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![Page 1: Thermal Analysis Dr. Lidia Tajber School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin.](https://reader035.fdocuments.us/reader035/viewer/2022062307/5517e347550346d0568b45df/html5/thumbnails/1.jpg)
Thermal Analysis
Dr. Lidia Tajber
School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin
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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
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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
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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
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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
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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
temperature control (furnace) PC
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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
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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
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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
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Typical Features of a DSC Trace
40 60 80 100 120 140 160 180 200 220 240 260 280 300
20mW
temperature [oC]
^exo
Exothermic upwardsEndothermic downwards
Y-axis – heat flowX-axis – temperature (and time)
DESOLVATIONGLASS TRANSITIONCRYSTALLISATION
MELTING
DECOMPOSITION
H2O
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Melting Point
40 60 80 100 120 140 160 180 200 220 240 260 280 300
20mW
^exo
temperature [oC]
DSC scan of a crystalline material – one polymorphic form
MELTING
Onset = melting point (mp)
Heat of fusion (melting) = integration of peak
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Polymorphic Forms
40 60 80 100 120 140 160 180 200 220 240 260 280 300
20mW
temperature [oC]
^exo
DSC scan of a crystalline material – polymorphic transition
METASTABLE FORM
TRANSITION
STABLE FORM
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Pseudopolymorphism
40 60 80 100 120 140 160 180 200 220 240 260 280 300
20mW
^exo
temperature [oC]
DSC scan of a hydrate
MELTING
DEHYDRATION
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Amorphous Material
40 60 80 100 120 140 160 180 200 220 240 260 280 300
temperature [°C]
1 mW
DEHYDRATION
GLASS TRANSITION
Midpoint = glass transition (Tg)
Polyvinylpyrrolidone (PVP) co-processed with hydroflumethiazide
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Purity Determination
Purity of phenacetin Source: TA Instruments, Cassel RB, Purity Determination and DSC Tzero™ Technology
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Compatibility Studies
Source: Schmitt E et al. Thermochim Acta 2001, 380 , 175 – 183
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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
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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
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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
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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
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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
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Example of a MTDSC Curve
Polyethylene terephthalate (PET)Source: Craig DQM and Reading MThermal analysis of pharmaceuticals
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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
furnacepurge gas
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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
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Examples of TGA Curves
0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320
2mg
temperature [oC]
TGA curves of crystalline and amorphous substance
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Lactose monohydrate0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 3400
^exo
20mW
temperature [oC]
2mg
DSC and TGA scans of lactose monohydrate
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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