Thermal Analysis
Dr. Lidia Tajber
School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin
Characterisation for Pharma
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Active pharmaceutical ingredients (API, drugs)
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Excipients (additives, fillers etc.)
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Organic, inorganic
Not always single components
Solids or liquids
Not always pure
Formulations (dosage forms, delivery systems)
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Organic molecules, peptides, proteins
Single components
Mainly solids (crystalline, amorphous or semi-crystalline)
Pure molecules
Mixtures of APIs and excipients
Packaging materials
Physical Forms of Solids
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Polymorphism - the ability of a
compound to crystallise in more
than one crystal form
Pseudopolymorphic forms
(solvated forms) - crystalline solids
containing solvent molecules as an
integral part of their crystal
structure
Amorphism - the absence of
regular or crystalline structure in a
body solid; amorphous materials
do not possess three-dimensional
long-range molecular order
Different thermal behaviour
Polymorph A
Polymorph B
Solvate A
Solvate B
Importance of Solid State Forms in Pharma
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Bioavailability (solubility/dissolution rate)
Stability (physical and chemical)
Processing factors
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Hygroscopicity
Bulk and mechanical properties
Ease of isolation, filtration and drying
Degree of purity
Thermal Analysis Techniques
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IUPAC definition - a group of techniques in which a
physical property is measured as a function of
temperature, while the sample is subjected to a
controlled temperature programme (heating, cooling or
isothermal).
A range of techniques e.g.:
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Differential Thermal Analysis (DTA) – temperature
Differential Scanning Calorimetry (DSC) – energy
Thermogravimetric Analysis (TGA) – mass
Thermomechanical Analysis (TMA) – dimensions
Dielectric Analysis (DEA) – dielectric/electric properties
Basic Principles of Thermal Analysis
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Modern instrumentation used for thermal analysis
usually consists of the following parts:
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sample holder/compartment for the sample
sensors to detect/measure a property of the sample and the
temperature
an enclosure within which the experimental parameters
(temperature, speed, environment) may be controlled
a computer to control data collection and processing
temperature
control (furnace)
sample
sensors
PC
Differential Scanning Calorimetry (DSC)
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Most popular thermal technique
DSC measures the heat absorbed or liberated during the
various transitions in the sample due to temperature
treatment
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Differential: sample relative to reference
Scanning: temperature is ramped
Calorimeter: measures heat
DSC measurements are both qualitative and
quantitative and provide information about physical and
chemical changes involving:
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Endothermic processes – sample absorbs energy
Exothermic processes – sample releases energy
Changes in heat capacity
Principles of DSC Analysis
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Power Compensation DSC
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High resolution / high sensitivity research studies
Absolute specific heat measurement
Very sensitive to contamination of sample holders
Heat Flux DSC
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Routine applications
Near / at line testing in harsh environments
Automated operation
Cost-sensitive laboratories
Summary of Pharmaceutically Relevant Information
Derived from DSC Analysis
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Melting points – crystalline materials
Desolvation – adsorbed and bound solvents
Glass transitions – amorphous materials
Heats of transitions – melting, crystallisation
Purity determination – contamination,
crystalline/amorphous phase quantification
Polymorphic transitions – polymorphs and
pseudopolymorphs
Processing conditions – environmental factors
Compatibility – interactions between components
Decomposition kinetics – chemical and thermal stability
Typical Features of a DSC Trace
^exo Exothermic upwards
Endothermic downwards
MELTING
CRYSTALLISATION
GLASS TRANSITION
DESOLVATION
H2O
20
mW
DECOMPOSITION
Y-axis – heat flow
X-axis – temperature (and time)
40
60
80
100 120 140 160 180 200 220 240 260 280 300
o
temperature [ C]
Melting Point
Onset = melting point (mp)
^exo
MELTING
20
mW
Heat of fusion (melting) = integration of peak
40
60
80
100 120 140 160 180 200 220 240 260 280 300
o
temperature [ C]
DSC scan of a crystalline material – one polymorphic form
Polymorphic Forms
^exo
TRANSITION
STABLE
FORM
METASTABLE
FORM
20
mW
40
60
80
100 120 140 160 180 200 220 240 260 280 300
o
temperature [ C]
DSC scan of a crystalline material – polymorphic transition
Pseudopolymorphism
^exo
MELTING
DEHYDRATION
20
mW
40
60
80
100 120 140 160 180 200 220 240 260 280 300
o
temperature [ C]
DSC scan of a hydrate
Amorphous Material
DEHYDRATION
Midpoint = glass transition (Tg)
GLASS TRANSITION
1 mW
40
60
80
100
120
140
160
180
200
220
240
260
280
300
temperature [°C]
Polyvinylpyrrolidone (PVP) co-processed with hydroflumethiazide
Purity Determination
Purity of phenacetin
Source: TA Instruments, Cassel RB,
Purity Determination and DSC Tzero™ Technology
Compatibility Studies
Source: Schmitt E et al.
Thermochim Acta 2001, 380 , 175 – 183
Variants of DSC
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Conventional – linear temperature (cooling, heating)
programme
Fast scan DSC – very fast scan rates (also linear)
MTDSC (modulated temperature DSC) – more
complex temperature programmes, particularly
useful in the investigation of glass transitions
(amorphous materials)
HPDSC (high pressure DSC) – stability of materials,
oxidation processes
Fast Scan DSC, Rapid Scanning DSC, (HyperDSCTM)
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This method provides the ability to perform valid heat flow
measurements while heating or cooling a sample with fast
linear controlled rates
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Benefits:
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HyperDSCTM - rates up to 500°C/min
Other non-commercial systems - up to 100,000°C/min
Increased sensitivity for detection of weak transitions
Analysis of samples without inducing changes
Small sampling requirements – a fraction of mg can be used
Fast screening for high throughput requirements - a quick overview
of new samples
Disadvantages:
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Accuracy: transitions can be shifted by as much as 40oC
Repeatabiliy: very sensitive to thermal lag and sample preparation
Fast Scan DSC, Rapid Scanning DSC, (HyperDSCTM)
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Pharma applications:
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Enhanced analysis of polymorphism
Detection of low level amorphous content
Suppression of decomposition – “true” melting points
Detection of low energy transitions
Characterisation close to processing conditions
Separation of overlapping events
Modulated Temperature DSC (MTDSC)
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This technique uses composite heating profile:
determines heat capacity and separates heat flow into
the reversible and non-reversible components
Benefits
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Increased sensitivity for detecting weak transitions –
especially glass transition
Separation of complex events into their:
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heat capacity (reversible) e.g. glass transition, melting and
kinetic components (non-reversible) e.g. evaporation,
crystallisation, decomposition
Disadvantages
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Slow data collection
Risk of sample transformation
Variants of MTDSC
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Sinusoidal modulation (easy, only one
frequency only) – TA Instruments
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Step scan modulation (easy, precise) –
PerkinElmer
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TOPEM® modulation (stochastic
modulation, complex calculations, but
multiple frequency data) – Mettler Toledo
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Saw tooth modulation
Rectangular modulation
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Example of a MTDSC Curve
Polyethylene terephthalate (PET)
Source: Craig DQM and Reading M
Thermal analysis of pharmaceuticals
Thermogravimetric Analysis (TGA)
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A technique measuring the
variation in mass of a sample
undergoing temperature
scanning in a controlled
atmosphere
Thermobalance allows for
monitoring sample weight as a
function of temperature
The sample hangs from the
balance inside the furnace and
the balance is thermally
isolated from the furnace
balance
sample
purge gas
furnace
Summary of Pharmaceutically Relevant Information
Derived from TGA Analysis
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Desolvation – adsorbed and bound solvents,
stoichiometry of hydrates and solvates
Decomposition – chemical and thermal stability
Compatibility – interactions between components
Examples of TGA Curves
2
mg
0
20
40
60
80 100 120 140 160 180 200 220 240 260 280 300 320
o
temperature [ C]
TGA curves of crystalline and amorphous substance
Lactose monohydrate
^exo
20
mW
0
20
2
mg
40
60
80 100 120 140 160 180 200 220 240 260 280 300 320 340
o
temperature [ C]
DSC and TGA scans of lactose monohydrate
Hyphenated Thermal Equipment
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Thermal techniques alone are insufficient to prove the
existence of polymorphs and solvates
Other complementary techniques are used e.g.
microscopy, diffraction and spectroscopy
Simultaneous analysis
Types:
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DSC-TGA
DSC-XRD – DSC coupled with X-ray diffraction
TGA-MS – TG system coupled with a mass spectrometer
TGA-FTIR – TG system coupled with a Fourier Transform
infrared spectrometer
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TGA -MS or -FTIR - evolved gas analysis (EGA)
others