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 Pseudopolymorphicforms (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 Different thermal behaviour Polymorph A Solvate A Polymorph B Solvate B
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 ThermomechanicalAnalysis (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 temperature control (furnace) sample sensors 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 qualitativeand quantitativeand 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 ^exo Exothermic upwards Endothermic downwards CRYSTALLISATION DESOLVATION GLASS TRANSITION MELTING 20 m W H 2 O DECOMPOSITION Y-axis heat flow X-axis temperature (and time) 40 60 80 100 120 140 160 180 200 220 240 260 280 300 tem perature [ o C ]
Melting Point ^exo Onset = melting point (mp) MELTING 20 mw Heat of fusion (melting) = integration of peak 4 0 60 80 100 120 14 0 160 1 80 200 220 24 0 260 2 80 300 tem perature [ o C] DSC scan of a crystalline material one polymorphic form
Polymorphic Forms ^exo TRANSITION METASTABLE FORM STABLE FORM 20 mw 40 60 80 100 120 140 160 180 200 220 240 260 280 300 tem perature [ o C] DSC scan of a crystalline material polymorphic transition
Pseudopolymorphism ^exo MELTING DEHYDRATION 20 mw 40 60 80 100 120 140 160 180 200 220 240 260 280 300 DSC scan of a hydrate temperature [ o C]
Amorphous Material DEHYDRATION Midpoint = glass transition (Tg) 1 m W GLASS TRANSITION 40 60 80 100 120 140 160 180 200 220 240 260 280 300 tem perature [ C] 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,(HyperDSC TM ) This method provides the ability to perform valid heat flow measurements while heating or cooling a sample with fast linear controlled rates HyperDSC TM -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 40 o C Repeatabiliy: very sensitive to thermal lag and sample preparation
Fast Scan DSC, Rapid Scanning DSC,(HyperDSC TM ) Pharmaapplications: 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 Sinusoidalmodulation (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 M Thermal analysis of pharmaceuticals
Thermogravimetric Analysis (TGA) A technique measuring the variation in mass of a sample undergoing temperature scanning in a controlled atmosphere Thermobalanceallows 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 purge gas sample furnace
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 2 mg 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 temperature [ o C] TGA curves of crystalline and amorphous substance
Lactose monohydrate ^exo 20 mw 2 mg 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 temperature [ o C] 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