1. Non-aqueous Acid-Base Titrations
Dr. Mohammad Khanfar

2. 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.

3. Non-aqueous Titrations

4. 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.

5. 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

6. 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:
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.
onium ion

7. 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

8. Non-aqueous Titrations
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 (why?)
Blank Titration : It is usually carried out to account for the possible reaction of atmospheric moisture with the titrant perchloric acid
undissociated
undissociated

9. Non-aqueous Titrations
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 Erlenmeyer
Titration
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 pyridin (C6H5N). Therefore, titration of CH3COOH2+ (from titrant solution) with CH3COO- (in analyte solution) will generate sharper end point.

10. 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, n-butyl amine, pyridine) or
3) aprotic solvents (N,N-dimethyl formaide (DMF), aceton, methylethayl keton)
which does compete strongly with weak acid for proton donation

11. 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

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. Non-aqueous Titrations
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.
From acetous HClO4
From the above rxn

14. Non-aqueous Titrations
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
g sample of a wheat flour 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