Validation of titration methods and qualification of a titrator using the content determination of ephedrine hydrochloride as an example
In contrast, for example, to HPLC, titration is an absolute method and therefore requires no reference method.
The reaction processes are known; the titration takes place strictly stoichiometrically and normally very rapidly.
If a titrant with a known titer is used then the content of the sample can be determined directly.
However, this applies only to raw materials and not to formulations that contain other components that could react with the titrant in a similar or identical manner.
It does not make sense to qualify the individual components of an analytical instrument or analysis system separately.
On the contrary, the complete titration system (titrator, buret, electrode, titration evaluation, sample changer if present) is subjected to a performance check.
The qualification of the titrator and the validation of the titration method are carried out at the same time.
General procedure.
Five to ten different amounts of the sample - in this case ephedrine hydrochloride (ephedrine x HCl, C10H15NO x HCl) - are weighed to the nearest 0.1mg (use a validated balance).
If a 20ml buret is used then the sample weights should be chosen to produce a titrant consumption between 2.5 and 15ml.
The sample is dissolved in the prescribed solvent, the auxiliary solution is added and titration is performed with c(titrant) = 0.1mol/L.
1 mL c(titrant) = 0.1 mol/L corresponds to 20.17 mg ephedrine x HCl.
Instruments and accessories used.
799 GPT Titrino.
2.728.0040 magnetic stirrer. 6.3014.223 exchange units (20ml).
6.0229.110 LL Solvotrode [reference electrolyte tetraethylammonium bromide c(TEABr) = 0.4mol/L in ehtylene glycol (6.2320.000)] with 6.2104.020 electrode cable.
Metrodata Vesuv 3.0 software.
Possibly printer and printer cable.
Analysis and evaluation.
Titration according to the European Pharmacopoeia, 3rd Edition, Supplement 2001. Titration according to USP 24 NF 19 (2000).
Statistical calculations and interpretation of the results.
Linear regression: titrant consumption as a function of the sample weight.
Linear regression (scatter diagram): mass fraction w(ephedrine x HCl) as a function of the titrant consumption. Precision (repeatability) and accuracy.
Comparison of the two titration methods.
Please note that Metrohm Application Bulletin No 252 contains all the necessary calculation formulae as well as an example of a validation protocol.
