Thermal Analysis

Dr. Lidia Tajber

School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin

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

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

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

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

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

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

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

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

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

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

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

Pseudopolymorphism

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20mW

^exo

temperature [oC]

DSC scan of a hydrate

MELTING

DEHYDRATION

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

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 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) 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

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

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

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

Example of a MTDSC Curve

Polyethylene terephthalate (PET)Source: Craig DQM and Reading MThermal analysis of pharmaceuticals

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

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

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

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

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