Non aqueous titration refers to a type of titration in which the analyte substance is dissolved in a solvent which does not contain water. This procedure is a very important one in pharmacopoeial assays.

1. NON-AQUEOUS ACID BASE TITRATION
PRESENTED BY
MS. KAD
DHANASHREE
ASSISTANT PROF.
PES MODERN COLLEGE OF PHARMACY
(FOR LADIES) MOSHI, PUNE 412105

2. NON-AQUEOUS ACID BASE TITRATIONS THEORY
• Non-aqueous titrations is the most titrimetric procedure used in
pharmacopoeia assays and serves a double purpose, as it suitable
for the titration of 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.
• Water behaves as both a weak acid and weak base; thus in
aqueous environment, it can compete effectively with very weak
acids and bases with regard to proton donation and acceptance.

4. THEORY
• The effect of this is that the inflection in the titration curves for
weak acids and 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 and acids with pKa > 7
cannot determined accurately in aqueous Solution Various organic
solvents may be used to replace water since they compete less
effectively with the analyte or proton donation and
acceptance.

5. ADVANTAGES OF NON-AQUEOUS TITRATIONS:
1) Provide suitable solvent
2) Increase the basicity or acidity of the analyte. No water to
interfere with
titration, which would give sharper inflection region

6. NON-AQUEOUS TITRATION OF WEAK BASES
• Solvent: neutral or acidic
•Acetic acid is the most common solvent for weak base titration
because it does not compete effectively with weak bases for
protons.
• Only very strong acid (like perchloric acid) will protonate acetic
acid:
•As the CH3COOH2+ ion can instantly donate its proton to a base,
therefore,a solution of perchloric acid in glacial acetic acid, behaves
as a strongly acidic solution.

7. •Benzene and chloroform (aprotic solvent) can also be used as neutral
Solvents
• Since dissociation is not an essential preliminary to neutralization,
aprotic solvents are added to ionizing solvents to depress solvolysis of
the neutralization product and so sharpen the end point
•Butanol can be added to enhance the solubility of insoluble
substances.
•Titrant: most commonly used titrant is perchloric acid.
•The choice of the titrant here is more crucial than in the case of
aqueous titration (How?)
•Acetic anhydride, measured but not in excess amount (why?), is used
to remove water from aqueous perchloric acid (the commercially
available form).
•Standarized with KHP

8. INDICATORS:
• Crystal violet (most common one)
• 3-quinaldine
• 4-naphthalein
When a base is in the form of a chloride or bromide salt, the counter
ion has to be removed prior to titration by addition of mercuric acetate.
• However, when the base in the form of a salt of a weak acid (tartrate,
acetate, or succinate) removal of an anionic counter ion prior to
titration is not necessary.
• Blank Titration : It is usually carried out to account for the possible
reaction of atmospheric moisture with the titrant perchloric acid

9. Example, Titration analysis of pyridine (very weak base, analyte)
dissolved in acetic acid (acidic solvent)
titrated with perchloric acid
(titrant) dissolved
in acetic acid.
Titrant solution, in burett
Analyte solution, in
ErlenmeyerTitration
• The whole idea of non-aqueous titration is to increase the acidity
and basicity for both the solvent and analyte by generating more
acidic and basic species, i.e., CH3COOH2+ is more acidic than
HClO4, and acetate (CH3COO-) is more basic then pyridine
(C6H5N). Therefore, titration of CH3COOH2+ (from titrant solution)
with CH3COO- (in analyte solution) will generate sharper end point.

10. NON-AQUEOUS TITRATION OF WEAK ACIDS
Solvent:
1) Alcohol (very weak acids, pKa 16 – 20, e.g. methanol, ethanol, t-
butyl alcohol)
2) Amines (weak bases, e.g. ethanediamne, n-butyl amine, pyridine)
or
3) Aprotic solvents (N,N-dimethyl formaide (DMF), aceton, methyl-
ethaylketon)
• Which does compete strongly with weak acid for proton donation

11. TITRANT:
• Lithium methoxide (CH3OLi), Sodium or potassium methoxide
(CH3ONa, CH3OK), tetrabutyl ammonium hydroxide
• Generally, drugs can be titrated directly in a dosage form
• If the dosage form is aqueous, analyte should be extracted to non-
aqueous solvent.

12. Example, Titration analysis of benzoic acid(weak acid, analyte)
dissolved in DMF titrated with sodium methoxide (titrant) dissolved
in methanol.
Analyte solution, in
Erlenmeyer
Titrant solution, in
burett
Titration

13. PRACTICAL APPLICATION
Example 1. 4 g tablet of methacholine cloride ( g / mol), dried and
stored in a vacuum desiccator, dissolved in 50 ml of glacial acetic
acid, 10 ml of mercuric acetate solution and one drop of crystal
violet was added and then titrated with 56 ml of 0.1 M perchloric
acid to a blue-green end point.
Blank titration was conducted and 1.7 ml of perchloloric aid used.
Calculate % w/w of methacholine cloride.

14. PRACTICAL APPLICATION
Example g tablet of Ethosuximide ( g/mol) dissolved in 50 ml of
dimethylformamide, 2 drops of azo-violet solution was added and
tirated with 12 ml of 0.1 N sodium methoxide to a deep blue end
point. 0.6 ml was needed in blank titration. Calculate the % w/w of
thosuximide.

15. EXAMPLE FOR KJELDAHL METHOD
0.9092 g sample of a wheat our was analyzed by the Kjeldahl
procedure. The arnmonia formed was distilled into mL of M HCI,
and then back titrated with 7.46-mL of M NaOH. Calculate the
percentage of protein in the flour.
Note. Since most proteins contain approximately the same
percentage of nitrogen, multiplication of this percentage by a
suitable factor (6.25 for meats, 6.38 for dairy products, and 5.70 for
cereals) gives the percentage of protein in a sample.
%N = Mass of N/ Sample mass x 100%
% of crude protein = %N x F