Thermal Analysis

Applications
Booklet

Thermal Analysis of Pharmaceuticals

Application Examples
Applications Booklet

Thermal Analysis of Pharmaceuticals

Application Examples

Preface

Thermal analysis was first used as a standard method for the investigation of polymers. However, it is well
proven that thermal analysis also benefits the testing of pharmaceuticals. Techniques and methods dedicated to
testing pharmaceutical products such as active ingredients, excipients and packaging materials have been well
developed over recent years.

The potential use of thermal analysis in the pharmaceutical industry can be credited to the different chemical-physi-
cal aspects of investigations performed in laboratories and on-site test stations. Purity, stability, polymorphism and
incompatibility are just some areas of investigation that are explained later in this guide. For the analytical investi-
gation and measurement results of pharmaceuticals it is also important to consider the quality of results, possible
errors, validation and calibration. Separate chapters comment on method validation, measurement uncertainty
and SOPs. However, a comprehensive presentation of these topics exceeds the scope of this guide.

We hope that the applications described here will be of interest and

• make you aware of the potential of thermal analysis methods for the investigation of pharmaceuticals.
• provide you with some hints to assess the quality of the results.
• encourage you to explore these topics further by reading the recommended application handbooks,
or by attending webinars.

Disclaimer

This application handbook presents selected application examples. The experiments were conducted with the
utmost care using the instruments specified in the description of each application. The results were evaluated
according to the current state of our knowledge.
This does not however absolve you from personally testing the suitability of the examples for your own methods,
instruments and purposes. Since the transfer and use of an application is beyond our control, we cannot of course
accept any responsibility.

When chemicals, solvents and gases are used, general safety rules and the instructions
given by the manufacturer or supplier must be observed.

® TM All names of commercial products can be registered trademarks, even if they are not denoted as such.

METTLER TOLEDO Thermal Analysis 3

4 METTLER TOLEDO Thermal Analysis
Contents

Preface 3

1 What Thermal Analysis Can Do for Pharmaceuticals  6

2 Applications and Their Thermal Analysis Techniques 8

3 Examples 9
3.1 Polymorphism – Sulfapyridine 9
3.2 Stability – Acetylsalicylic acid 11
3.3 Characterization/Identification – Vanillin 13
3.4 Characterization/Identification – Polyethylene glycol PEG 14
3.5 Purity – Phenacetin and PABA 15

4 Measurement Errors and Uncertainty of Measurement  17

5 Method Development 19

6 Instrument Calibration and Adjustment 21

7 Excellent Crucibles, Accessories and Reference Materials 22

8 For More Information 23

METTLER TOLEDO Thermal Analysis 5

 1. What Thermal Analysis Can Do for Pharmaceuticals

The most important effects or properties that can be investigated by thermal analysis in the pharmaceutical
industry are discussed briefly in the following sections.

Polymorphism
Polymorphism is the term used to describe the ability of a substance to exist in different crystalline forms.
Many pharmaceutical substances exist in several crystalline forms. Even though the chemical composition
is the same, different physical properties can result such as melting point, heat of fusion, solubility behavior
or bio-availability. These differences are substance dependent and can be quite large.

For instance, one polymorphic form can be absorbed much better while the other can be inactive or even
toxic. It is therefore important to be aware of the different modifications, to be able to detect them and to have
information on their transition behavior (stable/metastable) in order to be able to optimize the production and
storage conditions so that only the desired form is present. Polymorphism can be investigated using DSC and
hot-stage microscopy. The measurement parameters are especially important because these can influence the
transition kinetics of the different modifications.

Pseudopolymorphism
This expression is often used to describe hydrates or solvates of drugs or additives. The ideal method
of investigation is a combination of TGA and DSC.

Phase diagrams
Important questions in the development of pharmaceutical preparations are whether the components used are
miscible, whether there are miscibility gaps or whether a eutectic is formed. These questions can be answered
with a phase diagram, which describes the relationship between the melting temperature and composition
of a multi-component system. In order to construct such a phase diagram, mixtures of the components with
different compositions are measured with DSC and the data evaluated (e.g. melting point, melting range).

Stability
The subject of stability and the means of stabilizing pharmaceutical preparations is a topic of increasing
significance. It is, after all, very important to know how long a product can be kept, taking into account the
requirements of storage and distribution.

In the case of long-term tests, samples that have been stored for different periods of time under different
conditions are analyzed at regular intervals. Changes in the state of the product can be easily recognized as shift
or change of measurement results. In addition, there is a rapid procedure in which the decomposition reactions
are investigated kinetically by measuring samples under different dynamic conditions (heating rates). These
results allow certain predictions about the decomposition behavior in a much shorter time period. They should
however only be interpreted in the form of a trend analysis. Recommended techniques are DSC and TGA.

Interactions
The term interaction, in this context, means interaction between two or more components of a pharmaceutical
preparation. Such interactions can be desirable or undesirable. Desirable interactions are purposely brought
about in order to improve the solubility of an active ingredient. Undesirable interactions, also known
as incompatibility, are interactions that lead to changes in one or more of the components, which then brings
an adverse drug reaction (ADR).
Pharmaceutical preparations can easily be investigated by DSC or TGA by comparing the results for
the individual components and the mixture with each other. If the mixture exhibits thermal effects that are not
apparent in the individual components then this is an indication of an interaction.

6 METTLER TOLEDO Thermal Analysis

Purity determination
The use of pure active and inactive ingredients for the preparation of pharmaceutical products is absolutely
essential, since undesirable impurities could have very serious consequences. For this reason the determination
of purity is performed routinely. The thermal analysis method is based on the observation that the presence
of impurities in an organic compound depresses the melting point i.e. the melting point is lowered with increasing
amounts of impurity. The correlation between the melting point depression and the degree of impurity for dilute
systems is described by the van't Hoff equation.

Taking some limitations into account, this method is above all suitable for the routine analysis of sample lots.
The analysis of the melting curve of a single DSC measurement yields all the information required to determine
the purity, the melting point and the heat of fusion of a substance.

Packaging materials
Packaging materials of all types are also important in the pharmaceutical industry. One must distinguish
between packaging that is in direct contact with the pharmaceutical preparation and packaging that serves only
as external packaging. Very stringent requirements apply for the first type of packaging because it could in some
instances react with the pharmaceutical preparation. The choice of a suitable material and its identification is
therefore of great importance. Because synthetic polymers are increasingly being used as packaging material,
thermal analysis is also being employed for the quality control and identification purposes. DSC is widely
applied to the characterization of packaging materials.

Process optimization
Effects that can be measured with thermal analysis (e.g. melting) are also used to show indirectly whether
a substance suffers a change during processing. The process parameters must then be chosen so that, if possible,
this does not happen. DSC measurements can provide basic information that benefit process optimization.

More details
A comprehensive presentation is given in the application handbook
J. de Buhr: Pharmaceuticals – Collected applications, Mettler-Toledo AG, 51725006A, © 12/2009

METTLER TOLEDO Thermal Analysis 7

 2. Applications and Their Thermal Analysis Techniques

An overview regarding pharmaceuticals, summarizes the effects and properties of excipients and active
pharmaceutical ingredients (API) that can be investigated by thermal analysis techniques.

DSC Differential scanning calorimetry

TGA Thermal gravimetric analysis
EGA Evolved gas analysis
TOA Thermo-optical analysis – hot-stage

Applied to Suitable TA technique

Tasks Excipients API DSC TGA EGA TOA
Analysis of composition + •
Characterization + + • •
Crystallinity + •
Crystallization + •
Decomposition + + • • •
Desorption/evaporation + • •
Determination of content + + • •
Glass transition + •
Heat of fusion + + •
Identification + + • •
Interaction/compatibility + + • •
Kinetics (reaction, decomposition) + + • •
Melting point/melting range + + • •
Melting behavior/fraction melted + + •
Moisture determination + + •
Oxidation stability + • •
Phase diagrams + + • •
Phase transitions + •
Polymorphism + + • •
Pseudopolymorphism + • •
Purity determination + + • • •
Purity (optical purity) + •
Stability (thermal) + + • • •
Table 1: Overview.

8 METTLER TOLEDO Thermal Analysis

3. Examples

The following examples provide a short selection of thermal analysis techniques and methods to pharmaceutical
samples. All examples provide measurement parameters, interpretation remarks and a conclusion.

3.1 Polymorphism – Sulfapyridine

Sample Sulfapyridine

Application Active ingradient

Conditions Measuring cells: DSC, HS82 microscope hot stage
Crucibles: DSC: Aluminum 40 µL, hermetically sealed
FP82: Sample holder with cover glass
Sample preparation: As received, no preparation
DSC measurement: Shock-cooled from the melt.
Then heating from 40 °C to 200 °C at 5 K/min
Atmosphere: Nitrogen, 50 cm3/min

Interpretation
Shock-cooling (rapidly cooling) the sample to a temperature below the glass transition temperature Tg before
performing a heating run is often the best method of detecting poly- morphism. According to Oswald, the meta-
stable phase (B, if one exists at all) crystallizes above the glass transition Tg (A). This is transformed on further
heating first monotropically (C, solid-solid transition) and then, after the melting of the metastable phase (D),
by crystallization from the liquid phase (E) to the stable modification. This then finally melts (F).
It is known from other DSC measurements, that sulfapyridine exhibits further modifications.

METTLER TOLEDO Thermal Analysis 9

 Evaluation

Effect Onset, Peak in °C ΔH in J/g

A 54.8 — glass transition
B 99.9 64.9 cold crystallization
C 150.1 (2.4) monotropic transition
D 175.3 (24.4) melting of the metastable phase still present
E 177.3 (2.4) crystallization of the stable phase from the melt
F 190.3 (109.1) melting of the stable phase

Photographs were taken of the crystal modifications at different temperatures using the HS82 hot stage system
in order to gain additional information about the polymorphic behavior of the substance. The following photo-
graphs correspond to the crystal modifications at about 120 °C and 177 °C.

Crystal modification at about 120 °C.

Crystal modification at about 177 °C.

Conclusion
The possibility of a substance exhibiting polymorphism is best investigated by first of all melting it most care-
fully (rapidly, under nitrogen) and then immediately shock-cooling it under its glass transition temperature (rule
of thumb: Tg is roughly 3/4 Tf, both temperatures are in Kelvin). Afterwards, the different modifications can be
observed by slowly heating the sample in the DSC cell.

10 METTLER TOLEDO Thermal Analysis

3.2 Stability – Acetylsalicylic acid

Kinetic analysis of decomposition

Sample Acetylsalicylic acid

Application Analgesic
Measurement Measuring cell: TGA/DSC
Crucible: Aluminum 100 µL, with pierced lid
Sample preparation: As received, no preparation
TGA measurement: Heating from 25 °C to 300 °C at 1, 2, 5 und 10 K/min,
all measurements are blank curve corrected
Atmosphere: Air, 50 cm3/min

Interpretation
The first diagram shows the effect of the heating rate on the decomposition of acetylsalicylic acid. The decom-
position, that is the resulting weight loss, is shifted to higher temperature with increasing heating rates. The DTG
curves, i.e. the first derivative of the TGA curves, are formed in order to calculate the percentage conversion
curves that are used for further kinetic analysis. The DTG curves together with the choice of a suitable baseline
allow the separation of the first decomposition step from further overlapping decomposition reactions (the TGA
curves do not terminate horizontally).
The second diagram shows the complete evaluation using the model-free kinetics method. The conversion
curves are calculated from the DTG curves using the baseline type ‘integral horizontal’. These conversion curves
are, in turn, the basis for the model-free kinetics for the calculation of the activation energy. This lies in the range
100–140 kJ/mol and is a function of conversion, indicating a complex reaction. The activation energy allows a
simulation of the decomposition reaction for other conditions (temperature and time). This is shown graphically
and in tabular form in so-called iso-conversion plot and tables. In this presentation, the time required for the
substance to reach a given percentage conversion (or in other words degree of decomposition) at a given tem-
perature is evident.

METTLER TOLEDO Thermal Analysis 11

 Evaluation
The activation energy is determined as a function of the percentage conversion. The details are given in the diagrams.
Prediction of the storage time/storage temperature for a conversion of 1, 2, 3 or 4% (applied kinetics).
It is evident from the table, that a conversion of 1% is reached when the substance is stored at 15.2 °C for
10 000 hours; 1 year has 8760 hours.

Conversion
Time 1% 2% 3% 4%
10 000 h 15.3 °C 25.3 °C 33.1 °C 38.7 °C
20 000 h 10.6 °C 20.7 °C 28.7 °C 34.3 °C
30 000 h 8.0 °C 18.1 °C 26.1 °C 31.8 °C

Please note: Extrapolation of results from reactions performed in the liquid state to the solid state have a high
degree of uncertainty.

Conclusions
The example shows that thermal analysis and the application of model-free kinetics is an efficient means
of estimating the potential storage lifetime of pharmaceutical preparations at a minimum expense. The TGA can
of course only be used when the decomposition is coincidental with a significant weight loss.
It must be emphasized that this procedure can never replace a proper long-term test. The method is more useful
for the preliminary selection of formulations. The formulations that exhibit good properties can then be subjected
to the time-consuming and expensive final tests.

12 METTLER TOLEDO Thermal Analysis

3.3 Characterization/Identification – Vanillin

Characterization of the melting behavior

Sample Vanillin

Application Flavoring agent

Measurement Measuring cells: TGA/DSC
Crucible: Aluminum 40 µL, with pierced lid or open
Sample preparation: As received, no preparation
DSC measurement: Heating from 30 °C to 250 °C at 10 K/min
TGA measurement: Heating from 30 °C to 250 °C at 10 K/min, blank curve corrected
Atmosphere: Nitrogen, DSC: 50 cm3/min, TGA: 20 cm3/min

Interpretation
The melting curve provides a survey of possible events that can occur during the measurement. This informa-
tion cannot be gained from simple melting point determinations with capillary melting. For instance the DSC curve
shows a slight shift of the baseline after the melting process. The TGA curve shows no weight loss in this region,
which indicates that the DSC baseline shift is caused by a change in the specific heat capacity (cp). The SDTA signal
of the TGA/DSC allows a qualitative evaluation of the melting behavior along with the TGA measurement. An increas-
ing weight loss occurs at temperatures above 150 °C because the vanillin evaporates and decomposes.

Evaluation
Onset temperature determination and integration of the melting peak of the DSC curve.
Melting point (onset) 81.8 °C
Heat of fusion ΔH 133.5 J/g

Conclusion
The DSC is suitable for the rapid determination of melting points and heats of fusion. Additional information can
be gained from a TGA measurement.

METTLER TOLEDO Thermal Analysis 13

 3.4 Characterization/Identification – Polyethylene glycol PEG

Identification based on melting behavior

Sample Polyethylene glycols, PEG 400, 1000, 2000,

4000, 6000, 10000, different manufacturers

Application Inactive ingredient (basic material for ointments and suppositories, solubilizers etc.)
Measurement Measuring cell: DSC with IntraCooler
Crucible: Aluminum 40 µL, hermetically sealed
Sample preparation: As received, no preparation
DSC measurement: Held isothermally for 5 minutes at –60 °C,
then heated to 160 °C at 10 K/min
Atmosphere: Air, stationary environment, no flow rate

Interpretation
Polyethylene glycols are named after their average molecular mass. The melting point increases with increasing
chain length, i.e. with increasing molecular mass. The longer the chain length, the less the melting points of the
polyethylene glycols differ from each other. This makes it increasingly difficult to distinguish clearly between samples
of high molecular mass. The melting peak becomes sharper the greater the degree of purity of the substance or, in
the case of macromolecules, the greater the degree of uniformity of the size of the crystallites. The differences in the
heats of fusion as a function of chain length are relatively small and are also dependent on crystallinity, so that this
is not a suitable criterion for differentiation purposes.

Evaluation
Expected melting range in °C
Sample (manufacturer's data) Onset in°C ΔH in J/g
PEG 400 –3 to 8 –14.3 156.2
PEG 1000 30 to 40 37.5 194.4
PEG 2000 45 to 50 49.1 214.5
PEG 4000 50 to 58 54.8 207.8
PEG 6000 56 to 63 56.8 212.6
PEG 10000 — 59.4 218.6

14 METTLER TOLEDO Thermal Analysis

3.5 Purity – Phenacetin and 4-Aminobenzoic acid (PABA)

Characterization of the melting behavior

Samples Purity set NBS: Phenacetin + 0.7 mole % 4-Aminobenzoic acid

Phenacetin + 2.0 mole % 4-Aminobenzoic acid
Phenacetin + 5.0 mole % 4-Aminobenzoic acid

Application As a standard for purity determination

Measurement Measuring cell: DSC
Crucible: Aluminum 40 µL, hermetically sealed
Sample preparation: As received, no preparation
DSC measurement: Heating from 100 °C to 160 °C at 10 or 5 K/min
Heating from 110 °C to 150 °C at 2.5 or 1.25 K/min
Atmosphere: Nitrogen, 50 cm3/min

Interpretation
The diagram shows the melting curves of the pure sample and the contaminated samples of phenacetin. The melt-
ing peak becomes broader and shifts to lower temperature with increasing impurity. In addition, the eutectic peak
at about 114 °C becomes increasingly noticeable. The purity determination is based on the van't Hoff equation,
which states that the melting point depression is proportional to the mole fraction impurity (see the relevant litera-
ture). The diagram showing the equilibrium melting temperature from the melting curve plotted against the reciprocal
of the fraction melted (F) is known as the 1/F plot. After allowing for the heat of fusion of the eutectic (linearization
correction), a linear relationship is generated from which the purity can be determined.

METTLER TOLEDO Thermal Analysis 15

 Evaluation
The purity of each of the samples given below was determined at the heating rates indicated, according to
the method of van't Hoff. The melting curve was evaluated in the range from 10% to 50% of the peak height.

Heating rate in K/min

Substance Purity in mole %
1
1.25 2.5 5 10
Phenacetin pure2 99.9 ± 0.1 99.97 99.98 99.96 99.97
+0.7 mole % PABS 99.3 ± 0.2 99.39 99.29 99.34 99.50
+2.0 mole % PABS 98.0 ± 0.2 98.35 98.39 98.49 98.40
+5.0 mole % PABS 94.9 ± 0.2 98.30 97.07 96.79 97.04

1
certified value
2
mean value of 3 measurements

Conclusion
The DSC purity determination gives rapid results. The method may only be applied, however, if certain conditions are
fulfilled. In particular, only relatively pure substances (>98%) should be characterized with this technique. A number
of different parameters must be considered when developing a method for purity determination. These include par-
ticle size, sample weight, heating rate and choice of the data points to be used for the calculation. A variation in the
particle size can cause broader or irregular melting peaks, since the heat flow through larger crystals requires more
time. A large sample weight has the same effect because of the increased sample thickness. On the other hand,
trapped air in fine powders can lead to a delayed transfer of heat between the individual crystals.

16 METTLER TOLEDO Thermal Analysis

4. Measurement Errors and Uncertainty of Measurement

Measurement results should reflect reality and hence serve as a basis for drawing conclusions and making
decisions. In addition, one should be able to trust the result of a single measurement without having to perform
replicate (i.e. repeat) measurements. However, this requires a thorough understanding of the possible causes
of measurement errors and how these errors can be quantified.
The results of measurements performed under identical conditions are never free of error, but are scattered around
a central value. This deviates more or less from a recognized value that is considered to be the "true" value.
Deviations from the "true" value are due to systematic errors that cause all measurement results to be too high
or too low. A systematic error is often referred to as bias. Systematic errors occur with every measurement to the
same extent with the same sign and are usually difficult to eliminate. The scatter of results around the mean value
is due to random errors of measurement – some measurements are too high while others are too low.

Systematic measurement errors

A systematic measurement error cannot be identified as such or eliminated merely by repeating the
measurement. Systematic measurement errors can only be detected if a reference value for the expected
measurement quantity is available. The reference value must be determined using the same measurement
technique. Otherwise, systematic errors can occur due to the use of different techniques.
If systematic measurement errors are detected, their origins must be investigated and measures taken to
eliminate them. Sometimes, the origin of the systematic measurement error cannot be identified. In such cases,
a correction procedure is used that describes how the measurement quantity should be corrected in order
to obtain the right value.

Example: Buoyancy correction

A typical example of a systematic measurement error in thermogravimetric analysis is buoyancy. If a test
specimen is heated at ambient pressure, e.g. in air, the density of the air in the furnace decreases with
increasing temperature. As a result, the buoyancy experienced by the test specimen and the sample holder also
decreases. This effect leads to an apparent increase in mass of the test specimen. This systematic error in the
measured mass of the test specimen can be corrected by performing a blank measurement in which an empty
crucible is heated under otherwise identical conditions.

Random measurement errors

Random measurement errors refer to the scatter of individual measurement results around the mean value.
Random errors occur to different extents in every measurement and determine the precision of a measurement.
They cannot be eliminated. They can however be reduced through precise control of the experimental
conditions. Random measurement errors can be described by statistical parameters such as standard
deviation, distribution laws, etc.

Uncertainty of measurement
The uncertainty of measurement is a quantitative measure of the quality of the particular measurement results.
It allows the user to estimate the reliability of the measurement results. In simple terms, the uncertainty of mea-
surement is the value range within which the value of the quantity being measured (the measurand) is expected
to lie with a stated level of confidence. It is not the same as error because to estimate an error the "true" value
must be known.
The concept of the uncertainty of measurement concerns all sources of uncertainty in connection with the sam-
ple, sample preparation, environmental influences, experimental parameters, the analyst, the evaluation of the
measured data as well as the measurement procedure itself.
The cause-and-effect diagram (Ishikawa diagram, fishbone diagram) is a simple analysis tool for systematically
determining the factors that contribute to a particular problem. It subdivides the possible causes leading to an
overall effect into main and secondary factors. The resulting factors are presented in a clearly structured diagram
that resembles a fishbone. The clear overview allows you to identify all factors that contribute to a problem and

METTLER TOLEDO Thermal Analysis 17

 to assess their importance and dependencies. The fishbone diagram is often applied to estimate the uncertainty
of measurement, for example, the uncertainty of the heat of fusion in DSC measurements.
The following main influence factors were considered: sample preparation, method development, instrument
(measurement) and evaluation. Main and secondary factors have been put into a fishbone diagram (Fig. 4.1).
The uncertainty of measurement for this example is estimated to ±3.4%.

Fig 4.1: Cause-and-effect diagram to identify sources of uncertainty on the determination of the specific enthalpy of fusion in DSC measurements.

More details
For substantial explanations of measurement errors and uncertainty please refer to the validation handbook:
M. Schubnell: Validation in Thermal Analysis, Mettler-Toledo AG, 51725141, ©12/2008

18 METTLER TOLEDO Thermal Analysis

5. Method Development

The development and validation of methods is of major importance in today’s quality assurance systems.
The starting point is usually a trial method that is then optimized and validated in several iterative steps. The final
result is a validated method that is used for standard operating procedure.

The analytical task

Method development begins with precisely defining the information you hope to get from an analysis of the sample.
Typical questions could be for example:
• At what temperature does the glass transition occur?
• Does the sample exhibit polymorphism?
• How pure is my product?
• What is the moisture content of my sample? and so on.

Depending on the analytical task and the information required, you first design a draft method. The typical steps
towards this draft are presented in Fig 5.1.

Fig 5.1: Work steps for developing a draft thermal analysis method.

Performance parameters
When defining the analytical purpose, another set of questions need to be answered: The quantitative determina-
tion of the performance parameters. The quantitative targets and limits of the performance parameters show in
the end whether the foreseen procedure can be used to solve this particular analytical task. Furthermore, they
form the basis for the validation of the method. The following performance parameters may be considered:
• Trueness/accuracy
• Precision (repeatability, reproducibility
• Linearity
• Robustness, ruggedness
• Selectivity, specifity
• Limit of detection (LOD) and quantitation (LOQ)

METTLER TOLEDO Thermal Analysis 19

 Method validation and standard operating procedure (SOP)
Validation is a basic requirement for ensuring the quality and reliability of the results of an analytical procedure
or method, i.e. to demonstrate that the procedure or method is suitable for its intended purpose. How is valida-
tion carried out in practice? The starting point is always a draft standard operation procedure (SOP), which is
based on well defined analytical requirements. The SOP is considered as a draft as long as its usability is not
supported by appropriate validation data.
Validation begins with the experimental proof that an analytical procedure is "in state of statistical control".
This is the case when the mean values of the measurements of authentic samples are constant over a longer
period and when the precision is adequate and in particular constant. An implicit requirement is that all mea-
surements in connection with validation are performed using instruments that are in proper working order and
that have been correctly adjusted.
The next step of the validation is to demonstrate adequate trueness. This phase is usually more complex.
The following possibilities are available for establishing trueness:
• Measurement of certified reference materials
• Checking with a method of known trueness
• Comparison of the results with those obtained using an independent method
• Interlaboratory studies.
Similarly, all other performance characteristics specified in the validation plan have to be determined. If the per-
formance parameters resulting from the validation process do not meet the specified requirements, the procedure
and hence the draft SOP have to be modified. At the end of this process the draft SOP is validated and can be used
as SOP for routine operations. After the validation has been carried out, the results are documented in a validation
report which strictly adheres to the validation plan. Any deviation to this plan must be documented and approved.

Fig 5.2: Work steps for validating a method.

Apart from the initial validation, revalidation is necessary whenever changes are made to validated analytical
procedures. Typical reasons that could necessitate a revalidation are summarized here:
• New analyst
• New software version
• New instrument
• Small changes in the analytical methodology

More details
Typical performance parameters including practical examples and the process of validating a method are well explained in the following handbooks:
M. Wagner: Thermal Analysis in Practice, Mettler-Toledo AG, 51725244, ©12/2009
M. Schubnell: Validation in Thermal Analysis, Mettler-Toledo AG, 51725141, ©12/2008

20 METTLER TOLEDO Thermal Analysis

6. Instrument Calibration and Adjustment

Because of the high quality standards required for analytical procedures applied to the analysis of pharmaceutical
products, special importance is has to be given to instrument calibration and adjustment.
Calibration: Determines the difference of a measured value from a reference value. This procedure is also called
a "check".
Adjustment: Adjusts the instrument parameters so that the measured value agrees with the reference value.

A calibration shows that an instrument supplies you with the correct values. Depending on the number of sensors
in the instrument under consideration, you will have to perform different calibrations. The measured signal (ordinate)
and the physical properties in conjunction with the abscissa of a diagram need to be calibrated.

Ordinate • Heat flow, peak area (DSC)

• Mass (TGA, automatically performed in the electronic microbalance)
• Length (displacement) and force (TMA and DMA).
Abscissa • Temperatures
• τlag, which makes the temperature independent of the heating rate (at the sample crucible position)
• Time (e.g. for isothermal measurements); since it is derived from the quartz clock of a micropro-
cessor, it is extremely accurate.

We suggest to apply initially a calibration interval of once a month. If the results are repeatedly within acceptable
error limits, this interval can be doubled. If several measurements with unacceptable results are obtained, the inter-
val should be reduced to half. After an adjustment, one should always perform a calibration to verify that correct
values are obtained.

Fig 6.1: Flow chart for calibration, adjustment and measurements.

Calibration and adjustment require reference materials or standards. These are substances with known literature
values needed for calibration or traceable to recognized international standards. Calibration and adjustment are
therefore inextricably linked to preventive maintenance and then to analytical instrument qualification. Whenever
calibration involves adjustments, it is important to document the activity.
Conventional thermal analysis instruments are adjusted for specific conditions only. Whenever the experimental
conditions change, the instrument has to be readjusted. Opposite to this, the STARe FlexCal™ system keeps the
instrument properly adjusted under all conditions. This is especially helpful for

All heating rates With FlexCalTM, the temperature at the sample position becomes independent
of the heating rate when τlag has been properly adjusted.
All types of crucible Details of the various crucibles with their different geometry and mass are stored in
the database. This information is automatically taken into account.
All atmospheres Details of the different gases and their different heat conductivities are stored in the
database. The information is automatically taken into account.

METTLER TOLEDO Thermal Analysis 21

 7. Excellent Crucibles, Accessories and Reference Materials

Crucibles for thermal analysis

Crucibles serve as containers for samples during thermoanalytical measurements. They guarantee that the sen-
sor is not contaminated by the measurement. The type of crucible used for a measurement can have a large
effect on the quality of the results obtained, and in addition, also influences important characteristics of the DSC
measuring cell. Considering the relevant factors before the measurement can often help to save time later on
when interpreting the curve.

METTLER TOLEDO offers an extremely wide range of crucibles.

• Aluminum crucibles – various types and sizes
• Crucibles made from copper, platinum or gold
• Medium pressure crucible – stainless steel
• High pressure crucibles – stainless steel, gold plated, nimonic
• Alumina crucibles (aluminum oxide)
• Polycrystalline alumina oxide – a sapphire-like material
• Glass crucibles

Select the right crucible type – and improve your measurement quality.

Crucible sealing press

The press allows the pan to be sealed very easily. Under the pressure of the plunger the pan
is cold welded hermetically with the lid. With 3 exchangeable assemblies you adjust the sealing
press to the various crucibles. Also available: Sealing tools for high pressure crucibles.

Sample robot
All DSC and TGA models from METTLER TOLEDO can be automated. The sample robot can
process up to 34 samples even if every sample requires a different method and a different
crucible. The sample robot is very robust and operates reliably 24 hours a day and through-
out the whole year.

Reference materials
METTLER TOLEDO markets the reference substances needed for calibration and adjustment of thermal analysis
instruments. The following reference substances are traceable to the manufacturer.

Substance Indium Tin Lead Zinc Aluminum Gold Palladium

Symbol In Sn Pb Zn Al Au Pd
Tf [°C] 156.6 231.9 327.5 419.6 660.3 1064.2 1554.0
ΔHf [J/g] 28.5 60.1 23.0 107.5 397.0 63.7 162.0
Order no 00 119 442 51 140 621 00 650 013 00 119 441 51 119 701 51 140 816 51 140 817

22 METTLER TOLEDO Thermal Analysis

8. For More Information

Outstanding Services
METTLER TOLEDO offers you valuable support and services to keep you informed about new developments and
help you expand your knowledge and expertise, including:

News on Thermal Analysis

Informs you about new products, applications and events.
www.mt.com/ta-news
www.mt.com/ta-app

Handbooks
Written for thermal analysis users with background information, theory and practice, useful tables of material
properties and many interesting applications.
www.mt.com/ta-handbooks

Tutorial
The Tutorial Kit handbook with twenty-two well-chosen application examples and the corresponding test
substances provides an excellent introduction to thermal analysis techniques and is ideal for self-study.

Title Order Number

Tutorial Kit (handbook only) 30281946
Tutorial Kit (handbook and samples) 30249170

www.mt.com/ta-handbooks

Videos
Our technical videos explain complex issues concerning thermal analysis instrumentation and the STARe
software – whether it’s sample preparation, installation, creating experiments or evaluating measurement results.
www.mt.com/ta-videos

UserCom
Our popular, biannual technical customer magazine, where users and specialists publish applications from
different fields.
www.mt.com/ta-usercoms

Applications
If you have a specific application question, you may find the answer in the application database.
www.mt.com/ta-applications

Webinars
We offer web-based seminars (webinars) on different topics. After the presentation, you will have the opportunity
to discuss any points of interest with specialists or with other participants.
www.mt.com/ta-webinars (Live Webinars)
www.mt.com/ta-ondemand (On Demand Webinars)

Training
Classroom training is still one of the most effective ways to learn.
Our User Training Courses will help you get the most out of your equipment. We offer a variety of one-day theory
and hands-on courses aimed at familiarizing you with our thermal analysis systems and their applications.
www.mt.com/ta-training (Classroom)
www.mt.com/ta-etraining (Web-based)

METTLER TOLEDO Thermal Analysis 23

Overview of METTLER TOLEDO
Thermal Analysis Application Handbooks

The following application handbooks are available and can be purchased:

www.mt.com/ta-handbooks

Introductory Handbooks Language Order number Details

Thermal Analysis in Practice English 51725244
Volume 1
Fundamental Aspects (350 pages)
Thermal Analysis in Practice English 30832055
Volume 2
Tips and Hints (48 pages)
Thermal Analysis in Practice English 30281946 Handbook and
Volume 3 Tutorial samples
Tutorial Examples (92 pages) 30249170
Thermal Analysis in Practice English 51725141
Volume 4
Validation (280 pages)
Thermal Analysis in Practice English 30748024
Volume 5
Evolved Gas Analysis (40 pages)

Applications Handbooks Language Order number Details

Thermal Analysis of Elastomers English 51725061 Volumes 1 and 2
Volumes 1 and 2 51725057 Volume 1
Collected Applications (290 pages) 51725058 Volume 2
Thermal Analysis of Thermoplastics English 51725002
Collected Applications (154 pages)
Thermal Analysis of Thermosets English 51725069 Volumes 1 and 2
Volumes 1 and 2 51725067 Volume 1
Collected Applications (320 pages) 51725068 Volume 2
Thermal Analysis of Pharmaceuticals English 51725006
Collected Applications (104 pages)
Thermal Analysis of Food English 51725004
Collected Applications (68 pages)
Evolved Gas Analysis English 51725056
Collected Applications (216 pages)
Thermal Analysis of Polymers English 30832718
Selected Applications (56 pages)

www.mt.com/ta-news
For more information

METTLER TOLEDO Group

Analytical Instruments
Local contact: www.mt.com/contacts

Subject to technical changes

© 05/2016 METTLER TOLEDO
All rights reserved. 30335733A
Marketing MatChar / MarCom Analytical