สารบัญ

APPENDIX 6 ASSAYS

6.1 NON-AQUEOUS TITRATION​

      Acids and bases have long been defined by Arrhenius as substances which furnish, when dissolved in water, hydrogen and hydroxyl ions, respectively. A more generalized definition is that of Brönsted, who defined an acid as a proton donor, and a base as a proton acceptor. Even broader is the definition of Lewis, who defined an acid as any material that will accept an electron pair, a base as any material that will donate an electron pair, and neutralization as the formation of a coordination bond between an acid and a base. 

      The apparent strength of an acid or base is determined by the extent of its reaction with a solvent. In water solution, all strong acids appear equally strong because they react with the solvent to undergo almost complete conversion to hydronium ion (H₃O⁺ ) and the acid anion. In a weakly protophilic solvent such as acetic acid the strength of acids decreases in the series perchloric, hydrobromic, sulfuric, hydrochloric, and nitric. Acetic acid also enhances the basic properties of weak bases and it is possible to titrate such solution of weak bases with perchloric acid in acetic acid. On the other hand, weak acids tend to enhance their acid properties when dissolved in basic solvents and it is possible to titrate weak acids with strong bases. The order of decreasing strength for bases is potassium methoxide, sodium methoxide, lithium methoxide, and tetrabutylammonium hydroxide.

      Many water-insoluble compounds behave as weak acids or weak bases in water but acquire enhanced acidic or basic properties when dissolved in appropriate organic solvents. Thus, it is necessary to perform nonaqueous titrations by proper selection of solvent and titrant to increase the sensitivity of the end-points. Most of the pharmaceutical preparations can be titrated directly, but it is sometimes necessary to isolate the active ingredients from interfering excipients and carriers.

      The types of compounds that may be titrated as acids include acid halides, acid anhydrides, carboxylic acids, amino acids, enols such as barbiturates and xanthines, imides, phenols, pyrroles, and sulfonamides. The types of compounds that may be titrated as bases include amines, nitrogen-containing heterocyclic compounds, oxazolines, quaternary ammonium compounds, alkali salts of organic acids, alkali salts of weak inorganic acids, and some salts of amines. Many salts of halogen acids may be titrated in acetic acid or acetic anhydride after the addition of mercury(II) acetate, which removes halide ion as the un-ionized mercury(II) halide complex. In the case of hydrochlorides of weak bases not containing acetylatable groupings it is also possible to titrate in acetic anhydride without the addition of mercury(II) acetate and using an indicator such as malachite green or crystal violet.

      In the titration of a basic compound, a volumetric solution of perchloric acid in glacial acetic acid is preferred, although perchloric acid in dioxane is used in special cases. In the titration of an acidic compound, a volumetric solution of sodium methoxide in a mixture of methanol and toluene is preferred, although lithium methoxide in the methanol-toluene solvent may be used for those compounds yielding a gelatinous precipitate on titration with sodium methoxide.

      Care should be taken to avoid subsequent exposure to the atmospheric carbon dioxide for titration of acid substances. Absorption of carbon dioxide may be determined by performing a blank titration. The blank generally should not exceed 0.01 ml of a 0.1 M titrant per ml of solvent.

      The end-point may be determined visually by colour change, or potentiometrically (Appendix 6.4). If the calomel reference electrode is used, it is advantageous to replace the aqueous potassium chloride salt bridge with 0.1 M lithium perchlorate in glacial acetic acid for titrations in acidic solvents, or potassium chloride in methanol for titrations in basic solvents.

      Where these or other mixtures are specified in individual monographs, the calomel reference electrode is modified by first removing the aqueous potassium chloride solution and residual potassium chloride, if any, by rinsing with water, then eliminating residual water by rinsing with the required non-aqueous solvent, and finally filling the electrode with the designated nonaqueous mixture.

      When using titrants prepared with solvents of high coefficient of expansion, correction should be made to compensate for differences in temperature between the titration and standardization time.

Systems for Non-aqueous Titrations