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,

∆ 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, d∆ q/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 reference
pan pan

furnace

• alumina block containing sample and reference inert gas

cells vacuum

temperature controller Pt/Rh or chromel/alumel

thermocouples
• controls for temperature program and furnace
atmosphere
 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

DTA
disadvantages:

• uncertainty of heats of fusion, transition, or

reaction estimations is 20-50%
 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
controller ∆P

sample reference
pan pan

sample holder

• Al or Pt pans inert gas inert gas

vacuum vacuum

sensors thermocouple ∆ T=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 reference

pan pan

• sample and reference are connected by constantan

a low-resistance heat flow path chromel/alumel
wires
• Al or Pt pans placed on constantan disc
inert gas
vacuum thermocouples

sensors 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, d∆ q/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

Modulated DSC Heating Profile
• 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 crystallization

melting 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
heating block
Tfurnace

∆ TR ∆ TS
temperature

TRP
TSP
thermocouple is not in physical
TR ∆ TL contact with sample
reference
TS
sample

• thermal resistances of a heat-flux system change with temperature

• the measured temperature difference is not equal to the difference in temperature

∆ Texp ≠ TS – TR
between the sample and the reference
 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 metals
• In 156.6 °C; 28.45 J/g
• high purity • Sn 231.9 °C
• accurately known enthalpies • Al 660.4 °C
• thermally stable inorganics
• light stable (hν ) • KNO3 128.7 °C
• nonhygroscopic • KClO4 299.4 °C
• unreactive (pan, atmosphere) 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 using calibrated Sample: Calcium Oxalate File: Y:\Data\TGA\Calcium oxalate\032304.001

weights
Size: 7.9730 mg TGA Operator: SLT
Run Date: 23-Mar-04 14:57
Instrument: 2950 TGA HR V5.4A
120

• temperature calibration based on 100

12.15%

ferromagnetic transition of Curie point 80 19.32%

standards (e.g., Ni)

Weight (%)
60
29.99%

• larger sample masses, lower temperature 40

gradients, and higher purge rates

minimize undesirable buoyancy effects
20
0 20 40 60 80 100 120 140 160
Time (min) 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

crystallization
solid-solid transitions
sulphapyridine decomposition
chemical reactions

baseline shifts

glass transition
 Recognizing Artifacts

mechanical
sample pan cool air entry
sample topples shock of
distortion shifting
over in pan measuring cell into cell
of Al pan

sensor
contamination

RT changes intermittant
electrical effects, closing of hole
power spikes, etc. in pan lid
burst of
pan lid
Thermal Methods in the Study of Polymorphs and Solvates
polymorph screening/identification

thermal stability
• melting
1.0

• crystallization 0.5

• solid-state transformations
• desolvation
0.0

• glass transition

Heat Flow (W/g)

-0.5

• sublimation
• decomposition -1.0

heat flow
-1.5
––––––– Form
Form II
––––––– Form IIII
Form

• heat of fusion
––––––– Variable
Form III Hydrate
––––––– Dihydrate
-2.0 ––––––– Acetic acid solvate

• heat of transition
• heat capacity
-2.5
0 50 100 150 200 250 300 350
Exo Up Temperature (°C)

mixture analysis
• chemical purity
• physical purity (crystal forms, crystallinity)

phase diagrams
• eutectic formation (interactions with other molecules)
 Sample: INDIUM CRIMPED PAN CHECK File: C:...\10C per min crimped\DSC010920A.3
DSC
Definition of Transition Temperature
Size: 7.6300 mg Operator: Ron Vansickle
Method: indium Run Date: 20-Sep-01 09:13
Comment: P/N 56S-107 Instrument: 2920 MDSC V2.6A
0.5

156.50°C
28.87J/g
0.0

extrapolated
-0.5 onset temperature
Heat Flow (W/g)

-1.0

-1.5

peak melting
-2.0 temperature

157.81°C

-2.5
140 145 150 155 160 165 170 175
Exo Up Temperature (°C) Universal V3.3B TA Instruments
 Melting Processes by DSC

pure substances

• linear melting curve

impure substances
• melting point defined
by onset temperature eutectic
melt • concave melting curve

• melting characterized
at peak maxima

• eutectic impurities
may produce a second
melting with decomposition
peak
• exothermic

• endothermic
 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 File: C:...\10C per min crimped\DSC010920A.3
DSC
Enthalpy of Fusion
Size: 7.6300 mg Operator: Ron Vansickle
Method: indium Run Date: 20-Sep-01 09:13
Comment: P/N 56S-107 Instrument: 2920 MDSC V2.6A
0.5

156.50°C
28.87J/g
0.0

-0.5
Heat Flow (W/g)

-1.0

-1.5

-2.0

157.81°C

-2.5
140 145 150 155 160 165 170 175
Exo Up Temperature (°C) Universal V3.3B TA Instruments
 Burger’s Rules for Polymorphic Transitions
enantiotropy monotropy
endothermic

endothermic
Heat of Transition Rule
• endo-/exothermic solid-solid transition • exothermic solid-solid transition

Heat of Fusion Rule

• higher melting form; lower ∆ Hf • higher melting form; higher ∆ Hf
 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*
∆ HfA = ∆ HfB - ∆ HTR

crystallization of stable form (B) from melt of (A)

∆ HfA = 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

RTo2χ 1 97%

Tm = To - .
∆ Ho f
99%

• applies to dilute solutions, i.e., nearly

pure substances (purity ≥98%) benzoic acid 99.9%

• 1-3 mg samples in hermetically-sealed

pans are recommended melting endotherms as a function of purity.

• polymorphism interferes with purity

determination, especially when a
transition occurs in the middle of the
melting peak
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
DSC traces of a low melting polymorph collected
used 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

Lot A - pure
2046742
FILE# 022511DSC.1

-1
Heat Flow (W/g)

-2

Lot B - seeds
2046742
FILE# 022458 DSC.1 Form II ?
-3

-4

-5
80 130 180 230 280
Exo Up Temperature (°C) 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
-0.3
Heat Flow (W/g)

-0.5

Lot B
-0.7

-0.9

DSC010622b.1 483518 HCL (POLYMORPH 1)

DSC010622d.1 483518 HCL

-1.1
110 120 130 140 150 160 170 180
Exo Up Temperature (°C) 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 dQ/dt = Cp . dT/dt + f(t,T)
average heating rate

reversing signal non-reversing signal

heat flow resulting from (kinetic component)
sinusoidal temperature modulation
(heat capacity 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

0.00 0.2
Reversing (heat flow component)

reversing heat flow non-reversing heat flow

Non-reversing (heat flow component)

-0.05

-0.10 0.0

-0.15 Lot A Lot A

Nonrev Heat Flow (W/g)

Rev Heat Flow (W/g)

-0.20 -0.2

-0.25

-0.30
Lot B -0.4
Lot B
-0.35

-0.40 -0.6

-0.45 DSC010622b.1 483518 HCL (POLYMORPH 1) DSC010622b.1 483518 HCL (POLYMORPH 1)

DSC010622d.1 483518 HCL DSC010622d.1 483518 HCL

-0.50 -0.8
110 120 130 140 150 160 170 180 110 120 130 140 150 160 170 180
Exo Up Temperature (°C) Universal V3.3B TA Instruments
Exo Up Temperature (°C) 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 ) = ∆ Hm2 (Tm2 -Tm1 )/Tm2 0.4 GON-GY, kJ/mole

0.2

(G1-G2)(Tm2 ) = ∆ Hm1 (Tm2 -Tm1 )/Tm1 0 Y

sdf
Tt
-0.2 ON
• eutectic melting method developed
to establish thermodynamic stability -0.4
eutecticmelting melting
of polymorph pairs over larger
temperature range

DSC Signal
Y
Y
(b) ON ON
ON
ON
ON
TmA Tm1 Y Y Y
+benzil pureforms
A P1 Tm2 +thymol +azobenzene +acetanilide
40 60 80 100 120
P2 T, oC

TmRC
RC (G1-G2)(Te1 ) = ∆ Hme2 (Te2 -Te1 )/(xe2 Te2 )
Te2
Te1
(G1-G2)(Te2 ) = ∆ Hme1 (Te2 -Te1 )/(xe1 Te1 )

xe2 xe1
1 0 x 1 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) File: C:\TA\Data\Sdtcal\2004\TGA040105A.5
Size: 6.1176 mg TGA-DTA Operator: Ron Vansickle
Method: 25C TO 300 Run Date: 6-Jan-04 12:09
Comment: LOT# 22411A0 Instrument: 2960 SDT V3.0F

TG-DTA 120

15.55%
4.2

(0.9513mg)

24.80°C 3.2

TG-DSC
100.0%
80

Temperature Difference (µV/mg)

179.95°C
84.45%
2.2

TG-FTIR Weight (%) 40 1.2

evolved gas analysis 0.2

TG-MS (EGA) 0

-0.8

-40 -1.8
20 70 120 170 220 270
Exo Up Temperature (°C) 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