Development of Karl Fischer titration method using Duality by Design concept

Abstract

Modern trends in drug quality control are moving toward incorporating quality into the method during its development. That course is in accordance with Quality by Design (QbD) concept defined by ICH Q 8 (R2) guideline. This implies that the method development begins by defining the method goals and collecting the relevant data, i.e., analyzing the properties of a given active pharmaceutical ingredient and evaluating the optimal experimental conditions. It is followed by a risk assessment defined by systematic robustness testing with the application of experimental design, while the final confirmation of the method reliability is done through the complete validation tests. In this paper, development of Karl Fischer titration for water determination in active pharmaceutical substance clindamycin phosphate is presented. Karl Fischer titration (KFT) is a widely used method in the pharmaceutical industry for determination of water content. For the analyzed substance, the European Pharmacopoeia suggests a relatively large amount of samples for the determination of water, so the objective of this study is to confirm the applicability of the developed method for the determination of water in small amount of samples applying QbD approach. According to QbD rules, detail development of coulometric Karl Fischer titration for water determination in clindamycin phosphate was done. For robustness testing, fractional factorial design 24-1 was successful applied and confirmed that the method was robust. Robustness was evaluated using statistical and graphical methods. Also, design space was defined so the region in which factors could be changed without significant changes in water content was defined. At the end, other validation parameters were determined and it was proven that the analytical test system was capable of providing useful and valid analytical data.

Savremeni zahtevi u industriji, posebno farmaceutskoj, postavljeni su na konceptu ugrađivanja kvaliteta u metodu tokom njenog razvoja (eng. Quality by Design - QbD koncept). Ovo podrazumeva da razvoj metode započinje definisanjem cilja metode i prikupljanjem odgovarajućih podataka, nastavlja se procenom rizika, a konačna potvrda pouzdanosti metode dobija se njenom validacijom. Ovakav pristup uspešno je primenjen na metodi Karl Fišer-ove titracije za određivanje sadržaja vode u klindamicin-fosfatu. Dobijeni rezultati su u skladu sa postavljenim QbD konceptom i predstavljaju značajan napredak u primeni metode titracije po Karl Fišer-u u farmaceutskoj industriji.