1. Analisa Termal

2. Teknik Analisa Termal
Sejumlah teknik pengukuran dimana sifat-sifat fisik diukur sebagai fungsi dari suhu, dimana sampel dikenakan proses pemanasan atau pendinginan tertentu.
Differential Thermal Analysis (DTA)
Perbedaan suhu antara sampel dengan material standar yang inert, DT = TS - TR, diukur saat keduanya diberi perlakuan panas tertentu.
Differential Scanning Calorimetry (DSC)
Sampel dan standar dijaga pada suhu yang sama, bahkan selama terjadi perubahan-perubahan termal tertentu pada sampel.
Variabel yang diukur adalah besarnya energi yang diperlukan untuk menjaga perbedaan suhu sampel dan standar sama dengan nol, dDq/dt.
Thermogravimetric Analysis (TGA)
Pengukuran dilakukan pada perubahan massa sampel akibat pemanasan.
Power compensated DSC and heat flux DSC provide the same information but are fundamentally different.

3. Prinsip-prinsip dasar analisa termal
Instrumentasi modern yang digunakan pada analisa termal biasanya terdiri dari empat bagian:
Sample/sample holder
Sensor untuk mendeteksi/mengukur sifat-sifat tertentu sampel dan suhu.
Pengaturan yang memungkinkan paremeter-parameter eksperimen dapat dikontrol.
Komputer yang memungkinkan pengumpulan dan pemrosesan data.
A modern thermal analysis instrument is made up of a furnace for heating (or cooling) the sample at a controlled rate and a selective transducer (a thermocouple to measure heat flow (DSC or DTA)or a balance to monitor weight changes (TG)) to monitor changes in the substance.
DTA
power compensated DSC
heat flux DSC

4. Pt/Rh or chromel/alumel
Differential Thermal Analysis
sample holder
sample and reference cells (Al)
sensors
Pt/Rh atau chromel/alumel thermocouples
Satu untuk sampel dan satu untuk reference
Dihubungkan dengan pengontrol suhu diferensial
furnace
alumina block berisi sampel dan reference
temperature controller
Mengontrol program suhu dan atmosfer furnace
alumina block
heating
coil
sample
pan
reference
pan
inert gas
vacuum
Chromel-alumel system (150 – 500 °C) is well suited for pharmaceutical materials.
Thermocouples are joined so that the differential temperature between the sample and reference, and the actual sample temperature, can be monitored.
Choice between DTA and DSC is less clear than in the past:
results from early DTA instruments could not be converted to calorimetric values
When the thermocouples are in thermal (but not physical) contact with the sample and reference materials, the area under the exotherms or endotherms can be related to the enthalpy change during the phase transition
Pt/Rh or chromel/alumel
thermocouples

5. Differential Thermal Analysis
keuntungan:
Instrumen dapat digunakan pada suhu yang sangat tinggi
Instrumen sangat sensitif
Volume dan bentuk crucible fleksibel
Transisi atau suhu reaksi yang karakteristik dapat ditentukan dengan akurat,
kelemahan:
Ketidakpastian estimasi panas bagi reaksi, transisi dan fusi sekitar %
DTA

6. Differential Scanning Calorimetry
DSC differs fundamentally from DTA in that the sample and reference are both maintained at the temperature predetermined by the program.
during a thermal event in the sample, the system will transfer heat to or from the sample pan to maintain the same temperature in reference and sample pans
two basic types of DSC instruments: power compensation and heat-flux
endothermic processes will lower the sample temperature relative to that of reference, so the sample must be heated more in order to maintain equal T in both pans
power compensation DSC
heat flux DSC

7. Power Compensation DSC
sample
pan
DT = 0
inert gas
vacuum
individual
heaters
controller DP
reference
thermocouple
sample holder
Al or Pt pans
sensors
Pt resistance thermocouples
separate sensors and heaters for the sample and reference
furnace
separate blocks for sample and reference cells
temperature controller
differential thermal power is supplied to the heaters to maintain the temperature of the sample and reference at the program value
Power-compensated DSC was introduced in the early 1960s.

8. Sample Preparation accurately-weigh samples (~3-20 mg)
small sample pans (0.1 mL) of inert or treated metals (Al, Pt, Ni, etc.)
several pan configurations, e.g., open , pinhole, or hermetically-sealed pans
the same material and configuration should be used for the sample and the reference
material should completely cover the bottom of the pan to ensure good thermal contact
avoid overfilling the pan to minimize thermal lag from the bulk of the material to the sensor
Because DSC measures the difference in heat flow between a sample and reference, the baseline stabilizes faster if the difference in heat capacity between the sample and reference is kept small by adding weight (same material as pan) to the reference pan so that it is similar in total weight to the sample pan.
Aluminum pans can be used in most experiments, unless the sample reacts with aluminum or the temperature is to exceed 600 °C.
Purity determination 1-3 mg; melting 5-10 mg; Tg or weak transitions up to 20 mg; highly endo/exothermic responses less than 5 mg Al Pt
alumina Ni Cu
quartz
* small sample masses and low heating rates increase resolution, but at the expense of sensitivity

9. Heat Flux DSC sample holder sample and reference are connected by
pan
inert gas
vacuum
heating
coil
reference
thermocouples
chromel wafer
constantan
chromel/alumel
wires
sample holder
sample and reference are connected by
a low-resistance heat flow path
Al or Pt pans placed on constantan disc
sensors
chromel®-constantan area thermocouples (differential heat flow)
chromel®-alumel thermocouples (sample temperature)
furnace
one block for both sample and reference cells
temperature controller
the temperature difference between the sample and reference is converted to differential thermal power, dDq/dt, which is supplied to the heaters to maintain the temperature of the sample and reference at the program value
Ag heating block dissipates heat to the sample and reference via the constantan disc.

10. Modulated DSC (MDSC) Modulated DSC Heating Profile
introduced in 1993; “heat flux” design
sinusoidal (or square-wave or sawtooth) modulation is superimposed on the underlying heating ramp
total heat flow signal contains all of the thermal transitions of standard DSC
Fourier Transformation analysis is used to separate the total heat flow into its two components:
Modulated DSC Heating Profile
Typical reversing events are glass transitions and melting; non-reversing events are crystallization, evaporation, decomposition and solid-solid transitions.
underlying heating rate: °C/minute
modulation period: seconds
modulation temperature amplitude: +/ – 10 °C
The net effect of imposing the complex heating profile is the same as if two experiments were run simultaneously – one at the linear (average) heating rate and the other at a sinusoidal (instantaneous) rate.
heat capacity (reversing heat flow) kinetic (non-reversing heat flow)
glass transition crystallization
melting decomposition
evaporation
enthalpic relaxation
cure

11. Analysis of Heat-Flow in Heat Flux DSC
temperature difference may be deduced by considering the heat flow paths in the DSC system
thermal resistances of a heat-flux system change with temperature
the measured temperature difference is not equal to the difference in temperature between the sample and the reference
temperature
Tfurnace
TRP TR TS
TSP
heating block
DTR
DTS
reference
sample
DTL
thermocouple is not in physical contact with sample
Thermal resistances of the heat flux system changes with temperature. DSC instruments are therefore used in the “calibrated” mode, whereby the amplified DSC signal is automatically varied with temperature to maintain a constant calorimetric sensitivity with temperature.
Temperature difference may develop between the samples (S and R) and the thermocouples, since these are not in direct physical contact with the samples.
DTexp ≠ TS – TR

12. DSC Calibration baseline
evaluation of the thermal resistance of the sample and reference sensors
measurements over the temperature range of interest
2-step process
the temperature difference of two empty crucibles is measured
the thermal response is then acquired for a standard material, usually sapphire, on both the sample and reference platforms
organic compounds have been recommended as standards when studying organic material to minimize differences in thermal conductivity, heat capacity, and heat of fusion and may be used predominantly at temperatures below 300 K.
Standard procedures can be obtained from the American Society for Testing of Materials (ASTM).
amplified DSC signal is automatically varied with temperature to maintain a constant calorimetric sensitivity with temperature

13. DSC Calibration temperature
goal is to match the melting onset temperatures indicated by the furnace thermocouple readouts to the known melting points of standards analyzed by DSC
should be calibrated as close to the desired temperature range as possible
heat flow
use of calibration standards of known heat capacity, such as sapphire, slow accurate heating rates (0.5–2.0 °C/min), and similar sample and reference pan weights
calibrants
high purity
accurately known enthalpies
thermally stable
light stable (hn)
nonhygroscopic
unreactive (pan, atmosphere)
metals
In °C; J/g
Sn °C
Al °C
inorganics
KNO °C
KClO °C
organics
polystyrene 105 °C
benzoic acid °C; J/g
anthracene 216 °C; J/g

14. Thermogravimetric Analysis (TGA)
thermobalance allows for monitoring sample weight as a function of temperature
two most common instrument types
reflection
null
weight calibration using calibrated weights
temperature calibration based on ferromagnetic transition of Curie point standards (e.g., Ni)
larger sample masses, lower temperature gradients, and higher purge rates minimize undesirable buoyancy effects
For pharmaceutical samples, temperatures up to 350 °C and sample sizes of 5-20 mg are generally adequate.
Reflection-type TGA (like Perkin-Elmer TGA7)
depends on balance beam deflection about its fulcrum due to mass changes
change in restoring force, which is proportional to the change in the sample mass, is monitored
The sample hangs from the balance inside the furnace; the balance is thermally isolated from the furnace.
TG curve of calcium oxalate

15. solid-solid transitions
Typical Features of a DSC Trace for a Polymorphic System
endothermic events
melting
sublimation
solid-solid transitions
desolvation
chemical reactions
exothermic events
crystallization
decomposition
baseline shifts
glass transition
sulphapyridine

16. Thermal Methods in the Study of Polymorphs and Solvates
polymorph screening/identification
thermal stability
melting
crystallization
solid-state transformations
desolvation
glass transition
sublimation
decomposition
heat flow
heat of fusion
heat of transition
heat capacity
mixture analysis
chemical purity
physical purity (crystal forms, crystallinity)
phase diagrams
eutectic formation (interactions with other molecules)

17. Definition of Transition Temperature
extrapolated
onset temperature
peak melting
temperature
The melting peak temperature in DSC corresponds to the maximum melting rate.
The simplest approximation to the baseline is a straight line connecting the star and finish of the transformation, which is valid for sharp DSC peaks, but becomes more difficult for broader DSC peaks. Using the extrapolated onset of melting as the melting point often accounts for the thermal lag.
Impure samples, whose melting curves are concave in shape, are characterized by the peak melting temperatures.

18. Melting Processes by DSC
pure substances
linear melting curve
melting point defined by onset temperature
impure substances
concave melting curve
melting characterized at peak maxima
eutectic impurities may produce a second peak
eutectic melt
melting with decomposition
exothermic
endothermic

19. Glass Transitions
second-order transition characterized by change in heat capacity (no heat absorbed or evolved)
transition from a disordered solid to a liquid
appears as a step (endothermic direction) in the DSC curve
a gradual volume or enthalpy change may occur, producing an endothermic peak superimposed on the glass transition
structural relaxation can occur due to the restricted but finite mobility of the molecules below the glass transition.

20. Enthalpy of Fusion
The enthalpy of fusion, Hf, is obtained from the area of the endothermic transition.
The area of the transition is affected by the selection of the baseline.
The baseline is generally obtained by connecting the point at which the transition deviates from the baseline of the scan to where it rejoins the baseline after melting is completed.
For some materials that undergo a significant change in heat capacity change on melting, other baseline approximations (such as a sigmoidal baseline) are used.

21. Burger’s Rules for Polymorphic Transitions
enantiotropy
monotropy
endothermic
endothermic
Monotropy – transition is reversible; enantiotropy – transition is irreversible.
Heat of Transition Rule
endo-/exothermic solid-solid transition
Heat of Fusion Rule
higher melting form; lower DHf
exothermic solid-solid transition
higher melting form; higher DHf

22. Enthalpy of Fusion by DSC
single (well-defined) melting endotherm
area under peak
minimal decomposition/sublimation
readily measured for high melting polymorph
can be measured for low melting polymorph
multiple thermal events leading to stable melt
solid-solid transitions (A to B) from which the transition enthalpy (DHTR) can be measured*
crystallization of stable form (B) from melt of (A)
DHfA = DHfB - DHTR
Accurate measurement of heats of fusion require pure samples of polymorphs.
DHfA = area under all peaks from B to the stable melt
* assumes negligible heat capacity difference between polymorphs over temperatures of interest

23. Purity by DSC Tm = To - . DHo RTo2 c 1 f
eutectic impurities lower the melting point of a eutectic system
purity determination by DSC based on Van’t Hoff equation
applies to dilute solutions, i.e., nearly pure substances (purity ≥98%)
1-3 mg samples in hermetically-sealed pans are recommended
polymorphism interferes with purity determination, especially when a transition occurs in the middle of the melting peak
melting endotherms as a function of purity.
benzoic acid
97%
99%
99.9%
Tm = To
DHo
RTo2 c 1 f
The broadness of the peak defines the purity of the crystalline compound undergoing melting, with the less pure and less perfect smaller crystals melting first followed by melting of the purer larger crystals.
If there is no interaction between two compounds in the solid state, but their liquids are miscible, eutectic behavior will be observed. This is the basis of purity analysis by DSC.
The first thing that has to be checked when validating a method for purity determination is whether the substance forms a eutectic system with the impurity.
Plato, C.; Glasgow, Jr., A.R. Anal. Chem., 1969, 41(2),

24. Effect of Heating Rate
many transitions (evaporation, crystallization, decomposition, etc.) are kinetic events
… they will shift to higher temperature when heated at a higher rate
the total heat flow increases linearly with heating rate due to the heat capacity of the sample
… increasing the scanning rate increases sensitivity, while decreasing the scanning rate increases resolution
to obtain thermal event temperatures close to the true thermodynamic value, slow scanning rates (e.g., 1–5 K/min) should be used
DSC traces of a low melting polymorph collected at four different heating rates. (Burger, 1975)

25. Effect of Phase Impurities
lots A and B of lower melting polymorph (identical by XRD) are different by DSC
Lot A - pure
Lot B - seeds
Contrast the heating rate effects with phase contaminants – same effect, different cause.
Lot A: pure low melting polymorph – melting observed
Lot B: seeds of high melting polymorph induce solid-state transition below the melting temperature of the low melting polymorph

26. Polymorph Characterization: Variable Melting Point
lots A and B of lower melting polymorph (identical by XRD) appear to have a “variable” melting point
Lot A
Lot B
although melting usually happens at a fixed temperature, solid-solid transition temperatures can vary greatly owing to the sluggishness of solid-state processes

27. Polymorph Characterization: Variable Melting Point
the low temperature endotherm was predominantly non-reversing, suggestive of a solid-solid transition
small reversing component discernable on close inspection of endothermic conversions occurring at the higher temperatures, i.e., near the melting point
Lot A
Lot B
reversing heat flow
non-reversing heat flow
Note: The width of the melting transition is significantly narrower than that of the solid-solid transition.
As a result of its much larger free energy (in excess of the higher melting polymorph), the system was driven to undergo both melting and direct solid-state conversion from Form I to Form II. Which transition occurs is sample specific, and is likely related to crystal defects, particle size, chemical impurities, etc.
the “variable” melting point was related to the large stability difference between the two polymorphs; the system was driven to undergo both melting and solid-state conversion to the higher melting form

28. Polymorph Stability from Melting and Eutectic Melting Data
polymorph stability predicted from pure melting data near the melting temperatures
(G1-G2)(Tm1) = DHm2(Tm2-Tm1)/Tm2
(G1-G2)(Tm2) = DHm1(Tm2-Tm1)/Tm1
eutectic melting method developed to establish thermodynamic stability of polymorph pairs over larger temperature range
(G1-G2)(Te1) = DHme2(Te2-Te1)/(xe2Te2)
(G1-G2)(Te2) = DHme1(Te2-Te1)/(xe1Te1)
Yu, L. J. Pharm. Sci., 1995, 84(8),
Yu, L. J. Am. Chem. Soc, 2000, 122,

29. “Hyphenated” Techniques
thermal techniques alone are insufficient to prove the existence of polymorphs and solvates
other techniques should be used, e.g., microscopy, diffraction, and spectroscopy
development of “hyphenated” techniques for simultaneous analysis
TG-DTA
TG-DSC
TG-FTIR
TG-MS
evolved gas analysis
(EGA)
TG-DTA trace of sodium tartrate

30. Best Practices of Thermal Analysis
small sample size
good thermal contact between the sample and the temperature-sensing device
proper sample encapsulation
starting temperature well below expected transition temperature
slow scanning speeds
proper instrument calibration
use purge gas (N2 or He) to remove corrosive off-gases
avoid decomposition in the DSC
He improves the resolution of the DSC, but the DSC must be recalibrated for temperature and heat flow when using a helium flow due to its higher thermal conductivity.

31. dQ/dt = Cp . dT/dt + f(t,T) Reversing and Non-Reversing Contributions
to Total DSC Heat Flow
total heat flow resulting from average heating rate
dQ/dt = Cp . dT/dt + f(t,T)
reversing signal
heat flow resulting from
sinusoidal temperature modulation
(heat capacity component)
non-reversing signal
(kinetic component)
This component is a function of absolute time and temperature and will shift to higher temperatures as the heating rate is increased.
* whereas solid-solid transitions are generally too sluggish to be reversing at the time scale of the measurement, melting has a moderately strong reversing component

32. Recognizing Artifacts
mechanical shock of measuring cell
sample topples over in pan
sample pan distortion
shifting of Al pan
cool air entry into cell
electrical effects, power spikes, etc.
RT changes
burst of pan lid
intermittant closing of hole in pan lid
sensor contamination
Sample toppling over in pan causes abrupt change of the heat transfer between the sample and the pan.
Shifting of Al pan, caused by different coefficients of expansion (of Al vs DSC sensor), and distortion of sample pan, due to sample vapor pressure, cause abrupt change in heat transfer between the pan and the DSC sensor.
Mechanical shock of the measuring cell can cause the pans to jump around on the sensor.
If the cell lid is poorly adjusted, cool air entry into the measuring cell leads to temperature fluctuations (noisy signal).