Application of design space and quality by design methodologies combined with ultra high-performance liquid chromatography for the optimization of the sample preparation of complex pharmaceutical dosage forms.

Accurate and precise analytical measurements play a significant role in assessments and decisions that are made throughout the drug development process. Developing a robust and reliable sample preparation is essential for drug product formulations to generate consistent results guaranteeing the product quality. However, due to the complex nature of the different pharmaceutical formulations with diverse excipients, developing robust sample preparation methods can be challenging and time consuming. Ensuring sample extraction robustness of pharmaceutical dosage forms becomes increasingly important with the potential impact to patient safety, product efficacy, and business efficiency. In this work we demonstrate and evaluate potential application of Quality by Design (QbD) principles to develop and optimize a robust sample preparation method in combination with the chromatographic analytical technique for a solid pharmaceutical dosage form. Practicability and utility of a QbD approach in optimization of sample preparation of this drug product are demonstrated as the active pharmaceutical ingredient (API) used in the drug product is proven to be highly sensitive for hydrolysis during analysis. Finally, the ultra-high-performance liquid chromatography method with UV detection that was applied during the design of experiments (DoE) was validated as per regulatory requirements. This systematic approach in analytics could provide guidance for the pharmaceutical industry in the development of robust sample preparation methods for different pharmaceutical dosage forms thus significantly reduce risks associated with the method transfers at clinical and commercial manufacturing sites.

Development of an achiral-chiral 2-dimensional heart-cutting platform for enhanced pharmaceutical impurity analysis.

A new broadly applicable achiral-chiral 2-dimensional heart-cutting (LC-LC) platform is designed comprising a multi-column selection approach in the chiral dimension. As both dimensions are operated in a highly aqueous reversed-phase type mode, analysis of a broad range of pharmaceutical solutes (LogP: 1.49-5.7) and their impurities becomes possible, while breakthrough issues arising due to solvent immiscibility and peak broadening phenomena in the second dimension are practically circumvented. These aspects, together with the chromatographic and quantitative performances are systematically assessed for various transfer loop sizes (50, 100, 200 and 500 µl), column diameters (2.0 and 4.6 mm), and various gradients (10, 20 and 40 min) with a mixture of five racemates covering a broad range in polarity. In order to broaden the selectivity of the second dimension, an automated chiral screening is performed comprising six chiral columns, allowing baseline separation for all enantiomers and a chiral resolution up to 17.21 for some of the racemates. The performance of the platform is also assessed in pharmaceutical drug development samples. A hybrid high-resolution (HiRes) sample approach is thereby used, which proves to be effective for precise confirmation of the relative prevalence of the impurities compared to the principal compound in all studied cases. The co-eluted impurities were thereby effectively detected and quantified down to the 0.05% level. The obtained figures of merits indicate the suitability of the platform for implementation in industry.