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

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

20

m W

tem pera tu re [oC ]

^exo Exothermic upwards

Endothermic downwards

Y-axis – heat flow

X-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

20

mW

^exo

tem perature [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

20

mW

tem perature [oC]

^exo

DSC scan of a crystalline material – polymorphic transition

METASTABLE

FORM

TRANSITION

STABLE

FORM

Pseudopolymorphism

40 60 80 100 120 140 160 180 200 220 240 260 280 300

20

mW

^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

tem perature [°C ]

1 m W

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

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

2

mg

temperature [oC]

TGA curves of crystalline and amorphous substance

Lactose monohydrate

0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 3400

^exo

20

mW

temperature [oC]

2

mg

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