This document discusses non-aqueous titrations, which are used to analyze organic acids and bases that are insoluble or weakly reactive in water. It describes the principles, reasons for using non-aqueous titrations, common solvents like acetic acid, and provides examples of procedures to titrate drugs like ephedrine hydrochloride and sodium benzoate. The key steps involve dissolving the analyte in a non-aqueous solvent, titrating with an acid or base, and determining the endpoint using an indicator reaction.

1. Presented by:-
Meraj Khan
M Pharm(Pharmacology)
Gpat 2018
Assistat Professor
RCU Jharkhand

2. NON-AQUEOUS TITRATIONS
PRINCIPLE:-
The organic acids and bases are insoluble in water. these are extremely
weak and cannot be analysed using normal titrimetric methods. hence the
non aqueous titrimetric methods are employed.
The main principle involved in the non aqueous titrimetric methods
is the samples are dissolved in non aqueous solvents.

3. Why Non aqueous titration:-
These are employed due to the three vital problems of quality control,
both in pure and dosage forms by virtue of their inherent characteristics,
namely:-
(a) Reactants are insoluble in water or poor solubility.
(b) Reactants are weak reactive in aqueous medium.
(c) Reactants are very weak acidic and weak basic in nature.
Pka value >7 - weak Acid
Pka value <7 - weak base

4. Initially, the above three problems were usually avoided in the following
manner:-
1:-Amine salts:-
It is first changed to the water-soluble free base, extracted with an
appropriate organic solvent and treated with an excess volume of standard
acid subsequently, the solvent was evaporated, and the remaining acid
determined with a standard base.
2:- Sodium salts:-
It is first acidified to release the water-insoluble organic acid, extracted
with a suitable organic solvent, the solvent was removed and the residue
was subsequently dried and weighed.
3:-Nitrogen containing compounds:-
They are estimated by micro Kjeldahl’s Method. Nevertheless, such
specific quantitative methods gave rise to certain serious anomalies and
drawbacks.

5. ADVANTAGES OF NON-AQUEOUS TITRATIONS:-
• Elimination of poor solubility of organic acids and bases that are
insoluble in water.
• Enhancement of weak reactivity of substances.
• Selective titration by using suitable solvent and titrant of acidic/basic
components of physiologically active moiety of a salt.
• Weak bases which have Kb values less than 10–6 can be titrated by using
non-aqueous titrations.

6. THEORY:-
According to Bronsted - Lowry theory the various reactions that take place
during many non-aqueous titrations.
Where, an acid is a proton donor and a base is a proton acceptor. Therefore,
when an acid [HA] undergoes dissociation it gives rise to a proton and the
conjugate base [A] of the acid:-
HA H+ + A-

7. SOLVENTS:-
These are of four types and they will be discussed briefly here:-
(i) Protophillic Solvents:-
(ii) Protogenic Solvents:-
(iii) Amphiprotic Solvents:-
(iv) Aprotic Solvents:-
a) Polar Aprotic Solvents
b) Non Polar Aprotic Solvents

8. (i) Protophillic Solvents:-
The words “proto” means proton and “phillic” means loving.
The solvent which accept proton is called as protophillic solvents.
They are essentially basic in nature and normally react with acids to form
solvated protons:-
HA + Sol. Sol. H+ + A–
Example:-Liquid ammonia, NaOH, KOH, NH4OH
1. Levelling effect:-
Effect of protophillic solvents on the properties of acids and bases
2. Differentiating effect:-

9. Levelling effect:-
In leveling solvents, several acids are completely dissociates and
having same strength.
Weak acids are normally used in the presence of strongly protophilic
solvents(Strong Base) as their acidic strengths are then enhanced and
then become comparable to these of strong acids; this is known as the
levelling effect.
In other words, strong protophillic solvents convert weak acid to strong
acid is known as Levelling effect.
Generally stong bases are exert as lavelling solvents for strong acid
as well as weak acid.
Example:- H20 is act as levelling solvent for HCl and HBr.

10. Differentiating effect:-
In differentiating solvents, several acids are dissociates to different
degrees and having different strength.
Generally weak bases are exert as differentiating solvents for strong acid
as well as weak acid.
Example:- H20 is act as differentiating solvent for HF.

11. (ii) Protogenic Solvents:-
The words “proto” means proton and “genic” means generate.
The solvent which generate or donate proton is called as protogenic
solvents.
They are acidic in nature.
Example:- Anhydrous acids such as HF, H2SO4, HCl, HBr, HClO4 etc.

12. (iii) Amphiprotic Solvents:-
They possess both protophillic and protogenic characteristics.
These type of solvents able to donate protons as well as accept protons.
Examples:- Acetic acid, water and alcohols.
They undergo dissociation to a very less extent.
Acetic acid is mostly employed as a solvent for the titration of basic substances
and its dissociation can be depicted as shown below:-
CH3COOH H+ + CH3COO–
In the above instance acetic acid is behaving as an acid.

13. (iv) Aprotic Solvents:-
These type of solvents neither donate protons nor accept protons.
Aprotic solvents include those substances, which may be considered
chemically neutral, and virtually un-reactive or inert.
These may be fall in two types:-
a) Polar Aprotic Solvents:-Acetone, DMSO(Di methyl
sulfoxamide)
b) Non Polar Aprotic Solvents:-Benzene, Toluene, Hydrocarbon
Aprotic solvents are frequently used to dilute reaction mixture.

14. METHODOLOGY
For non-aqueous titrations, the following four steps are usually taken into
consideration, namely:-
(i) Preparation of 0.1 N Perchloric acid,
(ii) Standardization of 0.1 N Perchloric Acid,
(iii) Choice of Indicators
(iv) Effect of Temperature on Assays.

15. PREPARATION OF 0.1 N PERCHLORIC ACID
Procedure:-
Gradually mix 8.5 ml of perchloric acid to 900 ml of glacial acetic acid
with vigorous and continuous stirring.
Now add 30 ml acetic anhydride and make up the volume to 1 litre
with glacial acetic acid.
Allow to stand for 24 hours before use.

16. Procedure:-
Weigh accurately about 0.5 g of potassium hydrogen phthalate in a 100 ml
conical flask.
Add 25 ml of glacial acetic acid and attach a reflux condenser fitted with a
silica-gel drying tube.
Warm until the salt gets dissolved completely.
Cool and titrate with 0.1 N perchloric acid by making use of any indicators
observed end point
(a) Crystal violet:- Blue to Blue-Green
(b) Oracet blue B:- Blue to Pink.

17. ASSAY BY NON-AQUEOUS TITRATIONS
Non aqueous titrations can be categorized into two class:-
(i) Acidimetry in Non-aqueous Titrations
(ii) Alkalimetry in Non-aqueous Titrations
Fill the titrant in the Burette.
Take analyte & indicator in Conical Flask
Add titrant drop wise to the analyte with use
of indicator
Titrant neutralize the analyte or is visibly
spotted by the use of indicators.(End Point)
When completely neutralize the
analyte(equivalent Point)

18. (i) Acidimetry in Non-aqueous Titrations:-
It is used for quantitative estimation of basic drugs.
Titrant used in acidimetry is acidic in nature like Perchloric acid.
Solvents:- Protogenic solvents are used like Glacial acetic acid.
Indicators:- Crystal violet (End point observed as violet to light green).
Application:-
It may be used for analysis of Ephedrine, Morphine, Adrenaline, Acyclovir
and Caffeine.
It can be further sub-divided into two heads, namely as:-
(i) Titration of primary, secondary and tertiary amines like
Methlyldopa.
(ii) Titration of halogen acid salts of bases.

19. (ii) Alkalimetry in Non-aqueous Titrations:-
It is used for quantitative estimation of acidic drugs.
Titrant used in alkalimetry is basic in nature like sodium
methoxide(CH3COONa).
Solvents:- Protophillic solvents are used like DMF(Dimethyl formamide).
Indicators:-Thymol blue (End point observed as Pink to blue).
Application:-It may be used for analysis of Nalidixic acid, Acetazolamide,
Allopurinol, Mercaptopurin.

20. ESTIMATION OF EPHEDRINE HYDROCHLORIDE
Assay Procedure:-
Weigh accurately about 0.17 g of Ephedrine Hydrochloride, dissolve in 10
ml of mercuric acetate solution, warming gently, add 50 ml of acetone and
mix.
Titrate with 0.1 M perchloric acid, using 1 ml of a saturated solution of
methyl orange in acetone as indicator, until a Red Colour is obtained.
Where,
X ml = Volume of titrant consumed at end point
Normality Calculated = Normality of Perchloric acid after standardization
Normality Given = 0.1 N (theoretically)
Equivalent or I.P factor:- 1 ml of 0.1 M perchloric acid is equivalent to 0.02017 g
of C10H15NO.HCl.

21. ESTIMATION OF SODIUM BENZOATE
Assay Procedure:-
Weigh accurately about 0.25 g of Sodium Benzoate, dissolve in 20 ml of anhydrous
glacial acetic acid, warming to 50º if necessary, cool.
Titrate with 0.1 M perchloric acid, using 0.05 ml of 1-naphtholbenzein solution as
indicator.
Equivalent or I.P factor:-
1 ml of 0.1 M perchloric acid is equivalent to 0.01441 g of C7H5NaO2.
Where,
X ml = Volume of titrant consumed at end point
Normality Calculated = Normality of Perchloric acid after standardization
Normality Given = 0.1 N (theoretically)

22. Thank you……