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Classical and Thermal Methods. Lecture Date: March 26 th , 2012. Classical and Thermal Methods. Titrations Karl Fischer (moisture determination) Representative of a wide variety of high-performance, modern analytical titration methods

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Classical and Thermal Methods

Lecture Date: March 26th, 2012

classical and thermal methods
Classical and Thermal Methods
  • Titrations
  • 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)
analytical titrations

great flexibility large amount of analyte required

suitable for a wide range of analytes lacks speciation

manual, simple colorimetric -subjective

excellent precision an accuracy sensitive to skill of analyst

readily automated reagents can be unstable

Analytical Titrations
  • Definition: an analytical technique that measures concentration of an analyte by the volumetric addition of a reagent solution (titrant) that reacts quantitatively with the analyte.
    • Classes: acid-base, redox, complexation, and precipitation and
  • For titrations to be analytically useful, the reaction must generally be quantitative, fast and well-behaved
titration curves
Titration Curves

Strong acid - Strong base

Strong base - Weak acid

titration curves1
Titration Curves

Strong base - polyprotic acid

Strength of Acids and Bases


example 1
Example 1
  • 30 mL of 0.10M NaOH neutralised 25.0mL of hydrochloric acid. Determine the concentration of the acid
      • 1. Write the balanced chemical equation for the reactionNaOH(aq) + HCl(aq) -----> NaCl(aq) + H2O(l)
      • 2. Extract the relevant information from the question:NaOH V = 30mL , M = 0.10M HCl V = 25.0mL, M = ?
      • 3. Check the data for consistencyNaOH V = 30 x 10-3L , M = 0.10M HCl V = 25.0 x 10-3L, M = ?
  • 4. Calculate moles NaOH n(NaOH) = M x V = 0.10 x 30 x 10-3 = 3 x 10-3 moles
  • 5. From the balanced chemical equation find the mole ratio NaOH:HCl 1:1
example 1 continued
Example 1 (continued)

6. Find moles HClNaOH: HCl is 1:1

So n(NaOH) = n(HCl) = 3 x 10-3 moles at the equivalence point

Calculate concentration of HCl: M = n ÷ V

n = 3 x 10-3 mol, V = 25.0 x 10-3L

M(HCl) = 3 x 10-3 ÷ 25.0 x 10-3 = 0.12M or 0.12 mol L-1

example 2
Example 2
  • 50mL of 0.2mol L-1 NaOH neutralised 20mL of sulfuric acid. Determine the concentration of the acid
  • 1. Write the balanced chemical equation for the reaction NaOH(aq) + H2SO4(aq) -----> Na2SO4(aq) + 2H2O(l)
      • 2. Extract the relevant information from the question:NaOH V = 50mL, M = 0.2M H2SO4 V = 20mL, M = ?
  • 3. Check the data for consistencyNaOH V = 50 x 10-3L, M = 0.2M H2SO4 V = 20 x 10-3L, M = ?
  • 4. Calculate moles NaOH n(NaOH) = M x V = 0.2 x 50 x 10-3 = 0.01 mol
  • 5. From the balanced chemical equation find the mole ratio NaOH:H2SO4 2:1
example 2 continued
Example 2 (continued)

6. Find moles H2SO4 NaOH: H2SO4 is 2:1

So n(H2SO4) = ½ x n(NaOH) = ½ x 0.01 = 5 x 10-3 moles H2SO4 at the

equivalence point

7. Calculate concentration of H2SO4: M = n ÷ V n = 5 x 10-3 mol, V = 20 x 10-3L

M(H2SO4) = 5 x 10-3 ÷ 20 x 10-3 = 0.25M or 0.25 mol L-1

karl fischer titration kft
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 (a German chemist) developed a specific reaction for selectively and specifically determining water at low levels.
    • The 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
Karl Fischer Reaction and Reagents
  • Reaction:



[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 I- 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 Karl Fischer Titration
  • Volumetric KFT (recommended for larger samples > 50 mg)
    • One component
      • Titrating agent: one-component reagent (I2, SO2, imidazole or other 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 karl fischer titration
Columetric Karl Fischer Titration
  • Coulometric KFT (recommended for smaller samples < 50 mg)
    • Iodine is generated electrochemically via dedicated Pt electrodes

Q = 1 C = 1 A x 1 s 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
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 titrations1
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
Oven Karl Fischer
  • Some substances only release their water at high temperatures or undergo side reactions in the KF media
    • 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
  • 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
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
TG Instrumentation
  • Components:
    • Sensitive analytical balance
    • Furnace
    • Purge gas system
    • Computer
applications of tga
Decomposition of calcium oxalate

Sample Weight

200 400 600 800 1000

Sample Temperature (°C)







Applications of TGA
  • Composition
  • Moisture Content
  • Solvent Content
  • Additives
  • Polymer Content
  • Filler Content
  • Dehydration
  • Decarboxylation
  • Oxidation
  • Decomposition
  • Can be combined with MS or IR to identify gases evolved
typical tga of a pharmaceutical
Typical TGA of a Pharmaceutical

Green line shows mass changes

Blue line shows derivative

differential thermal analysis dta
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.
general principles of dta
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

applications of dta
Applications of DTA

T = Ts - Tr

Glass transitions





Phase transitions

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

Exothermic reactions : adsorption, crystallization, oxidation, polymerization and catalytic reactions

differential scanning calorimetry dsc
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
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
dsc instrumentation1
DSC Instrumentation
  • A modern heat flux DSC (the TA Q2000)
dsc step by step
DSC Step by Step


Glass transition


applications of dsc
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 dsc1
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
DSC of a Pharmaceutical Hydrate

Loss of water



modulated dsc
Modulated DSC
  • mDSC applies a sinusoidal heating rate modulation on top of a linear heating rate in order to measure the heat flow that responds to the changing heating rate (via Fourier transformation)
modulated dsc2
Modulated DSC

Total Heat Flow

Rev Heat Capacity

Glass transition

further reading
Further Reading
  • Optional:
    • KF:
      • Skoog et al. pgs 707-708
    • Thermal methods:
      • Skoog et al. Chapter 31