Pharm.analysis: NON-AQUEOUS TITRATIONS

                                              

It’s is used for the assay of certain materials which cannot be easily titrated in aqueous systems

Reasons for titration in NON-AQUEOUS solvents:-

-there are 3 common reasons

      The reactants or products might be insoluble in water.

      The reactants or products might react with water.

      The analyte too weak an acid or base to be titrated in water.

Solvents in NON-AQUEOUS TITRATIONS:-

The solvents are classified into 4 types

1)    Protogenic solvents

2)    Protophillic solvents

3)    Amphiprotic solvents

4)    Aprotic solvents

1) Protogenic solvents:-

            They are acidic solvents they enhances the basicity of weak bases.

         E.g.:- sulfuric acid, formic acid

2) Protophilic solvents:-

            They are basic in nature .they enhances the acidity of weak acids.

         E.g.:-pyridine, n-butylamine, ethylene-di-amine,

3) Amphiprotic solvents:-

            They category of solvents behave as acid or base depending upon the substance dissolved in it.

            They accept or donate protons.

         E.g.:- Glacial acetic acid , Dioxon

4)Aprotic solvents:-

            Solvents in neutral in nature

            These solvents do not accept or donate protons.

            These are useful in dissolving the drugs & they act as solvents.

         E.g.:- Benzene, Carbon tetrachloride.

In non-aqueous solutions the Selection of solvents based on the following considerations:-

1)    Solubility & nature of sample

2)    There should not be any side reactions between the sample or titrant & the solvent

3)    The solvent should not effect on the sharpness of the End-point during titrations.

4)    The titrant & solubility should be readily miscible with the solvent.

5)    The solvent should have high dielectric constant.

6)    The solvent should be readily available of low toxicity, easily purified and in expensive.

SOLVENTS	Dielectric constant	Example of drugs
Formic acid	58.5	Levodop, methyl dopa
Ethylene diamine	12.9	Phenols
Acitic acid,glacial acetic acid	6.13	Adrenaline

Titrating in NON-AQUEOUS solvents:-

Acidic titrants	Basic titrants
Perchloric acid in Dioxon	Tetra alkyl ammonium hydroxide
Perchloric acid in glacial acetic acid	Tetra butyl ammonium hydroxide
P-toluene sulphonic acid	Sodium methoxide
2,4-dinitrobenzene sulphonic acid	Potassium methoxide
2,4,6-trinitrobenzene sulphonic acid	Lithium methoxide

v  Among the acidic titrants perchloric acid in glacial acetic acid is mostly used.

v  In basic titrants methoxide of sodium or potassium or lithium & tetrabutylammonium hydroxide are widely used.

v  The titrants are standardized before the assay of any pharmaceutical substances.

v  The primary standards available for the standardization of acidic titrants are potassium hydrogen phthalate, diphenyl guanidine & anhydrous sodium carbonate.

v  Benzoic acid & phenyl cinchonic acid are suitable primary standards for the standardization of the basic titrations.

Detection of end point:-

            In non aqueous titrimetry, the end point can be detected by the color change of the indictors or by the potentiometric method.

            Ex:- crystal violet-violet-yellowish green

                    Orange blue –blue – pink

                    2-naphthol benzein – blue – dark green

Classification of  NON-AQUEOUS solvents:-

            They are mainly categorized mainly into two classes.

1)    Titration of basic substances

A.    Titration of primary, secondary & tertiary amines

B.    Titration of halogen acid slts of bases

2)    Titration of acidic substances

1) Titration of basic substances:-

                    Perchloric acid 0.1 N in glacial acetic acid:-

Preparation

Ø  Mix 8.5 ml Perchloric acid + 500ml  glacial acetic acid+ 30 ml of acetic anhydrade

Ø  Cool & add more glacial acetic acid to makeup 1000ml .Allow tht solution to stand for 24 hours before use.

Ø  Acetic anhydrade reacts with water in the perchloric acid & acetic anhydrade & readers the mixture virtually anhydrous.

Standardization

Ø  Weight accurately about 0.7g of potassium hydrogen phthalate dissolved in 50ml of glacial acetic acid.

Ø  Add 2 drops of crystal violet solution & titrate with perchloric acid solution until the violet changes to green.

Ø  Detect the volume of perchloric acid consumed by 50ml of  glacial acetic acid.

Each 0.0241g of potassium hydrogen phthalate is equivalent to 1ml of N\10 perchloric acid.

Titration of 1⁰, 2⁰ & 3⁰ amines

Ø  Ex:-Adrenaline can be titrated with acetous perchloric acid.

Titration of halogen acid salts of bases

Ø  Chlorides, Bromides, iodide are very weakly basic & do not react quantitatively with acetous perchloric acid.

Ø  A solution of mercuric acetate is added during the titration.

Ø  This replaces the halides ion by an equivalent quantity of acetate ion. Which is strong base in acetic acid?

2R.NH_2.Hcl                    2R⁺ NH₂ + 2Cl^-

(CH3 Coo)2 HG +2CL-                        HgCl2      +     2CH3Coo-

                                                                            (un dissolved)

                        2CH3 CooH2+ +2CH3Coo-               4CH3CooH

2) Titration of acedic substances:-

Ø  Basic titrants are used. Alkali methoxides or tetrabutyl ammonium hydroxide.

Ø  Lithium mithoxide is preferred because less quantity of lithium metal is required to prepare the solution & the solution is easy to prepare.

Ø  Solvents required to dissolves the substances include

·         dimethyl formamide

·         N-butylamine

·         Ethylene diamine

·         Pyridine

Lithium methoxide 0.1 N

Preparation

Ø  Dissolve 0.7 g of lithium +150ml of methyl alcohol cooling the flask during the addition of methyl

Ø  When the reaction is complete add 850ml of toluene

Ø  If cloudiness or precipitate occurs add sufficient methyl alcohol to clarity the solution

Ø  Store the solution in a container protected from co₂ & moisture.

Standardization

Ø  Weigh accurately 0.25g of benzoic acid dissolved in 25ml of dimethylformamide & titrates with lithium methoxide solution.

Ø  Indicator is QUINOLINE RED.

Ø  Protect the solution from carbon dioxide during the titration.

Ø  Perform the blank titration using 25ml of dimethyl formamide.

Ø  Each 0.01221g of benzoic acid is equivalent to 1ml of 0.1 lithium methoxide.

Tetrabutyl ammonium hydroxide 0.1 N

Preparation

Ø  Dissolve 40g of tetrabutyl ammonium iodide in 90ml of dehydrated methanol in a glass stoppered flask.

Ø  Place the flask in ice bath add 20g of powdered silver oxide, insert the stopper in the flask and agitate vigorously for one hour.

Ø  Centrifuge a few minutes & test the super titrant liquid for iodide.

Ø  If the test is positive add another 2g of silver oxide, and continue to stir for 30 min when all iodide has reacted.

Ø  Filter through fine sintered glass filter.

Ø  Rinse  the flask & filter with three quantities

Ø  Each of 50ml anhydrous toluene

Ø  Add washing to the filtrate and dilute to 1000 ml with anhydrous toluene.

Ø  Flush the solution for 10min with dry carbon dioxide free nitrogen

Ø  Store the container protected from carbon dioxide and moisture

Standardization

Ø  Weigh accurately 0.25g of benzoic acid dissolved in 80ml of dimethylformamide.

Ø  Add 3 drops of 1% solution of thymol blue in dimethylformamide & titrate with tetra butyl ammonium hydroxide.

Ø  End point is blue.

Ø  Perform blank titration

Ø  Each 0.01221g of benzoic acid is equivalent to 1ml of 0.1 tetrabutyl ammonium hydroxide.