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

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.

Development and Validation of an RP-HPLC-PDA Method for Determination of Paracetamol, Caffeine and Tramadol Hydrochloride in Pharmaceutical Formulations

“…When developing an analysis method for pharmaceuticals, it is necessary to assume the quality-by-design (QbD) guidelines from the International Conference on Harmonization (ICH) [ 58 , 59 ]. To validate the chromatographic procedure described here, suitability tests were carried out using freshly prepared stock standard solutions.…”

Experimental design in HPLC separation of pharmaceuticals

“…Commonly, 6-8 factors are assessed using PBD (34)(35)(36)(37)(38). In latest publications, PBD has been employed in the robustness testing of AQbD-supported LC methods (39) or as a screening tool (40)(41)(42).…”

Preparation and Optimization of Quick/Slow-release Bilayered Tablets of Prazosin HCl using DoE and PCA

“…Quality by design (QbD) is pointed as a systematic approach for the development of pharmaceutical products beginning with predefined objectives. PCA and Design of experiments (DoE) have been proved as extremely utile tools for the construction of design spaces, an important component of control strategy for QbD [8][9][10][11][12]. Central composite design is the most frequently used design in the response surface optimization technique [13][14][15][16].…”