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)

-0.50

-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