Lecture Date: March 26 th , 2008

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 707-708 • 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. Pyridine Free (e.g. imidazole) Karl Fischer Reaction and Reagents • Reaction: ester CH3OH + SO2+ RN [RNH]+SO3CH3- [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 • 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 = 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

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 15.0-16.4% 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. Decomposition of calcium oxalate Sample Weight 200 400 600 800 1000 Sample Temperature (°C) H20 Ca(C00)2 CO CaC03 CO2 Ca0 Applications of TGA • 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