Non-Aqueous titration in the pharmaceutical industries

Introduction and Outcome

Non-aqueous titration (perchloric acid titration) is one of the widely used titrations in the Pharmaceutical industry. This is used for quantification (assay) of both acidic pharmaceuticals and basic pharmaceuticals. In this article, I will share skill-based knowledge on principle, applications, need, procedure, advantages and disadvantages of perchloric acid titration with case studies. After reading this article, all your doubts will be cleared and your knowledge will be increased to the next level.

Table of Contents

• Introduction and Outcome
• Non-aqueous or Perchloric titration
• Principle of perchloric acid titration
• Need of Perchloric acid titration
• Chemical and reagents required for Perchloric titration
• Preparation of 0.1N Perchloric acid volumetric solution
• Why acetic anhydride is added during preparation of 0.1N Perchloric acid?
• Why acetic acid is used as a dissolving solvent in Perchloric titration?
• Applications of Perchloric titration
• Case studies
• Advantages of Perchloric titration
• Disadvantages of Perchloric titration
• Conclusion
• FAQs

Non-aqueous or Perchloric titration

In perchloric acid titration, the compound is dissolved in solvents which do not contain water or in other words dissolving solvent must be free from water. Generally, glacial acetic acid is used as a dissolving solvent in non-aqueous titration.

Principle of non-aqueous titration

RNH₂ + H⁺ → RNH⁺₃

Principle of Perchloric acid titration is similar to acid base titration. Glacial acetic acid is used as dissolving solvent . Very sharp end point is obtained in this titration.

Need of Perchloric acid titration

Water behaves as both a weak acid and a weak base and therefore it accepts proton in the presence of acid and donates proton in the presence of base. Therefor aqueous acid-base titration can not be used for too acidic compound and too basic compounds. Secondly, aqueous acid-base titration can also not be used for those compounds which are insoluble in water. That is why Perchloric acid titration is needed for quantification of such compounds.

Chemical and reagents required for Perchloric titration

The following chemicals and reagents are required for Perchloric acid titration:

• 0.1N Perchloric acid volumetric solution
• Crystal violet indicator: It has violet colour in the basic medium and yellowish green in the acidic medium.
• Glacial acetic acid
• 0.5% Mercuric acetate solution in glacial acetic acid: It is used during analysis of amine salts e.g. Ethambutol hydrochloride

Preparation of 0.1N Perchloric acid volumetric solution

Pipette out 8.5 ml of Perchloric acid (about 70%) and transfer in 1000ml of volumetric flask containing 500 ml of glacial acetic acid. Then and 25 ml of acetic anhydride and make up the volume with acetic acid. calculate the normality using potassium hydrogen phthalate.

Why acetic anhydride is added during preparation of 0.1N Perchloric acid?

Acetic anhydride absorbs residual water of the glacial acetic acid and converts into acetic acid by following reaction mechanism:

H₃C-OC-O-CO-CH₃ + H₂O → 2CH₃COOH

That is why acetic anhydride added during preparation of 0.1N Perchloric acid

Compounds analysed by perchloric acid titration

Both weak acidic compounds and basic compounds like amines, amine salts, amino acids and salts of acids can be quantified by perchloric acid titration.

End point determination

The following two methods are used to determine end point:

• Use of Crystal violet indicator
• Potentiometric titration

Why acetic acid is used as a dissolving solvent in Perchloric titration?

In the presence of base acetic acid donates protons

CH₃COOH → CH₃COO^– + H⁺

But in the presence of Perchloric acid acetic acid accepts protons:

CH₃COOH +HClO₄ → CH₃COOH₂⁺ (Onium ion)+ ClO4^–

Then CH₃COOH₂⁺ reacts with bases and gives its protons.

Applications of Non-aqueous titration

Perchloric acid titration is widely used in the assay and content tests in the following industries:

• Pharmaceutical industries
• Food industries
• Pesticides industries
• Research and development centres
• Testing laboratory

Case studies

Basic-pharmaceuticals like Aniline and Atenolol can be quantified by Perchloric acid titration

C₆H₅NH₂ + CH₃COOH → C₆H₅NH₃⁺ +CH3COO^–

CH₃COO^– + HClO₄ → CH₃COOH + ClO₄^–

• About 400 mg sample (e.g. Atenolol ) + 50 ml glacial acetic acid + 2 drops of crystal violet indicator. Shake to dissolve and titrate with 0.1 N Perchloric acid.
• Perform the blank titration and do the necessary correction
• End point: The colour changes at the end point is from blue to blue-green
• Calculate the assay

Different salts like Aniline hydrochloride, Ethambutol hydrochloride and Ephedrine hydrochloride can be quantified by Perchloric acid titration using Mercuric acetate solution

Cl^– + Hg(CH₃COOH)₂ → CH3COO^– + HgCl₂

CH₃COO^– + HClO₄ → CH₃COOH + ClO₄^–

• About 500 mg sample (e.g. Ethambutol hydrochloride) + 50 ml glacial acetic acid +Mercuric acetate solution 2 drops of crystal violet indicator. Shake to dissolve and titrate with 0.1 N Perchloric acid.
• Perform the blank titration and do the necessary correction
• End point: The colour changes at the end point is from blue to blue-green
• Calculate the assay

Advantages of Non-aqueous titration

The following are the advantages of the Perchloric acid titration:

1. Those compounds which are not soluble in water but soluble in acetic acid can easily be quantified by Perchloric acid titration
2. Both weak acidic compounds and weak basic compounds can easily be quantified.
3. Weak acidic and weak basic compounds which can not be quantified by aqueous acid base titration, can easily be quantified by Perchloric acid titration.
4. Easy, precise and accurate
5. No need of special skill
6. It is fast and cost effective analysis

Disadvantages of Non-aqueous titration

1. It is not specific and suitable for only pure compounds
2. Temperature, moisture and carbon dioxide should be controlled during titration
3. Volatile solvents are used which can pollute the environment
4. Dissolving solvent like acetic acid has nasty smell

Conclusion

Perchloric acid titration is the only titration which is used for quantification of acids, bases and their salts I hope this article has cleared all your doubts related to perchloric acid titration and your knowledge has increased to the next level. For any question or suggestion related to this article write in the comment section.

FAQs

What are the advantages of non-aqueous titration?

Non aqueous titration is fast, cost effective and it does not need any special skill. Secondly both weak acids and bases can be quantified using perchloric titration.

Which drugs are analysed by non-aqueous titration?

Several drugs like Aniline, Ethambutol,Ephedrine and their hydrochloride salt can be quantified using perchloric acid titration.

Which indicator is used in non-aqueous titration?

Crystal violet indicator is used in non aqueous titration

What are the classifications of non-aqueous solvents?

Non aqueous solvents can be classified into protophilic-solvent, protogenic-solvent and amphiprotic-solvent

Why is acetic acid used in the non-aqueous titration?

It accepts protons with weak acids and donates protons to bases and that is why acetic acid is used in the non aqueous titration

Why is Perchloric acid used in the non-aqueous titration?

It is strongest acid and weak acids, bases and their salts can be quantified by perchloric acid titration. That is why Perchloric acid used in the non aqueous titration.

What is the principle of non-aqueous titration?

Principle of Perchloric acid titration is similar to acid base titration. Glacial acetic acid is used as dissolving solvent. Very sharp end point is obtained in this titration.

RNH₂ + H⁺ → RNH⁺₃

What are the advantages and disadvantages of non-aqueous titration?

Advantages of non aqueous titration is; It fast, cost effective and it does not need any special skill. Secondly both weak acids and bases can be quantified using perchloric titration.

Its disadvantages are; It is only suitable for pure compounds and not suitable for impure compounds. secondly it is not specific titration

What is the role of acetic anhydride in non-aqueous titration?

The role of acetic anhydride is absorbs residual moisture.

Why water is not used in non-aqueous titration?

Water can accept the proton and can also donate the proton depending upon the nature of the molecule. Secondly it can decompose the Perchloric acid and that is why water is not used in the perchloric acid titration

What are non-aqueous titration application in the Pharmaceutical industries?

Non-aqueous titration application in the Pharmaceutical industries is to perform assay and contents tests.

Abbreviations

• N: Normal solution
• FAQs: Frequently asked questions
  

References

• Quantitative organic analysis; Vogel