Quality-by-Design Is a Tool for Quality Assurance in the Assessment of Enantioseparation of a Model Active Pharmaceutical Ingredient.

Dina Aboushady,Rasha S Hanafi,Maria Kristina Parr

doi:10.3390/ph13110364

Dina Aboushady, Rasha S Hanafi + Show 1 more

Open Access

https://doi.org/10.3390/ph13110364

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Abstract

The design of experiments (DoE) is one of the quality-by-design tools valued in analytical method development, not only for cost reduction and time effectiveness, but also for enabling analytical method control and understanding via a systematic workflow, leading to analytical methods with built-in quality. This work aimed at using DoE to enhance method understanding for a developed UHPLC enantioseparation of terbutaline (TER), a model chiral drug, and to define quality assurance parameters associated with using chiral mobile phase additives (CMPA). Within a response surface methodology workflow, the effect of different factors on both chiral resolution and retention was screened and optimized using Plackett-Burman and central composite designs, respectively, followed by multivariate mathematical modeling. This study was able to delimit method robustness and elucidate enantiorecognition mechanisms involved in interactions of TER with the chiral modifiers. Among many CMPAs, successful TER enantioresolution was achieved using hydroxypropyl β-cyclodextrin (HP-β-CD) added to the mobile phase as 5.4 mM HP-β-CD in 52.25 mM ammonium acetate. Yet, limited method robustness was observed upon switching between the different tested CMPA, concluding that quality can only be assured with specific minimal pre-run conditioning time with the CMPA, namely 16-column volume (60 min at 0.1 mL/min). For enantiorecognition understanding, computational molecular modeling revealed hydrogen bonding as the main binding interaction, in addition to dipole-dipole inside the CD cavity for the R enantiomer, while the S enantiomer was less interactive.

Highlights

The pharmaceutical industry is obliged to adopt quality-by-design (QbD) strategies as per the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines Q8, Q9, and Q10, in order to ensure robust manufacturing processes and enhanced product quality
UHPLC enantioseparation of terbutaline (TER), a model chiral drug, and to define quality assurance parameters associated with using chiral mobile phase additives (CMPA)
The concepts of QbD have been extrapolated to the development and verification of analytical methods in what is known as analytical quality-by-design (AQbD) [1,2,3,4]

Summary

Introduction

The pharmaceutical industry is obliged to adopt quality-by-design (QbD) strategies as per the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines Q8, Q9, and Q10, in order to ensure robust manufacturing processes and enhanced product quality. DoE mathematically determines main factor effects, as well as their interactions, on chromatographic separation and retention responses with a predefined number of experiments. The mathematical model and the graphical response surface allow superior, global, and accurate understanding of the simultaneous effects of variable factors on the measured response, minimizes costs and time spent during method development, and allows visualization of the design. Pharmaceuticals 2020, 13, 364 factors on the measured response, minimizes costs and time spent during method development, and allows visualization of the design space or response surface [7,8,9]. DoE is applied for the optimization space or response [7,8,9]. DoE ismethods, applied for the optimization of a wide range of Instead chromatographic of a wide range ofsurface chromatographic including chiral separations [9,10,11,12,13,14]

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