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Lecture Date: March 26
th
, 2008
Classical and Thermal Methods
Classical and Thermal Methods
Karl Fischer (moisture determination)
Representative of a wide variety of high-performance, modern
analytical titration methods
The only titration discussed in detail during this class
Thermal Methods
Thermogravimetry (TG)
Differential thermal analysis (DTA)
Differential scanning calorimetry (DSC)
Reading:
KF:
Skoog et al. pgs 707-708
Thermal methods:
Skoog et al. Chapter 31
Cazes et al. Chapter 15
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Karl Fischer Titration (KFT)
Applications
Food, pharma, consumer products
Anywhere where water can affect
stability or properties
Karl Fischer (German chemist)
developed a specific reaction for
selectively and specifically
determining water at low levels.
reaction uses a non-aqueous
system containing excess of sulfur
dioxide, with a primary alcohol as
the solvent and a base as the
buffering agent
A modern KF titrator
Karl Fischer titration is a widely used analytical technique
for quantitative analysis of total water content in a material
For moreinformationabout KFT, seeUS Pharmacopeia921
Karl Fischer Reaction and Reagents
CH
3
OH +SO
2
+RN [RNH]
+
SO
3
CH
3
-
[RNH]
+
SO
3
CH
3
-
+H
2
O +I
2
+2RN [RNH]
+
SO
4
CH
3
+2[RNH]
+
I
-
0.2 M I
2
, 0.6M SO
2
, 2.0 M pyridine in methanol/ethanol
Pyridine Free (e.g. imidazole)
Endpoint detection: bipotentiometric detection of by a
dedicated pair of Pt electrodes
Detector sees a constant current during the titration, sudden
drop when endpoint is reached (I
-
disappears, and only I
2
is
around when the reaction finishes)
Reaction:
Reagents:
ester
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Volumetric Karl Fischer Titration
Volumetric KFT (recommended for larger samples >50
mg)
One component
Titrating agent: one-component reagent (I
2
, SO
2
,
base)
Analyte of known mass added
Two component (reagents are separated)
Titrating agent (I
2
and methanol)
Solvent containing all other reagents used as
working medium in titration cell
Columetric of Karl Fischer Titration
Coulometric KFT (recommended for smaller samples <50
mg)
Iodine is generated electrochemically via dedicated Pt
electrodes
Q =1 C =1A x 1s where 1 mg H
2
O =10.72 C
Two methods:
Conventional (Fritted cell): frit separates the anode
from the cathode
Fritless Cell: innovative cell design (through a
combination of factors but not a frit), impossible for
Iodine to reach cathode and get reduced
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Common Problems with Karl Fischer Titrations
Titration solvents: stoichiometry of the KF reaction must be
complete and rapid
solvents must dissolve samples or water may remain trapped
solvents must not cause interferences
pH
Optimum pH is 4-7
Below pH 3, KF reaction proceeds slowly
Above pH 8, non-stoichiometric side reactions are significant
Other errors:
Atmospheric moisture is generally the largest cause of error in
routine analysis
When operated properly, KFT can yield reproducible water
titration values with 2-5% w/w precision
E.g. sodium tartrate hydrate (15.66% water theory) usually yields
KFT values in the 15.0-16.4% w/w range
Aldehydes and Ketones
Form acetals and ketals respectively with normal
methanol-containing reagents
Water formed in this reaction will then be titrated to give
erroneously high water results
With aldehydes a second side reaction can take place,
consuming water, which can lead to sample water
content being underestimated
Replacing methanol with another solvent can solve the
difficulties (commercial reagents are widely available)
Common Problems with Karl Fischer Titrations
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Oven Karl Fischer
Some substances only release their water at high
temperatures or undergo side reactions
The moisture in these substances can be driven off in
an oven at 100C to 300C.
The moisture is then transferred to the titration cell
using an inert gas
Uses:
Insoluble materials (plastics, inorganics)
Compounds that are oxidized by iodine
Results in anomalously high iodine consumption
leading to an erroneously high water contents
Includes: bicarbonates, carbonates, hydroxides,
peroxides, thiosulphates, sulphates, nitrites, metal
oxides, boric acid, and iron (III) salts.
Thermal Anal ysi s
Thermal analysis: determining a specific physical
property of a substance as a function of temperature
In modern practice:
The physical property and temperature are measured
and recorded simultaneously
The temperature is controlled in a pre-defined manner
Classification:
Methods which measure absolute properties (e.g.
mass, as in TGA)
Methods which measure the difference in some
property between the sample and a reference (e.g.
DTA)
Methods which measure the rate at which a property is
changing
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Thermal Gravimetric Anal ysis (TGA)
Concept: Sample is loaded onto an accurate balance
and it is heated at a controlled rate, while its mass is
monitored and recorded. The results show the
temperatures at which the mass of the sample changes.
Selected applications:
determining the presence and quantity of hydrated
water
determining oxygen content
studying decomposition
TG Instrumentati on
Components:
Sensitive analytical
balance
Furnace
Purge gas system
Computer
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Applications of TGA
H20
Ca(C00)2
CO
CaC03
CO2
Ca0
200 400 600 800 1000
Sample Temperature (C)
S
a
m
p
l
e

W
e
i
g
h
t
Decomposition of calcium oxalate
Composition
Moisture Content
Solvent Content
Additives
Polymer Content
Filler Content
Dehydration
Decarboxylation
Oxidation
Decomposition
Typical TGA of a Pharmaceutical
1.080%
(0.06419mg)
9.615%
(0.5717mg)
18.90%
(1.124mg)
0.0
0.2
0.4
0.6
0.8
1.0
1.2
D
e
r
i
v
.

W
e
i
g
h
t

(
%
/

C
)
20
40
60
80
100
W
e
i
g
h
t

(
%
)
0 50 100 150 200 250 300 350
Temperature (C)
Sample: SB332235
Size: 5.9460 mg
Method: Standard Method
Comment: CL42969-112A1
TGA
File: Y:...\TGA\SB332235\CL42969-112A1.001
Operator: J Brum
Run Date: 18-Feb-05 14:45
Instrument: TGA Q500 V6.3 Build 189
Universal V3.8B TA Instruments
Blue line shows derivative
Green line shows mass changes
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Differential Thermal Anal ysi s (DTA)
Concept: sample and a reference material are heated at
a constant rate while their temperatures are carefully
monitored. Whenever the sample undergoes a phase
transition (including decomposition) the temperature of
the sample and reference material will differ.
At a phase transition, a material absorbs heat without
its temperature changing
Useful for determining the presence and temperatures at
which phase transitions occur, and whether or not a
phase transition is exothermic or endothermic.
DTA Instrumentati on
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General Principles of DTA
H (+) endothermic reaction - temp of sample lags behindtemp of
reference
H (-) exothermic reaction - temp of sample exceeds that of
reference
General Principles of DTA
Glass transitions
Crystallization
Melting
Oxidation
Decomposition
T = T
s
- T
r
Endothermic Rxns:
fusion, vaporization, sublimation, ab/desorption
dehydration, reduction, decomposition
Exothermic Rxns:
Adsorption, Crystallization
oxidation, polymerization and catalytic reactions
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Applications of DTA
Jacobson (1969) - studied effects of stearic acid and sodium
oxacillin monohydrate
simple inorganic
species
Phase transitions
determine melting,
boiling,
decomposition
polymorphism
Differential Scanning Calorimetry (DSC)
Analogous to DTA, but the heat input to sample and
reference is varied in order to maintain both at a constant
temperature.
Key distinction:
In DSC, differences in energy are measured
In DTA, differences in temperature are measured
DSC is far easier to use routinely on a quantitative basis,
and has become the most widely used method for thermal
analysis
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DSC Instrumentati on
There are two common DSC methods
Power compensated DSC: temperature of sample and
reference are kept equal while both temperatures are
increased linearly
Heat flux DSC: the difference in heat flow into the
sample/reference is measured while the sample
temperature is changed at a constant rate
Heat Flow in DSC
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DSC Step by Step
Melting Glass transition
Recrystallization
Applications of DSC
DSC is usually carried
out in linear increasing-
temperature scan mode
(but can do isothermal
experiments)
In linear scan mode,
DSC provides
melting point data for
crystalline organic
compounds and T
g
for polymers
Easily used for detection of bound crystalline water
molecules or solvents, and measures the enthalpy of
phase changes and decomposition
DSC trace of polyethyleneterphthalate (PET)
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Applications of DSC
DSC is useful in studies
o polymorphism in
organic molecular
crystalline compounds
(e.g. pharmaceuticals,
explosives, food
products)
Example data from two
enantiotropic
polymorphs
DSC of a Pharmaceutical Hydrate
84.39C
56.35C
34.97J /g
153.30C
134.06C
116.0J /g
-1.5
-1.0
-0.5
0.0
0.5
H
e
a
t

F
l
o
w

(
W
/
g
)
0 50 100 150 200 250 300
Temperature (C)
Sample: SB332235
Size: 3.0160 mg
Method: STANDARD DSC METHOD
Comment: CL42969-112A1
DSC
File: Y:...\DSC\SB332235\CL42969-112A1.002
Operator: J Brum
Run Date: 24-Feb-05 09:53
Instrument: DSC Q1000 V9.0 Build 275
ExoUp Universal V3.8B TA Instruments
Loss of water
Melt Decomposition
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Optional Homework
Questions: 31-1, 31-3, 31-4, 31-6, 31-9, 31-10