1. Classical and Thermal Methods
Lecture Date: March 26th, 2008

2. 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
Thermal methods:
Skoog et al. Chapter 31
Cazes et al. Chapter 15

3. 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
A modern KF titrator
For more information about KFT, see US Pharmacopeia 921

4. Karl Fischer Reaction and Reagents
ester
CH3OH + SO2+ RN [RNH]+SO3CH3-
[RNH]+SO3CH3- + H2O + I2 + 2RN [RNH]+SO4CH3 + 2[RNH]+I-
Reagents:
Pyridine Free (e.g. imidazole)
0.2 M I2, 0.6M SO2, 2.0 M pyridine in methanol/ethanol
The Karl Fischer (KF) titration is a two-stage process. The first stage involves the reaction of sulphur dioxide with methanol to form an ester, which is neutralised by a nitrogen base (RN). The second stage is a rapid oxidation of the alkyl sulphite anion to alkyl sulphate by iodine - a reaction that consumes water.
SO2 + MeOH + RN → (RNH)SO3Me
(RNH)SO3Me + I2 + H2O + 2RN → (RNH)SO4Me + 2(RNH)I
There are two important requirements if the above reactions are to be stoichiometric. Firstly, the alcohol used should completely esterify the sulphur dioxide and secondly the base should be of suitable strength to completely neutralise the acids produced during the reaction. Initially, pyridine was used as the base. The basicity of this species is too low to completely neutralise the acid and the result is a slow titration. If the base is too strong the solution becomes alkaline and an end point may not be reached. It is most important that the pH of the Karl Fischer reaction is within the range 5 to 7. Outside the recommended pH range, the end-point may not be reached.
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)

5. 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

6. 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 = 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

7. 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 % w/w range

8. 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)

9. 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.

10. 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

11. 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

12. TG Instrumentation Components: Sensitive analytical balance Furnace
Purge gas system
Computer

13. Applications of TGA Decomposition of calcium oxalate Composition
H20
Ca(C00)2 CO
CaC03
CO2
Ca0
Sample Temperature (°C)
Sample Weight
Decomposition of calcium oxalate
Composition
Moisture Content
Solvent Content
Additives
Polymer Content
Filler Content
Dehydration
Decarboxylation
Oxidation
Decomposition

14. Typical TGA of a Pharmaceutical
Green line shows mass changes
Blue line shows derivative

15. 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.

16. DTA Instrumentation

17. 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

18. 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

19. Applications of DTA simple inorganic species Phase transitions
determine melting, boiling, decomposition
polymorphism
Jacobson (1969) - studied effects of stearic acid and sodium oxacillin monohydrate

20. 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

21. 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

22. Heat Flow in DSC

23. DSC Step by Step Recrystallization Glass transition Melting

24. 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)
Easily used for detection of bound crystalline water molecules or solvents, and measures the enthalpy of phase changes and decomposition

25. 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

26. DSC of a Pharmaceutical Hydrate
Loss of water
Melt
Decomposition

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