Classical and Thermal Methods

Lecture Date: March 26th, 2008

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)

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 (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
For more information about KFT, see US Pharmacopeia 921

A modern KF titrator

Karl Fischer Reaction and Reagents

Reaction: CH3OH + SO2+ RN [RNH]+SO3CH3ester

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

[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 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, 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

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 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 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

Composition Moisture Content Solvent Content Additives Polymer Content Filler Content Dehydration Decarboxylation Oxidation Decomposition

Decomposition of calcium oxalate Sample Weight

H20 Ca(C00)2 CO CaC03

CO2 Ca0

200

400

600

800

1000

Sample Temperature (C)

Typical TGA of a Pharmaceutical

Sample: SB332235 Size: 5.9460 mg Method: Standard Method Comment: CL42969-112A1 100
1.080% (0.06419mg) 9.615% (0.5717mg) 18.90% (1.124mg)

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 1.2

1.0 80

60

0.6

Blue line shows derivative

0.4 40 0.2

20 0 50 100 150 200 250 300

0.0 350
Universal V3.8B TA Instruments

Temperature (C)

Deriv. Weight (%/C)

Green line shows mass changes

Weight (%)

0.8

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

T = Ts - Tr

Glass transitions Crystallization Melting Oxidation Decomposition

Endothermic Rxns: fusion, vaporization, sublimation, ab/desorption dehydration, reduction, decomposition Exothermic Rxns: Adsorption, Crystallization oxidation, polymerization and catalytic reactions

Applications of DTA

simple inorganic species Phase transitions determine melting, boiling, decomposition

polymorphism

Jacobson (1969) - studied effects of stearic acid and sodium oxacillin monohydrate

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

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 0.5

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

0.0
56.35C 34.97J/g

Heat Flow (W/g)

134.06C 116.0J/g

-0.5
84.39C

-1.0

Loss of water
153.30C

Melt
-1.5 0
Exo Up

Decomposition
150 200 250 300
Universal V3.8B TA Instruments

50

100

Temperature (C)

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