1. Thermal Analysis Dr. Lidia Tajber
School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin

2. Characterisation for Pharma
Active pharmaceutical ingredients (API, drugs)
Organic molecules, peptides, proteins
Single components
Mainly solids (crystalline, amorphous or semi-crystalline)
Pure molecules
Excipients (additives, fillers etc.)
Organic, inorganic
Not always single components
Solids or liquids
Not always pure
Formulations (dosage forms, delivery systems)
Mixtures of APIs and excipients
Packaging materials

3. Physical Forms of Solids
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
Polymorph A
Polymorph B
Solvate A
Solvate B
Different thermal behaviour

4. Importance of Solid State Forms in Pharma
Bioavailability (solubility/dissolution rate)
Stability (physical and chemical)
Processing factors
Hygroscopicity
Bulk and mechanical properties
Ease of isolation, filtration and drying
Degree of purity

5. Thermal Analysis Techniques
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.:
Differential Thermal Analysis (DTA) – temperature
Differential Scanning Calorimetry (DSC) – energy
Thermogravimetric Analysis (TGA) – mass
Thermomechanical Analysis (TMA) – dimensions
Dielectric Analysis (DEA) – dielectric/electric properties

6. Basic Principles of Thermal Analysis
Modern instrumentation used for thermal analysis usually consists of the following parts:
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
sample
sensors PC
temperature
control (furnace)

7. Differential Scanning Calorimetry (DSC)
Most popular thermal technique
DSC measures the heat absorbed or liberated during the various transitions in the sample due to temperature treatment
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:
Endothermic processes – sample absorbs energy
Exothermic processes – sample releases energy
Changes in heat capacity

8. Principles of DSC Analysis
Power Compensation DSC
High resolution / high sensitivity research studies
Absolute specific heat measurement
Very sensitive to contamination of sample holders
Heat Flux DSC
Routine applications
Near / at line testing in harsh environments
Automated operation
Cost-sensitive laboratories

9. Summary of Pharmaceutically Relevant Information Derived from DSC Analysis
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

10. Typical Features of a DSC Trace
Exothermic upwards
Endothermic downwards
CRYSTALLISATION
DESOLVATION
GLASS TRANSITION
MELTING
DECOMPOSITION
H2O
Y-axis – heat flow
X-axis – temperature (and time)

11. Melting Point
Onset = melting point (mp)
MELTING
Heat of fusion (melting) = integration of peak
DSC scan of a crystalline material – one polymorphic form

12. Polymorphic Forms
TRANSITION
STABLE
FORM
METASTABLE
FORM
DSC scan of a crystalline material – polymorphic transition

13. Pseudopolymorphism
MELTING
DEHYDRATION
DSC scan of a hydrate

14. Amorphous Material
DEHYDRATION
Midpoint = glass transition (Tg)
GLASS TRANSITION
Polyvinylpyrrolidone (PVP) co-processed with hydroflumethiazide

15. Purity Determination Purity of phenacetin
Source: TA Instruments, Cassel RB,
Purity Determination and DSC Tzero™ Technology

16. Compatibility Studies
Source: Schmitt E et al. Thermochim Acta 2001, 380 , 175 – 183

17. Variants of DSC
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

18. Fast Scan DSC, Rapid Scanning DSC, (HyperDSCTM)
This method provides the ability to perform valid heat flow measurements while heating or cooling a sample with fast linear controlled rates
HyperDSCTM - rates up to 500°C/min
Other non-commercial systems - up to 100,000°C/min
Benefits:
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:
Accuracy: transitions can be shifted by as much as 40oC
Repeatabiliy: very sensitive to thermal lag and sample preparation

19. Fast Scan DSC, Rapid Scanning DSC, (HyperDSCTM)
Pharma applications:
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

20. Modulated Temperature DSC (MTDSC)
This technique uses composite heating profile: determines heat capacity and separates heat flow into the reversible and non-reversible components
Benefits
Increased sensitivity for detecting weak transitions – especially glass transition
Separation of complex events into their:
heat capacity (reversible) e.g. glass transition, melting and
kinetic components (non-reversible) e.g. evaporation, crystallisation, decomposition
Disadvantages
Slow data collection
Risk of sample transformation

21. Variants of MTDSC
Sinusoidal modulation (easy, only one frequency only) – TA Instruments
Step scan modulation (easy, precise) – PerkinElmer
TOPEM® modulation (stochastic modulation, complex calculations, but multiple frequency data) – Mettler Toledo
Saw tooth modulation
Rectangular modulation

22. Example of a MTDSC Curve
Source: Craig DQM and Reading M
Thermal analysis of pharmaceuticals
Polyethylene terephthalate (PET)

23. Thermogravimetric Analysis (TGA)
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
furnace
purge gas

24. Summary of Pharmaceutically Relevant Information Derived from TGA Analysis
Desolvation – adsorbed and bound solvents, stoichiometry of hydrates and solvates
Decomposition – chemical and thermal stability
Compatibility – interactions between components

25. Examples of TGA Curves
TGA curves of crystalline and amorphous substance

26. Lactose monohydrate
DSC and TGA scans of lactose monohydrate

27. Hyphenated Thermal Equipment
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:
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
TGA -MS or -FTIR - evolved gas analysis (EGA)
others