Non-aqueous titration


Non-aqueous titration refers to a type of titration in which the analyte substance is dissolved in a solvent that does not contain water. This procedure is significant in pharmacopoeial assays. The need for non-aqueous titration arises because water can behave as a weak base and a weak acid, and can hence compete in proton acceptance or proton donation with other weak acids and bases dissolved in it. In this article we will see Solvents, acidimetry and alkalimetry titrations and estimation of sodium benzoate and ephedrine HCl.

Non-aqueous titration is useful because it allows for the suitable titration of very weak acids or bases and provides a solvent with an ability to dissolve organic compounds. Many reactions which occur in non-aqueous titration procedures can be explained via the Bronsted-Lowry Theory and its definition of acids and bases.

Essentially, acids can be thought of as proton donors, whereas bases can be thought of as proton acceptors. Non-aqueous titrations are used for the quantitative determination of medicinal drugs. They are carried out when reactants are insoluble in water, reactive with water, or are very weak acid/base in nature where 100% dissociation cannot be achieved. Non-aqueous titrations can be used for weak acid or base titrations and can dissolve organic compounds.


In non-aqueous titrations, the solvents used can be broadly categorized into four types as follows.

  • Aprotic Solvents: These solvents are neutral in charge and chemically inert. They generally have a low dielectric constant. Examples include chloroform and benzene.
  • Protophilic Solvents: These solvents have a basic character and tend to react with the acids they come in contact with, leading to the formation of solvated protons. Examples include ammonia and pyridine.
  • Protogenic Solvents: These solvents have a more acidic character and tend to have a leveling effect on the bases they come in contact with. Examples include sulfuric acid and acetic acid.
  • Amphiprotic Solvents: These solvents have properties which are protophilic as well as protogenic. Examples include acetic acid and alcohols.

Some of the major solvents used in non-aqueous titration include glacial acetic acid, acetonitrile (CH3CN), alcohols, dioxane, and DMF.


Acidimetry is a specialized analytical technique that uses acid-base titration to determine the concentration of a basic (alkaline) substance using a standard acid. This method can be used for both weak and strong bases. Acidimetry essentially involves the direct or residual titrimetric analysis of alkaline substances (bases) employing an aliquot of acid. It is usually provided in the analytical control of a large number of substances included in various official compendia. The two methods used in acidimetry are the direct titration method and the residual titration method.

  • Direct Titration Method: This method involves directly titrating an exact quantity of the base with a standard acid solution. The resulting solution should have more or less the same equivalent concentration as that of the acid used in the titration. Methyl orange is the indicator of choice for this method.
  • Residual Titration Method: Also known as back titration, this method is normally employed when a chemical reaction proceeds rather slowly or when the substance under determination fails to give a sharp and distinctly visible end-point with an indicator by direct titration.


Alkalimetry, as the name suggests (derived from the word ‘alkali’ which means base), is a method of measuring the base concentration of a solution using a standard acid solution. This type of titration is frequently used. Alkalimetry and acidimetry are types of volumetric analyses in which the fundamental reaction is a neutralization reaction. They involve the controlled addition of either an acid or a base (titrant) of known concentration to the solution of the unknown concentration (titrate) until the reaction reaches its stoichiometric equivalence point. Acidic substances are usually determined quantitatively by methods similar to those used for the quantitative determinations of bases. However, two methods are generally adopted for the assay of acidic substances, namely: Direct Titration Methods and Residual Titration Methods.

  • Direct Titration Method: This method involves directly titrating an exact quantity of the acid, acid salt or other acidic substance with standard alkali solutions.
  • Residual Titration Method: This method involves the addition of an excess of the standard alkali solution and subsequently determining the amount in excess by residual titration with a standard acid solution.

In both acidimetry and alkalimetry, the endpoint of the titration is determined by a sudden color change of an indicator. The choice of indicator depends on the nature of the reaction and the specific requirements of the titration.

Estimation of sodium benzoate

Sodium benzoate is assayed by the help of perchloric acid. Here’s a step-by-step process.

Preparation of Perchloric Acid Solution: Mix 8.5 ml of perchloric acid (70%) with 500 ml of glacial acetic acid and 30 ml of acetic anhydride. Allow the prepared solution to stand for 1 day for the excess acetic anhydride to be combined, and determine the water content by the Karl Fischer Titrimetric Method.

Standardization of Perchloric Acid Solution: Weigh accurately about 700 mg of primary standard potassium biphthalate, KHC6H4(COO)2, previously dried at 105’ for 2 h, and dissolve it in 50 ml of glacial acetic acid in a 250-ml flask. Add 2 drops of crystal violet TS, and titrate with the perchloric acid solution until the violet color changes to emerald green.

Assay Procedure: Anhydrous glacial acetic acid, heated to 50 degrees if necessary and cooled with a saline solution of approximately 0.25 g of Sodium Benzoate. Test the solution with perchloric acid 0.1 M and 1-naphtholbenzein solution as an indicator. Measure the solution in a blank.

Calculation: The amount of sodium benzoate in the sample can be calculated using the following formula.

Percentage of sodium benzoate = (amount of solvent in ml X calculated normality X 0.01441 X 100) / (given normality X weight of sample in gm)

Estimation of ephedrine

Preparation of 0.1N Perchloric Acid Solution: Dissolve 8.5 ml of 72% HClO4 in about 900 ml of glacial acetic acid with constant stirring, add about 30 ml of acetic anhydride and make up the volume (1000 ml) with glacial acetic acid and keep the mixture for 24 hours. The acetic anhydride absorbs all the water from HClO4 and glacial acetic acid, rendering the solution virtually anhydrous.

Standardization of Perchloric Acid Solution: Add 25 ml of glacial acetic acid to 500 mg of potassium acid phthalate and add a few drops of 5% w/v crystal violet in glacial acetic acid as an indicator. This solution is titrated with 0.1 HClO4. The color changes from blue to blue-green.

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 an indicator, until a red color is obtained1. Carry out a blank titration.

Calculation: The amount of Ephedrine Hydrochloride in the sample can be calculated using the following formula.

Percentage of ephedrine HCl = (amount of solvent in ml X calculated normality X 0.02017 X 100) / (given normality X weight of sample in gm)


Non-aqueous titrations are analytical procedures where the analyte is dissolved in a non-aqueous solvent, often used for very weak acids or bases, or substances insoluble/reactive with water. Solvents used can be aprotic, protophilic, protogenic, or amphiprotic. Acidimetry and alkalimetry are titration methods where a standard acid or base is used to determine the concentration of an unknown base or acid, respectively. Sodium benzoate and Ephedrine HCl can be estimated using non-aqueous titrations. Sodium benzoate is assayed using perchloric acid, while Ephedrine HCl is estimated using a mercuric acetate solution and perchloric acid.

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