Titrations in Pharmaceutical Industries

Table of Contents

• Introduction and outcome
• Titration and their type
• Acid-base titration
  • Indicator for for acid-base titration
• Precipitation titration
  • Indicator for precipitation titration
• Redox titration or Oxidation-reduction titration
• Iodometric titration
• Iodimetric titration
  • Difference between Iodimetric titration and Iodometric titration
• Complexometric titration or EDTA titration
• Volumetric solution, titrant and Indicator
• Application of titrations
• Advantages of titrations
• Disadvantages
• How to design formula for titration
• 4 simple steps titration method development procedure
• Concussion
• FAQs

Introduction and outcome

Titration is one of the most used traditional analytical techniques in the pharmaceutical industry due to its simplicity and fast results. It is widely used for assay and content tests for drug substances and drug products. In this article, I will discuss the principles and applications of different types of titrations like acid-base titration, precipitation titration, oxidation-reduction titration, iodometric titration, iodimetric titration and complexometric titration with case studies. After reading this article, all your doubts will be cleared and your knowledge will be enhanced to the next level.

Titration and their type

The process of determining the strength of a solution with the help of a standard volumetric solution is called titration. The following types of titrations are widely used in the pharmaceutical industries:

• Acid-Base titration
• Precipitation titration
• Oxidation-reduction titration
  • Iodometric titration
  • Iodometric titration and
• Complexometric titration

Acid-Base titration

In this class of titration the strength of either acid or base is known and strength of other is determined with the help of the first.

HCl + NaOH = NaCl + H₂O

In an acid-base titration, H⁺ ion and OH^– ions are furnished from the acid and the base respectively and they combine to form unionised water molecule. That is why it is also called neutralisation titration.

Indicator for for acid-base titration

Methyl orange and Phenolphthalein are commonly used as indicators in acid-base titration. The following are the details of other indicators which are used in acid-base titration;

Precipitation titration

The titration, in which the strength of a solution is determined on the basis of completion of the precipitation and for precipitation the standard solution is used, is called Precipitation titration

AgNO₃ + NaCl = AgCl +NaNO₃

Indicator for precipitation titration

Potassium chromate is used as indicator for precipitation titration

Typical examples: Quantification of chloride salts like Potassium chloride and Sodium chloride can be performed by this method.

Redox titration or Oxidation-reduction titration

The process of estimating of strength of a solution of an oxidising substance with the help of a solution of a reducing substance of known strength or vice-versa is known as oxidation-reduction titration. In this titration, oxidation-reduction takes place simultaneously.

Typical example: Quantification of Oxalic acid using KMnO₄ standard solution

2KMn⁺⁷O₄ + 3H₂SO₄ = K₂SO4 + 2Mn⁺²SO₄ + 3H₂O + 5(O)

5 HOOC-COOH + 5(O) + 5H₂O +10CO₂

Indicator for Potassium permanganate titration

Potassium permanganate acts as a self-indicator and hence not any indicator used in this titration

Iodometric titration

In Iodometric titration, iodine is liberated due to chemical reaction. The liberated iodine is determined with the help of standard volumetric solution of a reducing agent.

Typical example: Assay of CuSO₄ (copper sulphate) with standard volumetric solution of Sodium thiosulphate

2CuSO₄+4KI = 2K₂SO₄ +Cu₂I2 +I₂

2Na₂S₂O₃ + I₂ = 2NaI + Na₂S

Indicator for Iodometric titration

The starch solution is used as an indicator

Iodimetric titration

In this titration strength of a solution is estimated by the standard volumetric solution of Iodine.

Typical example: Assay of Sodium thiosulphate with standard volumetric solution of Iodine

2Na₂S2O₃ + I₂ = 2NaI + Na₂S₄O₆

Indicator for Iodometric titration

The starch solution is used as an indicator

Difference between Iodimetric titration and Iodometric titration

In Iodometric titration, the iodine is liberated and liberated iodine us titrated with standard volumetric solution of reducing agent whereas in Iodometric titration a reducing agent substances is estimated with standard volumetric solution of Iodine.

Complexometric titration EDTA titration

In Complexometric titration, complex formation takes. A typical example is EDTA titration. Following is the structure of EDTA

From the above structure it is clear that:

• It has four -COOH (carboxylic groups), in which two are strongly acidic .
• It has two ammonium protons, in which one ionizes at pH of about 6.3 and second ionizes at pH about 11.5. That is why titration is performed in the basic condition
• It has six coordination sites (four from acetate oxygen atoms and two from nitrogen atoms.
• It makes a stable chelate complex with divalent metals like Mn²⁺, Pb²⁺ and Zn²⁺ That is why salt of these metals are estimated by EDTA titration.

Indicator for EDTA titration

Eriochrome black T, Pyrocatechol and Calmagite

Typical examples: Quantification of Divalent salts like Magnesium oxide and Zinc oxide are performed by EDTA titration.

Volumetric solution, titrant and Indicator

Volumetric solution

The solution of known strength is called a volumetric standard solution. It is prepared by dissolving known amount of the compound in the solvent and strength is determined by primary standard. For example: 0.1 N is prepared by dissolving 4.0 grom of NaOH in 100 ml of water and its actual normality is determined by using primary standard like KHP (Potassium hydrogen phthalate) . It is used as titrant in the titration.

Indicators

Indicator is the chemical compound that changes its colour in the presence of acid or base . It confirms the end point of the titration

General apparatus required for titration

General apparatus used for titration are conical flask and Burette

General chemicals required for titration

Dissolving solvent, indicator and standard volumetric solution of known normality

Application of titrations

Titration is widely used for quantification/assay test in

• Pharmaceutical industries
• Food industries
• Pesticide industries
• Research centres
• Testing laboratory

Advantages of titrations

• Fast analysis
• No special skill is required
• Easy to perform

Disadvantages

• Titrations are only suitable for pure compounds and not suitable for impure compounds
• Not suitable for racemic mixture or compounds containing isomers

How to design formula for titration

• Calculate the molecular weight
• Calculate the equivalent weight
• Multiply the equivalent weight with strength of the volumetric solution. For example if normality is 0.1 normal then equivalent weight will be multiplied with 0.1
• Use the following formula to calculate the assay

General Formula for assay:

$\mathbf{\%}\mathbf{ }\mathit{A}\mathit{s}\mathit{s}\mathit{a}\mathit{y}\mathbf{=}\frac{\mathit{V}\mathbf{\times }\mathit{F}\mathbf{\times }\mathit{N}\mathbf{\times }\mathbf{100}}{\mathit{W}\mathbf{\times }\mathbf{0.1}}$

Where: V is volume of volumetric solution in ml, W is the weight of sample in mg, F is the factor and N is the actual normality of the volumetric solution

For example, Ibuprofen having the molecular weight 206.29g/mole and assay is to be performed by titrating with 0.1N NaOH volumetric solution. Therefore assay formulae will be:

(V x 20.629xNx 100)/w (in mg) x 0.1

4 simple steps titration method development procedure

• Step-1: Evaluate the structure
• Step-2: Find out the nature of the molecule based on functional group
• Step-3: Decide the titration mode and standard volumetric solution
• Step-4: Perform the titration and calculate the saay

Typical Example:

4 steps procedure for titration

• Prepare standard volumetric solution (as per procedure) and find out normality and put the volumetric solution in the burette
• Weigh the sample and transfer in conical flask and dissolve in the dissolving solvent.
• Titrate the solution with standard volumetric solution using indicator
• Calculate the assay

Concussion

Titration is the backbone of pharmaceuticals analysis. I hope this post has enhance your knowledge to the next level and now you can develop the titration method independently. Write your learning and suggestions in the comment sections.

FAQs

What are the different applications of titration?

Titration is used for both quantitative (like assay and content tests) and qualitative (like identification).

What are the advantages and disadvantages of titration?

It is fast, and easy and no special skill is required to perform the titration.

What is the purpose of the titration?

The purpose of titration is to perform assay and identification tests of pharmaceuticals or any compounds

What are the three uses of titration?

The three uses of titration are assay test, content test and identification test

What precautions should be taken during titration?

The following precautions are taken during the titration:

• Choose the dissolving solvent in which compounds should be completely soluble
• Select suitable indicator
• Use accurate normality. Preferably determine the normality twice
• Stop the titration as endpoint is completed.

What is the use of Blank titration?

No analyte is added in the blank titration. In other words, blank titration includes everything except the analyte (such as solvent and its volume and indicators). The blank titration is used to eliminate the error caused by solvent or any other chemicals used in the titration.

What is a redox titration?

The process of estimating of strength of a solution of an oxidising substance with the help of a solution of a reducing substance of known strength or vice-versa is known as redox titration or oxidation-reduction titration. For example; Quantification of Oxalic acid using KMnO₄ volumetric standard solution

Why pH 10 buffer is used in EDTA titration?

Complete protonation of ammonium protons of EDTA take place at pH 10 (or higher than that). That is why pH 10 buffer is used in EDTA titration.What is the back titration?

Why we use an indicator in the titration?

The indicator confirms the completion of the titration.

What is the end point for the titration?

The endpoint of any titration confirms the completion of that titration.

What is the difference between normal titration and back titration?

In a back titration, error caused by solvent or any other chemicals used in the titration is considered/eliminated whereas in normal titration there is not any possibility of error due to solvent or chemicals.

Why is an indicator not needed in titration with KMnO4?

Potassium permanganate acts as a self-indicator and hence not any indicator is used in this titration

How do we calculate percentage assay or percentage purity in titrations?

Using the weight of thar analyte, volume consumed in the titration, the actual normality of the volumetric solution, the target normality of the volumetric solution and the molecular weight or equivalent weight of the analyte, percentage assay or percentage purity is calculated in the titration.

What is the volumetric solution?

The solution of known strength is called a volumetric standard solution

What is the Indicator?

The Indicator is the chemical compound that changes its colour in the presence of acid or base. It confirms the endpoint of the titration

To get answer of the following questions click on the same question:

What is the titration?

What are the types of titration?

Why is starch added at the end of the reaction of Iodometric titration?

Why do we not use starch in the beginning of titration in Iodometric titration?

What is iodimtric titration and how it is different form iodometric titration?

References

• Advanced practical Inorganic Chemistry; Dr Y. Thakur and Dr J. Thakur
• Wikipedia: https://en.wikipedia.org/wiki/Acid%E2%80%93base_titration

Abbreviations

• EDTA: Ethylenediaminetetraacetic acid