Lecture Date: March 26th, 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

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

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)

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 (I2 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 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

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

H20Ca(C00)2

COCaC03

CO2

Ca0

200 400 600 800 1000

Sample Temperature (°C)S

ampl

e W

eigh

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

Der

iv. W

eigh

t (%

/°C

)

20

40

60

80

100

Wei

ght (

%)

0 50 100 150 200 250 300 350

Temperature (°C)

Sample: SB332235Size: 5.9460 mgMethod: Standard MethodComment: CL42969-112A1

TGAFile: Y:...\TGA\SB332235\CL42969-112A1.001Operator: J BrumRun Date: 18-Feb-05 14:45Instrument: 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 transitionsCrystallizationMeltingOxidationDecomposition

T = Ts - Tr

Endothermic Rxns:fusion, vaporization, sublimation, ab/desorption dehydration, reduction, decomposition

Exothermic Rxns:Adsorption, Crystallizationoxidation, 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

MeltingGlass 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 Tg 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)

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°C34.97J/g

153.30°C

134.06°C116.0J/g

-1.5

-1.0

-0.5

0.0

0.5

Hea

t Flo

w (

W/g

)

0 50 100 150 200 250 300

Temperature (°C)

Sample: SB332235Size: 3.0160 mgMethod: STANDARD DSC METHODComment: CL42969-112A1

DSCFile: Y:...\DSC\SB332235\CL42969-112A1.002Operator: J BrumRun Date: 24-Feb-05 09:53Instrument: DSC Q1000 V9.0 Build 275

Exo Up Universal V3.8B TA Instruments

Loss of water

Melt Decomposition

Optional Homework

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