Differential Scanning

Calorimetry
Cooking with Chemicals
Clare Rawlinson
School of Pharmacy
University of Bradford
EYP 2006

Outline

Brief history of thermal analysis

Theory of thermal analysis techniques

Thermal Gravimetric Analysis (TGA)
Differential Scanning Calorimetry (DSC)

Generating valid data

Calibration
Sample preparation

Interpreting data and Applications

Real events
Artefacts

Recent advances

EYP 2006

Calorimetry

Calorimetry
The study of heat transfer during
physical and chemical processes

Calorimeter
A device for measuring the heat
transferred

Lavoisier and Laplace (1782-1784):

oil was burned in a lamp (Fig 9) held in
a bucket (Fig. 8) held in a wire mesh
cage (f)
surrounded by ice in spaces b and a of
the double walled container a foot in
diameter
lid (F) was topped with ice, as was a
mesh lid (not shown) beneath it that
covered the inner volume b
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Oil lamps to Guinea Pigs

Measured heat production of

the metabolic processes in
the ice bath calorimeter
Outer
jacket
prevented
conduction of heat from the
external environment which
would have also melted the
ice
From latent heat of fusion for
ice (334 J/gram ice at 0 C)
Lavoisier converted the rate
of water formation to heat
production
In 10 hours 370 grams of ice
melted

Guinea pig produced 12,358 J per hour of heat

(12.4 kJ/hr)
EYP 2006

Basic Principles of Thermal Analysis

Modern instrumentation used for thermal analysis usually
consists of four parts:

sample/sample holder

sensors to detect/measure a property of the sample and the

temperature

an enclosure within which the experimental parameters may be

controlled

a computer to control data collection and processing

EYP 2006

TGA and DSC

Thermogravimetric Analysis (TGA)

mass change of a substance measured as function of
temperature whilst the substance is subjected to a controlled
temperature programme1
mass is lost if the substance contains a volatile fraction

Differential Scanning Calorimetry (DSC)

provides information about thermal changes that do not involve a
change in sample mass1
more commonly used technique than TGA
Two basic types of DSC instruments: heat-flux and power
compensation
1Haines,

P. J. (2002) The Royal Society of Chemistry, Cambridge.

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Heat Flux DSC

Sample holder :
sample and reference are connected by a low-resistance heat flow
path
Aluminium, stainless, platinum sample pans
heating
coil

Sensors:

temperature sensors
usually thermocouples

sample
pan

reference
pan

Furnace:
one block for both sample
and reference cells

inert gas
vacuum

thermocouples

Temperature controller:
temperature difference between the sample and reference is
measured
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Power Compensated DSC

Sample holder :

Aluminium, platinum, stainless steel pans

individual
heaters

Sensors:
Pt resistance
thermocouples.
Separate sensors
and heaters for the
sample and reference

sample
pan

inert gas
vacuum

Furnace:

reference
pan

inert gas
vacuum
thermocouple

T = 0

separate blocks for sample and reference cells

Temperature controller:
differential thermal power is supplied to the heaters to maintain the
temperature of the sample and reference at the program value

EYP 2006

Outline

Brief history of thermal analysis

Theory of thermal analysis techniques

Thermal Gravimetric Analysis (TGA)
Differential Scanning Calorimetry (DSC)

Generating valid data

Calibration
Sample preparation

Interpreting data and Applications

Real events
Artefacts

Recent advances

EYP 2006

DSC Calibration
Baseline
Calibration
evaluation of the
thermal resistance of
the
sample
and
reference sensors
measurements
over the temperature
range of interest

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DSC Calibration
Temperature
match melting onset temperatures to the known melting points of
standards analyzed by DSC
should be calibrated as close to desired temperature range as possible

Heat flow
use calibration standards of known heat capacity, slow accurate heating
rates (0.52.0 C/min), and similar sample and reference pan weights

calibrants

high purity
accurately known enthalpies
thermally stable
light stable
not hygroscopic
do not react (pan, atmosphere)

metals
Indium 156.6 C; 28.45 J/g
Zinc 419.47C, 108.17 J/g
inorganics
KNO3 128.7 C
KClO4 299.4 C
organics
polystyrene 105 C
benzoic acid 122.3 C; 147.3 J/g
EYP 2006

Sample Preparation
accurately-weighed samples (~3-20 mg, usually 3-5 mg for simple
powders)
small sample pans (0.1 mL) of inert or treated metals (Al, Pt, stainless)
several pan configurations, e.g., open , pinhole, or hermetically-sealed
pans
same material and configuration should be used for the sample and the
reference
material should completely cover the bottom of the pan to ensure good
thermal contact
avoid overfilling the pan to minimize thermal lag from the bulk of the
material to the sensor
* small sample masses and
low
heating
rates
increase resolution, but
at the expense of
sensitivity

Al
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Pt

alumina

Ni

Cu

quartz

Purge Gases

Sample may react with air - oxidising or burning

Control moisture content of atmosphere

Use inert gas e.g. nitrogen or argon

Flowing purge gas

In some cases deliberately choose reactive gas, e.g.

hydrogen to reduce an oxide to metal
carbon dioxide which affects decomposition of metal carbonate

Removes waste products from sublimation or

decomposition
EYP 2006

Outline

Brief history of thermal analysis

Theory of thermal analysis techniques

Thermal Gravimetric Analysis (TGA)
Differential Scanning Calorimetry (DSC)

Generating valid data

Calibration
Sample preparation

Interpreting data and Applications

Real events
Artefacts

Recent advances

EYP 2006

Typical Features of a DSC Trace

(Polymorphic System)
endothermic events
melting
sublimation
solid-solid transitions
desolvation
chemical reactions

Exo

exothermic events
crystallization
solid-solid transitions
decomposition
chemical reactions

sulphapyridine

EYP 2006

baseline shifts
glass transition

Melting Processes by DSC

Pure substances

Impure
substances

linear melting curve

melting
defined by
temperature

point
onset

eutectic
melt

Broad,
asymmetric
melting peak
melting
characterized
peak maxima

Melting with
decomposition

at

eutectic impurities
may produce a
second peak

exothermic
endothermic
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Definition of Transition Temperature

0.5

156.50C
28.87J/g

0.0

Exo
extrapolated
onset temperature

Heat Flow (W/g)

-0.5

-1.0

-1.5

peak melting
temperature

-2.0

157.81C

-2.5
140
Exo Up

145

150

155

160

Temperature (C)

EYP 2006

165

170

175
Universal V3.3B TA Instruments

Enthalpy of Fusion
0.5

156.50C
28.87J/g

0.0

Exo

Heat Flow (W/g)

-0.5

-1.0

-1.5

-2.0

157.81C

-2.5
140
Exo Up

145

150

155

160

Temperature (C)

EYP 2006

165

170

175
Universal V3.3B TA Instruments

Enthalpy of Fusion by DSC

For a single (well-defined)
melting endotherm
area under peak
minimal
decomposition/sublimation
readily measured for high
melting polymorph
can be measured for low
melting polymorph

Endo

More difficult where multiple thermal events leading to stable melt

e.g. solid-solid transitions (A to B) before melt, or where melt /
recrystallisation before melt
Estimate from sum all areas
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Purity by DSC
1-3 mg samples in hermeticallysealed pans are recommended
Peak width a valuable measure
of purity:
impurities lower the melting
point
Less
pure
(non-perfect)
crystals melt first followed by
purer larger crystals
polymorphism interferes with
purity determination, especially
when a transition occurs in the
middle of the melting peak

Exo
97%

99%

benzoic acid

Accurate measurement of
Hf needs pure samples of
polymorphs

99.9%

Plato, C.; Glasgow, Jr., A.R. Anal.

Chem., 1969, 41(2), 330-336.
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Glass Transitions
characterized by change in heat capacity (no heat absorbed or
evolved)
transition from a disordered solid to a
liquid
appears as a step (endothermic
direction) in the DSC curve
gradual enthalpy change may occur,
producing
an
endothermic
peak
superimposed on the glass transition
Exo

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Effect of Heating Rate

many
transitions
(evaporation,
crystallization, decomposition, etc.) are
kinetic so shift to higher temp. when
heated at a higher rate
increasing the scanning rate increases
sensitivity, while decreasing the
scanning rate increases resolution
to obtain thermal event temperatures
close to the true thermodynamic value,
slow scanning rates (e.g., 15 K/min)
should be used
Rapid scanning can obscure thermal
events
Advantageous in fast scan DSC,
e.g. 500K/min
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Recognizing Artefacts
Sample
movement in
pan

sample
pan
distortion

mechanical
Pan
shock / knock
moves in
bench
furnace

cool air entry

into cell

sensor
contamination

atmosphere
electrical effects,
changes
power spikes, etc.
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burst of
pan lid

Closing /
opening pan
hole, e.g.
sublimation

Ensuring correct interpretation of DSC

You cant
Can minimise misinterpretation
Essential to have valid data to interpret
Calibration, reproducible data, appropriate sampling etc

Kinetics / thermodynamics at elevated temps

High temp can speed kinetics event would happen at room
temperature but slowly
Effect activated by increased temp (overcome activation energy)
- event would not happen at room temperature

DSC shows excipients interact at 120C

Does not necessarily show interaction at room temp
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Polymorph Screening and Indentification

Form
Form II
Form IIII
Form
Variable
Form
III Hydrate
Dihydrate
Acetic acid solvate

1.0

0.5

0.0

Heat Flow (W/g)

-0.5

thermal stability
melting
crystallization
solid-state transformations
desolvation
glass transition
Exo
sublimation
decomposition
mixture analysis
physical purity (crystal
heat flow
forms, crystallinity)
heat of fusion
chemical purity
heat of transition
phase diagrams / interactions
heat capacity
-1.0

-1.5

-2.0

-2.5

Exo Up

EYP 2006

Form II
Form IIII
Variable
Form
III Hydrate
Dihydrate
Acetic acid solvate

50

100

150

200

Temperature (C)

250

300

350

Effect of Phase Impurities

lots A & B of polymorph (identical by XRD) are different by DSC:
0

Lot A - pure

2046742
FILE# 022511DSC.1

Heat Flow (W/g)

-1

-2

2046742
FILE# 022458 DSC.1 Form II ?

-3

Lot B - seeds
-4

-5
Exo Up

80

130

180

Temperature (C)

230

280
Universal V3.3B TA Instruments

Lot A: pure low melting polymorph melting observed

Lot B: seeds of high melting polymorph induce solid-state transition
below the melting temperature of the low melting polymorph
EYP 2006

Outline

Brief history of thermal analysis

Theory of thermal analysis techniques

Thermal Gravimetric Analysis (TGA)
Differential Scanning Calorimetry (DSC)

Generating valid data

Calibration
Sample preparation

Interpreting data and Applications

Real events
Artefacts

Recent advances

EYP 2006

Microcalorimetry
High sensitivity DSC
Solutions
Scan range typically
0-120 C
Scanning rate of 0-120
C/hr
Reverse scan rate 0-45
C/hr
(depending on efficiency
of cooling tank)
Useful for looking at low
energy modifications
e.g. protein relaxation and
refolding, polymer
characterisation

EYP 2006

trehlose

Modulated DSC (MDSC)

Modulated DSC Heating Profile

introduced in 1993; heat flux

design
sinusoidal (or square-wave or
sawtooth)
modulation
is
superimposed on the underlying
heating ramp
total heat flow signal contains all
of the thermal transitions of
standard DSC

Fourier Transformation analysis is used to separate the total heat flow

into its two components: reversing and non-reversing heat flow
increased sensitivity, resolution and the ability to separate multiple
thermal events
EYP 2006

MDSC for Polymorph Characterization

Heat capacity
(reversing heat flow)
glass transition
melting

Kinetic
(non-reversing heat flow)
crystallization
decomposition
evaporation
0.2

0.00
Reversing (heat flow component)

Non-reversing (heat flow component)

reversing heat flow

-0.05

non-reversing heat flow

-0.10

0.0

Rev Heat Flow (W/g)

Nonrev Heat Flow (W/g)

Lot A

-0.15
-0.20
-0.25

Lot B

-0.30

Lot A
-0.2

Lot B

-0.4

-0.35
-0.40
-0.45

-0.6
DSC010622b.1 483518 HCL (POLYMORPH 1)
DSC010622d.1 483518 HCL

-0.50
110
Exo Up

120

130

DSC010622b.1 483518 HCL (POLYMORPH 1)

DSC010622d.1 483518 HCL

140

150

Temperature (C)

160

170

180
Universal V3.3B TA

-0.8
110
Exo Up

EYP 2006

120

130

140

150

Temperature (C)

160

170

180
Universal V3.3B TA

Hyper DSC

Fast scanning DSC

Only possible with power compensated
Normal equipment 100 C/min
Specialised up to 500 C/min
Increased sensitivity, loss of resolution
e.g. amorphous content in mainly crystalline sample
change of specific heat at Tg is linear relationship to the
amorphous content
Conventional DSC 10% amorphous limit of detection
Hyper DSC <1% amorphous easily detected
Lappalainen, M., I. Pitkanen, et al. (2006). International Journal of
Pharmaceutics 307(2): 150-155.

EYP 2006

Best Practices for Thermal Analysis

proper instrument calibration
use purge gas (N2 or He) to remove corrosive off-gases
small sample size
good thermal contact between the sample and the
temperature-sensing device
proper sample encapsulation
start temperature well below expected transition temperature
slow scanning speeds
(Unless aiming to obscure thermal transitions, e.g fast scan DSC)

avoid decomposition in the DSC

(Run TGA first its easier to clean up!)
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Caution

It is a bulk tool
Analysing the gross average of events in a sample
Conversely, small powder sample in DSC may not
represent packing of powder bulk in
decomposition studies

Instrument error in DSC typically 0.5 - 1C

In Scanning modes, thermal events may be

smeared by a thermal lag
Sample temperature not keeping up with
instrument
Bigger effect at higher heating rates
Typically 1C at 10C/min
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And more caution!

Thermal analysis tells you what is happening at

the temperature it happens at!
Care when extrapolating to room temperature
stability / interaction

Dont over-interpret data

Care when using thermal analysis in isolation

Artefacts / heating rate effects etc
Couple with other analytical tools
Heated X-ray, heated vibrational
spectroscopy, hot stage microscope
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Acknowledgements

Professor Adrian Williams, University of Reading

Dr Ian Grimsey, University of Bradford
Dr Peter Timmins, Bristol Myers Squibb
Dr Wendy Hulse, University of Bradford
Luciana DeMatos, University of Sheffield

EYP 2006

Questions

EYP 2006

Reversing and Non-Reversing

Contributions
to Total DSC Heat Flow
total heat flow
resulting from
average heating
rate

dQ/dt = Cp . dT/dt + f(t,T)

reversing signal
heat flow resulting from
sinusoidal temperature
modulation
(heat capacity component)

non-reversing
signal
(kinetic
component)

e.g. see Pharmaceutical Research: 17 (6): 696-700, June 2000 Craig, DQM et al.
EYP 2006

Some Common Thermal Analysis Techniques

There are various techniques in which a physical property is measured as a
function of temperature, while the sample is subjected to a predefined
heating or cooling program.
Differential Thermal Analysis (DTA)
the temperature difference between a sample and an inert reference material, T = TS TR, is measured as both are subjected to identical heat treatments

Differential Scanning Calorimetry (DSC)

the sample and reference are maintained at the same temperature, even during a
thermal event (in the sample)
the energy required to maintain zero temperature differential between the sample and
the reference, dq/dt, is measured

Isothermal titration calorimetry (ITC)

The temperature of a reaction is kept constant whilst the energy change is measured

Thermogravimetric Analysis (TGA)

the change in mass of a sample on heating is measured
EYP 2006

Thermogravimetric Analysis (TGA)

thermobalance to monitor
sample weight as a function
of temperature
weight
calibration
known weights

using

temperature
calibration
based on ferromagnetic
transition of Curie point
standards (e.g., Ni)
120

100

12.15%

80

Weight (%)

19.32%

larger sample masses, lower

temperature gradients, and
higher purge rates minimize
undesirable
buoyancy
effects
60

29.99%

40

20

20

40

60

80

Time (min)

100

120

140

160

Universal V3.7A TA Instruments

EYP 2006

Differential Thermal Analysis

Sample holder: Sample and reference cells
Sensors: Thermocouples, one for the sample
and one for the reference
Furnace: Block containing sample and
reference cells
Temperature controller: Controls temperature
program
Advantages:
instruments can be used at very high
temperatures
instruments are highly sensitive
flexibility in sample volume/form
characteristic transition or reaction
temperatures can be determined
EYP 2006

Disadvantages:
uncertainty of heats of
fusion and transition
temperatures

Hyphenated Techniques
thermal techniques alone are insufficient to prove the existence of polymorphs
and solvates
other techniques should be used, e.g., microscopy, diffraction, and spectroscopy
development of hyphenated techniques for simultaneous analysis
TG-DTA

120

4.2
15.55%
(0.9513mg)
24.80C
100.0%

3.2

80

TG-MS

2.2

Weight (%)

TG-FTIR

179.95C
84.45%

40

1.2

0.2

Temperature Difference (V/mg)

TG-DSC

0
-0.8

-40

20

70

120

170

Temperature (C)

Exo Up

220

270

TG-DTA trace of sodium tartrate

EYP 2006

-1.8

Universal V3.3B TA Instruments