title: A stepwise strategy employing automated screening and DryLab modeling for the development of robust methods for challenging high performance liquid chromatography separations: a case study.
abstract: A stepwise method development strategy has been employed to develop a robust HPLC method to resolve several closely eluting structurally related impurities in an active pharmaceutical ingredient (API). This strategy consisted of automated column screening, optimization of the most critical chromatographic parameters, DryLab(®) modeling, and experimental verification of optimized separation conditions. DryLab(®) was used to predict an optimized gradient profile and separation temperature and these predictions were verified experimentally. A discussion of the accuracy of these predictions is presented. The robustness of the method was verified and the ability of DryLab(®) to predict, with reasonable accuracy, the outcome of such robustness studies was also examined. Once the robustness was established by the DryLab(®) predictions the remainder of the subsequent verification by experiment becomes a simple reiterative exercise. This study also demonstrates that factors such as column chemistry and critical chromatographic parameters can have a profound and oftentimes interrelated effect on the chromatographic separation of isomers, bromo analogs and other structurally very similar impurities. Therefore, it is critical to adopt a rational strategy, as demonstrated here, to evaluate the interplay of these factors, thereby greatly enhancing method development efficiency.
authors.affiliation: Analytical & Bioanalytical Development, Bristol - Myers Squibb Company, New Brunswick, NJ 08903, USA.
authors.forename: K
authors.initials: K
authors.lastname: Jayaraman
authors.forename: A J
authors.initials: AJ
authors.lastname: Alexander
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
authors.forename: F P
authors.initials: FP
authors.lastname: Tomasella
mesh_terms: D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D003198:Computer Simulation; D004340:Drug Contamination; D008956:Models, Chemical; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012984:Software; D013696:Temperature
chemical_list: D004364:Pharmaceutical Preparations