2. Points to be covered
• Types of solvents,
• End point detection,
• Application in assay of Sodium acetate,
• Sodium benzoate,
• Norfloxacin tablet
• Nonaqueous titration is the titration of substances
dissolved in solvents other than water.
• It is the most common titrimetric procedure used in
pharmacopoeial assays and serves a double purpose:
▫ it is suitable for the titration of very weak acids and very
weak bases, and
▫ it provides a solvent in which organic compounds are
• The most commonly used procedure is the titration of
organic bases with perchloric acid in anhydrous acetic
• These assays sometimes take some perfecting in terms
of being able to judge the endpoint precisely.
4. Need of Non aqueous titrations
Oftentimes we need to perform an acid-base titration in non-
aqueous solvent due to:
▫ The analyte is too weak acid or a base to be
titrated in H2O
▫ Reactants or products are insoluble in H2O
▫ Reactants or products react with H2O
▫ Titration in H2O doesn’t allow a sharp end point
but in a nonaqueous solvent with a stronger base than
OH- it is possible to get an sharp end point
5. Definitions of acids and bases
• Bronsted Lowry; a general definition applicable
to both aqueous and non aqueous systems
▫ Acids: proton donors
▫ Bases: proton acceptors
• Lewis theory: Acids: electron pair acceptors
Bases: electron pair donors
• Strong acids in water
HCl + H2O -----------> H3O+ + Cl-
(acid) (base) (conjugate (conjugate
6. weak acids in water
HCOOH + H2O --------> H3O+ + HCOO
(acid) (base) (conjugate (conjugate
weak acids in non aqueous solvents
HCOOH + CH3NH2 -------> CH3NH4
+ + HCOO
(acid) (base) (conjugate (conjugate
It follows from these definitions that an acid may be either:
* an electrically neutral molecule, e.g. HCl, or
* a positively charged cation, e.g. C6H5NH3+, or
* a negatively charged anion, e.g. HSO4-.
A base may be either:
* an electricially neutral molecule, e.g. C6H5NH2, or an anion, e.g.
Substances which are potentially acidic can function as acids
only in the presence of a base to which they can donate a
proton. Conversely basic properties do not become apparent
unless an acid also is present
7. • The apparent strength of an acid or base is determined by
the extent of its reaction with a solvent.
• In aqueous solution all strong acids appear equally strong
because they react with the solvent to undergo almost
complete conversion to hydronium ion (H3O+) and the
• In a weakly protophilic solvent such as acetic acid, the
extent of formation of the acetonium ion (CH3COOH2+)
due to the addition of a proton provides a more sensitive
differentiation of the strength of acids and shows that the
order of decreasing strength for acids is perchloric,
hydrobromic, sulfuric, hydrochloric, and nitric.
• Acetic acid reacts incompletely with water to form
hydronium ion and is, therefore, a weak acid.
• In contrast, it dissolves in a base such as ethylenediamine,
and reacts so completely with the solvent that it behaves as
a strong acid.
• This so-called levelling effect
8. Leveling effect or solvent leveling
• Leveling effect or solvent: leveling refers to the effect of solvent on the
properties of acids and bases.
• The strength of a strong acid is limited ("leveled") by the basicity of the
solvent. Similarly the strength of a strong base is leveled by the acidity of
• When a strong acid is dissolved in water, it reacts with it to form hydronium
ion (H3O+). An example of this would be the following reaction, where
"HA" is the strong acid:
• HA + H2O → A− + H3O+
• Any acid that is stronger than H3O+ reacts with H2O to form H3O+.
Therefore, no acid stronger than H3O+ exists in H2O.
• Similarly, when ammonia is the solvent, the strongest acid is ammonium
(NH4+), thus HCl and a super acid exert the same acidifying effect.
• The same argument applies to bases. In water, OH− is the strongest base.
Thus, even though sodium amide (NaNH2) is an exceptional base (pKa of
NH3 ~ 33), in water it is only as good as sodium hydroxide.
• On the other hand, NaNH2 is a far more basic reagent in ammonia than is
9. Solvents used in non aqueous titration
• Solvent which are used in non aqueous titration
are called non aqueous solvent.
• They are following types:-
1. Aprotic Solvent
2. Protogenic Solvent
3. Protophillic Solvent
4. Amphiprotic Solvent
10. Aprotic solvents
• Aprotic solvents are neutral, chemically inert substances
such as benzene and chloroform. They have a low dielectric
constant, do not react with either acids or bases and
therefore do not favor ionization.
• The fact that picric acid gives a colorless solution in benzene
which becomes yellow on adding aniline shows that picric
acid is not dissociated in benzene solution and also that in
the presence of the base aniline it functions as an acid, the
development of yellow color being due to formation of the
• Carbon tetrachloride and toluene come in this group; they
possess low dielectric constants, do not cause ionization in
solutes and do not undergo reactions with acids and bases.
• Aprotic solvents are frequently used to dilute reaction
11. Protogenic solvents
• Protogenic solvents are acidic substances, e.g.
sulfuric acid. They exert a leveling effect on bases.
• Anhydrous acids such as hydrogen fluoride and
sulphuric acid fall in this category, because of their
strength and ability to donate protons, they enhance
the strength of weak bases.
• Ex:- sulphuric acid , formic acid, propanoic acid
,acetic anhydride etc.
• They have high dielectric constant and ionised
because of their strength and ability to donate
12. Protophilic Solvents :
• Protophilic solvents are the substances that
possess a high affinity for protons. The over all
reaction can be represented as:
▫ HB+S ↔ SH+ + B-
• The equilibrium in this reversible reaction will be
generally influenced by the nature of the acid and
• Weak acids are normally used in the presence of
strongly protophilic solvents as their acidic
strengths are then enhanced and then become
comparable to these of strong acids; this is
known as the levelling effect.
13. Amphiprotic solvents
• Amphiprotic solvents have both protophilic and protogenic
properties. Examples are acetic acid and the alcohols. They are
dissociated to a slight extent. The dissociation of acetic acid,
which is frequently used as a solvent for titration of basic
substances, is shown in the equation below:
• CH3COOH ⇌ H+ + CH3COO−
• Here the acetic acid is functioning as an acid. If a very strong
acid such as perchloric acid is dissolved in acetic acid, the
latter can function as a base and combine with protons
donated by the perchloric acid to form protonated acetic acid,
an onium ion:
• HClO4 ⇌ H+ + ClO4−
• CH3COOH + H+ ⇌ CH3COOH2+ (onium ion)
• Since the CH3COOH2+ ion readily donates its proton to a
base, a solution of perchloric acid in glacial acetic acid
functions as a strongly acidic solution.
14. Glacial acetic acid
• It is a solvent for base in particular
• The water content should be less than 1%
• Acetic anhydiride is added
• When a weak base, such as pyridine, is dissolved in
acetic acid, the acetic acid exerts its levelling effect
and enhances the basic properties of the pyridine. It
is possible, therefore, to titrate a solution of a weak
base in acetic acid with perchloric acid in acetic acid,
and obtain a sharp endpoint when attempts to carry
out the titration in aqueous solution are
15. Other solvent
• Formic acid: is only used for the titratin of
weakest base eg caffeine or urea
• Trifluoroacetic acid: suitable as solvent for
weakest base where acetic anhydride cannot be
used because of acetylation. But it is expensive
• Amphipotic basic solvent: eg Ethylendiamine,
• Aprotic basic solvent: Pyridine,
16. DETECTION OF END POINT
• Visual indicator are found to the most suitable for the
detection of end point in non-aqueous titration. The
important indicator used for non-aqueous titration are
• 1. Crystal voilet:- It is used as 0.5% solution in glacial
acetic acid, it gives voilet colour in basic medium and
yellowish green in acidic medium. It is most widely use
for the titration of pyridine with prechloride acid.
• 2. Oracet Blue B Indicator:- It is prepared o.5% glacial
acetic acid. It gives blue colour in basic medium while
pink colour in acidic medium.
• 3. Quinaldine Red Indicator:- It is used 0.1% solution in
methenol/ethenol. Methenol is more stable. It gives
yellow colour in basic medium while almost colourless in
acidic medium. a
17. Other Indicator used
• Methyl Red: Used as a 0.2% w/v solution in
dioxane with a yellow to red colour change.
• Naphthol Benzein: When employed as a 0.2%
w/v solution in ethanoic acid gives a yellow to
green colour change. It gives sharp end points in
nitro methane containing ethanoic anhydride for
titration of weak bases against perchloric acid.
• Thymol Blue: Used extensively as an indicator
for titrations of substances acting as acids in
dimethyl formamide solution. A 0.2% w/v
solution in methanol gives a sharp colour change
from yellow to blue at the end point.
18. Visual indicators
basic neutral acidic
Crystal violet (0.5 per cent
in glacial acetic acid)
per cent in glacial acetic
Oracet Blue B (0.5 per cent
in glacial acetic acid)
blue purple pink
Quinaldine Red (0.1 per
cent in methanol)
20. ASSAY BY NON-AQUEOUS TITRATIONS
• Acidimetry in Non-aqueous Titrations
• It can be further sub-divided into two heads,
1. Titration of primary, secondary and tertiary
2. Titration of halogen acid salts of bases.
• Alkalimetry in Non-aqueous Titrations—
titration of acidic substances
21. Preparation of 0.1N solution of HClO4
and its standardization
• Dissolve 8.5 ml of 72% HClO4 in about 900 ml
glacial acetic acid with constant stirring, add about
30 ml acetic anhydride and make up the volume
(1000 ml) with glacial acetic acid and keep the
mixture for 24 hour.
• Acetic anhydride absorbed all the water from HClO4
and glacial acetic acid and renders the solution
virtually anhydrous. HClO4 must be well diluted
with glacial acetic acid before adding acetic
anhydride because reaction between HClO4 and
acetic anhydride is explosive.
• Standardize the above prepared 0.1N HClO4 with
A.R. Grade Potassium acid Phthalate.
• Solution in HClO4 in dioxane may be the 2nd titrant
• Perchloric acid is usually available as a 70 to 72% mixture with
water .It usually undergoes a spontaneous explosive
decomposition and, therefore, it is available always in the form
of a solution.
• Conversion of acetic anhydride to acetic acid requires 40-45
minutes for its completion.
• It being an exothermic reaction, the solution must be allowed
to cool to room temperature before adding glacial acetic acid
• Avoid adding an excess of acetic anhydride especially when
primary and secondary amines are to be assayed, because
these may be converted rapidly to their corresponding
acetylated non-basic products :
• R—NH2 + (CH3CO)2O → R.NH.(CH3CO) + CH3COOH
Primary amine Acetylated product
• Perchloric acid is not only a powerful oxidising agent but also a
strong acid. Hence, it must be handled very carefully.
25. Alkali Metry
• Many weakly acidic pharmaceutical substances may
be titrated effectively by making use of a suitable
non-aqueous solvent with a sharp end-point.
• 0.1 N Potassium Methoxide in Toluene-Methanol
• 0.1 N Sodium Methoxide or 0.1 N Lithium
26. ADVANTAGES OF NON AQUEOUS TITRATIONS
1. Organic acids and bases that are insoluble in water are
soluble in non-aqueous solvent.
2. Organic acid, which is of comparable strength to water, can
be titrated easily in non-aqueous solvent. Bases also follow
the same rules.
3. A non-aqueous solvent may help two are more acids in
mixture. The individual acid can give separate end point in
4. By the proper choice of the solvents or indicator, the
biological ingredients of a substance whether acidic or basic
can be selectively titrated.
5. Non aqueous titrations are simple and accurate, examples of
non aqueous titration are: Ephedrine preparations, codeine
phosphate in APC, tetracycline, teramycin, Antihistamines
and various piperazine preparations.