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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
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Thermal analysis
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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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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
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Thermal Gravimetric
Analysis (TGA)
Measure change in
weight during heating or
cooling
Thermomechanical
Analysis (TMA)
Measure change in
dimensions during
heating or cooling
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THERMOGAVIMETRIC ANALYSIS
(TGA)
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Instrument:
Instrument
used
for
thermogravimetry is Thermobalance. Data
recorded in form of curve known as
Thermogram.
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Thermogravimetric Analysis
(TGA)
The furnace can raise the temperature as high
as 1000C 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 a sample as a
function of temperature
and/or as a function of
time at a desired
temperature
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Thermogravimetric Analysis
(TGA)
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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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Miscellaneous
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Calibration
Blank test
Calibration of mass changes
Calibration of temperature
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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 1000C.
A typical example is the TGA of calcium oxalate hydrate,
heated to 1000C 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.
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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 a DSC experiment (especially for pharmaceuticals).
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 50C below those
temperatures.
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TGA+Spectroscopy/Chromatography
Combination
Gases, vapors
TGA
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IR or MS or GC
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Definitions
A calorimeter measures the heat into or out of a
sample.
A differential calorimeter 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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Exothermal dQ/dT
Temperature
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Circuitry of a DSC
Two separat heating circuits:
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)
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Conventional DSC
Empty
Sample
Metal
1
Sample
Temperature
Metal Metal
2
1
Metal
2
Reference
Temperature
Temperature
Difference =
Heat Flow
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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 500C/min
Mimic processing conditions
StepScan DSC
Short dynamic and isothermal scan steps
Separate reversible and irreversible effects
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Variants of 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
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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.
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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
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Principle Of DSC
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DSC Thermogram
Cross-Linking
(Cure)
Crystallisation
Oxidation
Glass
Transition
Melting
Temperature
6
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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 sampleatmosphere 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
T between the sample and reference.
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Power Compensation
Small individual furnaces use different amounts of power
to maintain a constant T 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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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 composites or blends the sample mass is
>10mg.
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 10C/min heating rate the run
should start at least 20C below the transition
onset temperature.
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End Temperature
Allowing a 2-minute baseline after the
transition of interest is considered appropriate
in order to correctly select integration or
analysis limits.
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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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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Purity by DSC
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Purity Determination
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Melting Point
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Melting
dH/dt, mJ/s
Negative peak on
thermogram
Ordered to disordered
transition
Tm, melting temperature
Melting happens to
crystalline polymers;
Glassing happens to
amorphous polymers
Thermogram
Melting
Tm
Temperature, K
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Polymorphic Forms
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Pseudopolymorphism
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Amorphous Material
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Variants of MTDSC
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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
156.7C and the observed in calibration is 157.4C.
It is 0.7C high and the instrument values must be
adjusted down to accommodate the true melting
temperature.
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DSC Applications
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Glass Transition
dH/dt, mJ/s
Step in thermogram
Transition from
disordered solid to
liquid
Observed in glassy
solids, e.g., polymers
Tg glass transition
temperature
Thermogram
Glass transition
Tg
Temperature, K
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Crystallization
Crystallization
dH/dt, mJ/s
Thermogram
Tc
Temperature, K
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Analysis
Crystallization
Disordered to ordered
transition
Observed in glassy
solids, e.g., polymers
Tc crystallization
temperature
dH/dt, mJ/s
Tc
Temperature, K
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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
10C/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).
The DSC curves are shown below along with the SEM
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Tm Melting point
Temperature (C) at which a crystalline polymer melts
Tc Crystallization Point
Temperature at which a polymer crystallizes upon heating or cooling
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Contamination
Thermal lag
Heating/Cooling rates
Sample mass
Processing errors
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Lactose monohydrate
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Temperature Scales
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Maxwell-Boltzmann Distribution
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DSC Applications In
Pharmaceutical Industry
Characterization - melting point, heat
of
fusion,
specific heat capacity, water
of
crystallization, etc.
Purity
Polymorphism
Screening Tests For Compatibility
Stability Tests
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DSC Applications In
Pharmaceutical Industry
Fast and reliable research tool.
DSC allows fast evaluation of possible
incompatibilities, because it shows change in the
appearance, shift or disappearance of melting,
endosperms and 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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Compatibility Studies
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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, metals,
glass, ceramics, fibres and other materials.
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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 temperatures, and glass
transition temperatures.
The different TMA probe types and recorded as a
function of temperature.
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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
10C /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 Applications
TMA is used to obtain the melting
temperature, softening temperature, coefficient
of thermal expansion (CTE) and glass
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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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
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Thermal Analysis
Characteristic:
Thermal properties:
Morphological change
Dimensional change
Viscoelastic properties
Mass change
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Haake
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NETZSCH Instruments
http://www.netzsch.com/ta/
SETARAM Instruments
http://setaram.com/
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 nanoand micro-scale heterogeneity in the solid-state
properties of drugpolymer 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 siliconbased 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)
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THANK YOU
Cell No: 00919742431000
E-mail: nanjwadebk@gmail.com
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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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