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Titrations
Muh. Nur Khoiru Wihadi, S.Pd.,
M.Sc.
Non-aqueous Titrations
Theory
Non-aqueous titrations is the most titrimetric
procedure used in pharmacopoeial 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.
Non-aqueous Titrations
Non-aqueous Titrations
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.
Non-aqueous Titrations
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
Non-aqueous Titrations
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:
onium ion
Non-aqueous Titrations
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
Non-aqueous Titrations
Indicators:
Crystal violet (most common one)
3-quinaldine
4-naphthalein
undissociated
undissociated
Non-aqueous Titrations
Example, Titration analysis of pyridine (very weak
base, analyte) dissolved in acetic acid (acidic
solvent) titrated with perchloric acid (titrant)
dissolved
inburett
acetic acid.
Titrant
solution, in
Analyte solution, in
Erlenmeyer
Titration
Non-aqueous Titrations
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, nbutyl amine, pyridine) or
3) aprotic solvents (N,N-dimethyl formaide (DMF),
aceton, methylethayl keton)
which does compete strongly with weak acid for
proton donation
Non-aqueous Titrations
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
Analyte solution, in
Erlenmeyer
Titrant solution, in
burett
Titration
Non-aqueous Titrations
Practical application
Example 1. 4 g tablet of methacholine cloride (195.69 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
O
O cloride.
+ Hg(CH COO)
HgCl + 2CH COO +
O
Cl
2CH 3 COOH2 + + 2CH 3COO From acetous HClO4 From the above rxn
4CH3 COOH
Non-aqueous Titrations
Practical application
Example 2. 0.5 g tablet of Ethosuximide (141.17
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
Hthe % w/w of thosuximide.
Na
O
O + CH3ONa
CH3OH +
ONa