Titration

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Titration

Principles
An analyte is chemically reacted with a standard solution of a reagent
of precisely known concentration or with a concentration that can be
precisely determined. The amount of a standard solution required to
completely react with all of the sample is used to estimate the purity
of the sample.
The process of determining the quantity of a substance A by
adding measured increments of substance B, with which it reacts
(almost always as a standardized solution called the titrant, but also
by electrolytic generation, as in coulometric titration) with
provision for some means of recognizing (indicating) the endpoint
at which essentially all of A has reacted.
If the endpoint coincides with the addition of the exact chemical
equivalence, it is called the equivalence point or stoichiometric or
theoretical endpoint, thus allowing the amount of A to be found
from known amounts of B added up to this point, the reacting
weight ratio of A to B being known from stoichiometry or
otherwise.
Terms for varieties of titration can reflect the nature of the
reaction between A and B.
Thus, there are acid– base, complexometric, chelatometric,
oxidation–reduction, and precipitation titrations.
Additionally, the term can reflect the nature of the titrant, such
as acidimetric, alkalimetric, and iodometric titrations as well as
coulometric titrations, in which the titrant is generated
electrolytically rather than being added as a standard solution
Titration curve
 A plot of a variable related to a relevant concentration
(activity) as the ordinate vs. some measure of the amount of
titrant, usually titration volume (titre) as the abscissa.
 If the variable is linearly related to concentrations, such as the
electrical conductance or the photometric absorbance, the term
linear titration curve is used.
When a logarithmic expression of the concentration or activity
is used, such as the or the electrical potential in , the curve is
referred to as a logarithmic titration curve.
 Titrimetric methods are still widely used in pharmaceutical
analysis because of their robustness, cheapness and capability for
high precision.
The only requirement of an analytical method that they lack is
specificity.
Primary standards and standard solutions
Primary standards are stable chemical compounds that are
available in high purity and which can be used to standardise the
standard solutions used in titrations.
Titrants such as sodium hydroxide or hydrochloric acid cannot
be considered as primary standards since their purity is quite
variable.
So, for instance, sodium hydroxide standard solution may be
standardised against potassium hydrogen phthalate, which is
available in high purity.
The standardised sodium hydroxide solution (secondary
standard) may then be used to standardise a standard
solution of hydrochloric acid.
Direct acid/base titrations in the aqueous phase
Strong acid/strong base titrations
Figure shows the titration curve obtained from the titration of a
strong acid with a strong base.
The pH remains low until just before the equivalence point, when
it rises rapidly to a high value.
 In many titrations a coloured indicator is used, although
electrochemical methods of end-point detection are also used.
An indicator is a weak acid or base that changes colour between
its ionised and un-ionised forms; the useful range for an indicator is
1 pH either side of its pKa value.
For example, phenolphthalein (PP) pKa 9.4 (colour changes
between pH 8.4 and pH 10.4) undergoes a structural rearrangement
as a proton is removed from one of its phenol groups when the pH
rises, and this causes the colour change (Fig. ).
Methyl orange (MO) pKa 3.7 (colour changes between pH 2.7 and
pH 4.7) undergoes a similar pH-dependent structural change. Both
these indicators fall within the range of the inflection of the strong
acid/strong base titration curve.
There are only a few direct strong acid/strong base titrations
carried out in pharmacopoeial assays. Strong acid/strong base
titrations are used in pharmacopoeial assays of: perchloric acid,
hydrochloric acid, sulphuric acid and thiamine hydrochloride.
Weak acid/strong base and weak base/strong acid titrations
 On addition of a small volume of the strong acid or strong base to
a solution of the weak base or weak acid, the pH rises or falls rapidly
to about 1 pH unit below or above the pKa value of the acid or base.
Often a water-miscible organic solvent such as ethanol is used to
dissolve the analyte prior to the addition of the aqueous titrant.
Figure shows a plot of pH when 1 M NaOH is added to 25 ml of a
1 M solution of the weak acid aspirin.
In the case of aspirin, the choice of indicator is restricted by where
the inflection in its titration curve lies; PP is suitable as an indicator
whereas MO is not.
In the example of the titration of quinine with hydrochloric acid
(Fig, MO is a suitable indicator because it falls within the
inflection of the titration curve whereas PP is not suitable
Some acids or bases can donate or accept more than one
proton, i.e. 1 mole of analyte is equivalent to more than 1
mole of titrant.
If the pKa values of any acidic or basic groups differ by
more than ca 4, then the compound will have more than one
inflection in its titration curve.
Sodium carbonate is a salt of carbonic acid and it can
accept two protons. The pKa values of carbonate and
bicarbonate are sufficiently different (pKa 10.32 and 6.38)
for there to be two inflections in the titration curve. The two
stages in the titration are:
In a titration of sodium carbonate, the first inflection is
indicated by PP and the whole titration by MO (Fig).

Weak acid/strong base titration is used in the pharmacopoeial


assays of: benzoic acid, citric acid, chlorambucil injection,
mustine injection, nicotinic acid tablets and undecanoic acid.
Titrations of the salts of weak bases in mixed aqueous/non-
aqueous media
Non-aqueous titrations are still used for the analysis of acids and
salts of weak bases.
In many instances it is simpler to titrate weak bases as their salts
in a mixed non-aqueous/aqueous medium using potentiometric
end-point detection.
The protonated base behaves as a weak acid when titrated with
sodium hydroxide.
RNH+3 + HO- →RNH2 + H2O
The advantage of adding a water-miscible solvent such as methanol
to the titration is twofold.
Firstly, the addition of the organic solvent effectively lowers the
pKa value
of the base, since the ionised form of the base is less stable in a
mixed solvent system where the dielectric constant is lower, and,
secondly, the organic solvent keeps the base in solution as it is
converted to its free base form during the titration.
An example of this can be seen for the titration of lidocaine
(lignocaine) hydrochloride in methanol/water mixtures (Fig.), where
the size of the inflection in the titration curve increases when moving
from 30% methanol to 70% methanol.
This is a very convenient procedure for many organic bases.

Potentiometric titration of lidocaine (lignocaine) hydrochloride with 0.1 M NaOH.


The samples were dissolved in methanol/ water (30:70, 50 ml) and methanol/water
(70:30, 50 ml)
Indirect titrations in the aqueous phase
These can be of the strong acid/strong base, weak acid/strong
base or weak base/strong acid type.
The more common examples are weak acid/strong base.
Estimation of esters by back titration
Excess of sodium hydroxide is added to the ester. The
following reaction occurs:

The XSNaOH is back titrated with HCl using PP as an indicator.


This procedure is used in pharmacopoeial assays of: benzyl benzoate,
dimethyl phthalate, ethyl oleate, methyl salicylate, cetostearyl alcohol,
emulsifying wax, castor oil, arachis oil, cod liver oil and coconut oil.
Saponification value
The assay of fixed oils provides a special case of ester hydrolysis
since they are triesters of glycerol.
The saponification value for a fixed oil is the number of mg of
potassium hydroxide (KOH) equivalent to 1 g of oil.
A high value means rancidity, a low value possible adulteration
with mineral oil.
Almost all edible oils have a saponification value between 188 and
196.
 Hydrolysis of the fixed oil is carried out with ethanolic KOH. This
procedure is used in the pharmacopoeial assays of: castor oil, cod
liver oil, cotton seed oil, almond oil and sesame seed oil.
Acid values are also determined for fixed oils. The acid value
for a substance is the number of mg of KOH required to
neutralise 1 g of the test substance when it is titrated with 0.1 M
ethanolic KOH to a PP end-point.
This value is quoted for many fixed oils in order to eliminate
rancid oils, which contain large amounts of free fatty acid.
Typically acid values for fixed oils are in the range of 1–2.
Estimation of alcohols and hydroxyl values by reaction with
acetic anhydride (AA)
Alcohols can be determined by reaction with excess acetic
anhydride (AA) (Fig. ). This is a useful titrimetric method because
the alcohol group is difficult to estimate by any other means.
The excess AA and acetic acid may be back titrated with NaOH
using PP as an indicator.
In a related assay, a hydroxyl value is determined for a fixed oil.
A 1:3 mixture of AA in pyridine is used in the determination; the
pyridine is present as a catalyst.
The hydroxyl value may be defined as: The number of mg of
KOH required to neutralise a blank titration of the reagents – the
number of mg KOH required to neutralise excess AA + acetic acid
after reaction with 1 g of the test substance.
Reaction with acetic anhydride is used in pharmacopoeial assays
of benzyl alcohol and dienestrol, and determination of hydroxyl
values of castor oil, cetosteryl alcohol and cetomacrogol
Non-aqueous titrations
Theory Non-aqueous titration is the most common titrimetric
procedure used in pharmacopoeial assays and serves a double
purpose, as it is suitable for the titration of very weak acids and
bases and provides a solvent in which organic compounds are
soluble.
The most commonly used procedure is the titration of organic
bases with perchloric acid in acetic acid. These assays sometimes
take some perfecting in terms of being able to judge the end-point
precisely.
The theory is, very briefly, as follows: water behaves as both
a weak acid and a weak base; thus, in an aqueous environment,
it can compete effectively with very weak acids and bases with
regard to proton donation and acceptance, as shown in figure.
The effect of this is that the inflection in the titration curves for
very weak acids and very weak bases is small, because they
approach the pH limits in water of 14 and 0 respectively, thus
making end-point detection more difficult.
A general rule is that bases with pKa < 7 or acids with pKa > 7
cannot be determined accurately in aqueous solution.
Various organic solvents may be used to replace water since
they compete less effectively with the analyte for proton
donation or acceptance.
Non-aqueous titration of weak bases
Acetic acid is a very weak proton acceptor and thus does not
compete effectively with weak bases for protons. Only very
strong acids will protonate acetic acid appreciably according to
the equation shown below:

Perchloric acid is the strongest of the common acids in acetic acid


solution, and the titration medium usually used for non-aqueous
titration of bases is perchloric acid in acetic acid. Addition of acetic
anhydride, which hydrolyses to acetic acid, is used to remove water
from aqueous perchloric acid.
Weak bases compete very effectively with acetic acid for protons.
Oracet blue, quinalidine red and crystal violet (very weak bases)
are used as indicators in this type of titration. A typical analysis is
shown in Figure for L-3,4-dihydroxyphenylalanine (LDOPA).

When the base is in the form of a salt of a weak acid, removal of


an anionic counter ion prior to titration is not necessary, e.g. for
salts of bases with weak acids such as tartrate, acetate or
succinate.
However, when a base is in the form of a chloride or bromide salt,
the counter ion has to be removed prior to titration. This is achieved
by the addition of mercuric acetate; the liberated acetate is then
titrated with acetous perchloric acid. This is illustrated in Figure for
the example of phenylephrine HCl. Non-aqueous titration with
acetous perchloric acid is used in the pharmacopoeial assays of:
adrenaline, metronidazole, codeine, chlorhexidine acetate,
chlorpromazine, amitriptyline HCl, propranolol HCl, lidocaine
(lignocaine) HCl, and HCl and quaternary amine salts, such as
neostigmine bromide and pancuronium bromide.
Non-aqueous titration of weak acids
For the non-aqueous titration of weak acids, a solvent such as
an alcohol or an aprotic solvent is used, which does not
compete strongly with the weak acid for proton donation.
Typical titrants are lithium methoxide in methanol or tetrabutyl
ammonium hydroxide in dimethylformamide. End-point
detection may be carried out with thymol blue as an indicator
or potentiometrically.
Non-aqueous titration of acidic groups is carried out in
pharmacopoeial assays of: barbiturates, uracils and
sulphonamides.
Argentimetric titrations
Argentimetric titrations are based on the reaction:

Potassium chromate may be used as an indicator, producing a red


colour with excess Ag+ ion. More widely applicable is the method
of back titration. Excess AgNO3 is added to the sample

containing chloride or bromide ions. The excess AgNO3 is then


titrated with ammonium thiocyanate, and ammonium ferrous
sulphate is used as an indicator of excess SCN:
Before the back titration can be carried out, the precipitated AgCl
has to be filtered off or coated with diethylphthalate to prevent SCN
causing dissociation of AgCl.
Organically combined chlorine has to be liberated by hydrolysis
with sodium hydroxide prior to titration.
A halogen attached to an aromatic ring cannot be liberated by
hydrolysis and aromatic halides have to be burnt in an oxygen flask in
order to release the halogen for titration.
Argentimetric titration is used in pharmacopoeial assays of: sodium
chloride and potassium chloride tablets, thiamine hydrochloride,
mustine chloride and carbromal.
Compleximetric titrations
These titrations are used in the estimation of metal salts.
Ethylenediamine tetracetic acid (EDTA) shown in Figure is the
usual titrant used. It forms stable 1:1 complexes with all metals
except alkali metals such as sodium and potassium. The alkaline
earth metals such as calcium and magnesium form complexes
which are unstable at low pH values and are titrated in ammonium
chloride buffer at pH 10. The general equation for the titration is:
The end-point of the reaction is detected using an indicator dye. The
dye is added to the metal solution at the start of the titration, and
forms a coloured complex with a small amount of the metal. The first
drop of excess EDTA causes this complex to break up, resulting in a
colour change. Titration with EDTA is used in the pharmacopoeial
assays of: bismuthsubcarbonate, calcium acetate, calcium chloride,
calcium gluconate, magnesium carbonate, magnesium hydroxide,
magnesium trisilicate, bacitracin zinc, zinc chloride and zinc
undecanoate.
Insoluble metal salts are estimated by back titration; the sample
is heated with excess EDTA to form the soluble EDTA complex
of the metal and then the excess EDTA is titrated with salt
solutions containing Mg2+ or Zn2+ of known concentration.
Back titration with EDTA is used in the pharmacopoeial assays
of: aluminium glycinate, aluminium hydroxide, aluminium
sulphate, calcium hydrogen phosphate.
Redox titrations
Redox titrations are based on the transfer of electrons between the
titrant and the analyte. These types of titrations are usually followed
by potentiometry, although dyes which change colour when oxidised
by excess titrant may be used. Theory Reduction potential is a
measure of how thermodynamically favourable it is for a compound
to gain electrons. A high positive value for a reduction potential
indicates that a compound is readily reduced and, consequently, is a
strong oxidising agent, i.e. it removes electrons from substances with
lower reduction potentials. The oxidised and reduced forms of a
substance are known as a redox pair. Table lists the standard
reduction potentials for some typical redox pairs.
A substance with a higher reduction potential will oxidise one with
a lower reduction potential. The difference in potential between
two substances is the reaction potential and is approximately the
potential difference which would be measured if the substances
comprised two halves of an electrical cell. For example Cl2 will
oxidise Br according to the following equation:

Taking values from Table 3.2, the reaction potential is given by:
1.36 – 1.065 =0.29 V

The reaction potential is given by: 1.36 – (–2.888) = 4.248 V


(i.e. a large difference and calcium burns in chlorine).
In the above examples we have ignored the effect of concentration
of oxidant and reductant on Eo values; in fact, E (the observed
electrode potential) is stable over a wide range of concentrations.
The E-value for a solution containing a redox pair is governed by
the Nernst equation:

where [Ox] is the concentration of the oxidised form of a


particular substance and [Red] is the concentration of the reduced
form of a particular substance:
F =Faraday’s constant
n =number of electrons transferred in the reaction
By substituting a value for the constant terms, this equation can
also be written as:

where n is the number of electrons transferred during the reaction.


It is clear that E is approximately equal to Eo except when there is a
large difference between [Ox] and [Red].
The titration curve for Fe2+ against Ce4+ is shown in Figure .
This curve is for a titration carried out with a standard
hydrogen electrode as the reference electrode. Where a
reference electrode has a reduction potential > 0, then the
predicted reading of the potential for a redox pair is obtained
by subtracting the reduction potential for the reference
electrode, e.g. for an Ag/AgCl reference electrode, 0.223 V is
subtracted.
In carrying out redox titrations, standard Ag/AgCl or Hg/Hg2Cl2
electrodes are used as a reference in conjunction with an inert
redox electrode, e.g platinum, which takes its potential from the
particular redox pair in the solution in which it is immersed.
Redox titration is used in pharmacopoeial assays of: ferrous salts,
hydrogen peroxide, sodium perborate and benzoyl peroxide by
titration with KMnO4. In the case of KMnO4 titrations, the end-
point may be detected when the purple colour of the permanganate
persists.

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