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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,

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:

– Thermal methods:

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 more information about KFT, see US Pharmacopeia 921

Karl Fischer Reaction and Reagents

CH3OH + SO2+ RN [RNH]+SO3CH3

-[RNH]+SO3CH3-+ H2O + I2+ 2RN [RNH]+SO4CH3+ 2[RNH]+I

-0.2 M I2, 0.6M SO2, 2.0 M pyridine in methanol/ethanol

Pyridine Free (e.g imidazole)

 Endpoint detection: bipotentiometric detection of by a

dedicated pair of Pt electrodes

 Reaction:

 Reagents:

ester

Volumetric Karl Fischer Titration

 Volumetric KFT (recommended for larger samples > 50

mg)

– One component

 Titrating agent: one-component reagent (I2, SO2,

base)

 Analyte of known mass added

– Two component (reagents are separated)

 Titrating agent (I2and 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 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

 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

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 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

H 2 0 Ca(C00) 2

CO CaC0 3

CO 2

Ca0

200 400 600 800 1000

Sample Temperature (°C)

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

20

40

60

80

100

Temperature (°C)

Sample: SB332235

Size: 5.9460 mg

Method: Standard Method

Comment: CL42969-112A1

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

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

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

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

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

Heat Flow in DSC

DSC Step by Step

Melting

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 Tg

for polymers

DSC trace of polyethyleneterphthalate (PET)

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

84.39°C

56.35°C 34.97J/g

153.30°C

134.06°C 116.0J/g

-1.5

-1.0

-0.5

0.0

0.5

Temperature (°C)

Sample: SB332235

Size: 3.0160 mg

Method: STANDARD DSC METHOD

Comment: CL42969-112A1

Run Date: 24-Feb-05 09:53 Instrument: DSC Q1000 V9.0 Build 275

Loss of water

Optional Homework

Questions: 31-1, 31-3, 31-4, 31-6, 31-9, 31-10