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

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)

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 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 Decomposition of calcium oxalate Composition H20 Ca(C00)2 CO CaC03 CO2 Ca0 200 400 600 800 1000 Sample Temperature (°C) Sample Weight Decomposition of calcium oxalate Composition Moisture Content Solvent Content Additives Polymer Content Filler Content Dehydration Decarboxylation Oxidation Decomposition

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

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 Recrystallization Glass transition Melting http://www.psrc.usm.edu/macrog/dsc.htm

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

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 Loss of water Melt Decomposition

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