the process spectra were obtained every

25 min with a mounted fiber-optic probe fitted to a

grating-based spectrometer ranging from 1100 to

2500 nm To determine moisture content quantita-

tively and thus allowing for exact endpoint deter-

mination the second derivative absorbance changes at

1932 nm were calibrated against LOD and Karl

Fischer reference data A linear relationship was

obtained with SEC values in the order of 05 for

both models ranging from 15 to 11 ww of

moisture For particle growth monitoring the authors

tried to develop another calibration model again

based on one single wavelength only namely 2282

nm However considering the complex full range

spectral effects of particle size changes (see also

Section 51) it is not surprising that the authors failed

to develop an acceptable quantitative calibration

model for particle size determination

Goebel and Steffens [168] presented successful

data for a simultaneous on-line determination of

particle size and moisture content of samples in a

fluid-bed granulation process using a FT spectrometer

The robustness of the PLS calibration models based

on Karl Fischer and laser diffraction reference data

was evaluated by applying them to development and

pilot-scale plants The results clearly revealed that

particle size measurements are a greater challenge for

NIR on-line monitoring configurations than moisture

content determination a fact that was attributed to

sample presentation eg density effects and certain

variables of the fiber-optic probes

Rantanen and co-workers published a series of

papers [169ndash171] dealing with the evaluation of a

NIR sensor of only a few wavelengths for in-line

moisture monitoring of fluid-bed granulation In one

of the papers [171] the authors investigated the effect

of particle size particle composition and binder type

on NIR moisture monitoring using a full range off-line

FT spectrometer The study revealed that wetting and

particle growth changes the reflection and refraction

properties of the granules in a complex manner

depending not only on the wavelength but also on the

absorption properties of the powder matrix and the


binder type Calibration of in-line NIR moisture

measurements even with a fixed-wavelength setup

therefore requires understanding and consideration of

these factors affecting NIR signals

The use of spectral changes of solid powders and

granules associated with moisture uptake andor

moisture loss is not limited to moisture content

determinations They can help to understand the

chemical and physical performance of active com-

pounds and excipients in wet granulation processes

Buckton et al [172] used NIR to study the effect of

granulation on the structure of microcrystalline

(MCC) and silicified (SMCC) microcrystalline cellu-

lose and to explain the compressibility changes of

MCC after wet granulation It was found that MCC

SMCC and wet granulated SMCC had essentially

identical physical structures while wet granulated

MCC exhibited structural changes in the NIR spec-

trum related to CndashH bonding With the NIR assess-

ment of the altered physical structure it was possible

to explain the change in compressibility of MCC after

wet granulation

Derbyshire et al [173] used NIR together with

other analytical techniques namely DSC NMR and

TDS to study the molecular properties of water in

hydrated mannitol In accordance with the results

obtained from the other methods NIR spectral data at

5172 cm1 (OndashH bond of water) and 5930 cm1

(CndashH stretching peak) clearly indicated two transition

points for the coordination between water molecules

and mannitol molecules namely at 011 and 025 gg

respectively The authors speculate that the transitions

are associated with different stages of microdissolu-

tion of the solid thereby changing the hydrogen-

bonded network between water and mannitol eg the

molecular response of water and mannitol in the

spectra This result argues for the potential of NIR in-

line measurements in predicting the quantity of water

required for the successful formation of granules

[174]

With the opportunity to monitor solidwater inter-

actions ie to detect different states of water

molecules in a solid it is not surprising that NIR

spectra may also provide information on pseudopoly-

morphic transitions during wet granulation In two

subsequent papers R7sanen et al [55] and Jorgensen

et al [56] demonstrated the efficiency of NIR

spectroscopy to study the state of water and thus

the hydrate formation of anhydrous theophylline and

caffeine during wet granulation

534 Pelletization

Interestingly only little literature data is available

on NIR monitoring of pelletization In 1996 Wargo

and Drennen [175] developed an at-line NIR method

to monitor the layering of non-pareil seeds with an

aqueous suspension containing diltiazem HCl poly-

vinyl pyrrolidone and micronized talcum Three

independent calibration models were developed to

determine endpoint pellet potency of 15 30 and 55

ww diltiazem beads The models were successfully

transferred from a laboratory scale to pilot scale

Radtke et al [176] described in- and at-line NIR

configurations for moisture monitoring during matrix

pellet production in a rotary fluidized bed The authors

found out that sample presentation is as critical in this

case as in granulation process monitoring

535 Tabletting and capsule-filling

High speed automatic capsule filling and tabletting

machines require non-segregating powder blends or

granule mixtures with good flow characteristics to

work properly and ensure content uniformity and

consistent dissolution profiles of the final product In

practice segregation of free-flowing particulate mix-

tures with differences in particle size andor density is

likely to occur through inherent vibrations during

blender discharge batch transfer to the filling or

compression area and even within the equipment

Since NIR techniques are able to recognize

chemical and physical changes of particulate blends

[177] whole tablets and filled capsules noninvasive

NIR monitoring of tabletting and capsule filling from

the very beginning to the very end of the process

would be valuable to increase production speed and

improve product quality A NIR sensor on the feed

hopper of a capsule-filling machine or a tablet press

could effectively identify the powder mixture and

detect segregation problems of particulate matter upon

feeding the equipment The final product could be

further assessed for content uniformity dissolution

properties and in the case of tablets for hardness (see

also Section 52) Indeed there are some industrial

approaches leaning in this direction although they

have not yet been fully exploited due to limitations in

spectra collection of tablets or capsules produced at

Fig 6 NIR discrimination of Eudragit L film coats on tablets effect

of spraying temperature before ageing (20bT 20 8C 30bT 30 8C)and after ageing (20aT 30aT)


high speed However it might be expected that

progress in process instrumentation and chemometric

data processing will speed up the development of NIR

process monitoring in tabletting and capsule filling in

the near future

536 Film coating

Film coating is a process commonly employed in

the pharmaceutical industry to either improve the taste

or swallowing of tablets or to control drug dissolution

rate from the solid dosage forms Regardless of the

intended use the functionality of a film coat is closely

related to its thickness and uniformity around the solid

core In most production settings the endpoint of a

coating process is determined by in-process sample

acquisition the weighing of a known sample size and

the determination of the theoretical amount of applied

polymer Correct film coat thickness and uniformity

are evaluated indirectly by disintegration andor

dissolution testing In the PAT sense this analytical

procedure has two major disadvantages first deter-

mination of mass increase does not account for mass

loss of core material thus reducing the accuracy of

the method and secondly disintegration andor

dissolution testing are only indirect rather time-

consuming methods for the measurement of coating

levels and uniformity

NIR techniques on the other hand allow for a

rapid noninvasive at-line and in-line monitoring and

control of film coating processes prior to biopharma-

ceutical testing Kirsch and Drennen [178] and Wargo

and Drennen [175] were among the first to describe

the use of NIR for at-line monitoring of film coating

processes on tablets and pellets A Wurster column

was retrofitted with a sample thief allowing with-

drawal of 10-tablet samples during coating Samples

were collected after different time intervals and

measured on a grating-based NIR spectrometer in

reflectance mode In the case of pellets [175] coating

samples were classified by a bootstrap pattern

recognition technique The bootstrap standard devia-

tion plot made a qualitative identification of coating

endpoints possible In the case of tablets [178]

quantitative calibration models for the determination

of applied polymer solids namely ethylcellulose and

hydroxypropylmethyl cellulose formulations were

developed based on mass increase reference data (0ndash

30 ww) corrected for core attrition The NIR

method provided predictions of applied polymer films

with SEP values of 107 or less depending on the

coating formulation For pigment-free coating formu-

lations the calibration model was based mainly on

distinct absorption peaks of the coating polymer In

formulations containing high concentrations of water-

insoluble dyes and opacifying agents such as titanium

dioxide baseline shifts were the primary spectral

change caused by an increase in film thickness

Subsequent papers on this topic were published by

Andersson et al [179180] who described an indus-

trial in-line approach for film coat monitoring of

pharmaceutical pellets with fiber-optic probes Cali-

bration models for the determination of film coat

thickness were based on reference data obtained from

image analysis [181]

Despite these interesting and excellent papers

clearly reflecting the great value of NIR techniques

for at-line or in-line monitoring of a coating process

the multivariate potential of NIR spectroscopic meth-

ods has not been fully exploited in this field As

indicated by Reich and Frickel in a series of conference

proceedings [97ndash102] NIRS could be implemented as

a useful at-line or in-line tool to survey and determine

the effect of process conditions on film coat uniformity

(Fig 6) and related biopharmaceutical properties (see

also Section 521) As will be discussed in section

63 imaging techniques might be an additional tool to

improve product quality and the production speed of

film-coated dosage forms [182]


537 Packaging

Packaging is the last step in the production line of

a pharmaceutical product To ensure the product

safety of pharmaceuticals a last identity check of the

product on the packaging line would be highly

desirable Such an inspection system based on the

combination of a conventional high resolution camera

with an on-line diode NIR spectrometer ranging from

900 to 1700 nm at 6 nm resolution has been

developed recently The system is supposed to

perform a 100 identity check at full line speed

(ie 12000 tablets per minute) before closing the

blister The potential of this type of equipment has

been evaluated in a feasibility study [183] Using

hard gelatin capsules of different shell and fill

compositions the authors could demonstrate that the

real-time algorithms used in this system work as

reliably and accurately as a PCA-based data evalua-

tion of spectra collected on an off-line lab spectro-

meter to ensure the identification of flawed products

It may therefore be expected that other configu-

rations based on high speed NIR spectrometer or NIR

imaging techniques will be developed in the near

future for identity check on packaging lines

ImagingOptic

Filter

FPASign

Proces

Sample

Fig 7 Basic configuration of a ne

6 NIR imaging

61 Basic principles and instrumentation

NIR imaging is a combination of NIR spectroscopy

with digital image processing A NIR imaging system

is basically composed of an illumination source an

imaging optic a spectral encoder selecting the wave-

lengths and a focal plane array (FPA) as indicated in

Fig 7 NIR light from an illumination system is

focussed upon the sample The diffuse reflectance

image of the sample is collected by an imaging optic

the configuration of which depends on the sample size

and type For macroscopic or microscopic images a

focusing lens or a microscope objective are used

respectively Data collection proceeds by recording a

series of images on the near-infrared (ie InSb or

InGaAs) FPA at each wavelength position selected by

a spectral encoder such as a liquid crystal tunable

filter element (LCTF) or an interferometer The result

is a three-dimensional data set known as a spectral

hypercube with the x and y axis representing spatial

information and the z axis representing the spectral

information

al

sing

False Colour Image

ar-infrared imaging system


Regarding instrumentation there are basically two

different approaches The first approach is the wave-

length scanning method also known as the bstaringimager methodQ Sample and camera are kept sta-

tionary and single images are recorded for each

wavelength The spectral information is provided

either by a number of discreet filters by tuneable

filters or by combination with an imaging Fourier-

transform spectrometer The images recorded for the

different wavelengths are combined by the software

and the spectra calculated The second approach also

known as bpush-broom scanningQ method requires a

relative movement between camera and sample to

scan over the surface The imaging system records the

spatial information linewise and provides the spectral

information for each pixel along the line by projection

along the second axis of the two-dimensional camera-

chip The spectral encoding is provided by either

linear variable filters a digital micro-mirror array in

combination with a grating or dispersive optics The

computer software combines the slices derives the

second axis and thus reconstructs the full image

Experimental setups based on the staring imager

method are mainly used in research and quality

control laboratories with data acquisition times of

typically 2 min or less The second approach is used

for conveyor belt survey with data acquisition times

depending on the spectral encoder A detailed

description of the different principles can be found

in some recent textbooks [184185]

62 Analytical targets and strengths

Conventional ie non-imaging NIR spectroscopy

analyzes the sample in bulk and determines an

average composition across the entire sample NIR

imaging on the other hand provides information

about the spatial distribution of the components

comprising the sample It is therefore a powerful

bline extensionb of conventional NIR analysis in a

number of different ways [186]

The opportunity to visualize the spatial distribution

of a chemical species throughout the sample enables

the degree of chemical andor physical heteroge-

neity within a given sample to be determined

The array-based spectral sensing of a NIR imaging

system also allows for trace sample measurements

because the spectral data are collected in parallel

and thus are not hampered by a dilution effect in

the same way as NIR bulk measurements are This

is a great advantage over conventional NIRS when

analyzing low dose actives or excipients in a

pharmaceutical formulation

Moreover NIR imaging enables quantitative infor-

mation to be obtained without running separate

calibration samples since pure component spectra

are directly available from the spectral imaging

data cube of heterogeneously mixed samples This

approach can help to save time and money when

building a quantitative calibration model for

pharmaceutical applications in particular for

expensive peptide or protein drug formulations

NIR spectroscopic imaging has only a short

history when compared with MIR and Raman

imaging techniques This is due to the fact that its

advantages over Raman and MIR imaging techni-

ques such as adaption to a wide variety of fields-

of-view (FOV) and extreme tolerance to variations

in sample geometry have only recently been fully

exploited [186] With the use of simple quartzndash

tungsten halogen sources and an image filtering

instead of a source filtering approach NIR imaging

techniques enable wide-field illumination for a

variety of magnifications and imaging modes

ranging from around 02 to 125 mm In addition

flatness of the sample is not a prerequisite as in

Raman and MIR imaging On the contrary NIR

imaging systems allow experiments to be performed

on very irregular samples since NIR imaging

systems perform well in the reflectance mode with

large depths-of-field and an excellent signal-to-noise

ratio of the arrays


With the addition of spatial information and

parallel data collection NIR imaging certainly meets

the challenging analytical needs of pharmaceutical

quality and process control and may serve as a

versatile adjunct to conventional non-imaging NIR

spectroscopy in many fields Despite the obvious

strengths of NIR imaging techniques the number of

scientific papers and technical notes describing their

practical use is limited and mainly in other fields


eg plastic sorting [187] high-throughput screening

of biological material [186] on conveyor belts

remnant analysis of works of art [188] and

identification of atherosclerotique plaques by means

of an intra-arterial catheter imaging system recently

developed at the University of Kentucky Pharma-

ceutical papers as discussed in more detail in the

following paragraphs focus on three different

aspects namely blend uniformity analysis in pow-

ders and tablets composition and morphological

features of coated tablets and multi-layer granules

and spatial changes in biodegradable PLGA matrix

systems upon matrix hydration degradation and

active release

El-Hagrasy et al [154] used an InSb imaging

camera with discrete bandpass filters encompassing

absorption bands of the blend components in

addition to a conventional NIR fiber-optic probe in

six sapphire windows mounted at different locations

in a V-blender to monitor powder blend homoge-

neity of salicylic acidlactose mixtures and compare

the potential of the two techniques Data analysis

indicated the necessity of using multiple sampling

points for mixing endpoint determination by tradi-

tional NIRS and clearly revealed that coupling both

techniques might provide a very robust tool for

monitoring powder blending since the volume of

powder captured by the imaging technique is much

larger

Koehler et al [186] demonstrated the use of NIR

imaging to visualize and quantify the spatial dis-

tribution of the active ingredient in a tablet The

authors used an unsupervised PCA score plot to

qualitatively visualise the degree of chemical hetero-

geneity of the formulation showing the active in

unevenly distributed clumps An alternate least

square regression method based on pure component

spectra isolated from the spectral data cube of the

tablet was used to build a quantitative concentration

distribution estimate of the active in the tablet

Although in this special case the active concen-

tration was 20 by weight the example clearly

demonstrates the strength of NIR imaging for the

analysis of low dose drugs

Correlation of physical properties and technolog-

ical functionality of powder blends with their chem-

ical heterogeneity is the approach described by

Hammond and Clarke [189] The group has used

NIR imaging to identify mixing problems as being

responsible for bad and good flow characteristics of

powder blends as well as tablet sticking and tablet

fracture The results clearly reveal that NIR imaging is

a powerful tool for matrix characterization not only in

final product control but also in research develop-

ment and scale-up of solid pharmaceutical dosage

forms ie for process and formulation optimization

purposes

The same group pointed out that matrix character-

ization of complex solid dosage forms requires an

understanding of the spatial relationship and inter-

action of drug formulation components NIR imaging

was therefore used to examine the internal structure

of time-release granules [190] The chemical image of

a bisected granule (09 mm2) was obtained at 10-nm

intervals from 1000 to 1700 nm through a 10microscope objective with a total acquisition time of

approximately 2 min In contrast to the visible image

the NIR chemical image clearly revealed that the

distinct layers and boundaries were consistent with the

expected physical structure and composition of this

particular formulation

Another interesting application of NIR imaging is

the chemical visualization of coating layers on

tablets In a technical note published at the AAPS

Annual Meeting in 2001 Lewis and co-workers

[190] showed the chemical image of a sectioned

multilayer-coated tablet The macroscopic chemical

image depicted the tablet core and two distinct

coating layers of different thickness Due to the large

field-of-view (FOV) a detailed examination of the

film coat uniformity on the tablet core was not

feasible Moreover sectioning of the tablet was

necessary to achieve the multilayer chemical image

of the tablet However considering that formulation-

andor process-induced microheterogeneities in film

coats on tablets or pellets might have rather

important implications on their biopharmaceutical

properties the necessity of spectroscopic imaging

techniques for film coat uniformity analysis is

obvious Interestingly the application of microscopic

ATR-FTIR imaging rather than NIR imaging has

been reported for this purpose [182] Nondestructive

chemical images (250 Am250 Am) of Eudragit FS

30 D film coats were obtained from different areas

(ie at the center part and at the edges) of the tablets

to visualize and relate different coating levels


process andor curing conditions to film coat

uniformity The study revealed that due to its low

penetration depth ATR-FTIR imaging may provide

interesting new insights in the processes involved in

film coating and thus a better understanding and

control of manufacturing defects resulting in func-

tionally important microheterogeneities Although

using the mid-IR this example again indicates the

overall great potential of spectroscopic imaging

techniques in research development scale-up and

production control of pharmaceutical dosage forms

Structurally even more complex than film-coated

oral tablets or granules are biodegradable poly(dl-

lactide-co-glycolide) (PLGA) matrix systems for

parenteral use As discussed in Section 524

hydration degradation and drug release kinetics can

be successfully monitored by classical NIR spectro-

scopy however without any information on the

spatial changes In an attempt to fill this gap NIR

imaging was used (1) to investigate the time-depend-

ent spatial microenvironmental changes within bio-

degradable PLGA films upon in vitro hydration and

degradation in different media [191] and (2) to

chemically visualize the distribution and relative

abundance of a model protein namely lysozyme in

PLGA matrix tablets immediately after processing

and during the release phase [182] Within these

studies it could be demonstrated for the first time

without fluorescence-labeling that during the release

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A

Fig 8 False-color near-infrared images of lysozyme distribution (10 ini

(A) after 4 days in PBS pH 74 and (B) after 14 days in PBS pH 74 (T=

phase protein adsorption on the PLGA matrix

certainly occurs (Fig 8)

In conclusion the literature data discussed in this

section clearly reveal that spectroscopic imaging

approaches with NIR imaging in particular have a

huge potential for gaining rapid information about the

chemical structure and related physical or biopharma-

ceutical properties of all types of pharmaceutical

dosage forms thus improving product quality and

enhancing production speed

7 Concluding Remarks

This review has covered some of the recent

methods and pharmaceutical applications of NIR

spectroscopy and imaging As a fast and noninvasive

multivariate technique conventional NIR spectro-

scopy has already gained wide industrial acceptance

for raw material identification andor qualification

and nondestructive chemical analysis of intact dosage

forms Considering the continuing improvements in

hardware and software design and the analytical

requirements of the most recent concepts of quality by

design and real-time or parametric release it is

anticipated that in the near future both NIR spectro-

scopy and imaging may progressively become routine

methods for pharmaceutical process monitoring and

process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B

tial loading) at the surface of a poly(dl-lactide-co-glycolide) tablet

37 8C)


References

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[2] EW Ciurczak Principles of near-infrared spectroscopy in

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Infrared Analysis 2nd edition Marcel Dekker Inc New

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[3] L Bokobza Origin of near-infrared absorption bands in

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Infrared Spectroscopy Principles Instruments Applications

Wiley-VCH Verlag GmbH Weinheim 2002 pp 11ndash41

[4] T Burger Radiative transfer in disperse mediamdashnew

procedures in spectroscopic infrared analysis PhD thesis

WqrzburgGermany 1998

[5] JM Olinger PR Griffiths T Burger Theory of diffuse

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(Eds) Handbook of Near-Infrared Analysis 2nd edition

Marcel Dekker Inc New YorkBasel 2001 pp 19ndash51

[6] S Kawata New techniques in near-infrared spectroscopy in




[7] JJ Workman Jr DA Burns Commercial NIR instrumen-

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Near-Infrared Analysis 2nd edition Marcel Dekker Inc

New YorkBasel 2001 pp 53ndash70

[8] WJ McCarthy GJ Kemeny in DA Burns EW Ciurczak



[9] S Kawata Instrumentation for near-infrared spectroscopy in




[10] A Candolfi DL Massart S Heuerding Investigation of

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measurement of pharmaceutical formulations Anal Chim

Acta 345 (1997) 185ndash196

[11] S Kawano Sampling and sample presentation in HW

Siesler Y Ozaki S Kawata HM Heise (Eds) Near



[12] M Blanco J Coello H Itirriaga S Maspoch C de la

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[13] HM Heise R Winzen Fundamental chemometric meth-

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(Eds) Near Infrared Spectroscopy Principles Instruments

Applications Wiley-VCH Verlag GmbH Weinheim 2002

pp 125ndash162

[14] Mark Howard Data analysis multilinear regression and

principal component analysis in DA Burns EW

Ciurczak (Eds) Handbook of Near-Infrared Analysis

2nd edition Marcel Dekker Inc New YorkBasel 2001

pp 129ndash184

[15] T Naes T Isaksson T Fearn T Davies Multivariate

Calibration and Classification NIR Publications Chichester

2002 pp 27ndash54



2002 pp 93ndash104

[17] W Plugge C van der Vlies The use of near infrared

spectroscopy in the quality control laboratory of the

pharmaceutical industry J Pharm Biomed Anal 10

(1992) 797ndash803



2002 pp 221ndash260

[19] W Plugge C van der Vlies Near-infrared spectroscopy as

an alternative to assess compliance of ampicillin trihydrate

with compendial specifications J Pharm Biomed Anal 11

(1993) 435ndash442

[20] Near-infrared spectrometry Chapter 2240 European Phar-

macopoeia 4th edition 2001 pp 55ndash56

[21] Near-infrared spectrophotometry Chapter 1119 United

States Pharmacopoeia USP26NF21 2003 pp 2388ndash2391

[22] American Society for Testing and Materials E1866-97

Standard Guide for Establishing Spectrophotometer Perform-

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multivariate quantitative analysis Official ASTM Publica-

tions Philadelphia PA 2000

[23] Report by the analytical methods committee evaluation of

analytical instrumentation Part XIII Instrumentation for

UVndashvisible-NIR spectrometry Analyst 125 (2000) 367ndash374

[24] Validation of compendial methods Chapter 1225 United

States Pharmacopoeia USP26 2002 pp 2439ndash2442

[25] ICH Quality Guidelines for Method Validation Q2A Text on

Validation of Analytical Procedures and Q2B Validation of

Analytical Procedures Methodology November 1996 FDA

(httpwwwifpmaorgich5html)

[26] AC Moffat AD Trafford RD Jee P Graham Meeting

the International Conference on Harmonisationrsquos Guidelines

on Validation of Analytical Procedures quantification as

exemplified by a near-infrared reflectance assay of para-

cetamol in intact tablets Analyst 125 (2000) 1341ndash1351

[27] PASG Guidelines for the Development and Validation of Near

Infrared (NIR) spectroscopic methods May 2001 pp 1ndash39

(httpwwwpasgorgukNIRmay01pdf)

[28] USFDA Draft Guidance for Industry PATmdasha framework for

innovative pharmaceutical manufacturing and quality assur-

ance 2003 pp 4ndash21 (httpCDS029CDERGUID5815dft

doc)

[29] P Corti L Savini E Dreassi G Ceramelli L Montecchi S

Lonardi Application of NIRS to the control of pharmaceut-

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Pharm Acta Helv 67 (1992) 57ndash61

[30] M Ulmschneider G Barth B Reder A Vfgel D SchillingTransferable basic library for the identification of active

substances using near-infrared spectroscopy Pharm Ind 62

(2000) 301ndash304

[31] M Ulmschneider G Barth E Trenke Building transferable

cluster calibrations for the identification of different solid


excipients with near-infrared spectroscopy Pharm Ind 62

(2000) 374ndash376

[32] K Kr7mer S Ebel Application of NIR reflectance spectro-

scopy for the identification of pharmaceutical excipients

Anal Chim Acta 420 (2000) 155ndash161

[33] K Beckenkamp M Ohm K Molt O Mandal The

challenge of identity testing Eur Pharm Rev (2001) 28ndash33

[34] M Glania Entwicklung NIR-spektroskopischer Qualit7ts-und Prozesskontrollmethoden fqr Gelatine und Phenolharze

Dissertation Essen (1998)

[35] SS Thosar RA Forbess M Kemper AJ Shukla

Determination of copolymer ratios of poly(lactide-co-glyco-

lide) using near-infrared spectroscopy J Pharm Biomed

Anal 20 (1999) 107ndash114

[36] C Gustafsson C Nystrfm H Lennholm MC Bonferoni

CM Caramella Characteristics of hydroxypropyl methyl-

cellulose influencing compactibility and prediction of particle

and tablet properties by infrared spectroscopy J Pharm Sci

92 (2003) 494ndash504

[37] E Storz Untersuchung funktioneller Parameter pharmazeu-

tischer Hilfsstoffe mittels Nahinfrarotspektroskopie Disser-

tation Bonn (2003)

[38] J Beyer Nahinfrarotspektroskopische Untersuchungen an

pharmazeutischen Hilfsstoffen und festen Arzneiformen

Dissertation Bonn (2003)

[39] CI Gerh7user K-A Kovar Strategies for constructing near-infrared spectral libraries for the identification of drug

substances Appl Spectrosc 51 (1997) 1504ndash1510

[40] WL Yoon RD Jee AC Moffat PD Blackler K Yeung

DC Lee Construction and transferability of a spectral

library for the identification of common solvents by near-

infrared transflectance spectroscopy Analyst 124 (1999)

1197ndash1203

[41] A Candolfi R De Maesschalck D Jonan-Rimbaud PA

Hailey DL Massart The influence of data processing in the

pattern recognition of excipients near infrared spectra

J Pharm Biomed Anal 21 (1999) 115ndash132

[42] MS Kemper LM Luchetta A guide to raw material

analysis using near infrared spectroscopy J Near Infrared

Spectrosc 11 (2003) 155ndash174

[43] JE Sinsheimer NM Poswalk Pharmaceutical applications

of the near infrared determination of water J Pharm Sci 57

(1968) 2007ndash2010

[44] X Zhou P Hines ME Borer Moisture determination in

hygroscopic drug substances by near infrared spectroscopy


[45] W Dziki JF Bauer JJ Szpylman JE Quick BC Nichols

The use of near-infrared spectroscopy to monitor the mobility

of water within the sarafloxacin crystal lattice J Pharm

Biomed Anal 22 (2000) 829

[46] EW Ciurczak RP Torlini MP Demkowicz Determination

of particle size of pharmaceutical raw materials using near-

infrared reflectance spectroscopy Spectroscopy 1 (1986)

36ndash39

[47] IL Ikari H Martens T Isaksson Determination of particle

size in powders by scatter correction in diffuse near-infrared

reflectance Appl Spectrosc 42 (1988) 722ndash728

[48] M Blanco J Coello H Iturriaga S Maspoch F Gonzalez

R Pous Chapter 64 in KI Hildrum T Isaksson T Naes

A Tandberg (Eds) Near Infra-Red Spectroscopy (Bridging

the Gap Between Data Analysis and NIR Applications) Ellis

Horwood Chichester 1992 pp 401ndash406

[49] AJ OrsquoNeil RD Jee AC Moffat The application of

multiple linear regression to the measurement of the

median particle size of drugs and pharmaceutical exci-

pients by near-infrared spectroscopy Analyst 123 (1998)

2297ndash2302

[50] P Frake I Gill CN Luscombe DR Rudd J Waterhouse

UA Jayasooriya Near-infrared mass median particle size

determination of lactose monohydrate evaluating several

chemometric approaches Analyst 123 (1998) 2043ndash2046

[51] AJ OrsquoNeil RD Jee AC Moffat Measurement of

cumulative particle size distribution of microcrystalline

cellulose using near infrared reflectance spectroscopy

Analyst 124 (1999) 33ndash36

[52] E Storz K-J Steffens Bestimmung der spezifischen

Oberfl7che hochdisperser Siliciumdioxide mittels Nahin-

frarot-Spektroskopie Pharm Ind 64 (2002) 398ndash402

[53] AD Patel PE Luner MS Kemper Quantitative analysis of

polymorphs in binary and multi-component powder mixtures

by near-infrared reflectance spectroscopy Int J Pharm 206

(2000) 63ndash74

[54] AD Patel PE Luner MS Kemper Low-level determi-

nation of polymorph composition in physical mixtures of

near-infrared reflectance spectroscopy J Pharm Sci 90

(2001) 360ndash370

[55] E R7sanen J Rantanen A Jargensen M Karjaleinen T

Paakkari J Yliruusi Novel identification of pseudopoly-

morphic changes of theophylline during wet granulation

using near infrared spectroscopy J Pharm Sci 90 (2001)

389ndash396

[56] A Jaergensen J Rantanen M Karjaleinen L

Khriachtchev E R7sanen J Yliruusi Hydrate formation

during wet granulation studied by spectroscopic methods

Pharm Res 19 (2002) 1285ndash1291

[57] G Buckton E Yonemochi J Hammond A Moffat The use

of near infra-red spectroscopy to detect changes in the form

of amorphous and crystalline lactose Int J Pharm 168

(1998) 231ndash241

[58] H Bauer T Herkert M Barthels K-A Kovar E Schwarz

PC Schmidt Investigations on polymorphism of mannitol

sorbitol mixtures after spray-drying using differential scan-

ning calorimetry X-ray diffraction and near-infrared spectro-

scopy Pharm Ind 62 (2000) 231ndash235

[59] JJ Seyer PE Luner MS Kemper Application of diffuse

reflectance near-infrared spectroscopy for determination of

crystallinity J Pharm Sci 89 (2000) 1305ndash1316

[60] SE Hogan G Buckton The application of near-infrared

spectroscopy and dynamic vapor sorption to quantify low

amorphous contents of crystalline lactose Pharm Res 18

(2001) 112ndash116

[61] SE Hogan G Buckton Water sorptiondesorption-near IR

and calorimetric study of crystalline and amorphous raffi-

nose Int J Pharm 227 (2001) 57ndash69


[62] A Columbano G Buckton P Wikeley A study of the

crystallization of amorphous salbutamol sulphate using water

vapour sorption and near infrared spectroscopy Int J Pharm

237 (2002) 171ndash178

[63] M Blanco A Villar Development and validation of a method

for the polymorphic analysis of pharmaceutical preparations


823ndash830

[64] T Burger J Kuhn R Caps J Fricke Quantitative

determination of the scattering and absorption coefficients

from diffuse reflectance and transmittance measurements

application to pharmaceutical powders Appl Spectrosc 51

(1997) 309ndash317

[65] T Burger J Fricke J Kuhn NIR radiative transfer

investigations to characterize pharmaceutical powders and

their mixtures J Near Infrared Spectrosc 6 (1998) 33ndash40

[66] JD Kirsch JK Drennen Near-infrared spectroscopy

applications in the analysis of tablets and solid pharma-

ceutical dosage forms Appl Spectrosc Rev 38 (1995)

139ndash174

[67] Pharmaceutical assays chapter 5 in EW Ciurczak JK

Drennen III (Eds) Pharmaceutical and Medical Applications

of Near-Infrared Spectroscopy Marcel Dekker New York

Basel 2002 pp 73ndash105

[68] MA Dempster JA Jones IR Last BF McDonald KA

Prebbe Near-infrared methods for the identification of tablets

in clinical trial supplies J Pharm Biomed Anal 11 (1992)

1087ndash1092

[69] PK Aldridge RF Mushinsky MM Andino CL Evans

Identification of tablet formulations inside blister packages

by near-infrared spectroscopy Appl Spectrosc 48 (1994)

1272ndash1276

[70] N Sondermann K-A Kovar Screening experiments of

ecstasy street samples uring near infared spectroscopy

Forensic Sci Int 106 (1999) 147ndash156

[71] J Gottfries H Depui M Fransson M Jongeneelen M

Josefson FW Langkilde DT Witte Vibrational spectro-

scopy for the assessment of active substance in metoprolol

tablets a comparison between transmission and diffuse

reflectance near-infrared spectrometry J Pharm Biomed

Anal 14 (1996) 1495ndash1503

[72] SS Thosar RA Forbess NK Ebube Y Chen RL

Rubinovitz MS Kemper GE Reier TA Wheatley AJ

Shukla A comparison of reflectance and transmittance near-

infrared spectroscopic techniques in determinung drug

content in intact tablets Pharm Dev Technol 6 (2001)

19ndash29

[73] JL Ramirez MK Bellamy RJ Romanach A novel

method for analyzing thick tablets by near infrared spectro-

scopy Pharm Sci Tech 2 (2001) (article 11 pp 1-10 (http

wwwpharmscitechcom))

[74] M Blanco J Coello A Eustaquio H Iturriaga S Maspoch

Development and validation of a method for the analysis of a

pharmaceutical preparation by near-infrared diffuse reflec-

tance spectroscopy J Pharm Sci 88 (1999) 551ndash556

[75] M Blanco A Eustaquio JM Gonzalez D Serrano

Identification and quantification assays for intact tablets of

two related pharmaceutical preparations by reflectance near-

infrared spectroscopy validation of the procedure J Pharm

Biomed Anal 22 (2000) 139ndash148

[76] T Li AD Donner CY Choi GP Frunzi KR Morris A

statistical support for using spectroscopic methods to validate

the content uniformity of solid dosage forms J Pharm Sci

92 (2003) 1526ndash1530

[77] M Blanco J Coello H Iturriaga S Maspoch C de la

Pezuela Quantitation of the active compound and major

excipients in a pharmaceutical formulation by near infrared

diffuse reflectance spectroscopy with fibre optical probe


[78] K Molt F Zeyen E Podpetschnig-Fopp Quantitative

near infrared spectrometry used for the determination of

the drug content of tolbutamide tablets Pharm Ind 58

(1996) 847ndash852

[79] BR Buchanan MA Baxter T-S Chen X-Z Quin PA

Robinson Use of near-infrared spectroscopy to evaluate an

active in a film coated tablet Pharm Res 13 (1996)

616ndash621

[80] P Merckle K-A Kovar Assay of effervescent tablets by

near-infrared spectroscopy in transmittance and reflectance

mode acetylsalicylic acid in mono and combination for-

mulations J Pharm Biomed Anal 17 (1998) 365ndash374

[81] A Eustaquio P Graham RD Jee AC Moffat AD

Trafford Quantification of paracetamol in intact tablets using

near-infrared transmittance spectroscopy Analyst 123 (1998)

2303ndash2306

[82] AD Trafford RD Jee AC Moffat P Graham A rapid

quantitative assay of intact paracetamol tablets by reflectance

near-infrared spectroscopy Analyst 124 (1999) 163ndash167

[83] P Corti G Ceramelli E Dreassi S Matti Near infrared

transmittance analysis for the assay of solid pharmaceutical

dosage forms Analyst 124 (1999) 755ndash758

[84] Y Chen SS Thosar RA Forbess MS Kemper RL

Rubinowitz AJ Shukla Prediction of drug content and

hardness of intact tablets using artificial neural network and

near-infrared spectroscopy Drug Dev Ind Pharm 27 (2001)

623ndash631

[85] J-K Drennen RA Lodder Non-destructive near-infrared

analysis of intact tablets for determination of degradation

products J Pharm Sci 79 (1990) 622ndash627

[86] G Reich Noninvasive and simultaneous monitoring of

chemical and physical properties an analytical approach to

lyophilized proteins sugars and proteinsugar mixtures

Proc 3rd World Meeting APVAPGI Berlin 36 April

(2000) pp 279ndash280

[87] JD Kirsch JK Drennen Determination of film-coated

tablet parameters by near-infrared spectroscopy J Pharm


[88] KM Morisseau CT Rhodes Near-infrared spectroscopy as

a nondestructive alternative to conventional hardness testing

Pharm Res 14 (1997) 108ndash111

[89] JD Kirsch JK Drennen Nondestructive tablet hardness

testing by near-infrared spectroscopy a new and robust

spectral best-fit algorithm J Pharm Biomed Anal 19

(1999) 351ndash362


[90] NK Ebube SS Thosar RA Roberts MS Kemper

RL Rubinowitz DL Martin GE Reier TA Wheatley

AJ Shukla Application of near-infrared spectroscopy

(NIRS) for nondestructive analysis of powders and tablets

simultaneous determination of avicel type crushing

strength and lubricant concentration of intact tablets by

diffuse reflectance technique Pharm Dev Technol 4

(1999) 19ndash26

[91] G Reich Use of NIR transmission spectroscopy for non-

destructive determination of tablet hardness Proc 3rd World

Meeting APVAPGI Berlin 36 2000 (April) pp 105ndash106





623ndash631

[93] C Nystrfm G Alderborn M Duberg P-G Karehill

Bonding surface area and bonding mechanism-two important

factors for the understanding of powder compactability Drug

Dev Ind Pharm 19 (1993) 2143ndash2196

[94] G Reich Nondestructive determination of tablet hardness

and consolidation characteristics using NIR transmission

spectroscopy AAPS Annual Meeting and Exposition Den-

ver 2001 p M 2283

[95] PN Zannikos W Li JK Drennen RA Lodder Spectro-

scopic prediction of the dissolution rate of carbamazepine

tablets Pharm Res 8 (1991) 974ndash978

[96] JK Drennen RA Lodder Qualitative analysis using near-

infrared spectroscopy A comparison of discriminant methods

in dissolution testing Spectroscopy 8 (1991) 34ndash39

[97] G Reich H Frickel Use of transmission spectroscopy to

determine physical and functional film coat properties on

tablets Proc Int Symp Control Release Bioact Mater 26

(1999) 905ndash906

[98] G Reich H Frickel NIR spectroscopymdasha rapid method to

evaluate gastroresistance and drug release kinetics of film-

coated tablets Proc 3rd World Meeting APVAPGI Berlin

36 2000 (April) pp 627ndash628

[99] H Frickel G Reich NIR spectroscopy of film-coated

tabletsmdashfast and nondestructive evaluation of film coat

uniformity and drug release kinetics Proc Int Symp

Control Release Bioact Mater 27 (2000) 740ndash741

[100] H Frickel G Reich Performance optimization of NIR

transmission spectroscopy of coated tabletsmdasha light-guided

journey Proc 3rd World Meeting APVAPGI Berlin 36

2000 (April) pp 625ndash626

[101] H Frickel G Reich Nondestructive monitoring of

physical and biopharmaceutical film coat properties on

tablets AAPS Annual Meeting and Exposition Denver

2001 p M 2309

[102] H Frickel P Aebi G Fricker G Reich Real thickness of

Eudragit-based film coats on tablet coresmdashnondestructive

analysis with near-infrared transmission spectroscopy

Pharm Sci Suppl 1 (1998) 22

[103] RA Lodder M Selby GM Hieftje Detection of capsule

tampering by near-infrared reflectance analysis Anal Chem

59 (1987) 1921ndash1930

[104] RG Buice Jr TB Gold RA Lodder GA Digenis

Determination of moisture in intact gelatin capsules by near-

infrared spectroscopy Pharm Res 12 (1995) 161ndash163

[105] O Berntsson G Zachrisson G Ostling Determination of

moisture in hard gelatin capsules using near-infrared spectro-

scopy applications to at-line process control of pharmaceu-

tics J Pharm Biomed Anal 15 (1997) 895ndash900

[106] G Reich Effect of drying on structure and properties of

gelatin capsule shells a study with model films Pharm Ind

57 (1995) 63ndash67

[107] TB Gold RG Buice Jr RA Lodder GA Digenis

Determination of extent of formaldehyde-induced crosslink-

ing in hard gelatin capsules by near infrared spectroscopy

Pharm Res 14 (1997) 1046ndash1050

[108] G Reich Use of DSC DMTA and NIRTS to determine hard

gelatin capsule characteristics associated with brittleness a

mechanistic study Pharm Sci Suppl 1 (1999)

[109] G Reich H Frickel AM Gil Bernabe Use of near-infrared

transmission spectroscopy to detect batch-to-batch variability

of hard gelatin capsule shells Pharm Sci Suppl 1 (1999)

[110] G Reich Fast and non-destructive quality control of gelatin

capsule shells Proc 3rd World Meeting APVAPGI Berlin


[111] M Rama G Reich Monitoring structural changes in hard

and soft gelatin films and capsules using NIR transmission

and reflectance spectroscopy Proc 3rd World Meeting APV

APGI Berlin 36 2000 (April) pp 507ndash508

[112] G Reich NIR spectroscopymdashan alternative approach to

assess the mechanical performance of hard gelatin

capsules AAPS Annual Meeting and Exposition Denver

2001 p M 2233

[113] G Reich Mechanism and optimization of plasticizers in soft

gelatin capsules Pharm Ind 56 (1994) 915ndash920

[114] G Reich Effect of sorbitol specification on structure and

properties of soft gelatin capsule shells Pharm Ind 58

(1996) 941ndash946


Detection of formaldehyde-induced crosslinking in soft

elastic gelatin capsules using near-infrared spectrophotom-

etry Pharm Dev Technol 3 (1998) 209ndash214

[116] J Mqller G Reich Importance of Wavelength Selection in

Quantitative Near-Infrared Spectroscopy of Polyols in Cap-

sule Formulations ICNIRS Cordoba 2003 p 67

[117] J Mqller G Reich A comparison of multivariate regression

models in quantitative near-infrared spectroscopy Poster at

DPhG Meeting of PhD students Frankfurt 2002

[118] J Mqller G Reich Influence of wavelength selection in

quantitative near-infrared spectroscopy Arch Pharm 335 (1)

(2002)

[119] J Mqller G Reich Determination of plasticizer content in

softgel capsule formulations using near-infrared spectroscopy

and multivariate regression methods AAPS Annual Meeting

and Exposition Toronto 2002 p W 5343

[120] MS Kamat RA Lodder PP DeLuca Near-infrared

spectroscopic determination of residual moisture in lyophi-

lised sucrose through intact glass vials Pharm Res 6 (1989)

961ndash965


[121] IR Last KA Prebbe Suitability of near-infrared methods

for the determination of moisture in a freeze-dried injection

product containing different amounts of active ingredient


[122] JA Jones IR Last BF Macdonald KA Prebbe Develop-

ment and transferability of near-infrared methods for

determination of moisture in a freeze-dried injection product


[123] MWJ Derksen PJM van de Oetelaar FA Maris The

use of near-infrared spectroscopy in the efficient prediction

of a specification for the residual moisture content of a

freeze-dried product J Pharm Biomed Anal 17 (1998)

473ndash480

[124] TP Lin CC Hsu Determination of residual moisture in

lyophilized protein pharmaceuticals using a rapid and non-

invasive method near infrared spectroscopy J Pharm Sci

Technol 56 (2002) 196ndash205

[125] L Sukowski M Ulmschneider Near Infrared Spectroscopy

High Speed Noninvasive Qualification of Lyophilized Vials

ICNIRS Cordoba 2003 p O61




Proc 3rd World Meeting APVAPGI Berlin 36 2000

(April) pp 279ndash280

[127] K K7lkert G Reich Near infrared spectroscopic evaluation

of stress-induced structural changes of proteins in solid and

solution state Proc 3rd World Meeting APVAPGI Berlin 3


[128] K Murayama B Czarnik-Matusewicz Y Wu R Tsenkova

Y Ozaki Comparison between conventional spectral analysis

methods chemometrics and two-dimensional correlation

spectroscopy in the analysis of near-infrared spectra of

protein Appl Spectrosc 54 (2000) 978ndash985

[129] RL Brashear DR Flanagan PE Luner JJ Seyer MS

Kemper Diffuse reflectance near-infrared spectroscopy as a

nondestructive analytical technique for polymer implants and

microspheres PharmSci 1 (1998) 20



nondestructive analytical technique for implants J Pharm

Sci 88 (1999) 1348ndash1353

[131] G Reich Use of DSC and NIR spectroscopy to study the

hydration degradation and drug release behavior of PLA

PLGA microparticles and films with free and blocked

carboxylic end groups Proc Int Symp Control Release

Bioact Mater 27 (2000) 642ndash643

[132] G Reich T Schfnbrodt Fast and noninvasive near infrared

analysis of PLA and PLGA microparticles films and tablets

Proc Int Symp Control Release Bioact Mater 28 (2001)

387ndash388

[133] T Schfnbrodt G Reich Near infrared spectroscopy-a novel

approach to monitor drug release kinetics from biodegradable

PLGA tablets Proc 4th World Meeting ADRITELFAPGI

APV Florence 811 2002 (April) pp 303ndash304

[134] T Schfnbrodt S Mohl G Winter G Reich Nondestruc-

tive quantification of lyophilised protein drugs in lipid

matrices AAPS Annual Meeting and Exposition Toronto

2002 p T 3355

[135] T Schfnbrodt G Reich Protein Release from Biodegradable

PLGA Tablets Monitored by Near Infrared Spectroscopy

ICNIRS Cordoba 2003 p P64

[136] HW Siesler Application to industrial process control in

HW Siesler Y Ozaki S Kawata HM Heise (Eds) Near-

Infrared Spectroscopy Wiley-VCH Verlag GmbH Wein-

heim Germany 2002 pp 247ndash268

[137] HW Ward II SS Sekulic MJ Wheeler G Taber FJ

Urbanski FF Sistare T Norris PK Aldridge On-line

determination of reaction completion in a closed-loop

hydrogenator using NIR spectroscopy Appl Spectrosc 52

(1998) 17ndash21

[138] C Coffey BE Cooley DS Walker Real time quantitaion

of a chemical reaction by fiber optic near-infrared spectro-

scopy Anal Chim Acta 395 (1999) 335ndash341

[139] T Norris PK Aldridge SS Sekulic Determination of end-

points for polymorph conversions of crystalline organic

compounds using on-line near-infrared spectroscopy Analyst

122 (1997) 549ndash552

[140] K De Braekeleer R De Maesschalk PA Hailey DCA

Sharp DL Massart On-line application of the orthogonal

projection approach (OPA) and the soft independent model-

ling of class analogy approach (SIMCA) for the detection of

the end point of a polymorph conversion reaction by near

infrared spectroscopy (NIR) Chemom Intell Lab Syst 46

(1999) 103ndash116

[141] H Chung MA Arnold M Rhiel DW Murhammer

Simultaneous measurements of glucose glutamine ammo-

nia lactate and glutamate in aqueous solution by near-

infrared spectroscopy Appl Spectrosc 50 (1996) 270ndash276

[142] KSY Yeung M Hoare NF Thornhill T Williams

JD Vaghjiani Near-infrared spectroscopy for bioprocess

monitoring and control Biotechnol Bioeng 63 (1999)

684ndash693

[143] MR Riley HM Crider The effect of analyte concentration

range on measurement errors obtained by NIR spectroscopy

Talanta 52 (2000) 473ndash484

[144] HJ Venables JI Wells Powder mixing Drug Dev Ind

Pharm 27 (2001) 599ndash612

[145] EW Ciurczak Pharmaceutical mixing studies using near-

infrared spectroscopy Pharm Technol 15 (1991) 140ndash145

[146] FC Sanchez J Toft B van den Bogaert DL Massart SS

Dive P Hailey Monitoring powder blending by NIR

spectroscopy Fresenius J Anal Chem 352 (1995) 771ndash778

[147] DJ Wargo JK Drennen Near-infrared spectroscopic

characterization of pharmaceutical powder blends J Pharm


[148] SS Sekulic HW Ward DR Brannegan ED Stanley CL

Evans ST Sciavolino PA Haily PK Aldridge Online

monitoring of powder homogeneity by near-infrared spectro-

scopy Anal Chem 68 (1996) 509ndash513

[149] PA Hailey P Doherty P Tapsell T Oliver PK Aldridge

Automated system for the on-line monitoring of powder

blending processes using near-infrared spectroscopy



[150] SS Sekulic J Wakeman P Doherty PA Hailey Auto-

mated system for the on-line monitoring of powder blending

processes using near-infrared spectroscopy Part II Qualita-

tive approaches to blend evaluation J Pharm Biomed Anal

17 (1998) 1285ndash1309

[151] R De Maesschalck F Cuesta Sanchez DL Massart P

Doherty P Hailey On-line monitoring of powder blending

with near-infrared spectroscopy Appl Spectrosc 52 (1998)

731ndash752

[152] C Ufret K Morris Modeling of powder blending using on-

line near-infrared measurements Drug Dev Ind Pharm 27

(2001) 719ndash729

[153] N-H Duong P Arratia F Muzzio A Lange J Timmer-

mans S Reynolds A homogeneity study using NIR

spectroscopy tracking magnesium stearate in Bohle bin-

blender Drug Dev Ind Pharm 29 (2003) 679ndash687

[154] AS El-Hagrasy HR Morris F DrsquoAmico RA Lodder

JK Drennen III Near-infrared spectroscopy and imaging for

the monitoring of powder blend homogeneity J Pharm Sci

90 (2001) 1298ndash1307

[155] O Berntsson L-G Danielsson S Folestad Characterization

of diffuse reflectance fiber probe sampling in moving solids

using a Fourier transform near-infrared spectrometer Anal

Chim Acta 431 (2001) 125ndash131

[156] O Berntsson Characterization and application of near infra-

red reflection spectroscopy for quantitative process analysis

of powder mixtures Doctoral Thesis Stockholm (2001)

[157] O Berntsson LG Danielsson B Lagerholm S Folestad

Quantitative in-line monitoring of powder blending by near

infrared reflection spectroscopy Powder Technol 123 (2002)

185ndash193

[158] JG White On-line moisture detection for a microwave

vacuum dryer Pharm Res 11 (1994) 728ndash732

[159] SC Harris DS Walker Quantitative real-time monitoring

of dryer effluent using fiber optic near infrared spectroscopy

J Pharm Sci 89 (2000) 1180ndash1186

[160] KR Morris JG Stowell SR Byrn AW Placette TD

Davis GE Peck Accelerated fluid-bed drying using NIR

monitoring and phenomenological modeling Drug Dev Ind

Pharm 26 (2000) 985ndash988

[161] PL Wildfong A-S Samy J Corfa GE Peck KR Morris

Accelerated fluid-bed drying using NIR monitoring and

phenomenological modeling method assessment and for-

mulation suitability J Pharm Sci 91 (2002) 631ndash639

[162] GX Zhou Z Ge J Dorwart B Izzo J Kukura G Bicker

J Wyvratt Determination and differentiation of surface and

bound water in drug substances by near infrared spectro-

scopy J Pharm Sci 92 (2003) 1058ndash1065

[163] M Brqlls S Folestad A Sparen A Rasmuson In-situ near-

infrared spectroscopy monitoring of the lyophilization

process Pharm Res 20 (2003) 494ndash499

[164] K List K-J Steffens Supervising and controlling of

granulation processes by near-infrared spectroscopy Pharm

Ind 58 (1996) 347ndash353

[165] S Watano K Terashita K Miyanami Posture feed-back

control and process automation in fluidized bed granulation

Adv Powder Technol 3 (1992) 255ndash265

[166] S Watano H Takashima Y Sato T Yasutomo K

Miyanami Measurement of moisture content by IR sensor

in fluidized bed granulation effects of operating variables on

the relationship between granule moisture content and

absorbance IR spectra Chem Pharm Bull 44 (1996)

1267ndash1269

[167] P Frake D Greenhalgh SM Grierson JM Hempemstall

DR Rud Process control and endpoint determination of a

fluid bed granulation by application of near infra-red

spectroscopy Int J Pharm 151 (1997) 75ndash80

[168] SG Goebel K-J Steffens On-line measurement of mois-

ture and particle size in the fluidized-bed processing with

near-infrared spectroscopy Pharm Ind 60 (1998) 889ndash895

[169] J Rantanen S Lehtola P R7met J-P Mannerma J

Yliruusi On-line monitoring of moisture content in a

instrumented fluidized bed granulator with a multi-cannel

NIR moisture sensor Powder Technol 99 (1998) 163ndash170

[170] J Rantanen O Antikainen J-P Mannerma J Yliruusi Use

of the near-infrared reflectance method for measurement of

moisture content during granulation Pharm Dev Technol 5

(2000) 209ndash217

[171] J Rantanen E R7sanen J Tenhunen M K7ns7koski J-PMannerma J Yliruusi Inline moisture measurement during

granulation with a four-wavelength near infrared sensor an

evaluation of particle size and binder effects Eur J Pharm

Biopharm 50 (2000) 271ndash276

[172] G Buckton E Yonemochi WL Yoon AC Moffat Water

sorption and near IR spectroscopy to study the differences

between microcrystalline cellulose and silicified microcrys-

talline cellulose before and after wet granulation Int J

Pharm 181 (1999) 41ndash47

[173] HM Derbyshire Y Feldman CR Bland J Broadhead G

Smith A study of the molecular properties of water in

hydrated mannitol J Pharm Sci 91 (2002) 1080ndash1088

[174] A Mica T Yajima S Itai Prediction of suitable amount of

water addition for wet granulation Int J Pharm 195 (2000)

81ndash92

[175] DJ Wargo JK Drennen AAPS Annual Meeting Seattle

WA 1996 (paper PT6116)

[176] G Radtke K Knop C Lippold In-process control of direct

pelletisation in the rotary fluidized bed using NIR spectro-

scopy NIR News 10 (1999) 4ndash12

[177] C Roeseler K-A Kovar In-process control Eur Pharm

Rev 2 (2003) 63ndash67

[178] JD Kirsch JK Drennen Near-infrared spectroscopic

monitoring of the film coating process Pharm Res 13

(1996) 234ndash237

[179] M Andersson M Josefson F Langkilde K-G Wahlund

Monitoring of a film coating process for tablets using near

infrared reflectance spectroscopy J Pharm Biomed Anal

20 (1999) 27ndash37

[180] M Andersson S Folestad J Gottfries MO Johansson M

Josefson K-GWahlund Anal Chem 72 (2000) 2099ndash2108

[181] M Andersson B Holmquist J Lindquist O Nilsson K-G

Wahlund Analysis of film coating thickness and surface area

of pharmaceutical pellets using fluorescence microscopy and

image analysis J Pharm Biomed Anal 22 (2000) 325ndash339


[182] G Reich Potential of attenuated total reflection infrared and

near-infrared imaging for quality assurancequality control of

solid pharmaceutical dosage forms Pharm Ind 64 (2002)

870ndash874

[183] T Herkert H Prinz K-A Kovar One hundred percent

online identity check of pharmaceutical products by near-

infrared spectroscopy on the packaging line Eur J Pharm


[184] F van der Meer SM De John (Eds) Imaging Spectrometry

Basic Principles and Prospective Applications Kluwer

Academic Publishers 2000

[185] GH Bearman RM Levenson D Cabib (Eds) Spectral

Imaging Instrumentation Applications and Analysis SPIE

Publications 2000

[186] FW Koehler IV E Lee LH Kidder EN Lewis Near

infrared spectroscopy the practical chemical imaging sol-

ution Spectrosc Eur 143 (2002) 12ndash19

[187] A Kulcke C Gurschler G Spfck R Leitner M Kraft

On-line classification of synthetic polymers using near

infrared spectral imaging Near Infrared Spectrosc 11

(2003) 71ndash81

[188] JR Mansfield MS Sowa C Majzels C Collins E

Clontis HH Mantsch Near infrared spectroscopic reflec-

tance imaging supervised vs unsupervised analysis using

an art conservation application Vibr Spectrosc 19 (1999)

33ndash45

[189] F Clarke NIR microscopy utilisation from research through

to full-scale manufacturing Presentation No 6 at the Euro-

pean Conference on Near Infrared Spectroscopy Heidelberg

2003

[190] EN Lewis JE Carroll F Clarke NIR imaging a near

infrared view of pharmaceutical formulation analysis NIR

News 12 (2001) 16ndash18

[191] G Reich Potential of ATR-IR and NIR spectroscopic

imaging for quality assurance of solid pharmaceutical dosage

forms Proc 4th World Meeting ADRITELFAPGIAPV

Florence April 8-11 2002 pp 291ndash292

Near-infrared spectroscopy and imaging Basic principles and pharmaceutical applications

Introduction

Basic principles of near-infrared (NIR) spectroscopy

Origin and characteristics of NIR absorption bands

Instrumentation and sample presentation

Theory and practice of chemometric data processing

Data pretreatments

Reduction of variables by principal component analysis (PCA)

Multivariate calibration for quantitative analysis

Multivariate classification for qualitative analysis

Regulatory aspects

Actual status of pharmaceutical NIR analysis

NIR spectroscopy in view of the USFDA initiative on PAT

Pharmaceutical applications

Identification and qualification of raw materials and intermediates

Library approach

Conformity approach

Quantitative calibration models

Analysis of intact dosage forms

Tablets

Capsules

Lyophilized products

Polymeric implants and microspheres

Process monitoring and process control

Powder blending

Drying

Granulation

Pelletization

Tabletting and capsule-filling

Film coating

Packaging

NIR imaging

Basic principles and instrumentation

Analytical targets and strengths


Concluding Remarks

References


4 Regulatory aspects 1116

41 Actual status of pharmaceutical NIR analysis 1116

42 NIR spectroscopy in view of the USFDA initiative on PAT 1117


51 Identification and qualification of raw materials and intermediates 1118

511 Library approach 1118

512 Conformity approach 1119

513 Quantitative calibration models 1119

52 Analysis of intact dosage forms 1121

521 Tablets 1121

522 Capsules 1124

523 Lyophilized products 1126

524 Polymeric implants and microspheres 1126

53 Process monitoring and process control 1127

531 Powder blending 1128

532 Drying 1129

533 Granulation 1130

534 Pelletization 1131

535 Tabletting and capsule-filling 1131

536 Film coating 1132

537 Packaging 1133

6 NIR imaging 1133

61 Basic principles and instrumentation 1133

62 Analytical targets and strengths 1134


7 Concluding Remarks 1136

References 1137

1 Introduction

Near-infrared spectroscopy (NIRS) is a fast and

nondestructive technique that provides multi-constit-

uent analysis of virtually any matrix It covers the

wavelength range adjacent to the mid infrared and

extends up to the visible region Historically the

discovery of the NIR region in 1800 is ascribed to

Herschel who separated the electromagnetic spectrum

with a prism and found out that the temperature

increased markedly towards and beyond the red ie in

the region that is now called the near-infrared

Although a number of NIR experiments were carried

out in the early 1920s it was not before the mid to late

1960s that NIR spectroscopy was practically used It

was Karl Norris from the US Department of

Agriculture who recognized the potential of this

analytical technique and introduced bmodern NIRSQinto industrial practice [1] From then on the break-

through of the method as an industrial quality- and

process-control tool proceeded in jumps coinciding

with the introduction of efficient chemometric data

processing techniques and the development of novel

spectrometer configurations based on fiber optic

probes

In recent years NIR spectroscopy has gained wide

acceptance within the pharmaceutical industry for raw

material testing product quality control and process

monitoring The growing pharmaceutical interest in

NIR spectroscopy is probably a direct result of its

major advantages over other analytical techniques

namely an easy sample preparation without any

pretreatments the possibility of separating the sample

measurement position and spectrometer by use of

fiber optic probes and the prediction of chemical and

physical sample parameters from one single spectrum

This paper is dedicated to pharmaceutical applica-

tions of NIR spectroscopy To fully appreciate the

analytical versatility of this spectroscopic technique a

short introduction into the principles of the method is


















spectroscopy


bands





































constant
















spectroscopy






















































DetDiffuse R





































ectoreflectance


Sample

eter configurations

Transmittance

DiffuseReflectance

Transflectance

(A)

(B)

(C)

(D)

(E)



































processing




















































algorithms


analysis (PCA)







Inte

nsity

λ1 λ2 λ3

λ1

λ2

λ3

λ2

λ3 F3



















dimensional space









Mark [14]

λ1

λ2

λ3

λ1

F1F2

F2F3

F1











values


target property























































dendrograms









































tion changes









also Section 51)







































Chemistry [23]















[25]




























initiative on PAT
















not be identified
















































characteristics




























dosage forms


and intermediates































economically



























































or lactose






















Candolfi et al [41]














tion [42]



























calibration work





































































































































521 Tablets



















































































































































































































development




























































questions

522 Capsules







separately





























































bone respectively









































(see Section 535)










shells
























































































































ditions were shown







(see Section 532)
















weeks or months































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References


















spectroscopy


bands





































constant
















spectroscopy






















































DetDiffuse R





































ectoreflectance


Sample

eter configurations

Transmittance

DiffuseReflectance

Transflectance

(A)

(B)

(C)

(D)

(E)



































processing




















































algorithms


analysis (PCA)







Inte

nsity

λ1 λ2 λ3

λ1

λ2

λ3

λ2

λ3 F3



















dimensional space









Mark [14]

λ1

λ2

λ3

λ1

F1F2

F2F3

F1











values


target property























































dendrograms









































tion changes









also Section 51)







































Chemistry [23]















[25]




























initiative on PAT
















not be identified
















































characteristics




























dosage forms


and intermediates































economically



























































or lactose






















Candolfi et al [41]














tion [42]



























calibration work





































































































































521 Tablets



















































































































































































































development




























































questions

522 Capsules







separately





























































bone respectively









































(see Section 535)










shells
























































































































ditions were shown







(see Section 532)
















weeks or months































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References




































DetDiffuse R





































ectoreflectance


Sample

eter configurations

Transmittance

DiffuseReflectance

Transflectance

(A)

(B)

(C)

(D)

(E)



































processing




















































algorithms


analysis (PCA)







Inte

nsity

λ1 λ2 λ3

λ1

λ2

λ3

λ2

λ3 F3



















dimensional space









Mark [14]

λ1

λ2

λ3

λ1

F1F2

F2F3

F1











values


target property























































dendrograms









































tion changes









also Section 51)







































Chemistry [23]















[25]




























initiative on PAT
















not be identified
















































characteristics




























dosage forms


and intermediates































economically



























































or lactose






















Candolfi et al [41]














tion [42]



























calibration work





































































































































521 Tablets



















































































































































































































development




























































questions

522 Capsules







separately





























































bone respectively









































(see Section 535)










shells
























































































































ditions were shown







(see Section 532)
















weeks or months































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References

Transmittance

DiffuseReflectance

Transflectance

(A)

(B)

(C)

(D)

(E)



































processing




















































algorithms


analysis (PCA)







Inte

nsity

λ1 λ2 λ3

λ1

λ2

λ3

λ2

λ3 F3



















dimensional space









Mark [14]

λ1

λ2

λ3

λ1

F1F2

F2F3

F1











values


target property























































dendrograms









































tion changes









also Section 51)







































Chemistry [23]















[25]




























initiative on PAT
















not be identified
















































characteristics




























dosage forms


and intermediates































economically



























































or lactose






















Candolfi et al [41]














tion [42]



























calibration work





































































































































521 Tablets



















































































































































































































development




























































questions

522 Capsules







separately





























































bone respectively









































(see Section 535)










shells
























































































































ditions were shown







(see Section 532)
















weeks or months































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References
















algorithms


analysis (PCA)







Inte

nsity

λ1 λ2 λ3

λ1

λ2

λ3

λ2

λ3 F3



















dimensional space









Mark [14]

λ1

λ2

λ3

λ1

F1F2

F2F3

F1











values


target property























































dendrograms









































tion changes









also Section 51)







































Chemistry [23]















[25]




























initiative on PAT
















not be identified
















































characteristics




























dosage forms


and intermediates































economically



























































or lactose






















Candolfi et al [41]














tion [42]



























calibration work





































































































































521 Tablets



















































































































































































































development




























































questions

522 Capsules







separately





























































bone respectively









































(see Section 535)










shells
























































































































ditions were shown







(see Section 532)
















weeks or months































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References









values


target property























































dendrograms









































tion changes









also Section 51)







































Chemistry [23]















[25]




























initiative on PAT
















not be identified
















































characteristics




























dosage forms


and intermediates































economically



























































or lactose






















Candolfi et al [41]














tion [42]



























calibration work





































































































































521 Tablets



















































































































































































































development




























































questions

522 Capsules







separately





























































bone respectively









































(see Section 535)










shells
























































































































ditions were shown







(see Section 532)
















weeks or months































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References


















tion changes









also Section 51)







































Chemistry [23]















[25]




























initiative on PAT
















not be identified
















































characteristics




























dosage forms


and intermediates































economically



























































or lactose






















Candolfi et al [41]














tion [42]



























calibration work





































































































































521 Tablets



















































































































































































































development




























































questions

522 Capsules







separately





























































bone respectively









































(see Section 535)










shells
























































































































ditions were shown







(see Section 532)
















weeks or months































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References


















initiative on PAT
















not be identified
















































characteristics




























dosage forms


and intermediates































economically



























































or lactose






















Candolfi et al [41]














tion [42]



























calibration work





































































































































521 Tablets



















































































































































































































development




























































questions

522 Capsules







separately





























































bone respectively









































(see Section 535)










shells
























































































































ditions were shown







(see Section 532)
















weeks or months































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References



















dosage forms


and intermediates































economically



























































or lactose






















Candolfi et al [41]














tion [42]



























calibration work





































































































































521 Tablets



















































































































































































































development




























































questions

522 Capsules







separately





























































bone respectively









































(see Section 535)










shells
























































































































ditions were shown







(see Section 532)
















weeks or months































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References



















or lactose






















Candolfi et al [41]














tion [42]



























calibration work





































































































































521 Tablets



















































































































































































































development




























































questions

522 Capsules







separately





























































bone respectively









































(see Section 535)










shells
























































































































ditions were shown







(see Section 532)
















weeks or months































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References



























































































































521 Tablets



















































































































































































































development




























































questions

522 Capsules







separately





























































bone respectively









































(see Section 535)










shells
























































































































ditions were shown







(see Section 532)
















weeks or months































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References















































































































































development




























































questions

522 Capsules







separately





























































bone respectively









































(see Section 535)










shells
























































































































ditions were shown







(see Section 532)
















weeks or months































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References












questions

522 Capsules







separately





























































bone respectively









































(see Section 535)










shells
























































































































ditions were shown







(see Section 532)
















weeks or months































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References



























(see Section 535)










shells
























































































































ditions were shown







(see Section 532)
















weeks or months































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References








































































ditions were shown







(see Section 532)
















weeks or months































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References































Lysozym rele


2

4

6



Lyso

zym

in t

able

t af

ter

incu

batio

n [m

g]-

NIR

mea

sure

men

t


7437 8C)





















and packaging







ase from PLGA


0974755

=0988771






















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References




















531 Powder blending













content uniformity



















































































calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References























calibration







control only

532 Drying




































calibration model








































533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References











533 Granulation












































































































wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References























wet granulation


















[174]











534 Pelletization



















































the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References








the near future

536 Film coating









































































537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References


537 Packaging
























ImagingOptic

Filter

FPASign

Proces

Sample


6 NIR imaging





















information

al

sing

False Colour Image

















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References
















































































ratio of the arrays

























active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References















active release















larger




























purposes





































































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References































25750

25700

25650

25600

25550

53400 53450 53500 53550 53600

15

10

5

-5

-10

0

Micron

Mic

ron

A




























process control

50

40

30

20

10

0

25750

25700

25650

25600

25550

53400 53450 53500 53550 53600Micron

Mic

ron

B


37 8C)


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References


References





































Acta 345 (1997) 185ndash196












pp 125ndash162





pp 129ndash184



2002 pp 27ndash54



2002 pp 93ndash104




(1992) 797ndash803



2002 pp 221ndash260




(1993) 435ndash442






























doc)







(2000) 301ndash304





(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References



(2000) 374ndash376











Anal 20 (1999) 107ndash114





92 (2003) 494ndash504



tation Bonn (2003)










1197ndash1203










(1968) 2007ndash2010











36ndash39













2297ndash2302















(2000) 63ndash74




(2001) 360ndash370





389ndash396




Pharm Res 19 (2002) 1285ndash1291




(1998) 231ndash241












(2001) 112ndash116








237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References





237 (2002) 171ndash178




823ndash830





(1997) 309ndash317







139ndash174








1087ndash1092




1272ndash1276









Anal 14 (1996) 1495ndash1503






19ndash29

















92 (2003) 1526ndash1530









(1996) 847ndash852




616ndash621








2303ndash2306











623ndash631








(2000) pp 279ndash280










(1999) 351ndash362









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References









(1999) 19ndash26








623ndash631








ver 2001 p M 2283










(1999) 905ndash906
















2001 p M 2309







59 (1987) 1921ndash1930










57 (1995) 63ndash67




Pharm Res 14 (1997) 1046ndash1050

















2001 p M 2233





(1996) 941ndash946













(2002)








961ndash965














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References














473ndash480





























Sci 88 (1999) 1348ndash1353









387ndash388








2002 p T 3355












(1998) 17ndash21







122 (1997) 549ndash552







(1999) 103ndash116








684ndash693





Pharm 27 (2001) 599ndash612






















17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References






17 (1998) 1285ndash1309




731ndash752



(2001) 719ndash729








90 (2001) 1298ndash1307











185ndash193









Pharm 26 (2000) 985ndash988














Ind 58 (1996) 347ndash353









1267ndash1269















(2000) 209ndash217









Pharm 181 (1999) 41ndash47






81ndash92







Rev 2 (2003) 63ndash67



(1996) 234ndash237




20 (1999) 27ndash37











870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References





870ndash874










Publications 2000







(2003) 71ndash81





33ndash45




2003



News 12 (2001) 16ndash18






Introduction





Data pretreatments




Regulatory aspects





Library approach

Conformity approach



Tablets

Capsules




Powder blending

Drying

Granulation

Pelletization


Film coating

Packaging

NIR imaging




Concluding Remarks

References

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