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 35 th Crystallographic Course at the Ettore Majorana Centre) Erice, Sicily June 9-20, 2004
32
Embed
Thermal Methods in the Study of Polymorphs and Solvates Susan M. Reutzel-Edens, Ph.D. Research Advisor Lilly Research Laboratories Eli Lilly & Company.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
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
• 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)
• 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)
• 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
• 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