Non-aqueous Titration third year pharmacy

Non aqueous titration

1. Non-aqueous Titration Dr. Aneeqa Saleem

2. NON AQUEOUS TITRATION Non aqueous titration is the most common titrimetric method used in pharmaceutical analysis. The key difference between aqueous and non-aqueous titration is that aqueous titrations use water as the solvent for dissolving the analyte samples for the titration, whereas non-aqueous titrations use organic solvents for dissolving the sample. Principle: The principle of acid-base titration and non-aqueous titration is the same. It states that an acid donates a proton to another chemical and a base accepts a proton .

3. Theory: Following are the three major reasons for using non aqueous titration method: There may be difficulty in performing titrations if the analyte is insoluble in water or is reactive towards water. Analyte is either too weak acid or too weak base. The amphoteric nature of water. Suppose if analyte is a weak acid (HA) in comparison to water and it is titrated with standard base (B). Both analyte and water will compete each other to give up its proton to the standard base. Hence weak acids are not titratable in aqueous media.

4. Cont.. Similarly, in the titration of weak base, there is a competition between analyte (base) and water. HA + B = HB + A- H2O + B = HB + OH- Thus neither weak acid nor weak base can be titrated in aqueous solution due to dual behaviour of water as corresponding acid or base. The simple solution to this problem is the replace of water with organic solvents. So, these types of titrations are known as non aqeuous titrations .

5. Types of solvents used in non-aqueous titrations: They are the following types; Aprotic solvent Protogenic solvent Protophillic solvent Amphiprotic solvent

6. 1. Aprotic solvent These are most important solvent in this titration. This solvent is chemically inert because it is neither acid nor base i.e neutral in nature. These solvents neither accept the proton nor donate proton. They have low dielectric constant, therefore do not favour ionization. They are useful in dissolving the drugs specially insoluble in water. Example ; Bnezene , chloroform, carbon tetrachoride etc.

7. 2. Protogenic solvent These solvents are acidic in nature and used to enhance the basicity of weak bases. It donate the proton. It has high dielectric constant and ionised. It is used to dissolve basic analyte . Example; Glacial acetic acid Formic acid Propanoic acid

8. 3. Protophilic solvent These solvents are basic in nature and used to enhance the acidity od weak bases. It possess high affinity for proton so accept proton readily. It is used to disslve acidic analytes . Example; Amines and ketones Pyrdine Ethylene diamine Dimethyl formamide

9. 4. Amphiprotic solvent This group of solvents behave as acid as well as base depending on the solvents dissolved in it. They work as both mean protogenic and protophillic . They can both accept or donate protons and have levelling effect on the intrinsic strength of drugs. Example; Water Alcohol Weak organic acids

10. Levelling effect The acidity of the weak acids can be enhanced by using basic solvents because basic solvents has higher affinity to take up protons from acids. Similarly, the basicity of weak bases can be enhanced in the presence of acidic solvent. This is called levelling effect of the solvent. Example ; Acetic acid behaves as strong acid in ammonia solution

11. Selection of solvent i . Solubility of drugs ; The weak acidic or basic drug should be soluble in solvent which at the same time miscible with titrant. ii. Nature of the drug ; The solvent is used according to the nature of the drug whether it is acid or base. iii. Reactivity of analyte ; There should not be side reaction between solvent with drug or titrant . It should not interfere in detection of end point.

12. Properties of a solvent The choice of a particular solvent for the particular titration is very critical. The solvent should dissolve the substance to be titrated, Should not introduce interfering side reactions with either the substance to be titrated or the titrant, Should permit a large change in the solvated proton concentration near the equivalence point Should be easily purifies Should be less expensive. If the solvent is to be used for a differentiating titration if should be neither strongly acidic nor strongly basic to avoid leveling effects.

13. Selection of solvents for nat Acetic acid Used for titration of; weak bases Nitrogen containing compounds Acetonitrile/with ACOH : Metal ethanoats Alcohols: soaps and salts of organic acids DMF  ( Dimethylformamide ) : benzoic acid,amides etc

14. ACIDIMETRY: It is used for the quantitative estimation of weak basic drugs Solvents: Solvents used in acidimetry is of two types: Aprotic (benzene, chloroform, dioxane ) They are used for their solvency action but they don’t enhance dissociation. Protogenic ( glacial acetic acid, propionic acid, acetic anhydride) They are acidic in nature and enhances the basicity of weak base.

15. ACIDIMETRY Acetic acid is used for the estimation of ethylenediamine . Acetic anhydride is used for estimation of theophylline . Titrant : Standard perchloric acid is used as a titrant . Hydrogen bromide and organic acids are also used as titrant to limited extant.

16. ACIDIMETRY Indicators: Indicators used are as follow: Crystal voilet : (0.5% in glacial acetic acid) Colour changes from voilet to yellowish green. a- Naphthol benzein : (0.2% in glacial acetic acid) Colour changes from blue to dark green . Oracet blue: (0.5% in glacial acetic acid) Color changes from blue to pink

17. ACIDIMETRY Quinadine red: (0.1% in glacial acetic acid) Color changes from magenta to colorless . Assay: Acidimetry is used for the assay of Ephedrine and Ephedrine hydrocloride

18. ALKALIMETRY It is used for the estimation of weak acidic drugs. Solvents: Solvents used in alkalimetry increases the acidity of drugs Commonly used solvent are: Ethylene diamine Acetone Chloroform Morphine

19. ALKALIMETRY Ethylenediamine , n- butylamine and morphine are considered strong bases and are used for weak acids. For Sulphonamides containing N-alkyl substituents , Preferred solvent is Ethylenediamine . For sulphonamides containing N-phenyl or N- pyridyl substituents , Preferred solvent is DimethyIformamide (DMF). Atmospheric moisture and CO2 will interfare . Precautions are : Use of dried solvent. Titration in closed system under nitrogen to evacuate CO2.

20. ALKALIMETRY Methoxide of potassium, sodium and lithium are used as titrant . Potassium methoxide is stronger titrant and is not used as titrant of choice due to gelatinous reaction products. Sodium methoxide is a commonly used titrant but where itform gelatinous products, it is replaced by lithium methoxide . Indicators: 0.5% w/v thymol blue in anhydrous methanol. 0.2% w/v azo violet solution in benzene. 0.15% w/ ortho nitroaniline solution in benzene.

21. Indicator method: Indictor Basic  Neutral  Acidic Crystal violet(0.5 per cent in glacial acetic acid) Violet  Blue green Yellowish green a-Naphtholbenzein(0.2 per cent in glacial acetic acid) Blue or blue green Orange Dark green Oracet Blue B (0.5 per cent in glacial acetic acid) Blue Purple Pink Quinaldine Red (0.1 percent in methanol Magenta ……… Almost colourless  Thymol Blue Yellow Blue

22. Application of non-aqueous titration 1. Basic drugs: Adrenaline : Treatment of severe shock produced allergic reaction. Amantadine : Treatment of Parkinson’s diesase Atropine sulphate : Treatment of ambylopia , Cycloplegia . Biscodyl : Laxative. 2. Acidic drugs: Acetazolamide : Treat glaucoma. Allopurinol : Treat lower level of uric acid in blood. Amylobarbitone : Sedative and Hepnotics Bendrofluazide : Treat hypertension.

23. Application of non-aqueous titration 3. Determination of analyte concentration 4. Determination of hydrophobic drugs like steriods , phenobarbitone , tetracyclines and diuretics. 5. Determination of drug concentration of adrenergic drugs.