Thermal Methods in the Study of Polymorphs and Solvates
Susan M. Reutzel-Edens, Ph.D.Research Advisor
Lilly Research LaboratoriesEli Lilly & Company
Indianapolis, IN 46285
Presented at:
“Diversity Amidst Similarity:A Multidisciplinary Approach to Polymorphs, Solvates and Phase Relationships”
(The 35th Crystallographic Course at the Ettore Majorana Centre)Erice, Sicily
June 9-20, 2004
Thermal Analysis Techniques
Differential Thermal Analysis (DTA)
• the temperature difference between a sample and an inert reference material, T = TS - TR, is measured as both are subjected to identical heat treatments
Differential Scanning Calorimetry (DSC)
• the sample and reference are maintained at the same temperature, even during a thermal event (in the sample)
• the energy required to maintain zero temperature differential between the sample and the reference, dq/dt, is measured
Thermogravimetric Analysis (TGA)
• the change in mass of a sample on heating is measured
A group of techniques in which a physical property is measured as a function of temperature, while the sample is subjected to a predefined heating or cooling program.
Basic Principles of Thermal Analysis
Modern instrumentation used for thermal analysis usually consists of four parts:
1) sample/sample holder
2) sensors to detect/measure a property of the sample and the temperature
3) an enclosure within which the experimental parameters may be controlled
4) a computer to control data collection and processing
DTA power compensated DSC heat flux DSC
Differential Thermal Analysis
samplepan
inert gasvacuum
referencepan
heatingcoil
sample holder
• sample and reference cells (Al)
sensors
• Pt/Rh or chromel/alumel thermocouples • one for the sample and one for the
reference• joined to differential temperature controller
furnace
• alumina block containing sample and reference cells
temperature controller
• controls for temperature program and furnace atmosphere
alumina block
Pt/Rh or chromel/alumelthermocouples
Differential Thermal Analysis
advantages:
• instruments can be used at very high temperatures
• instruments are highly sensitive
• flexibility in crucible volume/form
• characteristic transition or reaction temperatures can be accurately determined
disadvantages:
• uncertainty of heats of fusion, transition, or reaction estimations is 20-50%
DTA
• 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
Differential Scanning Calorimetry
power compensation DSC heat flux DSC
Power Compensation DSC
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
samplepan
T = 0
inert gasvacuum
inert gasvacuum
individualheaters
controller P
referencepan
thermocouple
sample holder
• sample and reference are connected bya 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, dq/dt, which is supplied to the heaters to maintain the temperature of the sample and reference at the program value
Heat Flux DSC
samplepan
inert gasvacuum
heatingcoil
referencepan
thermocouples
chromel wafer
constantan
chromel/alumelwires
Modulated DSC Heating Profile
Modulated DSC (MDSC)
• 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:heat capacity (reversing heat flow) kinetic (non-reversing heat flow)
glass transition crystallizationmelting decomposition
evaporationenthalpic relaxation
cure
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
Texp ≠ TS – TR
tem
pera
ture
Tfurnace
TRP
TR
TS
TSP
heating block
TR TS
reference
sample
TL
thermocouple is not in physical contact with sample
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
• amplified DSC signal is automatically varied with temperature to maintain a constant calorimetric sensitivity with temperature
• 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
DSC Calibrationtemperature
• 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
calibrants
• high purity• accurately known enthalpies• thermally stable• light stable (h)• nonhygroscopic• unreactive (pan, atmosphere)
metals• In 156.6 °C; 28.45 J/g• Sn 231.9 °C• Al 660.4 °Cinorganics• KNO3 128.7 °C• KClO4 299.4 °Corganics• polystyrene 105 °C• benzoic acid 122.3 °C; 147.3 J/g• anthracene 216 °C; 161.9 J/g
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
* small sample masses and low heating rates increase resolution, but at the expense of sensitivity Al Pt alumin
aNi Cu quart
z
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
TG curve of calcium oxalate
12.15%
19.32%
29.99%
20
40
60
80
100
120
Wei
ght (
%)
0 20 40 60 80 100 120 140 160
Time (min)
Sample: Calcium OxalateSize: 7.9730 mg TGA
File: Y:\Data\TGA\Calcium oxalate\032304.001Operator: SLTRun Date: 23-Mar-04 14:57Instrument: 2950 TGA HR V5.4A
Universal V3.7A TA Instruments
Typical Features of a DSC Trace for a Polymorphic System
sulphapyridine
endothermic events
meltingsublimation
solid-solid transitionsdesolvation
chemical reactions
exothermic events
crystallizationsolid-solid transitions
decompositionchemical reactions
baseline shifts
glass transition
Recognizing Artifacts
mechanical shock of
measuring cell
sample topples over
in pan
sample pan
distortionshifting
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 contaminatio
n
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
Hea
t Flo
w (
W/g
)
0 50 100 150 200 250 300 350
Temperature (°C)
––––––– Form I––––––– Form II––––––– Variable Hydrate––––––– Dihydrate––––––– Acetic acid solvate
Exo Up
Form III
Form IForm II
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
Hea
t Flo
w (
W/g
)
0 50 100 150 200 250 300 350
Temperature (°C)
––––––– Form I––––––– Form II––––––– Variable Hydrate––––––– Dihydrate––––––– Acetic acid solvate
Exo Up
Form III
Form IForm II
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)
Definition of Transition Temperature
157.81°C
156.50°C28.87J/g
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
Hea
t Flo
w (
W/g
)
140 145 150 155 160 165 170 175
Temperature (°C)
Sample: INDIUM CRIMPED PAN CHECKSize: 7.6300 mgMethod: indiumComment: P/N 56S-107
DSCFile: C:...\10C per min crimped\DSC010920A.3Operator: Ron VansickleRun Date: 20-Sep-01 09:13Instrument: 2920 MDSC V2.6A
Exo Up Universal V3.3B TA Instruments
extrapolatedonset temperature
peak melting temperature
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
melting with decomposition
• exothermic
• endothermic
eutectic melt
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
Enthalpy of Fusion
157.81°C
156.50°C28.87J/g
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
Hea
t Flo
w (
W/g
)
140 145 150 155 160 165 170 175
Temperature (°C)
Sample: INDIUM CRIMPED PAN CHECKSize: 7.6300 mgMethod: indiumComment: P/N 56S-107
DSCFile: C:...\10C per min crimped\DSC010920A.3Operator: Ron VansickleRun Date: 20-Sep-01 09:13Instrument: 2920 MDSC V2.6A
Exo Up Universal V3.3B TA Instruments
Burger’s Rules for Polymorphic Transitions
enantiotropy
endoth
erm
ic
Heat of Transition Rule• endo-/exothermic solid-solid
transition
Heat of Fusion Rule• higher melting form; lower Hf
• exothermic solid-solid transition
• higher melting form; higher Hf
monotropy
endoth
erm
ic
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 (HTR) can be measured*
crystallization of stable form (B) from melt of (A)
HfA = Hf
B - HTR
* assumes negligible heat capacity difference between polymorphs over temperatures of interest
HfA = area under all peaks from B to the stable melt
Purity by DSC
• 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
Tm = To - .
Ho
RTo2 1
f
melting endotherms as a function of purity.
benzoic acid
97%
99%
99.9%
Plato, C.; Glasgow, Jr., A.R. Anal. Chem., 1969, 41(2), 330-336.
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)
Effect of Phase Impurities
• 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
2046742FILE# 022511DSC.1
2046742FILE# 022458 DSC.1 Form II ?
-5
-4
-3
-2
-1
0
Hea
t Flo
w (
W/g
)
80 130 180 230 280
Temperature (°C)Exo Up Universal V3.3B TA Instruments
Lot A - pure
Lot B - seeds
• lots A and B of lower melting polymorph (identical by XRD) are different by DSC
Polymorph Characterization: Variable Melting Point
• lots A and B of lower melting polymorph (identical by XRD) appear to have a “variable” melting point
-1.1
-0.9
-0.7
-0.5
-0.3
-0.1
0.1
He
at
Flo
w (
W/g
)
110 120 130 140 150 160 170 180
Temperature (°C)
DSC010622b.1 483518 HCL (POLYMORPH 1)DSC010622d.1 483518 HCL
Exo Up Universal V3.3B TA Instruments
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
Reversing and Non-Reversing Contributionsto Total DSC Heat Flow
* 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
dQ/dt = Cp . dT/dt + f(t,T)
reversing signal heat flow resulting fromsinusoidal temperature
modulation(heat capacity component)
non-reversing signal
(kinetic component)
total heat flow resulting from
average heating rate
• 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
Polymorph Characterization: Variable Melting Point
Reversing (heat flow component)
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-0.45
-0.40
-0.35
-0.30
-0.25
-0.20
-0.15
-0.10
-0.05
0.00
Rev
Hea
t Flo
w (
W/g
)
110 120 130 140 150 160 170 180
Temperature (°C)
DSC010622b.1 483518 HCL (POLYMORPH 1)DSC010622d.1 483518 HCL
Exo Up Universal V3.3B TA Instruments
Non-reversing (heat flow component)
-0.8
-0.6
-0.4
-0.2
0.0
0.2
Non
rev
Hea
t Flo
w (
W/g
)
110 120 130 140 150 160 170 180
Temperature (°C)
DSC010622b.1 483518 HCL (POLYMORPH 1)DSC010622d.1 483518 HCL
Exo Up Universal V3.3B TA Instruments
Lot A
Lot B
Lot A
Lot B
reversing heat flow non-reversing heat flow
• 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
T1
x0 1
TmA
TmB
xe
Te
x0 1
Tm1
xe1
Te1
Tm2
xe2
Te2
TmRC
A
B RC
P1
P2
(a) (b)
Polymorph Stability from Melting and Eutectic Melting Data
40 60 80 100 120
DS
C S
ign
al
+thymol +azobenzene+benzil
+acetanilidepure formsYY
ON
YY
ONON
Y
ONON
meltingeutectic melting
T, oC
-0.4
-0.2
0
0.2
0.4
sdf
GON-GY, kJ/mole
Tt ON
Y
• polymorph stability predicted from pure melting data near the melting temperatures
(G1-G2)(Te1) = Hme2(Te2-Te1)/(xe2Te2)
(G1-G2)(Te2) = Hme1(Te2-Te1)/(xe1Te1)
Yu, L. J. Am. Chem. Soc, 2000, 122, 585-591.
Yu, L. J. Pharm. Sci., 1995, 84(8), 966-974.
(G1-G2)(Tm1) = Hm2(Tm2-Tm1)/Tm2
(G1-G2)(Tm2) = Hm1(Tm2-Tm1)/Tm1
• eutectic melting method developed to establish thermodynamic stability of polymorph pairs over larger temperature range
• development of “hyphenated” techniques for simultaneous analysis
TG-DTA
TG-DSC
TG-FTIR
TG-MS
15.55%(0.9513mg)
24.80°C100.0%
179.95°C84.45%
-1.8
-0.8
0.2
1.2
2.2
3.2
4.2
Tem
pera
ture
Diff
eren
ce (
µV
/mg)
-40
0
40
80
120
Wei
ght (
%)
20 70 120 170 220 270
Temperature (°C)
Sample: SODIUM TARTRATE (ALDRICH)Size: 6.1176 mgMethod: 25C TO 300Comment: LOT# 22411A0
TGA-DTAFile: C:\TA\Data\Sdtcal\2004\TGA040105A.5Operator: Ron VansickleRun Date: 6-Jan-04 12:09Instrument: 2960 SDT V3.0F
Exo Up Universal V3.3B TA Instruments
“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
evolved gas analysis(EGA)
TG-DTA trace of sodium tartrate
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