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NON-AQUEOUS TITRATIONS
INTRODUCTION
During the past four decades a several newer complex
organic medicinal compounds have been proved of
therapeutic value.
Evidently, these compounds posed two vital problems
during their analysis
(a) poor solubility
(b) weak reactivity in aqueous medium
Such substances which give poor end point due to
being weak acids or bases in aqueous solutions can be
analysed by non-aqueous titrations.
Additionally the substances which are insoluble in
water dissolve in organic solvents and can be titrated in
non-aqueous media.
Nonaqueous titration is the titration of substances
dissolved in no aqueous solvent.
It is suitable for the titration of very weak acids and weak
bases.
Weak bases which have Kb values less than
10–6 can not be assayed accurately in aqueous medium.
However such weak bases can be titrated
satisfactorily by non-aqueous titrations.
Consider assay of a weak base
In aqueous solution a very weak base may act as a weaker
proton acceptor compared to water and cannot be titrated
properly with distinct end point.
However this difficulty can be overcome using non-
aqueous solvents….
In non-aqueous solvents like glacial acetic acid, it can
accept proton readily when perchloric acid is used as
titrant.
HClO4 + CH3COOH CH3COOH2
+
CH3COOH2
+ + B BH+ + CH3COOH
Similarly, substances which are weakly acidic in nature like
phenol, barbiturates can be satisfactorily titrated in
dimethylformamide solvent and using alkali methoxide as
titrant.
Non–aqueous solvents are classified into four groups
A) Aprotic
B) Protophilic
C) Protogenic
D) Amphiprotic
A) Aprotic solvents
These are chemically neutral and unreactive
substances having low dielectric constant and don’t
cause ionization of solutes and do not undergo
reactions with acids and bases
e.g. toluene and carbon tetrachloride.
B) Protophilic solvents
These solvents possess high affinity for protons. In
presence of such strongly protophilic solvents acidic
strength of weak acids is enhanced and they become
comparable to strong acids
e.g. liquid ammonia, amines and ketones.
This is called as levelling effect.
C) Protogenic solvents
Thse solvents are acidic in nature and readily donate
protons.Due to their ability to donate portons they
enhance strength of weak bases
e.g. sulhuric acid, hydrogen fluoride.
D) Amphiprotic solvents
These solvents are slightly ionized. They possess
protogenic as well as protophilic properties. Thus they
donate as well as accept protons e.g. water, alcohol, weak
organic acids.
Ethanoic acid generally displays acidic properties and
dissociates to produce protons
CH3COOH CH3COO- + H+
In presence of perchoric acid (stronger acid) it accepts a
proton
CH3COOH + HClO4 CH3COOH2
+ + ClO4
3
3
LEVELLING SOLVENTS
strongly protophilic or strongly protogenic solvents act as
leveling solvents in non-aqueous titrations.
In presence of strongly protophilic solvents, all acids act
to be of similar strength.
The converse occurs with strongly protogenic solvents
which cause all the bases to act as if they were of
similar strength.
Solvents which act in this manner are levelling solvents.
Strong bases are levelling solvent for acids.
DIFFERENTIATING SOLVENTS
Strong protogenic/protophilic solvents exert a levelling
effect on weak bases/acids
A strong protogenic solvent cannot differentiate between
weak base and a very weak base as it forces both to accept
proton .
• A relatively weak protogenic solvent can differentiate
between a weak base and slightly weaker base by
causing the relatively more basic substance to act as a
base while not affecting the weaker one.
• Thus exerting a differentiating effect.
• Similarly weak protophilic solvents differentiate between
weak acid and slightly weaker acid.
SELECTION OF SOLVENT
Selection of a proper solvent is essential in non-aqueous
titrations.
Especially important factors are the basicity and the
dielectric properties of the solvent.
Increased basicity of the solvent enhances the acidic
properties of a dissolved acid (sample).
A low dielectric constant of the solvent depresses the
ionisation and thereby enhances the acid strength or base
strength of the sample to be assayed.
ASSAY BY NON-AQUEOUS TITRATIONS
(a) Acidimetry in Non-aqueous Titrations
It can be further sub-divided into two heads namely :
(1) Titration of primary, secondary and tertiary amines
(2) Titration of halogen acid salts of bases.
(b) Alkalimetry in Non-aqueous Titrations
Titration of acidic substances
Acidimetry in Non-aqueous Titrations (TITRATION OF WEAK
BASES)
TITRANT -
Perchloric Acid : It is a very strong acid and when it is
made to dissolve in acetic acid, acetic acid behaves as a
base and forms an ‘onium ion’ after combining with
protons donated by the perchloric 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.
e.g. Pyridine, a weak base, when dissolved in acetic acid,
acetic acid exerts its levelling effect and subsequently
increases the basic characteristics of the pyridine.
Therefore, it is practically feasible to titrate a solution of a
weak base in acetic acid against a mixture of perchloric
acid in acetic acid.
Thus, a sharp end point is achieved which otherwise
cannot be obtained when the titration is performed in an
aqueous medium.
REACTIONS INVOLVED IN PYRIDINE ASSAY
For non-aqueous titrations of weak bases, 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
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 and allow to stand for 24
hours before use.
The acetic anhydride reacts with the water (approx. 30%)
in perchloric acid and some traces in glacial acetic acid
thereby making the resulting mixture practically
anhydrous.
STANDARDIZATION OF 0.1 N PERCHLORIC ACID -
• Usually potassium hydrogen phthalate is used
as a standardizing agent for acetous perchloric
acid.
• To 500 mg of potassium acid phthalate add 25 ml
of glacial acetic acid and add few drops of 5% w/v
crystal violet in glacial acetic acid as indicator. This
solution is titrated with 0.1 HClO4. The colour
changes from blue to blue green.
• 1 ml of 0.1N HClO4 = 0.020414 gms of potassium
acid Phthalate.
PRECAUTIONS DURING PREPARATION OF PERCHLORIC
ACID
(a) Perchloric acid is usually available as a 70 to 72%
mixture with water.
It usually undergoes explosive decomposition and,
therefore, it is available always in the form of a
solution.
(b) Conversion of acetic anhydride to acetic acid
requires 40-45 minutes for its completion. It being
an exothermic reaction, the solution must be
allowed to cool to room temperature before adding
glacial acetic acid to volume
CHOICE OF INDICATORS
Indicators commonly used in non-aqueous titrations are
Thymol Blue, Thymolphthalein , Phenolphthalein Azo Violet
,O-nitroaniline.
Following indicators are also widely used ….
EFFECT OF TEMPERATURE ON ASSAYS
Generally, most non-aqueous solvents possess greater
coefficients of expansion as compared to water which is
why small differences in temperature may afford
significant and appreciable errors .
Hence, it is always advisable to carry out standardization
and titration preferably at the same temperature.
EXAMPLES OF ACIDIMETRY
1) Titration of primary, secondary and tertiary amines
Methyldopa
Methacholine Chloride
Adrenaline
Chlordiazepoxide
Quinine sulphate
Salbutamol sulphate
Sodium benzoate
2)Titration of Halogen Acid Salts of Bases-
In general, the halide ions, namely chloride, bromide and
iodide are very weakly basic in character so they cannot
react quantitatively with acetous perchloric acid.
To overcome this problem, mercuric acetate is usually
added to a halide salt thereby causing the replacement
of halide ion by an equivalent amount of acetate ion,
which serves as a strong base in acetic acid
e.g. Amitriptyline Hydrochloride
Ephedrine hydrochloride
Lignocaine hydrochloride
Assay of Ephedrine HCl
PRINCIPLE
• Non-aqueous acid base titration
• Very weakly basic
• Can not react quantitatively with acetous perchloric
acid
• Hence Mercuric acetate is added to replace halide
ion with an equivalent quantity of acetate ion, which
is a strong base in acetic acid
Assay of Ephedrine HCl
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. Carry out a blank titration. Subtract blank
from sample reading. Calculate percent purity of the
sample.
Ephedrine HCl assay reaction
Factor for assay of Ephedrine HCl
201.7 gms ≡ 1000 ml 1 M HClO4
0.02017 gms C10H15NO,HCl ≡ 1 ml 0.1 M
HClO4
Standardization of HClO4
To 500 mg of potassium acid phthalate add 25 ml of
glacial acetic acid and add few drops of 5% w/v
crystal violet in glacial acetic acid as indicator.
This solution is titrated with 0.1 HClO4. The color
changes from blue to blue green.
Assay of Ephedrine HCl
Assay of sodium benzoate
Preparation and standardization of titrant 0.1N
solution of HClO4
Dissolve 8.5 ml of 72% HClO4 in about 900 ml
glacial acetic acid with constant stirring, add about
30 ml acetic anhydride and make up the volume
(1000 ml) with glacial acetic acid and keep the
mixture for 24 hours. Acetic anhydride absorbs all
the water from HClO4 and glacial acetic acid and
renders the solution virtually anhydrous. HClO4
must be well diluted with glacial acetic acid before
adding acetic anhydride because reaction between
HClO4 and acetic anhydride is explosive.
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. Carry out a blank titration.
1 ml of 0.1 M perchloric acid is equivalent to
0.01441 g of C7H5NaO2.
ALKALIMETRY IN NON-AQUEOUS TITRATIONS
Weakly acidic pharmaceutical substances may be
titrated effectively by making use of a suitable non-
aqueous solvent with a sharp end-point.
such organic compounds include….
Anhydrides, Acids, Amino Acids, Acid Halides.
Titrants used-
0.1 N Potassium Methoxide in Toluene-Methanol
Sodium Methoxide
Lithium Methoxide
Tetrabutylammonium Hydroxide
Primary standard : Benzoic acid
Indicator: Thymol blue
Dimethylformamide (DMF) is used as solvent
Standardization of 0.1 N Methoxide Solution
• Procedure:. Transfer 10 ml of DMF in a
conical flask and add to it 3 to 4 drops of
thymol blue and first neutralize the acidic
impurities present in DMF by titrating with
0.1 N lithium methoxide in toluene-methanol.
Quickly introduce 0.06g of benzoic acid and
titrate immediately with methoxide in
toluene-methanol.
• Caution: Care must be taken to avoid
contamination of neutralized liquid with
atmospheric carbon dioxide.
• The clear solution of sodium methoxide must be
kept away from moisture and atmospheric CO2
as far as possible so as to avoid the following
two chemical reactions that might ultimately
result into the formation of turbidity.
H2O + CH3ONa → CH3OH + NaOH
H2CO3 + 2CH3ONa → 2CH3OH + Na2CO3
Assay of Ethosuximide
• Procedure: Weigh accurately about 0.2 g of the
sample, dissolve in 50 ml of dimethylformamide,
add 2 drops of azo-violet solution and titrate with
0.1 N sodium methoxide to a deep blue end
point, taking precautions to prevent absorption
of atmospheric carbon dioxide. Perform a blank
determination and make any necessary
correction.
• Each ml of 0.1 N sodium methoxide is equivalent
to 0.01412 g of C7H11NO2
.
Reaction involved in Ethosuximide Assay
Examples of drugs assayed by alkalimetry
 AcetazolamideEthosuximide
 Ethosuximide
 Allopurinol
 Nalidixic Acid
 Diloxanide Furoate
 Hydrochlorothiazide

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NON AQUEOUS FINAL - Copy.pptx

  • 2. INTRODUCTION During the past four decades a several newer complex organic medicinal compounds have been proved of therapeutic value. Evidently, these compounds posed two vital problems during their analysis (a) poor solubility (b) weak reactivity in aqueous medium
  • 3. Such substances which give poor end point due to being weak acids or bases in aqueous solutions can be analysed by non-aqueous titrations. Additionally the substances which are insoluble in water dissolve in organic solvents and can be titrated in non-aqueous media.
  • 4. Nonaqueous titration is the titration of substances dissolved in no aqueous solvent. It is suitable for the titration of very weak acids and weak bases.
  • 5. Weak bases which have Kb values less than 10–6 can not be assayed accurately in aqueous medium. However such weak bases can be titrated satisfactorily by non-aqueous titrations.
  • 6. Consider assay of a weak base In aqueous solution a very weak base may act as a weaker proton acceptor compared to water and cannot be titrated properly with distinct end point. However this difficulty can be overcome using non- aqueous solvents….
  • 7. In non-aqueous solvents like glacial acetic acid, it can accept proton readily when perchloric acid is used as titrant. HClO4 + CH3COOH CH3COOH2 + CH3COOH2 + + B BH+ + CH3COOH Similarly, substances which are weakly acidic in nature like phenol, barbiturates can be satisfactorily titrated in dimethylformamide solvent and using alkali methoxide as titrant.
  • 8. Non–aqueous solvents are classified into four groups A) Aprotic B) Protophilic C) Protogenic D) Amphiprotic
  • 9. A) Aprotic solvents These are chemically neutral and unreactive substances having low dielectric constant and don’t cause ionization of solutes and do not undergo reactions with acids and bases e.g. toluene and carbon tetrachloride.
  • 10. B) Protophilic solvents These solvents possess high affinity for protons. In presence of such strongly protophilic solvents acidic strength of weak acids is enhanced and they become comparable to strong acids e.g. liquid ammonia, amines and ketones. This is called as levelling effect.
  • 11. C) Protogenic solvents Thse solvents are acidic in nature and readily donate protons.Due to their ability to donate portons they enhance strength of weak bases e.g. sulhuric acid, hydrogen fluoride.
  • 12. D) Amphiprotic solvents These solvents are slightly ionized. They possess protogenic as well as protophilic properties. Thus they donate as well as accept protons e.g. water, alcohol, weak organic acids. Ethanoic acid generally displays acidic properties and dissociates to produce protons CH3COOH CH3COO- + H+ In presence of perchoric acid (stronger acid) it accepts a proton CH3COOH + HClO4 CH3COOH2 + + ClO4 3 3
  • 13. LEVELLING SOLVENTS strongly protophilic or strongly protogenic solvents act as leveling solvents in non-aqueous titrations. In presence of strongly protophilic solvents, all acids act to be of similar strength.
  • 14. The converse occurs with strongly protogenic solvents which cause all the bases to act as if they were of similar strength. Solvents which act in this manner are levelling solvents. Strong bases are levelling solvent for acids.
  • 15. DIFFERENTIATING SOLVENTS Strong protogenic/protophilic solvents exert a levelling effect on weak bases/acids A strong protogenic solvent cannot differentiate between weak base and a very weak base as it forces both to accept proton .
  • 16. • A relatively weak protogenic solvent can differentiate between a weak base and slightly weaker base by causing the relatively more basic substance to act as a base while not affecting the weaker one. • Thus exerting a differentiating effect. • Similarly weak protophilic solvents differentiate between weak acid and slightly weaker acid.
  • 17. SELECTION OF SOLVENT Selection of a proper solvent is essential in non-aqueous titrations. Especially important factors are the basicity and the dielectric properties of the solvent. Increased basicity of the solvent enhances the acidic properties of a dissolved acid (sample). A low dielectric constant of the solvent depresses the ionisation and thereby enhances the acid strength or base strength of the sample to be assayed.
  • 18. ASSAY BY NON-AQUEOUS TITRATIONS (a) Acidimetry in Non-aqueous Titrations It can be further sub-divided into two heads namely : (1) Titration of primary, secondary and tertiary amines (2) Titration of halogen acid salts of bases.
  • 19. (b) Alkalimetry in Non-aqueous Titrations Titration of acidic substances
  • 20. Acidimetry in Non-aqueous Titrations (TITRATION OF WEAK BASES) TITRANT - Perchloric Acid : It is a very strong acid and when it is made to dissolve in acetic acid, acetic acid behaves as a base and forms an ‘onium ion’ after combining with protons donated by the perchloric acid.
  • 21. 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.
  • 22. e.g. Pyridine, a weak base, when dissolved in acetic acid, acetic acid exerts its levelling effect and subsequently increases the basic characteristics of the pyridine. Therefore, it is practically feasible to titrate a solution of a weak base in acetic acid against a mixture of perchloric acid in acetic acid. Thus, a sharp end point is achieved which otherwise cannot be obtained when the titration is performed in an aqueous medium.
  • 23. REACTIONS INVOLVED IN PYRIDINE ASSAY
  • 24. For non-aqueous titrations of weak bases, 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
  • 25. 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 and allow to stand for 24 hours before use.
  • 26. The acetic anhydride reacts with the water (approx. 30%) in perchloric acid and some traces in glacial acetic acid thereby making the resulting mixture practically anhydrous.
  • 27. STANDARDIZATION OF 0.1 N PERCHLORIC ACID - • Usually potassium hydrogen phthalate is used as a standardizing agent for acetous perchloric acid. • To 500 mg of potassium acid phthalate add 25 ml of glacial acetic acid and add few drops of 5% w/v crystal violet in glacial acetic acid as indicator. This solution is titrated with 0.1 HClO4. The colour changes from blue to blue green. • 1 ml of 0.1N HClO4 = 0.020414 gms of potassium acid Phthalate.
  • 28. PRECAUTIONS DURING PREPARATION OF PERCHLORIC ACID (a) Perchloric acid is usually available as a 70 to 72% mixture with water. It usually undergoes explosive decomposition and, therefore, it is available always in the form of a solution.
  • 29. (b) Conversion of acetic anhydride to acetic acid requires 40-45 minutes for its completion. It being an exothermic reaction, the solution must be allowed to cool to room temperature before adding glacial acetic acid to volume
  • 30. CHOICE OF INDICATORS Indicators commonly used in non-aqueous titrations are Thymol Blue, Thymolphthalein , Phenolphthalein Azo Violet ,O-nitroaniline. Following indicators are also widely used ….
  • 31. EFFECT OF TEMPERATURE ON ASSAYS Generally, most non-aqueous solvents possess greater coefficients of expansion as compared to water which is why small differences in temperature may afford significant and appreciable errors . Hence, it is always advisable to carry out standardization and titration preferably at the same temperature.
  • 32. EXAMPLES OF ACIDIMETRY 1) Titration of primary, secondary and tertiary amines Methyldopa Methacholine Chloride Adrenaline Chlordiazepoxide Quinine sulphate Salbutamol sulphate Sodium benzoate
  • 33. 2)Titration of Halogen Acid Salts of Bases- In general, the halide ions, namely chloride, bromide and iodide are very weakly basic in character so they cannot react quantitatively with acetous perchloric acid.
  • 34. To overcome this problem, mercuric acetate is usually added to a halide salt thereby causing the replacement of halide ion by an equivalent amount of acetate ion, which serves as a strong base in acetic acid e.g. Amitriptyline Hydrochloride Ephedrine hydrochloride Lignocaine hydrochloride
  • 36. PRINCIPLE • Non-aqueous acid base titration • Very weakly basic • Can not react quantitatively with acetous perchloric acid • Hence Mercuric acetate is added to replace halide ion with an equivalent quantity of acetate ion, which is a strong base in acetic acid Assay of Ephedrine HCl
  • 37. 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. Carry out a blank titration. Subtract blank from sample reading. Calculate percent purity of the sample.
  • 39. Factor for assay of Ephedrine HCl 201.7 gms ≡ 1000 ml 1 M HClO4 0.02017 gms C10H15NO,HCl ≡ 1 ml 0.1 M HClO4
  • 40. Standardization of HClO4 To 500 mg of potassium acid phthalate add 25 ml of glacial acetic acid and add few drops of 5% w/v crystal violet in glacial acetic acid as indicator. This solution is titrated with 0.1 HClO4. The color changes from blue to blue green.
  • 42. Assay of sodium benzoate
  • 43. Preparation and standardization of titrant 0.1N solution of HClO4 Dissolve 8.5 ml of 72% HClO4 in about 900 ml glacial acetic acid with constant stirring, add about 30 ml acetic anhydride and make up the volume (1000 ml) with glacial acetic acid and keep the mixture for 24 hours. Acetic anhydride absorbs all the water from HClO4 and glacial acetic acid and renders the solution virtually anhydrous. HClO4 must be well diluted with glacial acetic acid before adding acetic anhydride because reaction between HClO4 and acetic anhydride is explosive.
  • 44. 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. Carry out a blank titration. 1 ml of 0.1 M perchloric acid is equivalent to 0.01441 g of C7H5NaO2.
  • 45. ALKALIMETRY IN NON-AQUEOUS TITRATIONS Weakly acidic pharmaceutical substances may be titrated effectively by making use of a suitable non- aqueous solvent with a sharp end-point. such organic compounds include…. Anhydrides, Acids, Amino Acids, Acid Halides.
  • 46. Titrants used- 0.1 N Potassium Methoxide in Toluene-Methanol Sodium Methoxide Lithium Methoxide Tetrabutylammonium Hydroxide Primary standard : Benzoic acid Indicator: Thymol blue Dimethylformamide (DMF) is used as solvent
  • 47. Standardization of 0.1 N Methoxide Solution • Procedure:. Transfer 10 ml of DMF in a conical flask and add to it 3 to 4 drops of thymol blue and first neutralize the acidic impurities present in DMF by titrating with 0.1 N lithium methoxide in toluene-methanol. Quickly introduce 0.06g of benzoic acid and titrate immediately with methoxide in toluene-methanol. • Caution: Care must be taken to avoid contamination of neutralized liquid with atmospheric carbon dioxide.
  • 48. • The clear solution of sodium methoxide must be kept away from moisture and atmospheric CO2 as far as possible so as to avoid the following two chemical reactions that might ultimately result into the formation of turbidity. H2O + CH3ONa → CH3OH + NaOH H2CO3 + 2CH3ONa → 2CH3OH + Na2CO3
  • 49. Assay of Ethosuximide • Procedure: Weigh accurately about 0.2 g of the sample, dissolve in 50 ml of dimethylformamide, add 2 drops of azo-violet solution and titrate with 0.1 N sodium methoxide to a deep blue end point, taking precautions to prevent absorption of atmospheric carbon dioxide. Perform a blank determination and make any necessary correction. • Each ml of 0.1 N sodium methoxide is equivalent to 0.01412 g of C7H11NO2 .
  • 50. Reaction involved in Ethosuximide Assay
  • 51. Examples of drugs assayed by alkalimetry  AcetazolamideEthosuximide  Ethosuximide  Allopurinol  Nalidixic Acid  Diloxanide Furoate  Hydrochlorothiazide