Determination of Bupropion and Its Impurities via a Chaotropic Chromatography Method Following Analytical Quality-by-Design Principles for Method Development

Abstract

A novel chaotropic chromatography method for the quantitative determination of bupropion and its impurities, following analytical quality-by-design (AQbD) principles, is presented. The analytical target profile (ATP) was defined on the basis of the efficient separation and reliable determination of bupropion and its five impurities in tablets. Preliminary experiments revealed the need for the addition of a gradient elution part. A screening fractional factorial experimental design was employed to select the critical method parameters (CMPs) and a Box-Behnken design (BBD) was utilized to investigate their influence on predefined critical method attributes (CMAs). In order to compute the design space (DS), where CMPs meet predefined acceptance limits with a high level of probability (π ≥ 85%), Monte Carlo simulations were performed. The working point selected from the DS corresponded to the following conditions: 37.5% acetonitrile at the start of the gradient program (up to 70% at the end of the gradient program), 45 mM of potassium hexafluorophosphate in the water phase, and the start of the linear gradient step in the gradient program at 10 min. The method was validated according to ICH guidelines and applied to the analysis of Wellbutrin^® tablets containing bupropion hydrochloride.

Keywords: bupropion; chaotropic chromatography; experimental design; impurities; quality-by-design.

Figure 1

Chemical structures of BUP and its 5 impurities.

Figure 2

Three-dimensional graphs of (A) t_{e_bup} = f (%ACN at the start of the gradient, salt concentration—mM) and (B) t_{b_imp2} = f (%ACN at the start of the gradient, gradient start time—min).

Figure 3

(A) 3D representation of DS for the predefined CMAs achieved with probability π ≥ 85%. (B) 2D representation of DS after setting a fixed value for C (gradient start time) = 10.0 min. The yellow part corresponds to the region of the design space where the working point should be situated.

Figure 4

Chromatograms obtained under conditions suggested by the working point: (A) placebo mixture of excipients, (B) sample solution containing 400 μg/mL BUP spiked with all impurities at their SL.