What Is Nonaqueous Titration: Learn Quickly With Case study And FAQs

Nonaqueous titration is an analytical technique in which acid-base reactions are conducted in a solvent other than water, making it ideal for analysing substances that are insoluble or unstable in aqueous solutions. This is a powerful technique for analysing substances that are weakly acidic or basic or are not soluble in water, as water can interfere with the titration of these substances. 

In this article, I will discuss the definition, principle, applications, and a case study of nonaqueous titration, offering both students and professionals a comprehensive overview of this essential analytical method.

Major Takeaway: FAQs

What is Nonaqueous Titration?

Nonaqueous titration is a type of titration in which a solvent other than water is used as the reaction medium. This method is particularly beneficial when analysing compounds that are either insoluble or chemically unstable in water, such as weak acids and weak bases.

It’s extensively used in pharmaceutical analysis, where precision and sensitivity are paramount.

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Principle of Nonaqueous Titration

The principle of nonaqueous titration is based on acid-base reactions that occur in nonaqueous solvents. These solvents either enhance the acidic or basic nature of a compound by stabilising or destabilising ions, making the titration reaction more detectable.

RNH₂ + H⁺ → RNH⁺₃

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

Types of Nonaqueous Titrations:

1. Acidimetry – Titration of a base with a nonaqueous acid.
2. Alkalimetry – Titration of an acid with a nonaqueous base.

Common Solvents Used:

• Glacial acetic acid (acts as both solvent and acid)
• Methanol
• Ethanol
• Acetone
• Dimethylformamide (DMF)

Common Titrants:

• Perchloric acid (in glacial acetic acid) – strong acid
• Sodium methoxide (in methanol) – strong base

Expert Tips:

• Mostly, Glacial acetic acid is used as a dissolving solvent and Perchloric acid (in glacial acetic acid) is used as titrant in pharmaceutical analysis

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 is acetic acid 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 Nonaqueous Titration

1. Pharmaceutical Industry
   • Estimation of weakly basic drugs like ephedrine, chlorpheniramine, and diphenhydramine.
   • Estimation of weakly acidic drugs like aspirin and barbiturates.
2. Chemical Industry
   • Analysis of polymers, dyes, and resins where water reacts undesirably.
3. Quality Control
   • Accurate concentration determination in drug formulations and raw materials.
4. Research Laboratories
   • Precise analytical method for nonaqueous systems in organic synthesis.

Case Study: Nonaqueous Titration

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 Nonaqueous Titration

• Those compounds which are not soluble in water but soluble in acetic acid can easily be quantified by Perchloric acid titration
• Both weak acidic compounds and weak basic compounds can easily be quantified.
• Weak acidic and weak basic compounds which can not be quantified by aqueous acid base titration, can easily be quantified by Perchloric acid titration.
• Easy, precise and accurate
• No need of special skill
• It is fast and cost effective analysis
• Better solubility and stability in organic solvents.
• Sharp endpoints using appropriate indicators.
• Applicable for non-aqueous drug formulations such as Ethambutol hydrochloride

Limitations

• Temperature, moisture and carbon dioxide should be controlled during titration
• Volatile solvents are used which can pollute the environment
• Dissolving solvent like acetic acid has nasty smell
• Requires toxic and volatile solvents – proper handling is essential.
• Glassware and apparatus must be scrupulously clean and dry.
• Specialised training is often needed for accurate endpoint detection.

Conclusion

Nonaqueous titration is a versatile and precise tool in the analytical chemist’s arsenal, particularly when dealing with substances that are incompatible with water. Its applications in pharmaceutical analysis make it indispensable for ensuring the quality and efficacy of drug formulations.

Whether you’re a student preparing for your analytical chemistry exam or a professional working in a lab, understanding nonaqueous titration is key to tackling complex analysis challenges with confidence.

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Further Reading:

• Indian Pharmacopoeia
• Principle of Analytical and Industrial Chemistry: A.K. Singh | Vijay kumar | Surendra Kunwar
• Advanced Practical Inorganic Chemistry: Dr Y. Thakur | Dr J. Thakur
• USP (United States Pharmacopeia)
• ICH Guidelines for Analytical Method Validation