Classical and Thermal Methods
Lecture Date: March 26th, 2012
Classical and Thermal Methods


Titrations
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)
Analytical Titrations

Definition: an analytical technique that measures
concentration of an analyte by the volumetric addition of
a reagent solution (titrant) that reacts quantitatively with
the analyte.

Classes: acid-base, redox, complexation, and
precipitation and
 For titrations to be analytically useful, the reaction must
generally be quantitative, fast and well-behaved
Advantages
great flexibility
suitable for a wide range of analytes
manual, simple
excellent precision an accuracy
readily automated
Disadvantages
large amount of analyte required
lacks speciation
colorimetric -subjective
sensitive to skill of analyst
reagents can be unstable
Titration Curves
Strong acid - Strong base
Strong base - Weak acid
Titration Curves
Strong base - polyprotic acid
Strength of Acids and Bases
Source: http://cwx.prenhall.com/petrucci/medialib/media_portfolio/text_images/TB17_03.JPG
Example 1
30 mL of 0.10M NaOH neutralised 25.0mL of hydrochloric acid. Determine the
concentration of the acid
1. Write the balanced chemical equation for the reaction
NaOH(aq) + HCl(aq) -----> NaCl(aq) + H2O(l)
2. Extract the relevant information from the question:
NaOH V = 30mL , M = 0.10M HCl V = 25.0mL, M = ?
3. Check the data for consistency
NaOH V = 30 x 10-3L , M = 0.10M HCl V = 25.0 x 10-3L, M = ?
4. Calculate moles NaOH
n(NaOH) = M x V = 0.10 x 30 x 10-3 = 3 x 10-3 moles
5. From the balanced chemical equation find the mole ratio
NaOH:HCl
1:1
Example 1 (continued)
6. Find moles HCl
NaOH: HCl is 1:1
So n(NaOH) = n(HCl) = 3 x 10-3 moles at the equivalence point
Calculate concentration of HCl: M = n ÷ V
n = 3 x 10-3 mol, V = 25.0 x 10-3L
M(HCl) = 3 x 10-3 ÷ 25.0 x 10-3 = 0.12M or 0.12 mol L-1
Example 2
50mL of 0.2mol L-1 NaOH neutralised 20mL of sulfuric acid. Determine the
concentration of the acid
1. Write the balanced chemical equation for the reaction
NaOH(aq) + H2SO4(aq) -----> Na2SO4(aq) + 2H2O(l)
2. Extract the relevant information from the question:
NaOH V = 50mL, M = 0.2M H2SO4 V = 20mL, M = ?
3. Check the data for consistency
NaOH V = 50 x 10-3L, M = 0.2M H2SO4 V = 20 x 10-3L, M = ?
4. Calculate moles NaOH
n(NaOH) = M x V = 0.2 x 50 x 10-3 = 0.01 mol
5. From the balanced chemical equation find the mole ratio
NaOH:H2SO4
2:1
Example 2 (continued)
6. Find moles H2SO4
NaOH: H2SO4 is 2:1
So n(H2SO4) = ½ x n(NaOH) = ½ x 0.01 = 5 x 10-3 moles H2SO4 at the
equivalence point
7. Calculate concentration of H2SO4: M = n ÷ V
n = 5 x 10-3 mol, V = 20 x 10-3L
M(H2SO4) = 5 x 10-3 ÷ 20 x 10-3 = 0.25M or 0.25 mol L-1
Karl Fischer Titration (KFT)


Karl Fischer titration is a widely used analytical technique
for quantitative analysis of total water content in a material
Applications
– Food, pharma, consumer products
– Anywhere where water can affect
stability or properties

Karl Fischer (a German
chemist) developed a specific
reaction for selectively and
specifically determining water at
low levels.
– The 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
For more information about KFT, see US Pharmacopeia 921
A modern KF titrator

Karl Fischer Reaction and Reagents
Reaction:
ester
CH3OH + SO2+ RN
[RNH]+SO3CH3- + H2O + I2 + 2RN

[RNH]+SO3CH3-
[RNH]+SO4CH3 + 2[RNH]+I-
Reagents:
0.2 M I2, 0.6M SO2, 2.0 M pyridine in methanol/ethanol
Pyridine free (e.g. imidazole)


Endpoint detection: bipotentiometric detection of I- 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 I2 is
around when the reaction finishes)
Volumetric Karl Fischer Titration

Volumetric KFT (recommended for larger samples > 50
mg)
– One component
 Titrating agent: one-component reagent (I2, SO2,
imidazole or other base)
 Analyte of known mass added
– Two component (reagents are separated)
 Titrating agent (I2 and methanol)
 Solvent containing all other reagents used as
working medium in titration cell
Columetric Karl Fischer Titration


Coulometric KFT (recommended for smaller samples < 50
mg)
– Iodine is generated electrochemically via dedicated Pt
electrodes
Q = 1 C = 1 A x 1 s where 1 mg H2O = 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
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
Common Problems with Karl Fischer Titrations

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)
Oven Karl Fischer


Some substances only release their water at high
temperatures or undergo side reactions in the KF media
– The moisture in these substances can be driven off in
an oven at 100°C to 300°C.
– 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 Analysis


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
Thermal Gravimetric Analysis (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 Instrumentation

Components:
– Sensitive analytical
balance
– Furnace
– Purge gas system
– Computer
Applications of TGA
Sample Weight
Decomposition of calcium oxalate
 Composition
 Moisture Content
 Solvent Content
 Additives
 Polymer Content
 Filler Content
 Dehydration
 Decarboxylation
Sample Temperature (°C)
 Oxidation
 Decomposition
 Can be combined with MS or IR to identify gases evolved
H20
Ca(C00)2
CO
CaC03
CO2
Ca0
200
400
600
800
1000
Typical TGA of a Pharmaceutical
Sample: SB332235
Size: 5.9460 mg
Method: Standard Method
Comment: CL42969-112A1
File: Y:...\TGA\SB332235\CL42969-112A1.001
Operator: J Brum
Run Date: 18-Feb-05 14:45
Instrument: TGA Q500 V6.3 Build 189
TGA
100
1.2
1.080%
(0.06419mg)
9.615%
(0.5717mg)
18.90%
(1.124mg)
1.0
80
Weight (%)
60
0.6
Blue line shows derivative
Deriv. Weight (%/°C)
0.8
Green line shows mass changes
0.4
40
0.2
20
0
50
100
150
200
Temperature (°C)
250
300
0.0
350
Universal V3.8B TA Instruments
Differential Thermal Analysis (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 Instrumentation
General Principles of DTA
H (+) endothermic reaction - temp of sample lags behind temp of
reference
H (-) exothermic reaction - temp of sample exceeds that of
reference
Applications of DTA
T = Ts - Tr
Glass transitions
Crystallization
Melting
Oxidation
Decomposition
Phase transitions
Endothermic reactions: fusion, vaporization,
sublimation, ab/desorption, dehydration,
reduction, decomposition
Exothermic reactions : adsorption,
crystallization, oxidation, polymerization and
catalytic reactions
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
DSC Instrumentation

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
DSC Instrumentation

A modern heat flux DSC (the TA Q2000)
Heat Flow in DSC
DSC Step by Step
Glass transition
Recrystallization
Melting
Applications of DSC


DSC is usually carried
out in linear increasingtemperature scan mode
(but can do isothermal
experiments)
– In linear scan mode,
DSC provides
melting point data for
crystalline organic
compounds and Tg
for polymers
DSC trace of polyethyleneterphthalate (PET)
Easily used for detection of bound crystalline water
molecules or solvents, and measures the enthalpy of
phase changes and decomposition
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
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
0.5
0.0
Heat Flow (W/g)
56.35°C
34.97J/g
134.06°C
116.0J/g
-0.5
84.39°C
-1.0
Loss of water
153.30°C
Melt
Decomposition
-1.5
0
Exo Up
50
100
150
Temperature (°C)
200
250
300
Universal V3.8B TA Instruments
Modulated
DSC DSC
File: I:...\25% 412 - HPMCAS SDD MDSC.001
Operator: rf
Run Date: 03-Mar-2010 14:50
Instrument: DSC Q2000 V24.2 Build 107
30
30
25
25
20
20
5
6
7
8
Time (min)

Temperature (°C)
Modulated Temperature (°C)
Sample: 25% 412:HPMCAS SDD mDSC
Size: 1.8250 mg
Method: mDSC 223412:HPMC SDD
9
10
11
Universal V4.2E TA Instruments
mDSC applies a sinusoidal heating rate modulation on
top of a linear heating rate in order to measure the heat
flow that responds to the changing heating rate (via
Fourier transformation)
Modulated DSC
Sample heat
capacity
DSC heat
flow signal
Heating rate
dH
dT
 Cp
 f (T, t)
dt
dt
Total Heat
Flow
•All Transitions
Reversing
Heat Flow
•Heat capacity
•Glass transition
•Most melting
Heat flow that is
a function of
time and temp
(kinetic)
Non-Reversing
Heat Flow
•Evaporation
•Crystallization
•Enthalpic Recovery
•Denaturation
•Decomposition
•Some melting
Modulated DSC
Total Heat Flow
Rev Heat Capacity
Glass transition
Further Reading

Optional:
– KF:
 Skoog et al. pgs 707-708
– Thermal methods:
 Skoog et al. Chapter 31