Thermal Methods in the Study of Polymorphs
and Solvates
Susan M. Reutzel-Edens, Ph.D.
Research Advisor
Lilly Research Laboratories
Eli 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
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.
Differential Thermal Analysis (DTA)
• the temperature difference between a sample and an inert reference material, DT
= 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, dDq/dt, is measured
Thermogravimetric Analysis (TGA)
• the change in mass of a sample on heating is measured
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
sample holder
• sample and reference cells (Al)
alumina block
sensors
heating
coil
• Pt/Rh or chromel/alumel thermocouples
• one for the sample and one for the reference
• joined to differential temperature controller
sample
pan
reference
pan
furnace
• alumina block containing sample and reference
cells
temperature controller
• controls for temperature program and furnace
atmosphere
inert gas
vacuum
Pt/Rh or chromel/alumel
thermocouples
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
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
power compensation DSC
heat flux DSC
Power Compensation DSC
individual
heaters
sample
pan
controller
DP
reference
pan
sample holder
• Al or Pt pans
sensors
inert gas
vacuum
inert gas
vacuum
thermocouple
DT = 0
• 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
Heat Flux DSC
heating
coil
sample holder
• sample and reference are connected by
a low-resistance heat flow path
• Al or Pt pans placed on constantan disc
sample
pan
reference
pan
constantan
chromel/alumel
wires
sensors
inert gas
vacuum
thermocouples
chromel wafer
• 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
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)
glass transition
melting
Modulated DSC Heating Profile
kinetic (non-reversing heat flow)
crystallization
decomposition
evaporation
enthalpic 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
temperature
heating block
DTR
Tfurnace
DTS
TRP
TSP
TR
reference
DTL
sample
TS
thermocouple is not in physical
contact with sample
• 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
DTexp ≠ TS – TR
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
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 156.6 °C; 28.45 J/g
• Sn 231.9 °C
• Al 660.4 °C
inorganics
• KNO3 128.7 °C
• KClO4 299.4 °C
organics
• 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
alumina
Ni
Cu
quartz
Thermogravimetric Analysis (TGA)
• thermobalance allows for monitoring
sample weight as a function of
temperature
• two most common instrument types
reflection
null
• weight calibration
weights
using
calibrated
Sample: Calcium Oxalate
Size: 7.9730 mg
File: Y:\Data\TGA\Calcium oxalate\032304.001
Operator: SLT
Run Date: 23-Mar-04 14:57
Instrument: 2950 TGA HR V5.4A
TGA
120
• larger sample masses, lower temperature
gradients, and higher purge rates
minimize undesirable buoyancy effects
100
12.15%
80
19.32%
Weight (%)
• temperature
calibration
based
on
ferromagnetic transition of Curie point
standards (e.g., Ni)
60
29.99%
40
20
0
20
40
60
80
Time (min)
100
120
140
160
Universal V3.7A TA Instruments
TG curve of calcium oxalate
Typical Features of a DSC Trace for a Polymorphic System
endothermic events
melting
sublimation
solid-solid transitions
desolvation
chemical reactions
exothermic events
sulphapyridine
crystallization
solid-solid transitions
decomposition
chemical reactions
baseline shifts
glass transition
Recognizing Artifacts
sample topples
over in pan
sample pan
distortion
shifting
of Al pan
mechanical
shock of
measuring cell
cool air entry
into cell
sensor
contamination
electrical effects,
power spikes, etc.
RT changes
intermittant
closing of hole
in pan lid
burst of
pan lid
Thermal Methods in the Study of Polymorphs and Solvates
polymorph screening/identification
heat flow
• heat of fusion
• heat of transition
• heat capacity
1.0
0.5
0.0
Heat Flow (W/g)
thermal stability
• melting
• crystallization
• solid-state transformations
• desolvation
• glass transition
• sublimation
• decomposition
-0.5
-1.0
-1.5
–––––––
–––––––
–––––––
–––––––
–––––––
-2.0
Form II
Form
Form IIII
Form
Variable
Form
III Hydrate
Dihydrate
Acetic acid solvate
-2.5
0
50
100
Exo Up
150
200
Temperature (°C)
mixture analysis
• chemical purity
• physical purity (crystal forms, crystallinity)
phase diagrams
• eutectic formation (interactions with other molecules)
250
300
350
Sample: INDIUM CRIMPED PAN CHECK
Size: 7.6300 mg
Method: indium
Comment: P/N 56S-107
File: C:...\10C per min crimped\DSC010920A.3
Operator: Ron Vansickle
Run Date: 20-Sep-01 09:13
Instrument: 2920 MDSC V2.6A
Definition of Transition Temperature
DSC
0.5
156.50°C
28.87J/g
0.0
extrapolated
onset temperature
Heat Flow (W/g)
-0.5
-1.0
-1.5
peak melting
temperature
-2.0
157.81°C
-2.5
140
Exo Up
145
150
155
160
Temperature (°C)
165
170
175
Universal V3.3B TA Instruments
Melting Processes by DSC
pure substances
• linear melting curve
• melting point defined
by onset temperature
impure substances
eutectic
melt
• concave melting curve
• melting characterized
at peak maxima
melting with decomposition
• exothermic
• endothermic
• eutectic
impurities
may produce a second
peak
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
Sample: INDIUM CRIMPED PAN CHECK
Size: 7.6300 mg
Method: indium
Comment: P/N 56S-107
File: C:...\10C per min crimped\DSC010920A.3
Operator: Ron Vansickle
Run Date: 20-Sep-01 09:13
Instrument: 2920 MDSC V2.6A
Enthalpy of Fusion
DSC
0.5
156.50°C
28.87J/g
0.0
Heat Flow (W/g)
-0.5
-1.0
-1.5
-2.0
157.81°C
-2.5
140
Exo Up
145
150
155
160
Temperature (°C)
165
170
175
Universal V3.3B TA Instruments
Burger’s Rules for Polymorphic Transitions
monotropy
endothermic
endothermic
enantiotropy
Heat of Transition Rule
• endo-/exothermic solid-solid transition
• exothermic solid-solid transition
Heat of Fusion Rule
• higher melting form; lower DHf
• higher melting form; higher DHf
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*
DHfA = DHfB - DHTR
crystallization of stable form (B) from melt of (A)
DHfA = area under all peaks from B to the stable melt
* assumes negligible heat capacity difference between polymorphs over temperatures of interest
Purity by DSC
• eutectic impurities lower the melting
point of a eutectic system
• purity determination by DSC based on
Van’t Hoff equation
RTo2 c
Tm = To DHo
.
1
f
• applies to dilute solutions, i.e., nearly
pure substances (purity ≥98%)
97%
99%
benzoic acid
99.9%
• 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.
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
• lots A and B of lower melting polymorph (identical by XRD) are different by DSC
0
Lot A - pure
2046742
FILE# 022511DSC.1
Heat Flow (W/g)
-1
-2
Lot B - seeds
2046742
FILE# 022458 DSC.1 Form II ?
-3
-4
-5
80
Exo Up
130
180
230
Temperature (°C)
280
Universal V3.3B TA Instruments
• 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
Polymorph Characterization: Variable Melting Point
• lots A and B of lower melting polymorph (identical by XRD) appear to have a “variable”
melting point
0.1
-0.1
Lot A
Heat Flow (W/g)
-0.3
-0.5
Lot B
-0.7
-0.9
DSC010622b.1 483518 HCL (POLYMORPH 1)
DSC010622d.1 483518 HCL
-1.1
110
Exo Up
120
130
140
150
Temperature (°C)
160
170
180
Universal V3.3B TA Instruments
• 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 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)
* 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
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
0.2
0.00
reversing heat flow
non-reversing heat flow
Reversing (heat flow component)
-0.05
Non-reversing (heat flow component)
-0.10
0.0
Rev Heat Flow (W/g)
Nonrev Heat Flow (W/g)
Lot A
-0.15
-0.20
-0.25
Lot B
-0.30
Lot A
-0.2
Lot B
-0.4
-0.35
-0.40
-0.45
-0.6
DSC010622b.1 483518 HCL (POLYMORPH 1)
DSC010622d.1 483518 HCL
-0.50
110
Exo Up
120
130
DSC010622b.1 483518 HCL (POLYMORPH 1)
DSC010622d.1 483518 HCL
140
150
Temperature (°C)
160
170
180
-0.8
110
Universal V3.3B TA Instruments
Exo Up
120
130
140
150
Temperature (°C)
160
170
180
Universal V3.3B TA Instruments
• 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
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
0.4
GON-GY, kJ/mole
• eutectic melting method developed
to establish thermodynamic stability
of polymorph pairs over larger
temperature range
(b)
TmA
P1
A
Tm1
Tm2
Y
0
Tt
-0.2
-0.4
DSC Signal
(G1-G2)(Tm2) = DHm1(Tm2-Tm1)/Tm1
sdf
0.2
eutectic melting
ON
TmRC
0
ON
melting
Y
ON
Y
ON
Y
+benzil
+thymol +azobenzene
+acetanilide
60
T, oC
80
100
pure forms
120
(G1-G2)(Te1) = DHme2(Te2-Te1)/(xe2Te2)
RC
Te2
Te1
1
Y
ON
Y
40
P2
ON
xe2 xe1
x
1
(G1-G2)(Te2) = DHme1(Te2-Te1)/(xe1Te1)
Yu, L. J. Pharm. Sci., 1995, 84(8), 966-974.
Yu, L. J. Am. Chem. Soc, 2000, 122, 585-591.
“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
Sample: SODIUM TARTRATE (ALDRICH)
Size: 6.1176 mg
Method: 25C TO 300
Comment: LOT# 22411A0
TG-DTA
File: C:\TA\Data\Sdtcal\2004\TGA040105A.5
Operator: Ron Vansickle
Run Date: 6-Jan-04 12:09
Instrument: 2960 SDT V3.0F
TGA-DTA
120
4.2
15.55%
(0.9513mg)
24.80°C
100.0%
179.95°C
84.45%
Weight (%)
2.2
TG-FTIR
TG-MS
evolved gas analysis
(EGA)
40
1.2
0.2
Temperature Difference (µV/mg)
TG-DSC
3.2
80
0
-0.8
-40
-1.8
20
Exo Up
70
120
170
Temperature (°C)
220
270
Universal V3.3B TA Instruments
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