Thermal Analysis Dr. Basavaraj K. Nanjwade M. Pharm., Ph.D KLE University College of Pharmacy BELGAUM-590010, Karnataka, India. Cell No: 00919742431000 E-mail: [email protected] 02 January 2013 Goa College.
Download ReportTranscript Thermal Analysis Dr. Basavaraj K. Nanjwade M. Pharm., Ph.D KLE University College of Pharmacy BELGAUM-590010, Karnataka, India. Cell No: 00919742431000 E-mail: [email protected] 02 January 2013 Goa College.
Thermal Analysis
Dr. Basavaraj K. Nanjwade
M. Pharm., Ph.D
KLE University College of Pharmacy BELGAUM-590010, Karnataka, India.
Cell No: 00919742431000 E-mail: [email protected]
02 January 2013 Goa College of Pharmacy, Goa.
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Thermal analysis
•
Thermal analysis
is a branch of materials science where the properties of materials are studied as they change with temperature .
• Several methods are commonly used – these are distinguished from one another by the property which is measured.
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ABBREVIATIONS
• • • • • • • • • • • • • • • • 02 January 2013 ICTAC - International Confederation for Thermal Analysis and Calorimetry DEA- Dielectric Analysis DSC- Differential Scanning Calorimetry TGA- Thermogravimetric Analysis TMA- Thermomechanical Analysis ÄHf- Heat of Fusion Tm - Melting Temperature, extrapolated endothermic onset temperature Tp- Peak Melting endothermic Temperature ÄHc-Heat of exothermic Crystallization Tc- Crystallization Temperature, extrapolated exothermic onset temperature Tcp- Peak exothermic Crystallization temperature ÄHv - Heat of endothermic Vaporization Tv - Vaporization temperature, extrapolated endothermic onset temperature Tvp - Peak Vaporization temperature Tg -Glass transition temperature ASTM- American Standards for Testing Materials Goa College of Pharmacy, Goa.
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Thermal analysis
• • • • • • • • • • Dielectric thermal analysis (DEA): dielectric permittivity and loss factor Differential thermal analysis (DTA): temperature difference
Differential scanning calorimetry (DSC): heat difference
Dilatometry (DIL): volume Dynamic mechanical analysis (DMA) : mechanical stiffness and damping Evolved gas analysis (EGA) : gaseous decomposition products Laser flash analysis (LFA): thermal diffusivity and thermal conductivity
Thermogravimetric analysis (TGA): mass Thermomechanical analysis (TMA): dimension
Thermo-optical analysis (TOA): optical properties 02 January 2013 Goa College of Pharmacy, Goa.
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Common Thermal Analysis Methods and the Properties Measured
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Introduction
• Thermal analysis is defined as “series of techniques for measuring the temperature dependency of a physical property of a certain substance while varying the temperature of the substance according to a specific program.” • The substance referred to here includes reaction products.
• Physical properties include mass, temperature, enthalpy, dimension, dynamic characteristics, and others, and depending on the physical properties to be measured, the techniques of thermal analysis.
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Introduction
• Conventionally thermal analysis has been mainly employed in measurements for research and development, but in recent times it is used in many practical applications, as the testing standards on the basis of thermal analysis have been established, for example, in quality control in the production field, process control, and material acceptance inspection.
• It is also applied in wide fields, including polymer, glass, ceramics, metal, explosives, semiconductors, medicines, and foods.
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Introduction
• Introduce thermal analysis at an entry level chemist or a new function for the experienced pharmaceutical scientist.
• This teaching tool describes the introductory use of Differential Scanning Calorimetry (DSC), Thermo-Mechanical Analysis (TMA) and to some extent Thermo-gravimetric Analysis (TGA) for characterizing pharmaceuticals.
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OBJECTIVES
• • • The main objective to introduce thermal analysis and its applications at an entry level in the pharmaceutical industry.
In the process, instruments were successfully calibrated using pharmaceuticals.
Studying the behavior of pharmaceuticals by different thermal analysis instruments, under different conditions and then compare the results was another objective.
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Basic Principles of Thermal Analysis
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Thermal Analysis of Pharma Materials
• DSC,TG/DTA and TG/DTA-IR are often used for characterisation of pharma materials.
• DSC, alone or in combination with hot-stage microscopy, is able to differentiate between different polymorphic structures and, by using different heating rates, can investigate the transformations which occur during the polymorphic transformation.
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Thermal Analysis of Pharma Materials
• By using appropriate heating rates, polymorphic purity can be determined, and can involve heating rates up to 750°C/min.
• TGA is often used to measure residual solvents and moisture, but can also be used to determine solubility of pharma materials in solvents.
• Analysis of pharma materials is probably the largest area of application for thermal analysis.
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Thermal Analysis of Polymers
• Polymers represent another large area in which thermal analysis finds strong applications.
• Thermoplastic polymers are commonly found in everyday packaging and household items, but for the analysis of the raw materials, effects of the many additive used (including stabilisers and colours) and fine-tuning of the moulding or extrusion processing used can be achieved by using DSC.
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Thermal Analysis of Polymers
• An example is oxidation induction time (OIT) by DSC which can determine the amount of oxidation stabiliser present in a thermoplastic (usually a polyolefin) polymer material.
• Compositional analysis is often made using TGA, which can separate fillers, polymer resin and other additives.
• TGA can also give an indication of thermal stability and the effects of additives such as flame retardants 02 January 2013 Goa College of Pharmacy, Goa.
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Thermal Analysis Methods Used in Pharmaceutical
• Even though most of the
thermal analysis
methods can handle samples such as solids, semi-solids or liquids, an evaluation of the contemporary literature would recommend that solid-state portrayal could apply to most of the pharmaceutical research applications.
• Common applications used in thermal analysis incorporate the categorization of the physicochemical attributes of crystalline solids and the discovery and classification of polymorphic forms.
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Thermal Analysis Methods Used in Pharmaceutical
• With the usage of solid dispersions and other polymeric dosage forms in an increased manner, thermal analytical techniques have been required more frequently to assist researchers with the characterization and development.
• Thermal analytical techniques are also utilized for studying the results of lyophilization and developing optimal lyophilization formulations and cycles.
• Differential techniques are also used to review kinetics in the solid-state, which includes accelerated stability, decomposition and the aging effects on various formulations.
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Thermal Analysis Methods Used in Pharmaceutical
• If any laboratory - be it a pharmaceutical industry or an academic research institute, needs to purchase no more than one piece of thermal analysis equipment, it is most likely to be a DSC.
• These instruments can be purchased from numerous manufacturers with wide options of price and applications.
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Thermal Analysis Methods Used in Pharmaceutical
• The DSC concept was formerly derived from earlier DTA instruments. While DTA measures the difference in temperature, DSC grants for the measurement of a modification in enthalpy.
• ‘The International Confederation for Thermal Analysis and Calorimetry’ (ICTAC) has defined DSC as a technique where “the heat flow rate difference into a sample and reference material is measured." 02 January 2013 Goa College of Pharmacy, Goa.
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Thermal Analysis Methods Used in Pharmaceutical
• • • • Two types of basic DSC instruments are available today commercially heat-flux DSC (hf-DSC) and power compensation DSC (pc-DSC).
As per the latest audits, both the instruments are extremely versatile and very comparable.
While engaging different techniques to inspect the measurement, both the types of instruments are employed to measure heat flow and this seems to be certified as DSC under the
ICTAC (
International Confederation for Thermal Analysis and Calorimetry
)
definition.
Originally the term heat-flux DSC was used to illustrate quantitative DTA instruments.
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Thermal Analysis Methods Used in Pharmaceutical
• • • • Now, it is universally denoted as a DSC method.
This progress was an improvement over DTA, which allowed for a measurement in the changes in heat flow as compared to only temperature.
This was reached by the accumulation of a second sequence of thermocouples in order to measure the temperature of a furnace and a heat sensitive plate.
By measuring the capacity of the heat sensitive plate as a task of temperature during the process of manufacturing, an estimation of the enthalpy of transition can be prepared by the incremental temperature fluctuation.
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Thermal Analysis Methods Used in Pharmaceutical
• • • Power-compensation DSC is different from hf-DSC in operating principle as well as in basic instrument design.
Just as the name can notes, pc-DSC measures the change in power or energy essential to preserve the sample and references material at the identical temperature all through the heating or cooling cycle.
This is carried out through an instrument design which is different than that normally found in hf-DSC instruments.
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Thermal Analysis Methods Used in Pharmaceutical
• Two individual heaters are used with pc-DSC to control the flow of heat to the sample and reference holders.
• Individual resistance sensors are positioned within each holder and temperature is measured at the base of each.
• When a phase change takes place in a in thermal analysis and a temperature difference is observed between the sample and reference, energy is removed or supplied until the temperature difference is lower than the threshold.
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Techniques and Applications in the Pharmaceutical Sciences
• • • • The current field of thermal analysis is both diverse and dynamic.
Although not a new field, more advanced instrumentation, techniques and applications are constantly appearing on the market and in the literature.
Theoretically, almost any substance whether solid, semi-solid or liquid can be analyzed and characterized with thermal analytical techniques.
Common materials include foods, pharmaceuticals, electronic materials, polymers, ceramics, organic and inorganic compounds, even biological organisms.
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Techniques and Applications in the Pharmaceutical Sciences
• • • In theory, all thermal analytical techniques simply measure the change of a specific property of a material as a function of temperature.
This in turn allows researchers access to information regarding macroscopic theories of matter including, equilibrium and irreversible thermodynamics and kinetics.
While numerous techniques are available, the primary differences in the techniques are the properties of the material being studied.
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Techniques and Applications in the Pharmaceutical Sciences
• • • In the pharmaceutical sciences, only a handful of the techniques are commonly employed but the information gained and phenomena that can be explored are countless.
The primary workhorses in the pharmaceutical sciences include, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), differential analysis (DTA) and thermomechnical analysis (TMA).
thermal Admittedly, as the needs of the researcher change and new materials are identified in formulation development, less commonly used techniques are being utilized and developed resulting in a very dynamic and exciting field of research.
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Techniques and Applications in the Pharmaceutical Sciences
• The first will be thermal techniques), TGA and TMA.
analytical methods commonly used in the pharmaceutical sciences, primarily DSC (including several specialized • The second will focus on applications in the pharmaceutical sciences including solid-state characterization of polymorphism, solid dispersions and polymeric dosage forms.
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Thermal Analysis Techniques
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IUPAC: International Union of Pure and Applied Chemistry
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Thermal Analysis
• Differential Scanning Calorimetry (DSC) – Measure heat absorbed or liberated during heating or cooling • Differential Thermal Analysis (DTA) • They are use for thermal investigation where thermal change can be observed and characterised • • Thermal Gravimetric Analysis (TGA) – Measure change in weight during heating or cooling Thermomechanical Analysis (TMA) – Measure change in dimensions during heating or cooling 02 January 2013 Goa College of Pharmacy, Goa.
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THERMOGAVIMETRIC ANALYSIS (TGA)
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Thermogravimetric Analysis (TGA)
•
Principle:
TGA measures the amount and the rate of weight change of a material with respect to temperature or time in controlled environments.
• A TGA consists of three major parts a furnace, 1. A microgram balance, 2. An auto sampler and 3. A thermocouple.
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GENERAL PRINCIPLES INVOLVED IN THERMOGRAVIMETRY
•
PRINCIPLE
: temperature or time.
Thermogravimetry is a technique in which a change in the weight of a substance is recorded as a function of •
Instrument:
Instrument used for thermogravimetry is “Thermobalance”. Data recorded in ‘Thermogram’.
form of curve known as 02 January 2013 Goa College of Pharmacy, Goa.
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Thermogravimetric Analysis (TGA)
• • • The furnace can raise the temperature as high as 1000°C which is made of quartz.
• The auto sampler helps to load the samples on to the microbalance.
The thermocouple sits right above the sample.
Care should be taken at all times that the thermocouple is not in touch with the sample which is in a platinum pan.
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Thermogravimetric Analysis (TGA)
• A technique that permits the continuous weighing of time a at sample a as a function of temperature and/or as a function of desired temperature 33 02 January 2013 Goa College of Pharmacy, Goa.
Differential Thermal Analysis
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Thermogravimetric Analysis (TGA)
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Interpretation of TG and DTG curves
i.
ii.
iii.
iv.
v.
vi.
vii.
The sample undergoes no decomposition with loss of volatile products over the temperature range shown but solid phase transformation, melting ,etc can not be detected by TG , The rapid initial mass loss is characteristic of desorption or drying. If it is true, then re-run the sample should result in type (i) curves , Single stage decomposition , Multi-stage decomposition with relatively stable intermediates : provide information on the temperature limit of stability of reactants and intermediate products and also stoichiometry , Multi-stage decomposition with no stable intermediate product. However heating-rate effect must be considered. At low heating rate, type (v) resemble type (iv). At high heating rate, type (iv) and (v) resemble type (iii) and lose all the details , Gain in mass due to reaction atmosphere, e.g. oxidation of metals , with Oxidation product decompose again at higher temperature; this is not often encountered.
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TGA Curve of Calcium Oxalate
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Examples of TGA Curves
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Sample Preparation
• • • • • • Sample preparation has a significant effect in obtaining good data.
It is suggested that maximizing the surface area of the sample in a TGA pan improves resolution and reproducibility of weight loss temperatures.
The sample weight affects the accuracy of weight loss measurements.
Typically 10-20mg of sample is preferred in most applications.
Whereas, if the sample has volatiles 50-100mg of sample is considered adequate.
It is to be noted that most TGA instruments have baseline drift of ±0.025mg which is ±0.25% of a 10mg sample.
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Experimental Conditions
• •
Heating Rate Purge gas
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Experimental Conditions -Heating Rate
• • • Samples are heated at a rate of 10 or 20°C/min in most cases.
Lowering the heating rates is known to improve the resolution of overlapping weight losses.
Advances in the technology have made it possible for variable heating rates (High Resolution TGA) to improve resolution by automatically reducing the heating rate during periods of weight loss.
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Experimental Conditions -Purge gas
• • • • • Nitrogen is the most common gas used to purge samples in TGA due to its inert nature.
Whereas, helium provides the best baseline.
Air is known to improve resolution because of a difference in the oxidative stability of components in the sample.
Vacuum may be used where the sample contains volatile components, which helps improve separation from the onset of decomposition since the volatiles come off at lower temperatures in vacuum.
e.g. oil in a rubber tire product.
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Miscellaneous
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Calibration
• • •
Blank test Calibration of mass changes Calibration of temperature
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Calibration- Blank test
• Without sample, air is passed at 20 ml/mm, and the temperature is raised up to 1000 °C at heating rate of 10°C min-1.
• By this blank test, the general condition of the apparatus can be known.
• The TGA curve can drift slightly as the temperature is increased.
• This is owing to the changes in the buoyancy and convection.
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Calibration- Blank test
• • • When noise appears in the TG curve, the possible cause may include contact between sample dish and thermocouple, contact between quartz suspension wire and purge gas feed pipe, and contact between weight pan and arid glass cap.
Vibration and shock may also cause noise.
When the sample pan or suspension wire is contaminated with deposit of decomposition product or the like, the TGA curve shows a slight decreasing curve.
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Calibration- Calibration of mass
changes
• • • Since the TGA is usually measured by the rate of the weight change to the sample weight, calibration of absolute value of weight is hardly necessary.
A weight of 20 mg is read to a precision of 10 microgms by a precision balance, and the mean (So) is determined.
The furnace is put on, and when the TGA signal is stabilized, the instrument balance control is adjusted to set the automatic zero.
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Calibration- Calibration of mass
changes
• • • • • Then the furnace is put into place and the furnace is set again, and the TGA signal value is read. This value is S1.
Repeating the same operation several times, the mean of S1 is obtained as S.
In this operation it is known that a signal corresponding to S1 mg is delivered with the weight of So mg is placed on the balance.
The measuring precision of TGA is within ±1 % of the range.
When calibrating the apparatus, the calibration function is utilized.
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Calibration-Calibration of
temperature
• • • • The temperature of the TGA may be calibrated in two manners: The method of making use of the melting point of a pure metal, and the method of utilizing the Curie point temperature.
In the former method, one of the metals processed in a ribbon shape, and it is suspended on the TGA suspension wire, and a weight of about 100mg is attached at its tip.
When the pure metal is fused by heating, the weight drops, and a weight drop appears on the TGA curve.
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Calibration-Calibration of
temperature
• In the latter method, the standard substance verified by
International Congress on Thermal Analysis, ICTA
, is measured. The standard substances are Ferromagnets, and have different Curie temperatures.
• It is intended to calibrate by measuring the apparent weight change appearing in steps at Curie temperatures by making use of a permanent magnet.
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•
Calibration-Calibration of
temperature
Based on the TGA data, thermal stability of materials and their compositions can be predicted depending on the weight changes caused by evaporation, dehydration, oxidation and decomposition, up to temperatures as high as 1000°C.
• A typical example is the TGA of calcium oxalate hydrate, heated to 1000°C which shows three steps in its decomposition curve.
• The weight loss data is recorded every half second throughout the run time.
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Applications of TGA
• • • • • • • There is a wide range of applications of TGA, e.g, Composition of multi-component system Thermal stability of materials Oxidative stability of materials Estimated lifetime of a product Decomposition Kinetics of materials The effect of reactive or corrosive atmosphere on materials Moisture and volatiles contents on materials.
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Applications of TGA
• • • Evaporation of free (unbound) water begins at room temperature due to dry gas flowing over the sample.
Dehydration/Desolvation of bound water almost always begins at temperatures above room temperature and typically 125°C.
• Decomposition can have multiple stages (weight losses) but the presence of multiple weight loss steps can also indicate the presence of multiple components in the sample.
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Applications of TGA
• Determination of the bound and unbound water in the suspension of Milk of Magnesia (MoM), used as a laxative.
• • Comparison of the generic and a brand MoM.
In an overview of thermal analysis testing it is always preferable to do a TGA experiment on unknown samples before doing pharmaceuticals).
a DSC experiment (especially for • Decomposition of pharmaceuticals renders products which are insoluble and generally sticky on the inside of a DSC cell.
• • These products will lower the life use of a DSC cell.
Therefore, know the decomposition temperatures of all drugs and heat in a DSC evaluation to 50°C below those temperatures.
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TGA+Spectroscopy/Chromatography Combination
Gases, vapors TGA IR or MS or GC 02 January 2013 Goa College of Pharmacy, Goa.
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Thermogravimetry thermal analysis (TGA) testing
• Thermogravimetric (TGA) analysis provides determination of endotherms, exotherms, weight loss on heating, cooling, and more.
• Materials analyzed by TGA include polymers, plastics, composites, laminates, adhesives, food, coatings, pharmaceuticals, organic materials, rubber, petroleum, chemicals, explosives and biological samples.
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TGA materials analysis
• Thermogravimetric analysis uses heat to force reactions and physical changes in materials.
• TGA provides quantitative measurement of mass change in materials associated with transition and thermal degradation.
• TGA records change in mass from dehydration, decomposition, and oxidation of a sample with time and temperature.
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TGA materials analysis
• Characteristic thermogravimetric curves are given for specific materials and chemical compounds due to unique sequence from physicochemical reactions occurring over specific temperature ranges and heating rates.
• These unique characteristics are related to the molecular structure of the sample.
• When TGA is used in combination with FTIR, TGA/FTIR is capable of detailed FTIR analysis of evolved gases produced from the TGA.
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TGA thermogravimetric capabilities
• • • • • • • • Compositional analysis of materials Decomposition temperatures Rate of degradation Product lifetimes Oxidative stability Evaluation of polymer flammabilities Thermal stabilities Determination of rancidity of edible oils 02 January 2013 Goa College of Pharmacy, Goa.
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TGA thermogravimetric capabilities
• • • • • • • • • Fingerprinting unknown polymers Moisture Content Volatiles content, VOC analysis Analysis of evolved gases using TGA/FTIR Competitive product evaluation Measurement of oil extender content in elastomers Effects of reactive atmospheres on materials Determination of inert filler or ash contents ASTM D6375 Noack Method 02 January 2013 Goa College of Pharmacy, Goa.
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Summary of Pharmaceutically Relevant information Derivation from TGA Analysis
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Major difference between TGA and DTA (DSC)
• TGA reveals changes of a sample due to weight, whereas DTA and DSC reveal changes not related to the weight (mainly due to phase transitions ) 02 January 2013 Goa College of Pharmacy, Goa.
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DIFFERENTIAL SCANNING CALORIMETRY (DSC)
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Differencial Scanning Calorimetry (DSC)
• Characterization of pharmaceutical compounds and analysis of complex modern formulations, together with an increasing need for data to support regulatory submissions, means that the pharmaceutical industry now depends on the range of thermal analysis techniques.
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Definitions
• • • • • A
calorimeter
measures the heat into or out of a sample.
A
differential calorimete
r measures the heat of a sample relative to a reference.
A
differential scanning calorimeter
does all of the above and heats the sample with a linear temperature ramp.
Endothermic
heat flows into the sample.
Exothermic
heat flows out of the sample.
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Differential Scanning Calorimetry (DSC)
Temperature DSC measures differences in the amount of heat required to increase the temperature of a sample and a reference as a function of temperature 02 January 2013 Goa College of Pharmacy, Goa.
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Circuitry of a DSC
• •
Two separat heating circuits:
The average-heating controller
(The temperatures of the sample (Ts) and reference (Tr) are measured and averaged and the heat output is automatically adjusted to increase the average temperature of the sample and reference in a linear rate)
Differential-heating circuit
(Monitor the difference in Ts and Tr, and automatically adjust the power to either the reference or sample chambers to keep the temperatures equal) 02 January 2013 Goa College of Pharmacy, Goa.
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Sample containers and sampling
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Differential Scanning Calorimeter
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Conventional DSC
Sample Empty Metal 1 Sample Temperature Metal 2 Metal 1 Reference Metal 2 Temperature Temperature Difference = Heat Flow Goa College of Pharmacy, Goa.
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Variants of DSC
• • • • Heat flux – 1955 Boersma – 1 large (30 – 100 g) furnace Power compensated – Separate small (1 g) microheaters for sample and reference Hyper DSC – Very fast scan rates 500°C/min – Mimic processing conditions StepScan DSC – Short dynamic and isothermal scan steps – Separate reversible and irreversible effects 02 January 2013 Goa College of Pharmacy, Goa.
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Variants of DSC
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Differential Scanning Calorimetry (DSC)
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DSC Technique
• • • • • • • Principle Heat Flux Power Compensation Sample Preparation - Sample Shape - Sample pans - Sample Weight Experimental Conditions - Start Temperature - End Temperature - Reference Pan - Heating Rate - Effects of heating rate Purge Gas DSC Calibration 02 January 2013 Goa College of Pharmacy, Goa.
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DSC- Principle
•
Principle DSC is a thermo-analytical technique in which the difference in the amount of heat required to increase the temperature of a sample and reference is measured as a function of temperature.
The differences in heat flow occur with the occurrence of two major events: 1) The heat capacity of the sample which increases with temperature (baseline) 2) Transitions that occur in the sample (events superimposed on the heat capacity baseline) 02 January 2013 Goa College of Pharmacy, Goa.
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DSC- Principle
• Heat Flow Rate is expressed in a variety of units which can also be normalized for the weight of sample used 02 January 2013 Goa College of Pharmacy, Goa.
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Principle Of DSC
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Typical DSC Curve
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6 02 January 2013 Glass Transition
DSC Thermogram
Crystallisation Cross-Linking (Cure) Oxidation Melting Temperature Goa College of Pharmacy, Goa.
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Transitions in a DSC Curve
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Differential Scanning Calorimeter
• A DSC consists of a cell, which is the heart of a DSC.
• The cell is connected with a gas inlet through which different gases are purged depending on the data required.
• Based on the DSC cells there are two primary types: 1.
Heat Flux 2. Power Compensation
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DSC
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Heat Flux
• This consists of a large single furnace which acts as an infinite heat sink to provide or absorb heat from the sample.
• The advantages generally include a better baseline, sensitivity and sample–atmosphere interaction.
• The key components are the Sample pan (typically an aluminum pan and lid) which is combined with the Reference pan (always the same material as the Sample pan, aluminum).
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Heat Flux
• The Dynamic sample chamber is the environment of the sample pan compartment and the purge gas.
• Nitrogen is the most common gas, but alternate inert gas is helium or argon.
• When using an oxidative atmosphere air or oxygen are the gases of choice.
• The heat flux DSC is based on the Change in Temperature ΔT between the sample and reference.
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Heat Flux Type DSC
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Heat Flux and DSC
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Heat Flux Type DSC
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Power Compensation
• Small individual furnaces use different amounts of power to maintain a constant ΔT between sample and reference and the advantage here include faster heating and cooling, and better resolution.
• This type of cell, with two individually heated with platinum heaters monitors the difference between the sample and reference.
• Platinum resistance thermometers track the temperature variations for the sample and reference cells.
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Power Compensation
• Holes in the compartment lids allow the purge gas to enter and contact the sample and reference.
• There are physical differences between the heat flux and power compensated thermal analysis, the resulting fusion and crystallization temperatures are the same.
• The heat of transition is comparable quantitatively.
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Power Compensation DSC Cell Design
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Power Compensated DSC
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Principles of DSC Analysis
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Sample Preparation
•
Sample Shape
•
Sample Pans
•
Sample Weight
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Sample Preparation
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Sample Shape
• It is recommended that the sample is as thin as possible and covers as much of the pan bottom as possible.
• Samples in the form of cakes (as in case of polymers) must preferably be cut rather than crushed to obtain a thin sample.
• Crushing the sample, whether in crystalline form or a polymer, induces a stress, which can in turn affect the results.
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Sample Shape
• In most cases lids should always be used in order to more uniformly heat the sample and to keep the sample in contact with the bottom of the pan.
• In case where oxidation properties of a sample are to be studied no lid is used and the purge gas is usually oxygen as described in ASTM Standard Test Methods E1858, Oxidative Induction Time or ASTM E2009, Oxidation onset temperature.
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Sample Pans
• Lightest, flattest pans are known to have the least effect on the results obtained from a DSC.
• Crimped pans on the other hand provide the highest sensitivity and resolution.
• Hermetic pans are used where the sample is expected to have some volatile content.
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Sample Pans
• These pans prevent evaporation.
• Two main reasons for the use of these pans are: The Tg of a polymer or amorphous material shifts with volatile content.
• Evaporation peaks look just like melting endotherm .
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Sample Weight
• Though 5 to 10 mg is considered to be an appropriate sample weight for a DSC test, selection of the optimum weight is dependent on a number of factors: the sample to be analyzed must be representative of the total sample and the change in heat flow due to the transition of interest should be in the range of 0.1
- 10mW • A recommendation for metal or chemical melting sample is < 5mg.
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Sample Weight
• For polymer glass transition Tg or melting sample the mass should be » 10mg.
• Polymer >10mg.
composites or blends the sample mass is • The accuracy of the analytical balance used to measure the sample weight should be accurate to ± 1%.
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Experimental Conditions
•
Start Temperature
•
End Temperature
•
Reference Pan
•
Heating Rate
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Start Temperature
• Generally, the baseline should have 2 minutes to completely stabilize prior to the transition of interest.
• Therefore, at 10°C/min heating rate the run should start at least 20°C below the transition onset temperature.
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End Temperature
• Allowing a analysis limits.
2-minute baseline after the transition of interest is considered appropriate in order to correctly select integration or • Care should be taken not to decompose samples in the DSC; it not only affects the baseline performance but the cell life.
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Reference Pan
• A reference pan of the same type used to prepare the sample should be used at all times.
• A material in the reference pan that has a transition in the temperature range of interest should never be used.
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Heating Rate
• Heating the samples at low heating rates increases resolution by providing more time at any temperature.
• Transitions due to kinetic processes (such as crystallization) are shifted to lower temperature at highest cooling rates or higher temperatures at high heating rates.
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Heating Rate
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Effects of heating rate
• DSC curves Phenacetin.
of Acetophenetidin and • The Acetophenetidin DSC at 0.5°C/min and 10°C/min showed no effect of heating rate.
• If there were some minor eutectic in this sample then they would have been detected at the lower heating rate.
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DSC curves of Acetophenetidin
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Effects of heating rate
• The melting temperature of pure drugs or chemicals will have the same extrapolated onset temperature or the melting point as seen at two varying heating rates.
• The DSC Curve for Phenacetin viewed at heating rates of 1.0, 5.0 and 20°C/min yielded the same Tm of 135°C ±1°C.
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DSC curves of Phenacetin
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Effects of heating rate
• If you use multiple heating rates then start with 1.0
and 10°C/min.
• Melting is a thermodynamic process and the onset of melting does not change significantly with heating rate.
• Evaporation, desolvation and decomposition are kinetic processes that will move to higher temperatures as heating rate increases.
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Effect of Heating Rate
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Purge Gas
• Nitrogen being a relatively poor thermal conductor increases sensitivity whereas helium which is a good conductor of heat to or from the sample increases resolution.
• DSC is used in studying the melting, crystallization, glass transition, oxidation and decomposition of pharmaceuticals.
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Purge Gas
• By selecting different parameters useful data such as the purity, polymorphic transitions can be obtained.
• A typical DSC curve could give glass transition temperature, melting temperature, crystallization temperature and decomposition temperatures.
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Purge Gases
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Summary of DSC experimental conditions
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Purity by DSC
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Purity Determination
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Summary of Pharmaceutically Relevant Information Derived from DSC Analysis
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Typical Features of a DSC Trace
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Melting Point
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Melting Process by DSC
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Melting
Thermogram • • • • Negative peak on thermogram Ordered to disordered transition T m , melting temperature Melting happens to crystalline polymers; Glassing happens to amorphous polymers Melting T m Temperature, K 02 January 2013 Goa College of Pharmacy, Goa.
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Polymorphic Forms
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Pseudopolymorphism
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Amorphous Material
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Modulated Temperature – DSC (MT-DSC)
• • • • Most transitions detected by DSC will appear as peaks, where a change (exothermic or endothermic) is detected and then there is a return of the heat flow to a baseline.
These results are typical of first-order or second-order thermodynamic phase transitions, which are in an equilibrium state.
Glass transitions, on the other hand, are neither first-order nor second-order transitions since neither the glassy state nor the viscous state is an equilibrium state.
Typical DSC thermograms will reveal glass transitions as step wise increases in the heat capacity (Cp) of the sample.
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Modulated Temperature – DSC (MT-DSC)
• • • This is due primarily to the increase in molecular motion of the sample above the Tg.
In some cases, the determination of Tg is relatively straightforward but this work can be some of the most challenging done with DSC.
More on detecting and determining Tg’s will be presented in the applications section of this review but glass transitions are mentioned here because this application has help drive the development of modulated-temperature DSC instruments and methods.
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Modulated DSC (MDSC)
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Modulated Temperature DSC (MTDSC)
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MDSC for Polymorph Characterization
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Variants of MTDSC
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Example of a MTDSC Curve
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Fast Scan DSC, Rapid Scanning DSC
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Fast Scan DSC, Rapid Scanning DSC
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‘Hyper’ DSC
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DSC Calibration
• • • • • Calibration of DSC is done using Indium metal.
Calibrating an instrument with a metal when pharmaceuticals are to be studied appears to be not appropriate.
To overcome this, an effort has been made to calibrate DSC with pharmaceuticals.
The true melting temperature of indium metal is 156.7°C and the observed in calibration is 157.4°C.
It is 0.7°C high and the instrument values must be adjusted down to accommodate the true melting temperature.
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DSC Calibration curve of indium
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DSC – Applications
• • • • •
Glass Transition Temperature (Tg) Glass Transition Size (ΔCp) Crystallization temperature (Tc) Crystallinity (based on J/g and adjusted to %) Polymorphic Transitions.
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Glass Transition Temperature (Tg)
• • • • The glass transition is due to the presence of amorphous structures in the sample.
It is detected by DSC based on a step-change in molecular mobility that results in a step increase in heat capacity and heat flow rate.
Amorphous materials flow, they do not melt and hence no DSC melt peak.
The physical and reactive properties of amorphous structure are different than crystalline structure.
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Glass Transition Temperature (Tg)
• • The physical and reactive properties of amorphous structure are significantly different at temperatures above and below Tg.
• The glass transition temperature, Tg, is a second order pseudo transition.
It constitutes a parameter of high interest in the study of amorphous and semi-crystalline drugs since amorphous drugs are more bio available and soluble.
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Glass Transition
Thermogram • • • • Step in thermogram Transition from disordered solid to liquid Observed in glassy solids, e.g., polymers T g glass transition temperature Glass transition T g Temperature, K 02 January 2013 Goa College of Pharmacy, Goa.
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Glass Transition Size (ΔCp)
• The ΔCp at Tg is a measure of the flexibility associated with the Tg.
• A larger value implies a more rubbery material, e.g., polybutadiene.
• Stiffer polymers like polystyrene have a lower value.
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Crystallization temperature (Tc)
• The Tc of many drugs has been determined in our lab based on a DSC that can program heat and cool.
• The difference in Tm to determine the Tc is a measure of super cooling, e.g. Vanillin has a 50°C super cooling temperature while indium melts and crystallizes at the same temperature or super cooling is zero °C 02 January 2013 Goa College of Pharmacy, Goa.
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Crystallization
Thermogram • • • • • Sharp positive peak Disordered to ordered transition Material can crystallize!
Observed in glassy solids, e.g., polymers T c crystallization temperature Crystallization T c Temperature, K 02 January 2013 Goa College of Pharmacy, Goa.
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• Sharp positive peak
Analysis
Crystallization • Disordered to ordered transition • • Observed in glassy solids, e.g., polymers T c crystallization temperature 02 January 2013 Goa College of Pharmacy, Goa.
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•
Crystallinity (based on J/g and adjusted to %)
The Crystallinity measured by comparing successive heat and cool DSC runs on a drug will yield the change in crystallinity by comparing the Heat of Crystallization to the Heat of Fusion x100.
• This % crystallinity by this method was 78% for Acetophenetidin, 20% for Sulfapyradine and 0% for Lidocaine.
• This implies that Lidocaine remains amorphous for a period of time.
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Polymorphic Transitions.
• • • Sulfanilamide Polymorphs: It was observed that sulfanilamide polymorphs are stable and do not show transition among its forms at heating rates between 1 and 10°C/min.
DSC of Polymorphs of Tolbutamide: Tolbutamide A (Form 1) and B (Form 3): When tolbutamide polymorphs were observed by DSC a significant difference was seen in their behavior. The difference is due to their structures which were observed by scanning electron microscope (SEM).
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DSC curves of Sulfanilamide Polymorphs
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DSC of Polymorphs of Tolbutamide: Tolbutamide A (Form 1) and B (Form 3)
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SEM of Tolbutamide polymorphs
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Typical Features of a DSC Trace (Polymorphic System)
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Polymorph Screening and Identification
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DSC thermal analysis
• • • • • • • • • • • Thermal Phase Change Thermal Glass Transition Temperature (Tg) Crystalline Melt Temperature Endothermic Effects Exothermic Effects Thermal Stability Thermal Formulation Stability Oxidative Stability Studies Transition Phenomena Solid State Structure Analysis of a Diverse Range of Materials 02 January 2013 Goa College of Pharmacy, Goa.
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DSC analysis determines
• Tg Glass Transition Temperature – Temperature (°C) at which amorphous polymers or an amorphous part of a crystalline polymer go from a hard brittle state to a soft rubbery state • Tm Melting point – Temperature (°C) at which a crystalline polymer melts • Δ Hm Energy Absorbed (joules/gram) – Amount of energy a sample absorbs when melting • Tc Crystallization Point – Temperature at which a polymer crystallizes upon heating or cooling • Δ Hc Energy Released (joules/gram) – Amount of energy a sample releases when crystallizing 02 January 2013 Goa College of Pharmacy, Goa.
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DSC Test Methods
• • • • • • • ASTM E1269-05 Determination Specific Heat Capacity by DSC NEN-EN 728 Bepaling van de Oxidatieve Inductietijd ISO22768 Rubber, Determination of the glass transition temperature by DSC ASTM D1519-95 Rubber, Determination of Melting Range ASTM D3418-03 Transition Temperatures of Polymers By DSC ISO11357-4 Determination of Specific Heat Capacity ISO11357-3 Determination of Enthalpy Temperature of Melting and Crystallization 02 January 2013 Goa College of Pharmacy, Goa.
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Sources for Errors
• • • • • • Calibration Contamination Sample preparation – how sample is loaded into a pan Residual solvents and moisture.
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TGA and DSC
• Thermogravimetric Analysis (TGA) • Mass change of a substance measured as function of temperature whilst the substance is subjected to a controlled temperature programme.
• Mass is lost if the substance contains a volatile fraction.
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TGA and DSC
• Differential Scanning Calorimetry (DSC) • Provides information about thermal changes that do not involve a change in sample mass • More commonly used technique than TGA • Two basic types of DSC instruments: heat-flux and power compensation 02 January 2013 Goa College of Pharmacy, Goa.
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Typical TGA and DSC Results for Various Transitions
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Lactose monohydrate
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Hyphenated Thermal Equipment
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Temperature Scales
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Maxwell-Boltzmann Distribution
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DSC Applications In Pharmaceutical Industry
Characterization fusion, specific heat capacity, crystallization, etc.
melting point, heat water Purity Polymorphism Screening Tests For Compatibility Stability Tests of of 02 January 2013 Goa College of Pharmacy, Goa.
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DSC Applications In Pharmaceutical Industry
Fast and reliable research tool.
DSC melting, allows fast endosperms evaluation and of possible incompatibilities, because it shows change in the appearance, shift or disappearance of exotherms or variations in the corresponding enthalpies of reaction.
Rapid analysis, easy handling, high significance for research, development and quality control.
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Characterization for Pharma
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Physical Forms of Solids
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Importance of Solid State Forms in Pharma
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Compatibility Studies
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DSC in Polymer Analysis
Main transitions which can be studied by DSC: • • • Melting Freezing Glass transition 02 January 2013 Goa College of Pharmacy, Goa.
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Polymer DSC Analysis Capabilities
• • • • • • • • • Melting point / Melting Range Heat Capacity Crystallization Glass Transition Identification Thermal stability Decomposition Temperature Oxidative Induction Times (OIT) by DSC Purity 02 January 2013 Goa College of Pharmacy, Goa.
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THERMOMECHANICAL ANALYSIS (TMA)
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Thermo-Mechanical Analysis (TMA)
• Thermo-mechanical analysis (TMA) provides dimensional properties data for materials.
• Materials tested by thermo-mechanical anlaysis include polymers, composites, laminates, adhesives, coatings, pharmaceuticals, glass, ceramics, fibres and other materials.
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Thermo-Mechanical Analysis (TMA)
• Measurement of Dimensional Change • Coefficient of Linear Thermal Expansion • Determination of Material Anisotropy • Softening Temperatures and Glass Transition • Linear Thermal Expansion 02 January 2013 Goa College of Pharmacy, Goa.
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• • • •
Thermomechanical Analysis (TMA)
TMA is a thermal analysis technique used to measure changes in the physical dimensions (length or volume) of a sample as a function of temperature and time under a non oscillatory load.
This technique is widely applicable to variety of materials such as pharmaceuticals, polymers, ceramics and metals etc.
TMA has been used in pharmaceutical analysis.
Variables considered while performing the thermal mechanical analysis are applied load, gas environment, temperature range and heating rate as well as TMA probe type.
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Thermomechanical Analysis (TMA)
• The tests are run in a heating mode at a desired heating rate and temperature range of interest.
• Probe displacement profiles are subsequently analyzed in terms of coefficient of thermal expansion, softening and melting transition temperatures.
temperatures, and glass • The different TMA probe types and recorded as a function of temperature.
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Types of TMA probes and resulting measured properties
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Thermomechanical Analysis (TMA)
• TMA consists of a quartz stage, a quartz probe, furnace which sits on top of the stage, equipped with inlet for purge gas, thermocouple adjacent to the stage and a LVDT (linear variable differential transformer) attached to the probe, which measures the difference in the dimensions caused under the probe.
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Sample preparation
• The use of TMA in the pharmaceutical industry is limited to polymers.
• In order to examine powdered samples, the sample is packed into a flat DSC pan.
• The dimension of the sample is measured by TMA in millimeters.
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Experimental Conditions
• The TMA is operated under the following conditions and includes the heating rate at 10°C /min, applied stress of 0.1 N; flat tip quartz expansion probe with outer diameter 0.125 mm, gas purge nitrogen at 50 mL/min, sample in a DSC pan and the probe is applied onto the packed crystalline powder, and the sample size in the DSC pan is 100 mgs.
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Calibration
• Calibration of TMA is done using an Indium metal.
• Calibrating an instrument with a metal when pharmaceuticals are to be studied does not sound appropriate.
• To overcome this, an effort has been made to calibrate TMA with pharmaceuticals.
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TMA Curve of Indium
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TMA Applications
• TMA is used to obtain transitions (Tg) of materials.
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DIFFERENTIAL THERMAL ANALYSIS
Useful for investigation of solid-solid interactions.
Thermograms are obtained for pure drugs and for mixtures using different ratios.
In absence of any interaction thermograms of mixture show pattern corresponding to that of individual components.
But if interactions occur it is indicated in thermograms by appearance of one/ more peaks corresponding to those components.
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ROLE OF THERMAL ANALYSIS IN PREFORMULAION
• They are unique methods in the field of polymer analysis & of high value for a solid state analysis - They finds wide application in a) Study of complexation b) Detection of impurity c) Study of polymorphism 02 January 2013 Goa College of Pharmacy, Goa.
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APPLICATION OF THERMAL ANALYSIS IN PREFORMULATION
• Characterization of hydrates and solvates Preformulation studies is to identify the ability of drug to take up water and characterize the state of this water.
• TGA is useful for characterization of hydrates & solvates.
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INNOVATION IN THERMAL ANALYSIS
1) MULTIELEMENTAL SCANNING THERMAL ANALYSIS (MESTA) 2) MICROTHERMAL ANALYSIS 3) MODULATED DSC 4) ROBOTIC SYSTEM 5) FAST SCAN DSC 6) DYNAMIC MECHANICAL ANALYSIS 02 January 2013 Goa College of Pharmacy, Goa.
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Limitations of Thermal Analysis
1) Low sensitivity for transitions involving small energies.
2) Impurity consisting of molecules of same size,shape,& character as those of the major component are not detected by DSC.
3) TGA used to studies hydrates & moisture study are not always reliable.
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Thermal analysis capabilities
• • • • • • • • • • • • • Thermal Phase Change Glass Transition Temperature Crystalline Melt Temperature Endothermic Effects Exothermic Effects Flashpoint Testing Linear Thermal Expansion Thermal Stability Thermal Formulation Stability Oxidative Stability Studies Flammability Testing of Materials Microscopy of Thermal Processes Thermal Analysis of a diverse range of materials 02 January 2013 Goa College of Pharmacy, Goa.
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Characteristic:
Morphological change Dimensional change Viscoelastic properties Mass change
Thermal Analysis
Thermal properties:
Melting points, glass transition (Tg), crystallinity, thermal history, nucleation, enthalpy of fusion or re-crystallisation, specific heat capacity (Cp) Coefficient of thermal expansion (CLTE), shrinkage data, anisotropy due to fillers, reinforcing materials, softening temperatures Stiffness and damping properties, molecular phase interactions by mechanical loss Thermal stability, thermal oxidative stability, thermal transitions, solvent loss, water / filler content, organic ratios, inorganic ratios Goa College of Pharmacy, Goa.
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Thermal Analysis Instrument Manufacturers
• Perkin Elmer Thermal Analysis Systems •
http://www.perkin-elmer.com/thermal/index.html
TA Instruments •
http://www.tainst.com/
Mettler Toledo Thermal Analysis Systems •
http://www.mt.com/
Rheometric Scientific •
http://www.rheosci.com/
Haake •
http://polysort.com/haake/
NETZSCH Instruments •
http://www.netzsch.com/ta/
SETARAM Instruments •
http://setaram.com/
Instrument Specialists, Inc.
http://www.instrument-specialists.com/
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‘Nanothermal Analysis’ (Nano-TA)
• • A new technology ‘nanothermal analysis’ (nano-TA), which in conjunction with other techniques provides a powerful analytical strategy for characterising nano and micro-scale heterogeneity in the solid-state properties of drug–polymer formulations.
Nanothermal analysis is an emerging localized thermal analysis technique which combines the high resolution imaging capabilities of atomic force microscopy (AFM) with the ability to characterize the thermal properties of materials .
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‘Nanothermal Analysis’ (Nano-TA)
• It offers significantly enhanced spatial resolution compared with its predecessor, scanning thermal microscopy.
• In nano-TA the conventional silicon based AFM tip is replaced by a specialized micro fabricated silicon based probe with a miniature heater that has a topographic spatial resolution of around 5 nm and a thermal property measurement resolution of up to 20nm.
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‘Nanothermal Analysis’
•
(Nano-TA)
Importantly this probe enables a surface to be studied with the most widely applied AFM imaging mode, tapping mode, enabling the analysis of softer samples, such as polymers, without damage from the imaging probe.
• As nano-TA can be used to map thermal properties during imaging, or to carry out local thermal analysis (LTA) at defined points on a surface.
• LTA, where the probe is heated in a temperature cycle not dissimilar to DSC whilst in contact with the sample, can provide quantitative information on thermally induced phase transitions.
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THANK YOU
Cell No: 00919742431000 E-mail: [email protected]
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