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Development and validation of a differential scanning calorimetry purity

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Accred Qual Assur (2010) 15:269–281
DOI 10.1007/s00769-010-0632-6
GENERAL PAPER
Development and validation of a differential scanning calorimetry
purity determination method for polycyclic aromatic
hydrocarbons
Vikram Kestens • Gert Roebben • Thomas Linsinger
Received: 8 May 2009 / Accepted: 4 January 2010 / Published online: 22 January 2010
Ó Springer-Verlag 2010
Abstract Based on a standard test method for purity by
differential scanning calorimetry (DSC), ASTM E 928, a
purity determination method for highly pure polycyclic
aromatic hydrocarbons (PAHs) has been developed and
validated. The robustness of the developed method was
investigated by determining, under varying measurement
conditions, the purity of two PAH certified reference mate-
rials (CRMs), benzo[c]phenanthrene and dibenzo[a,h]
anthracene. The repeatability and intermediate precision of
the developed method was determined by analysing the
purity of benzo[c]phenanthrene and dibenzo[a,h]anthracene
and PAH candidate CRMs indeno[1,2,3-c,d]pyrene,
6-methylchrysene and benzo[a]pyrene. The trueness of the
method was studied using the same (candidate) CRMs and a
series of 42 other PAH CRMs. For each of the five (candi-
date) CRMs, a full measurement uncertainty budget was
developed. Also for PAH materials for which the DSC purity
determination method has not been explicitly validated, the
relative expanded measurement uncertainty was estimated.
Keywords Certified reference materials 
Differential scanning calorimetry  Measurement
Certain commercial equipment, instruments, and materials are
identified in this paper to specify adequately the experimental
procedure. In no case does such identification imply recommendation
or endorsement by the European Commission, nor does it imply that
the material or equipment is necessarily the best available for the
purpose.
V. Kestens (&)  G. Roebben  T. Linsinger
Institute for Reference Materials and Measurements (IRMM),
Joint Research Centre, European Commission,
2440 Geel, Belgium
e-mail: vikram.kestens@ec.europa.eu
URL: http://irmm.jrc.ec.europa.eu
uncertainty  Polycyclic aromatic hydrocarbons 
Purity  Trueness  Validation
Introduction
Polycyclic aromatic hydrocarbons
Polycyclic aromatic hydrocarbons (PAHs) are environmen-
tal compounds composed of two or more fused benzene rings
substituted by N, O, methyl, hydroxyl or nitro groups. They
are mainly emitted through natural (e.g. volcanic eruptions,
forest fires, etc.) and anthropogenic (e.g. fossil fuels, iron and
steel production, etc.) incomplete combustion processes.
PAHs have been detected in air, water, soils and sediments
and in plant, animal and human tissues [1–4], where they
accumulate. Based on genotoxicity studies, the US Envi-
ronmental Protection Agency has identified and classified a
number of PAHs as group B, probable human carcinogens
[5–8]. European legislation has been put in place over the
years to protect public health and environment from these
contaminants. In 2000 and 2004, the European Parliament
and Council have adopted the Water Framework Directive
2000/60/EC and Directive 2004/107/EC on arsenic, cad-
mium, mercury, nickel and PAHs in ambient air [9, 10]. The
monitoring and toxicologically acceptable maximum levels
of PAHs in drinking water and food products are imple-
mented by amending Regulation (EC) No. 188/2006 and
Council Directive 98/83/EC, respectively [11, 12]. As a
result, the levels of PAHs in foodstuffs and environment
need to be continuously monitored by qualified testing
laboratories. To ensure the traceability and uniformity of
measurement data and to allow intra- and interlaboratory
comparisons, the availability of standardised analytical
methods and fit-for-purpose certified reference materials
(CRMs) is of paramount importance [13–16].
123
270
PAH certified reference materials
To facilitate the implementation of European legislation
concerning PAH monitoring and to support testing labo-
ratories in analytical quality assurance/quality control (QA/
QC) and for the validation of analytical procedures, the
Institute for Reference Materials and Measurements
(IRMM) of the Joint Research Centre (JRC) of the Euro-
pean Commission has produced a group of high-purity
PAH CRMs. These CRMs are the basis for the preparation
of calibration standards when dissolved into appropriate
solvents. The CRM production activities at the IRMM are
accredited according to ISO Guide 34 [17, 18]. The pure
PAH raw materials are produced under subcontract to the
IRMM. After being tested for homogeneity and short- and
long-term stability, the candidate RMs are then tested in an
interlaboratory comparison study which is led and super-
vised by the IRMM. In this characterisation stage of the
certification project, different laboratories are asked to
determine the PAH purity using independent analytical
methods such as GC–FID and GC–MS, HPLC–UV and
direct probe inlet MS. The data obtained from the labora-
tory intercomparisons are then technically and statistically
evaluated to establish on a metrological basis (traceable to
SI units) an assigned purity and corresponding measure-
ment uncertainty value for the tested candidate RMs.
Differential scanning calorimetry
It has been suggested to also use differential scanning
calorimetry (DSC) in the certification of PAH reference
materials. DSC is a technique from the group of thermal
analysis methods in which a physical property of a material
is studied while it is subjected to a controlled temperature
programme. Many of these thermal analysis techniques are
used on a large scale in research and quality control
laboratories in different industries (e.g. polymers, phar-
maceutics, chemicals, etc.) [19, 20]. DSC determines the
enthalpy change during phase transitions by measuring as a
function of temperature or time the difference in heat flow
(heat-flux DSC) or power (power-compensated DSC)
between a test sample and a reference sample. A variety of
methods applying the principles of DSC have been devel-
oped [21]. The theory and practical aspects of conventional
DSC are well known and have already been intensively
investigated and described in the literature [22].
DSC for purity assessments
The use of DSC for purity analysis is common in phar-
maceutical industries [23]. A ‘‘dynamic method’’ was
described for the first time by Gray in 1966 [24], and has
since then been continuously and critically evaluated by
123
Accred Qual Assur (2010) 15:269–281
many researchers [25]. In this method, a sample is heated at
constant rate through its melting range. Since thermody-
namic equilibration of the whole sample during the DSC
measurement is of crucial importance, both sample mass
and heating rate should be kept as low as possible. Gen-
erally, a sample mass and linear heating rate of maximum
3 mg and 1 K min-1, respectively, should not be exceeded.
The dynamic purity method has led to the development of a
standard method (ASTM E 928), by Committee E-37 on
Thermal Measurements of the American Society of Testing
and Materials in 1983. This standard method is claimed to
produce SI traceable results and has been revised several
times [26]. In 1974, Staub and Perron [27] established and
proposed another approach, the isothermal step method, in
which a sample is heated stepwise through its melting
range. However, all commercial instruments use the
dynamic method to provide values for the measurand
defined in ASTM E 928. The stepwise method is not fur-
ther discussed and the term ‘‘purity determination method’’
as used throughout this paper refers to the dynamic method.
van’t Hoff theory
The principle of purity determination by DSC is based
upon the colligative properties of the test material, as
increasing levels of impurities in a material broaden the
melting range and lower the melting point compared to the
pure compound. In the case of a eutectic system of near
purity [amount (mole) fraction C98.5%], and with impu-
rities that dissolve in the liquid phase, but not in the solid
phase, this melting point depression is captured in the
following relationship, Eq. 1:
RT02 x2
T0  Tm ¼ ð1Þ
Dfus H 
where T0 is the melting temperature of a 100% pure
compound, Tm is the melting temperature of the test
sample containing impurities, DfusH° is the enthalpy
change of fusion (J mol-1), R is the molar gas constant
(J mol-1 K-1) and x2 is the amount fraction of the
detectable impurity component in the sample system.
DSC purity determinations are performed by measur-
ing the enthalpy of fusion of the primary component
(melting peak area) and integrating at least ten series of
partial peak areas (between 10 and 50% of the total
peak area), at a number of temperatures Ts between the
onset of melting and the temperature of the melting
peak maximum. These data are used to construct an
enthalpy-corrected linear relationship in the following
way [28].
As can be seen from Eq. 2, while the fraction of liquid
phase (F) grows during melting, the amount fraction of
impurities in the liquid phase (x) decreases.
Accred Qual Assur (2010) 15:269–281
1 Also, inorganic contaminants as well as volatiles (water,
x ¼ x2 : ð2Þ
F solvents) and compounds that become volatile before or
Equation 3 shows the relationship between T0, the melting
temperature of a 100% pure compound, Tm, the melting
temperature of the sample system and Ts, the sample
temperature at which a certain fraction, F, is molten.
T0  Tm
F¼ ð3Þ
T0  Ts
After rearranging Eq. 3 and substituting into Eq. 1, a linear
relation, given by Eq. 4 and known as the van’t Hoff
relationship, from which the sample impurity can be
calculated, is obtained.
RT02 x2 1
Ts ¼ T0  : ð4Þ
Dfus H  F
Theoretically, plotting the reciprocal of the melt fraction
against the sample temperature Ts should give a straight
line. In practice, the obtained curve shows non-linearities
due to instrument effects, the absence of thermodynamic
equilibrium in a dynamic experiment, thermal gradients in
the sample and pre-melting behaviour or non-detection of
the eutectic melting [26, 29]. To eliminate these non-
linearities, different methods have been implemented.
After linearisation, the intercept with the Y-axis is T0 and
the slope of the curve can be used to determine x2, the
amount fraction of the impurity component. The amount
fraction of the primary component is then obtained as
x1 = 1 - x2, requiring the assumption that all impurities in
the sample are detected by the DSC method.
Limitations of the DSC method for purity assessments
Compared to traditional analytical techniques, DSC does
not require difficult sample preparation. Moreover, DSC
sample preparation is less time consuming since the com-
pound after encapsulation can be directly placed in the
instrument and measured. It is therefore tempting to
neglect the different limitations of the DSC purity method.
Several assumptions are made when applying the van’t
Hoff theory: (1) impurities dissolve in the melt phase of the
primary component; (2) the fraction of impurities forming
a solid solution is regarded as negligible; (3) thermody-
namic equilibrium throughout the whole sample during
melting; and (4) the relative molecular mass of the present
impurities is close to the relative molecular mass of the
primary component. As a result, the method cannot be
applied when the amount fraction of the primary compo-
nent is below 0.985 mol mol-1, and the specificity of the
method is an issue as well. Many impurities may cause
broadening of the melting peak; however, the method
cannot identify the nature of the individual impurities.
271
during melting will not be detected.
Method-defined measurands
The assumptions made in the DSC method are critical, and
therefore the method always needs to be stated when
reporting DSC results, for example in the following way:
purity (amount fraction) as determined by DSC in accor-
dance with ASTM E 928. In other words, the measurand,
being the fraction of impurities detected by DSC, is method
defined [30]. From this point of view, DSC does not differ
that much from other existing purity determination meth-
ods: all methods have their own limitations towards certain
groups of impurities and also their measurands are method
defined [31]. An important advantage of DSC compared to
traditional purity determination methods is its potential to
determine impurities (e.g. isomers, polymorphisms) that
are chemically and/or physically very similar to that of the
primary component [32]. Chromatography-based tech-
niques are often not able to separate these kinds of
impurities from the primary component, resulting in
overestimated purity results. This has been recently con-
firmed during a study in which different grades of
commercially available high-purity chloramphenicol sam-
ples have been tested by means of different purity
determination methods (e.g. GC–MS, HPLC–DAD, DSC
and Karl Fischer). This study is still ongoing and the results
will be further discussed in a following paper (Kestens
et al., to be submitted). Acknowledging the limitations of
each of the different purity determination techniques and
methods, purity determination based on only one method
should be strongly discouraged since the intrinsic purity
will always be overestimated. A good estimate of the
intrinsic impurity can only approached by using different
methods and techniques. In this respect, DSC can be
regarded as a valuable tool for purity determination toge-
ther with other analytical techniques such as HPLC–DAD,
GC–MS and GC–FID [33].
Validation of the DSC method for purity assessment
However, in contrast to chromatographic techniques for
which validation procedures are well established, DSC
purity methods have rarely been validated and thus realistic
measurement uncertainties are not available. These mea-
surement uncertainties are critical to allow reliable
interpretation of purity values measured by DSC. The aim
of this paper is to report on the robustness investigation of
the developed DSC purity determination method for PAHs.
Furthermore, a top–down method validation study in which
the repeatability, intermediate precision and trueness of the
123
272
developed method was investigated, was performed. Sev-
eral reference materials such as SRM 1514 (NIST,
Gaithersburg, MD, USA) and LGC 2013 (Teddington, UK)
are commercially available and can be used for the vali-
dation of the DSC purity determination method. However,
since the suitability and validity of the method is strongly
defined by the nature and composition of the compound
under investigation, the matrix of the reference materials
used in the validation study should be as close as possible
to the matrix of the test samples under investigation.
Therefore, PAH (candidate) CRMs were used in this vali-
dation study.
In order to compare and interpret the quality of the
obtained DSC purity results in a metrologically sound and
rigorous manner, the measurement uncertainty for the
(candidate) PAH CRMs was estimated from repeatability
and intermediate precision data. To allow comparability of
the DSC purity results with purity results obtained by
means of other methods and techniques, a second uncer-
tainty budget was established also taking into account the
bias uncertainty. The latter approach clearly deviates from
the approach followed by ASTM E 928 which does not
foresee any corrections due to experimental bias.
Experimental
Differential scanning calorimetry
All DSC measurements were carried out under nitrogen
atmosphere (flow rate 50 mL min-1) using a Q1000 heat-
flux differential scanning calorimeter (TA Instruments-
Waters LLC, New Castle, DE, USA). The instrument was
cooled by a refrigerated cooling system (TA Instruments-
Waters LLC, New Castle, DE, USA). The general perfor-
mance of the instrument was tested monthly by melting a
sample of an indium CRM and evaluating the height/width
ratio of the obtained melting peak.
Calibration
Differential scanning calorimetry is a relative method
which means that all instrument responses require cali-
bration. The instrument was calibrated according to
TzeroTM, for enthalpy (transition peak area) and for tem-
perature. TzeroTM is a technology patented by TA
Instruments-Waters LLC, that consists of consecutively
heating the empty instrument cell in a first run, and a-
alumina (synthetic sapphire) CRM disks, located on both
sample and reference position, in a second run [34]. The
TzeroTM calibration allows detection and compensation for
instrument imbalances and sample–reference side asym-
metry that contribute to instrument baseline heat flow
123
Accred Qual Assur (2010) 15:269–281
artefacts. A two-point temperature and enthalpy calibration
was performed simultaneously by fusion of 2 mg of highly
pure (amount fractions [99.999%) indium LGC 2601
(Teddington, UK) and tin LGC 2609 (Teddington, UK)
CRM samples in standard aluminium crucibles at a
constant heating rate of 1 K min-1. The temperature cali-
bration was based on the determination of the extrapolated
peak onset temperatures (Te) for the applied heating rate
(b), followed by a linear extrapolation to zero heating rate
(b = 0). Subtracting Te (b = 0) from the experimental
transition temperature yielded the temperature calibration
factor. The enthalpy calibration factor was obtained as the
ratio of the certified enthalpy change of fusion and the area
enclosed by the transition peak and an interpolated
baseline.
PAH samples
High-purity polycyclic aromatic hydrocarbon CRMs
benzo[c]phenanthrene (BCR-134) and dibenzo[a,h]anthra-
cene (BCR-138) and candidate RMs indeno[1,2,3-c,d]
pyrene (ERM-AC053), 6-methylchrysene (ERM-AC082)
and benzo[a]pyrene (ERM-AC051) were all supplied by
the Reference Materials Unit of the IRMM in Geel, Bel-
gium. A commercial phenanthrene sample was supplied by
Dr. Ehrenstorfer GmbH (Augsburg, DE). An overview of
some characteristics of the tested PAH CRMs are given in
Table 1. Relative molecular masses, melting temperatures,
purity values (mass fraction) and the total mass fraction of
inorganic impurities were taken from the certificates and
certification reports. Both certificates and certification
reports can be accessed via the online CRM catalogue of
the IRMM [35].
During the method development and validation experi-
ments, samples were prepared in either standard aluminium
crucibles or aluminium crucibles that could be closed
hermetically. Sample masses between approximately 0.5
and 2 mg were carefully transferred into the crucibles and
accurately weighed using a microbalance with a readability
of 0.001 mg. The crucibles were then closed with an
appropriate aluminium lid and sealed using a crimper. An
empty crucible and lid of the same type were used as ref-
erence. The samples were then rapidly heated up to 25 K
below their theoretical melting point, followed by a con-
stant heating rate of 0.5 or 1.0 K min-1 until
approximately 25 K above the melting point.
Suitability of the PAH melting peaks for application
of the DSC purity method
The DSC purity method as outlined in standard ASTM E
928 is only valid for highly pure (amount fraction C98.5%)
Accred Qual Assur (2010) 15:269–281 273

Table 1 Properties of PAH CRMs selected for method development and validation study
CRM code Compound name, abbreviation, Mr (g mol-1) Tm (K) Purity (g g-1) Inorganic
formula and chemical structure l ± U(l) (k = 2) impurities (g g-1)

BCR-134 Benzo[c]phenanthrene, BcPh, C18H12 228.29 339.3 0.9968 ± 0.0014 0.0011

ERM-AC082 6-Methylchrysene, 6MC, C19H14 242.32 434.2 0.983 ± 0.010 0.0007

ERM-AC053 Indeno[1,2,3-c,d]pyrene, IcP, C22H12 276.33 436.8 0.996 ± 0.005 0.0003

ERM-AC051 Benzo[a]pyrene, BaP, C20H12 252.31 451.3 0.973 ± 0.013 0.0013

BCR-138 Dibenzo[a,h]anthracene, DhA, C22H14 278.35 539.7 0.990 ± 0.007 0.0013

Mr, relative molecular mass; Tm, melting temperature; l, certified purity; U(l), expanded uncertainty of l (k = 2)

and thermally stable organic and inorganic compounds.
Furthermore, the obtained endothermic melting peak must
not be interfered by any decomposition or other thermal
events and therefore, a critical evaluation of the melting
peak is of utmost importance before applying purity anal-
ysis [36]. For example, the main melting peak of IcP
contained an additional partially unresolved melting peak,
potentially disqualifying the use of this melting peak for
purity determination. However, when cooling down the
sample and heating it again for a second time, the unre-
solved melting peak was not present anymore and the
obtained melting peak could be used for purity assessment.
Furthermore, ASTM E 928 describes a procedure to test
the required thermal stability of compounds by comparing
the melting onset temperatures obtained at different heating
rates (1.0, 5.0 and 20.0 K min-1). According to this pro-
cedure, a compound is found to be thermally stable when
the onset temperatures of the melting peaks, measured at

123
274
the different heating rates, do not change by more than 1 K.
The different melting onset temperatures (not corrected for
b = 0) for BcPh, 6MC, IcP, BaP and DhA, measured at
different heating rates (b), are listed in Table 2.
When melting phenanthrene at a heating rate of
1 K min-1, a sharp and clear endothermic peak, at first
sight suitable for purity analysis, was obtained. Neverthe-
less, when subjecting the sample also to heating rates 5.0
and 20.0 K min-1, a shift by 1.5 K between the lowest and
highest melting onset temperature was observed. Although,
the temperature shift is rather small, it indicates that
phenanthrene might be thermally unstable at lower heating
rates. Measuring phenanthrene at a heating rate of
0.9 K min-1 resulted in an irregularly shaped endothermic
melting peak (Fig. 1) and confirmed this hypothesis. On the
other hand, the melting onset temperatures obtained for
BcPh, 6MC, IcP, BaP and DhA did not shift significantly
and therefore it was concluded that the purity of these
compounds could be assessed by means of DSC.
Robustness evaluation and method development
The DSC purity procedure described in ASTM E 928
involves the use of relatively small sample sizes, a tight
encapsulation of the sample in the crucible (to minimise
temperature gradients) and a slow heating rate [25, 28]. To
examine, for the case of PAH materials, the potential
sources of variability from these parameters (sample size,
crucible type and heating rate) a robustness study was
carried out. Based on preliminary tests, BcPh and DhA
were selected as model systems for the robustness study,
which was used to develop a general DSC purity deter-
mination method for PAHs. The different method
parameters and parameter levels that were considered and
investigated for both PAHs are listed in Table 3. Each level
of each parameter was tested in triplicate. The measure-
ments were carried out in a randomised sequence and were
spread over different days. As for each set of data only one
parameter was varied, possible synergistic effects could not
be investigated. Results are graphically represented in
Figs. 2, 3 and 4. The DSC method used during this
Table 2 Onset melting
PAH compound (CRM code)
temperatures (K) at different
heating rates (K min-1) of
PAHs selected for method
validation and validation study Benzo[c]phenanthrene (BCR-134)
6-Methylchrysene (ERM-AC082)
Indeno[1,2,3-c,d]pyrene (ERM-AC053)
Benzo[a]pyrene (ERM-AC051)
Dibenzo[a,h]anthracene (BCR-138)
Phenanthrene
123
Accred Qual Assur (2010) 15:269–281
Fig. 1 DSC scan of phenanthrene (heating rate 0.9 K min-1)
robustness study showed to be robust for the purity
assessment of DhA. Variation in sample size, heating rate
and crucible type did not result in significantly different
purity values based on one-way ANOVA (analysis of
variance). The mean amount fraction (n = 3) and corre-
sponding standard deviation of DhA were determined as
0.9996 and 0.0001 mol mol-1, respectively. The robust-
ness of the same method was also evaluated by analysing
the purity of BcPh. Compared to DhA, the method showed
to be less robust A Student’s t test identified significantly
different purity values (P B 0.05) between the different
sample sizes and crucible types. The standard deviations
were in all cases higher than these for DhA. The mean
amount fraction and standard deviation of BcPh were
0.9971 and 0.0007 mol mol-1.
Different factors can explain the less reproducible
results for BcPh compared to DhA. A first possible reason
is the presence of small fractions of compounds which
become volatile during melting. If standard crucibles are
used, the volatiles will easily escape from the sample pan
and interfere with the sample melting. The heat-flow
changes that arise from the evaporation are expected to be
rather small and hidden under the endothermic melting
peak of the primary component. If hermetically closed
crucibles are used, evaporation is initially suppressed and
Onset melting temperatures (K)
b = 1.0 b = 5.0 b = 20.0
339.2 339.8 340.2
432.6 432.6 432.9
437.4 437.0 437.3
451.4 451.4 451.4
539.9 539.8 540.4
369.9 370.1 371.4
Accred Qual Assur (2010) 15:269–281
Table 3 Method parameters selected for robustness study
Parameters Level
Sample size 0.5, 1.0 and 2.0 mg
Crucible type Standard and hermetically closed aluminium
Heating rate 0.5, 1.0, 1.5 and 5.0 K min-1
Fig. 2 Effect of the sample size (0.5 mg, white; 1.0 mg, light grey
and 2.0 mg, grey) on the measured amount fraction for BcPh (BCR-
134) and DhA (BCR-138). The error bars indicate the standard
deviation of three repeats. Purity determinations for DhA at sample
sizes 1.0 and 2.0 mg did not result in a detectable standard deviation
Fig. 3 Effect of the crucible type (standard aluminium, white and
hermetically closed aluminium, light grey) on the measured amount
fraction for BcPh (BCR-134) and DhA (BCR-138). The error bars
indicate the standard deviation of three repeats
can occur at temperatures above the melting temperature.
As a consequence, the evaporation would not interfere with
the sample melting. A second possible explanation can be
the nature of the sample. Although, all PAHs used in the
study are highly pure compounds, limited fractions of
different types of organic (e.g. intermediates and deriva-
tives of the primary component) and inorganic impurities
275
Fig. 4 Effect of the heating rate (0.5 K min-1, white; 1.0 K min-1,
light grey; 1.5 K min-1, grey and 5.0 K min-1, dark grey) on the
measured amount fraction for BcPh (BCR-134) and DhA (BCR-138).
The error bars indicate the standard deviation of three repeats. Purity
determinations for DhA at a heating rate of 5.0 K min-1 did not result
in a detectable standard deviation
Table 4 DSC purity method developed for PAHs
Parameters Levels
Sample size 0.5–2 mg
Crucible type Normal and hermetically closed aluminium
Pre-melt Compound dependent
Heating rate 0.5–1.0 K min-1
Atmosphere Nitrogen
Gas flow rate 50 mL min-1
are present and interfere with the primary component in an
unpredictable way.
Based on the robustness tests and the statistical evalu-
ation and preliminary characterisation tests, a generic DSC
purity determination method for PAHs was developed and
established (Table 4).
The two most common types of crucibles used for DSC
experiments are standard aluminium crucibles and alu-
minium crucibles that can be closed hermetically. Some
PAHs might contain volatile compounds which can evap-
orate before or during melting. In this case, hermetically
closed crucibles are recommended. To approach thermal
equilibrium conditions within the sample, only small
sample sizes and low heating rates were used. Nitrogen gas
pressure and flow rate were kept constant.
Method validation and uncertainty assessment
To diagnose the quality of the developed DSC purity
determination method for PAHs, a method validation
study was carried out, according to EURACHEM
123
276
Table 5 Parameters varied during method validation study
Parameters Day 1 Day 2 Day 3 Day 4
Crucible type Standard Standard Hermetic Hermetic Standard
Sample size *1 *2 *0.5 *2
(mg)
Heating rate 1.0 0.5 0.5 1.0
(K min-1)
recommendations [37]. The parameters that varied during
the validation study were determined during method
development and by experiences gained from earlier DSC
studies [38]. The different performance parameters con-
sidered and investigated during the validation study are
discussed below. For each of the five selected PAH CRMs,
five series of each three measurements were performed.
The measurement series were carried out on different days
and under varying conditions (Table 5).
Measurand definition
Purity determinations using DSC lead to values for a
method-defined measurand. In this study, tests are gener-
ally performed according to ASTM E928. The measurand
therefore is defined as the amount fraction (mol mol-1) of
impurities detected by DSC, according to ASTM E 928. It
is implicitly assumed that the organic impurity component
mainly consists of isomers of the primary component and
intermediates and/or products of side reactions that origi-
nate from PAH synthesis and that the relative molecular
masses of these organic impurities are not very different
from the relative molecular mass of the primary compo-
nent. By making this assumption, the conversion factor
between mass fraction and amount fraction is considered
not to be significantly different from 1.
Working range
The working range of the proposed DSC purity determi-
nation method for PAHs is defined by ASTM E 928 [26].
According to this standard, the method is only applicable to
thermally stable organic and inorganic compounds that
during melting form a eutectic system (impurity must
dissolve in the liquid phase and must be insoluble in the
solid phase). The method also requires that the amount
fraction of the primary component (purity) is at least
0.985 mol mol-1.
Calibration and linearity
As can be seen from the van’t Hoff relationship, a correct
melting temperature and enthalpy of fusion are crucial
123
Accred Qual Assur (2010) 15:269–281
factors for purity determination and thus proper instrument
Day 5
calibration (temperature, enthalpy and heat flow rate) is of
utmost importance [39, 40]. For the validation study, the
instrument was calibrated for temperature and enthalpy
*0.5 using indium and tin CRMs. The melting temperatures of
indium and tin are both defined points on the ITS-90
0.5 temperature scale. The central idea behind instrument
calibration is to identify and subsequently to rule out
sample and instrument dependences. This can only be done
by measuring appropriate CRMs and selecting calibration
conditions that are as close as possible to the experimental
conditions applied to the PAHs. Since the aim of this study
was to develop a general DSC purity determination method
for PAHs, calibration conditions were not varied with
respect to the type of PAH compound. Due to the instru-
ment calibration, the method-defined results of the DSC
purity determination method are SI traceable [30].
On the other hand, the current validation study was only
evaluated via the top–down approach and therefore
uncertainties due to instrument calibration were not
separately added to the overall uncertainty budget.
Uncertainties that originate from temperature and enthalpy
calibration are expected to be covered by the intermediate
precision uncertainty, whereas uncertainties due to any
systematic errors are assumed to be covered by the bias
uncertainty contribution.
Looking at Eq. 4, one would expect a linear relationship
between instrument response and sample impurity content.
However, in many cases, it is found that the van’t Hoff plot
deviates from the predicted straight line (Fig. 5). By
applying a correction factor, linearisation is achieved.
According to ASTM E 928, the method is considered to be
unreliable if the correction factor exceeds 20%. In our
study, the correction factors were always below 10%.
Fig. 5 van’t Hoff plot of BaP (ERM-AC051) before (circles) and
after (squares) linearisation and least-square fit (dashed line)
Accred Qual Assur (2010) 15:269–281 277

LOD/LOQ consists of three consecutive stages: bias calculation, esti-

According to the EURACHEM guidelines, the limit of
detection (LOD) is the lowest content of the analyte or
property that can be confidently detected by the method.
The limit of quantification (LOQ) is the lowest content of
the analyte that can be determined with an acceptable level
of precision and accuracy [37]. Since the van’t Hoff plot is
linearised, the LOD and LOQ of the DSC purity determi-
nation method could be estimated as three times and ten
times the intermediate precision standard deviation,
respectively. Based on the results obtained on DhA, which
gave the best repeatability, an LOD and LOQ of 0.0003
and 0.0010 mol mol-1 were calculated.
Selectivity and interferences
Due to the presence of different crystalline forms of the
same composition, some compounds (e.g. IcP) can reveal
different endothermic melting peaks during the first melt.
However, for some of these materials a single melting
peak, which allows DSC purity determination, can be
obtained by cooling down the molten compound slowly to
room temperature, followed by a second melting. Due to
the relatively slow, natural cooling and the large und-
ercooling (room temperature), it can be assumed that this
premelting will transform all crystals to the same phase.
Trueness
For the five PAH compounds that were investigated during
the method validation study, an individual trueness
assessment study was carried out. The trueness assessment
mation of the uncertainty related to trueness, and bias
evaluation. In the first stage, the experimental bias ( Dm)
was calculated from the absolute difference between the
certified purity value (corrected for inorganic impurities)
and the mean measured purity value. In the second stage,
the uncertainty related to trueness (uD), also called bias
uncertainty, was estimated from the measurement uncer-
tainty and the standard uncertainty of the certified purity
value. The standard uncertainty of the certified purity value
and the measurement uncertainty were then combined
according to the usual root-sum-of-squares manner, giving
the standard uncertainty of the bias assessment, uD. Finally,
for each of the PAH compounds, the experimental bias Dm
was compared with uD. If Dm B 2 uD, then the bias is not
significant. This trueness assessment procedure is discussed
in detail in ERM Application Note 1 [41].
The certified purity values, corresponding to standard
uncertainties and mass fraction of inorganic impurities
were taken from the certificates and certification reports
and are summarised in Table 1. Note that the uncertainty
values given in Table 1 are expanded uncertainties and that
they need to be divided by the coverage factor (k = 2) to
arrive at the standard uncertainty. The measurement
uncertainty was estimated as the standard deviation divided
by the square root of the number of measurement repli-
cates. An overview of the number of measurement
replicates, (nr), mean measured purity values, (ym), stan-
dard deviations, (s), and measurement uncertainties, u(ym),
is given in Table 6.
Using the multi-step trueness assessment approach, it
was observed that the DSC purity values for DhA, BaP and
6MC significantly deviated from their for inorganic

Table 6 Number of measurement replicates, nr; mean measured and bias, uD), experimental biases and relative expanded uncertainties
purity values, ym; standard deviations, s; and measurement uncer- (nr = 3) with, Uwith, and without, Uwithout, bias uncertainty and
tainties, u(ym), used for the assessment of trueness and relative experimental bias
standard uncertainties (repeatability, ur; intermediate precision, uip
PAH compound nr ym s u(ym) ur uip uD Dm Uwithout Uwith
(mol mol-1) (mol mol-1) (mol mol-1) (%) (%) (%) (%) (%) (k = 2) (%) (k = 2)

Benzo[c]phenanthrene 25 0.9974 0.0004 0.0001 0.04 0.02 0.07 0.05à 0.06 0.16
6-Methylchrysene 15 0.9963* 0.0007 0.0002 0.05 0.05 0.51 1.27 0.12 2.74
à
Indeno[1,2,3-c,d]pyrene 15 0.9957 0.0015 0.0004 0.13 0.09 0.25 0.07 0.23 0.56
Benzo[a]pyrene 15 0.9990* 0.0003 0.0001 0.03 0.01 0.67 2.47 0.05 5.13
Dibenzo[a,h]anthracene 25 0.9996* 0.0001 \0.0001 0.01 \0.01 0.35 0.83 0.01 1.82
PAHs for which the method has NA NA NA NA 0.03 0.05 0.25 0.30 0.11 0.79
not been validated (1 melt)
PAHs for which the method has NA NA NA NA 0.12 0.09 0.25 0.30 0.23 0.82
not been validated (2 melts)

* DSC purity value significantly higher than the certified purity (corrected for inorganic impurities), NA, not applicable; minimum uncertainty
component; u*ip, estimated from RSDr; à non-significant bias, not included in the overall expanded uncertainty U (k = 2)

123
278
impurities corrected certified purity values. The bias Dm
was therefore added to the overall uncertainty budget
(Table 6). On the contrary, the biases determined for BcPh
and IcP were found not to be significant and as a result,
there was no need to include the Dm values in their
uncertainty budget, only uD. 6MC and BaP are outside the
DSC working range since their certified purity is below
0.985 mol mol-1. During the DSC method validation
study, the certification study of both PAH compounds was
not yet finalised so this information concerning the impu-
rities was not yet available at that time.
There are a number of potential reasons that may (par-
tially) explain the experimental biases. As for all existing
purity analysis techniques, also DSC will not detect and
quantify all impurities. Only impurities that form during
melting a eutectic system will be detected. This means that
the DSC purity determination method is blind to inorganic
impurities and impurities or fractions of impurities that
form a solid solution during melting. This is why certified
values were corrected for inorganic impurity before com-
paring them with the DSC values. Also, volatile
compounds that evaporate before or during melting of the
primary component will not be detected. For the tested
PAHs, the potential mass fraction of volatile compounds
was assumed to be negligible, since baseline irregularities
that are caused by the evaporation effect were not
observed. If present, they were hidden under the endo-
thermic melting peak.
Another aspect which may contribute to the experi-
mental bias is the approach that was used to establish the
certified purity values. In general, these certified values
are obtained by means of different conventional tech-
niques, such as GC–MS, GC–FID and HPLC–UV. Since
each analytical method has its own (separation) limita-
tions towards certain groups of impurities, it was often
assumed that impurities detected by one method would
not be detected by the other methods. The total impurity
component of the PAH CRMs was then established as
being the sum of all impurity fractions determined by
each of the analytical methods used. Although, the
uncertainty related to this approach is included in the
overall uncertainty budget of each of the PAH CRMs, the
intrinsic purity might for this reason be rather
underestimated.
Further, the good repeatability of the DSC purity
determination method in combination with the relatively
high number of measurement replicates (Table 6) will
underestimate the real measurement uncertainty and sub-
sequently also the bias uncertainty. Finally, it is also
noteworthy that when determining the bias, one actually
compares the certified purity values, which are expressed
as mass fractions, with the DSC purity values, which are
obtained as amount fractions.
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Accred Qual Assur (2010) 15:269–281
The above discussed trueness and bias issues have also
been observed and reported during a previous study [38]. In
that study, a series of 34 different PAH CRMs have been
tested by DSC for trueness. Due to thermal instability of
the primary component, the purity of five compounds could
not be determined by DSC. For 11 out of the remaining 29
PAHs, the purity determined by DSC deviated significantly
from its SI-traceable certified value. After applying a cor-
rection for known inorganic impurities, for most of the
PAH compounds the value of the bias became insignificant.
Nevertheless, nine compounds still remained with a sig-
nificant bias. This indicates that inorganic impurities,
although they contribute to the experimental bias, should
not be regarded as the only source leading to systematic
errors.
When evaluating an experimental bias, it is important
that one can differentiate between the constant or method
bias and the bias due to the nature of the samples. This
aspect has been investigated and reported during another
recent study [42]. During that study, a selection of 42 high-
purity PAH CRMs were investigated for their purity,
melting temperature and enthalpy and entropy of fusion.
The method biases were additionally investigated based on
a series of DSC measurements on a high-purity indium
CRM. The obtained indium melting peaks were analysed
for melting temperature and enthalpy of fusion, both
identified as being the most crucial parameters in the DSC
purity determination method, and evaluated for trueness
following the same procedures as described above [41]. It
was found that the biases were not significant at a signifi-
cance level of 5%, neither for the melting temperature, nor
for the enthalpy of fusion. From this, we can conclude that
the major part of the total experimental bias for DSC purity
determinations on highly pure PAH compounds must
originate from the nature of the PAHs itself, rather than
from instrumental and/or method limitations. It would be
impossible to validate the DSC purity determination
method for each single PAH compound. However, when
reporting DSC purity results and uncertainties for these
kinds of PAHs, it would be incorrect not to include an
uncertainty contribution related to trueness, as it has been
proven that the uncertainty originating from trueness sig-
nificantly contributes to the overall uncertainty. From the
selection of 42 PAH CRMs that were analysed during the
previous study, a generic bias uncertainty value that fairly
reflects the uncertainty of the experimental bias for the
majority of PAH compounds was estimated [42]. For each
of the 42 PAHs, the individual biases and bias uncertainties
were determined. Both the biases and uncertainties were
then classified (bin size 0.05%). The bias (0.30%) and bias
uncertainty (0.25%), corresponding to a cumulative per-
centage of approximately 68%, were taken as being the
best estimate for the generic bias and bias uncertainty.
Accred Qual Assur (2010) 15:269–281
Repeatability and intermediate precision
Often, an important source of uncertainty is measurement
repeatability. Repeatability indicates the closeness between
results, performed over a short period, using the same
instrument and method and performed by the same oper-
ator. The relative standard uncertainty for repeatability (ur)
for a single measurement can be expressed as relative
standard deviation of the tests performed under repeat-
ability conditions (RSDr) and was estimated using Eq. 5.
The mean measured purity value is indicated by ym. The
mean of squares within measurement days (MSwithin) was
calculated using one-way ANOVA from the 15 measure-
ments that were spread over 5 different days.
pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
MSwithin
ur ¼ RSDr ¼ ð5Þ
ym
An overview of the relative standard uncertainties for
repeatability of the investigated PAHs is given in Table 6.
From the same data sets, relative standard uncertainties for
intermediate precision, uip, were estimated using Eq. 6.
The standard uncertainty for intermediate precision
expresses day-to-day variations. The number of replicates
per day is given by n, mean of squares between
measurement days is given by MSbetween.
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
MSbetween MSwithin
n
uip ¼ RSDip ¼ ð6Þ
ym
If the method gives highly reproducible results, then
MSbetween can be smaller than MSwithin. In such a case, uip
needs to be replaced by a minimum uncertainty
component, u*ip. This minimum uncertainty component
was calculated according to Eq. 7.
sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
RSD r 2
uip ¼ pffiffiffi
4
ð7Þ
n Nðn  1Þ
The total number of measurements in the validation study
is given by N.
For all tested PAHs, the repeatability and intermediate
precision uncertainties of the DSC purity determination
method were below 0.2%. In the field of CRM production,
this makes the method highly suitable to investigate the
homogeneity and short- and long-term stability of candi-
date (C)RMs. The good reproducibility of the DSC purity
determination method was also shown during the certifi-
cation study of 6MC, IcP and BaP [42].
Combined and expanded uncertainty
A complete overview of the standard deviations, mea-
surement uncertainties, relative expanded uncertainties,
279
experimental biases and the relative standard uncertainty
contributions from repeatability, intermediate precision and
trueness is given in Table 6. The different relative standard
uncertainties and biases (if applicable) were combined
according to Eq. 8, resulting in the relative expanded
uncertainty, Uwith. These expanded uncertainties are meant
for use when testing those PAH compounds for which the
DSC purity determination method has not been validated.
Additionally, use of Uwith allows the DSC purity results to
be compared with purity results obtained by means of other
methods and techniques. However, for within-method
comparison of DSC purity results, the bias and its uncer-
tainty do not have to be included in the uncertainty budget,
resulting in Uwithout (Eq. 9).
sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
u2r  
Uwith ¼ 2 þ u2ip þ u2D þ D2m ð8Þ
nr
sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
u2r
Uwithout ¼ 2 þ u2ip ð9Þ
nr
The relative expanded uncertainties, Uwith and Uwithout,
were obtained by multiplying the respective combined
standard uncertainties with a coverage factor, k = 2,
corresponding to a level of confidence of approximately
95%. As can be seen from Table 6, for all PAH
compounds, the largest contribution to Uwith comes from
trueness. In general, the repeatability uncertainty becomes
smaller with increasing measurement repeats, nr. However,
for the PAH compounds under investigation, it was found
that more than three repeats do not significantly reduce the
repeatability uncertainty anymore and thus also not Uwith.
Note that all standard uncertainties, listed in Table 6, are
relative values (amount fraction).
Conclusion
The results of the method validation study, obtained on five
(candidate) PAH CRMs, show that the proposed DSC
method for the purity determination of PAHs, which is
based on ASTM E 928, is robust and repeatable, within its
narrow but well-defined working range. On the other hand,
for two of the five PAH CRMs (BaP and 6MC) the
experimental bias, after correction for inorganic impurities,
was unacceptably large. These CRMs were recently pro-
duced and the certified purity values have only been
established after having run the tests for the DSC purity
method validation study. It is now known that both
candidate CRMs have a certified purity below
0.985 mol mol-1, and therefore they are outside the scope
of the proposed method. The large bias values explain the
high Uwith values reported for these two materials in
123
280
Table 6. Herewith, the validation study confirms that the
DSC purity determination method is only valid to those
compounds with an amount fraction of at least
0.985 mol mol-1.
Also for the PAH CRMs of higher purity, within the
working range of the DSC method, the method trueness
was checked. The DSC purity values were compared with
the certified values of the tested CRMs, and it is observed
that the DSC method systematically provides overestima-
tions of the PAH purity. From the new data, and supported
by data from previous studies, it is observed that the
experimental bias varies strongly between results obtained
on different PAH compounds, and is rather material
dependent than inherently due to the DSC method. Despite
this observation, a general bias and bias uncertainty of 0.30
and 0.25% were estimated for the large group of PAH
compounds for which the method has not been individually
validated, using data obtained on a series of 42 PAHs that
were analysed during a previous study [42]. These previ-
ously established values have now been combined with the
new repeatability and intermediate precision data. For
PAHs that have to be melted only once, a relative expanded
uncertainty of 0.79% was estimated based on the results
obtained on the BcPh and DhA (candidate) reference
materials. For PAHs that need to be melted twice to obtain
an endothermic melting peak fit for purity determination, a
relative expanded uncertainty of 0.82% was calculated
based on the data of the repeatability and intermediate
precision study of IcP, which is an example of such com-
pounds. It is acknowledged that the two generic
uncertainties that are valid for, respectively PAHs that have
to be melted only once and PAHs which have to be melted
twice, can be over- or under-estimations for particular
cases. However, rather than not including a trueness con-
tribution to uncertainty, the risk of underestimating the
measurement uncertainties of DSC purity results has been
avoided in this paper by explicitly taking into account the
trueness contribution.
DSC purity results tend to be different, and often higher,
than purity results obtained by more conventional tech-
niques such as HPLC–UV, direct probe MS, GC–MS and
GC–FID. However, all these techniques and methods,
including DSC, have in common that when they are used
for purity assessment, their measurand is method defined,
meaning that methods discriminate only certain groups of
impurities. In the case of DSC, inorganic and volatile
impurities as well as impurities that during melting do not
dissolve in the liquid melt phase, are not detected. There-
fore, the current study, once again, shows that purity
assessment, for example of reference materials, based on
only one analytical method should be strongly discouraged.
One single method that is capable of detecting and quan-
tifying all fractions of impurities does not exist. The bias
123
Accred Qual Assur (2010) 15:269–281
between apparent and intrinsic purity can only become
smaller, and sufficiently small for the certification of a
reference material, when purity is assessed by means of
different analytical techniques, all having their own spe-
cific affinities and limitations towards certain types of
impurities. In that perspective, the DSC purity determina-
tion method should be regarded as a valuable method
amongst other more traditional purity determination
methods for highly pure PAH CRMs.
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