Non-aqueous Acid-Base Titrations Dr. Mohammad Khanfar

Non-aqueous Titrations Theory Non-aqueous titrations is the most titrimetric procedure used in pharmacopoeial assays and serves a double purpose, as it suitable for the titration of weak acids and bases and provides a solvent in which organic compounds are soluble. The most commonly used procedure is the titration of organic bases with perchloric acid in acetic acid Water behaves as both a weak acid and weak base; thus in aqueous environment, it can compete effectively with very weak acids and bases with regard to proton donation and acceptance.

Non-aqueous Titrations

Non-aqueous Titrations Theory The effect of this is that the inflection in the titration curves for weak acids and weak bases is small, because they approach the pH limits in water of 14 and 0 respectively, thus making end-point detection more difficult. A general rule is that bases with pKa < 7 and acids with pKa > 7 cannot determined accurately in aqueous solution Various organic solvents may be used to replace water since they compete less effectively with the analyte or proton donation and acceptance.

Non-aqueous Titrations Advantages of non-aqueous titrations: 1) Provide suitable solvent 2) Increase the basicity or acidity of the analyte. No water to interfere with titration, which would give sharper inflection region

Non-aqueous Titrations Non-aqueous titration of weak bases Solvent: neutral or acidic Acetic acid is the most common solvent for weak base titration because it does not compete effectively with weak bases for protons. Only very strong acid (like perchloric acid) will protonate acetic 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. onium ion

Non-aqueous Titrations Benzene and chloroform (aprotic solvent) can also be used as neutral solvents Since dissociation is not an essential preliminary to neutralization, aprotic solvents are added to ionizing solvents to depress solvolysis of the neutralization product and so sharpen the end point Butanol can be added to enhance the solubility of insoluble substances. Titrant: most commonly used titrant is perchloric acid. The choice of the titrant here is more crucial than in the case of aqueous titration (How?) Acetic anhydride, measured but not in excess amount (why?), is used to remove water from aqueous perchloric acid (the commercially available form). Standarized with KHP

Non-aqueous Titrations Indicators: Crystal violet (most common one) 3-quinaldine 4-naphthalein When a base is in the form of a chloride or bromide salt, the counter ion has to be removed prior to titration by addition of mercuric acetate. However, when the base in the form of a salt of a weak acid (tartrate, acetate, or succinate) removal of an anionic counter ion prior to titration is not necessary (why?) Blank Titration : It is usually carried out to account for the possible reaction of atmospheric moisture with the titrant perchloric acid undissociated undissociated

Non-aqueous Titrations Example, Titration analysis of pyridine (very weak base, analyte) dissolved in acetic acid (acidic solvent) titrated with perchloric acid (titrant) dissolved in acetic acid. Titrant solution, in burett Analyte solution, in Erlenmeyer Titration The whole idea of non-aqueous titration is to increase the acidity and basicity for both the solvent and analyte by generating more acidic and basic species, i.e., CH3COOH2+ is more acidic than HClO4, and acetate (CH3COO-) is more basic then pyridin (C6H5N). Therefore, titration of CH3COOH2+ (from titrant solution) with CH3COO- (in analyte solution) will generate sharper end point.

Non-aqueous Titrations Non-aqueous titration of weak acids Solvent: 1) alcohol (very weak acids, pKa 16 – 20, e.g. methanol, ethanol, t-butyl alcohol), 2) amines (weak bases, e.g. ethanediamne, n-butyl amine, pyridine) or 3) aprotic solvents (N,N-dimethyl formaide (DMF), aceton, methylethayl keton) which does compete strongly with weak acid for proton donation

Non-aqueous Titrations Titrant: Lithium methoxide (CH3OLi), Sodium or potassium methoxide (CH3ONa, CH3OK), tetrabutyl ammonium hydroxide Generally, drugs can be titrated directly in a dosage form If the dosage form is aqueous, analyte should be extracted to non-aqueous solvent

Example, Titration analysis of benzoic acid(weak acid, analyte) dissolved in DMF titrated with sodium methoxide (titrant) dissolved in methanol. Analyte solution, in Erlenmeyer Titrant solution, in burett Titration

Non-aqueous Titrations Practical application Example 1. 4 g tablet of methacholine cloride (195.69 g / mol), dried and stored in a vacuum desiccator, dissolved in 50 ml of glacial acetic acid, 10 ml of mercuric acetate solution and one drop of crystal violet was added and then titrated with 56 ml of 0.1 M perchloric acid to a blue-green end point. Blank titration was conducted and 1.7 ml of perchloloric aid used. Calculate % w/w of methacholine cloride. From acetous HClO4 From the above rxn

Non-aqueous Titrations Practical application Example 2. 0.5 g tablet of Ethosuximide (141.17 g/mol) dissolved in 50 ml of dimethylformamide, 2 drops of azo-violet solution was added and tirated with 12 ml of 0.1 N sodium methoxide to a deep blue end point. 0.6 ml was needed in blank titration. Calculate the % w/w of thosuximide.

Example for Kjeldahl method 0.9092-g sample of a wheat flour was analyzed by the Kjeldahl procedure. The arnmonia formed was distilled into 50.00 mL of 0.05063 M HCI, and then back titrated with 7.46-mL of 0.04917 M NaOH. Calculate the percentage of protein in the flour. Note. Since most proteins contain approximately the same percentage of nitrogen, multiplication of this percentage by a suitable factor (6.25 for meats, 6.38 for dairy products, and 5.70 for cereals) gives the percentage of protein in a sample. %N = Mass of N/ Sample mass x 100% % of crude protein = %N x F