Drug substances titration methods

The British Pharmacopoeia [2] describes a potentiometric titration method for the determination of penicillamine as the pure drug substance. The method is performed by dissolving 100 mg of the substance in 30 mL of anhydrous acetic acid. The mixture is titrated with 0.1 M perchloric acid, and the endpoint determined potentiometrically. Each milliliter of 0.1 M perchloric acid is equivalent to 14.92 mg of C6HnN02S. 

Residual titration method is an alternative means of assay of drugs by Aqueous Titrations . Justify the statement with the help of assay of the following pharmaceutical substances ... 

The British Pharmacopoeia on the other hand, recommends the use of a non-aqueous titration method for the bulk drug substance [12], The method calls for the titration of isoxsuprine HCl against 0. 1 M perchloric acid (after dissolving the solid in acetic anhydride), and using 1-naphtho-benzein solution as the indicator. 

The effects of moisture content in drug substances iancthed dosage form have been widely studied. Static moisture content can be determined by many methods like Karl Fisher titration, loss on drying (LOD), and TGA. Dynamic hygroscopicity of a drug substance has beerLcWaato four... 

Issa et al. [9] used various metal ions for the volumetric determination of mefenamic acid. Mefenamic acid was precipitated from its neutral alcoholic solution by a standard solution of either silver nitrate, mercurous acetate, or potassium aluminum sulfate. In the argentimetric procedure, residual Ag(I) was titrated with standard NH4SCN. With Hg(OAc)2 or potash alum, the residual metal was determined by adding EDTA and conducting back titration of excess of EDTA with standard Pb(N03)2 using xylenol orange indicator. The applied methods were used for the determination in bulk drug substance, and in its formulations. 

However, these titration methods can be used in early development when a reference standard is not available. Also, the spectrometric-based assay methods such as ultraviolet (UV) may be nonspecific because most of the drug substance impurities contain a similar chromophore as the parent molecule. If UV is used, UV absorption is measured at one or more wavelengths and the absorbance value is recorded for a particular concentration. Sandor Gorog has critically evaluated the difference between specific and nonspecific assay methods in the European and US Pharmacopoeias [23]. The difference between the mean and the accepted true value with a defined confidence interval should be reported in the acceptance criteria. 

Optical rotation has the dual advantages of historical use and widespread recognition in the compendia. For an enantiopure material, it defines its configuration when used in conjunction with other valid chemical tests. However, optical rotation has been used ineffectively when the primary analytical goal is the determination of stereochemical purity. The limits selected for the specification seem to be unrelated to the purity required by other methods. For example, the compendial monograph for naproxen requires that the drug substance meet a specification of "between -f-63.0 and -1-68.5"" in a chloroform solution. Based on the published specific rotation, this corresponds to a stereochemical purity of 95.5 to 103.7%, compared to the assay limits of 98.5 to 100,5%, determined by titration with sodium hydroxide (5). 

Avdeef (1998) has reported an automated potentiometric titration method for the determination of solubilities of drug substances containing ionizable groups, where a graphical procedure is used for the estimation of solubility constants based on Bjerrum difference plots. One useful relation derived in this work was ... 

Release testing of raw materials or drug substances must be performed before they can be used for manufacturing a batch of the product. Assay and ordinary impurity determinations are usually performed by HPLC methods. However, when a reference standard for the active ingredient is not available, assay by titration is the method of choice. 

The USP method (12) for the assay of sulfacetamide is based on nitrite titration followed by electrometric end-point determination using platinum electrodes. A 500 mg quantity of the drug is transferred to an open vessel. 20 ml of hydrochloric acid and 50 ml of water are added, the solution stirred until the content dissolved, cooled to about 15°, and slowly titrated with 0.1 M sodium nitrite. Each ml of 0.1 M sodium nitrite is equivalent to 21.42 mg of C8H10N2O3S. In the BP method (13), sulfacetamide sodium is assayed by amperometric titration. A 0.5 g quantity of the substance is dissolved in a mixture of 50 ml of water and 20 ml of 2 M hydrochloric acid and 3 g of potassium bromide are added. The solution is cooled in ice and sulfacetamide content determined amperometrically by titration with sodium nitrite. Each ml of 0.1 M sodium nitrite is equivalent to 0.02362 g of CsH9N2Na03S. 

The range of applications of potentiometric titrations for determination of acids and bases is very wide, as illustrated by the following examples. Carbonate, hydrogencarbonate, and hydroxide ions are all bases that can be titrated with a strong acid such as hydrochloric acid. The most popular method for determination of nitrogen, which is found in many important substances such as proteins, fertilizers, drugs, pesticides, natural waters, is the Kjeldahl method, based on the conversion of the bound nitrogen to ammonia, which is then separated by distillation and determined by titration with hydrochloric... 

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