Automated High-Sensitivity Biorelevant Solubility Workflow for Applications in Long-Acting Injectable Pharmaceutical Drug Development

Description:
The adoption of high-throughput automation for analytical screening has alleviated the challenges associated with determining pharmacokinetic and chemical properties for large numbers of potential compounds in early-stage drug development. The ability to quickly achieve differentiation in properties such as solubility using these workflows is invaluable for making decisions on scale-up. Long-acting injectable (LAI) formulations are an attractive avenue for drug delivery by minimizing strain on patients to take a daily oral medication but introduces additional analytical challenges into the screening process. These compounds yield inherently low solubility (< 1.0 µg/mL) under biological conditions to control extended release once administered, requiring that detection limits be sufficiently low to quantify concentrations at saturation levels. By combining the sensitivity enhancements of UHPLC and the efficiency benefits of high-throughput automation, automated workflows can be developed to reduce turnaround time for early candidate screens.
The primary objective of this work was to develop a UHPLC method to meet the sensitivity constraints required for LAI candidates and to implement the method into a fully automated workflow. Previous work obtained solubility down to 1 µg/mL, above the saturation concentration for nearly all samples. Here, solubility was measured in triplicate for 11 biorelevant solutions covering both oral and parenteral administration. The UHPLC method was optimized by utilizing large volume injections to increase the moles loaded on-column, with sample composition carefully selected to mitigate detrimental volume overload effects through solvent focusing. Overall, detection down to 10 ng/mL was achieved for 10 LAI candidates in all test media. Sample preparation was fully automated with the Chemspeed SWILE handling sub-milligram dispenses, the Andrew Robot platform preparing working standards, and the Hamilton Nimbus executing all dilutions.

Speaker: Michael Rerick - GSK
I’m currently an Investigator in the High-Throughput Automation team at the GSK site in Collegeville, PA, working to develop efficient analytical protocols for the rapid screening of GSK therapeutic candidates to determine their physicochemical properties. Our group utilizes an array of solid and liquid dispensing automated platforms to deliver solubility, forced degradation, and crystallization screens to aid in small molecule drug development. My role is to serve as a point of contact for internal and external GSK stakeholders by designing, executing, and communicating the results of our analytical workflows. Prior to joining GSK, I received my Ph.D. in Analytical Chemistry at the University of Pittsburgh. My dissertation focused on developing capillary-scale UHPLC methods for biochemical applications including sub-minute online microdialysis separations of neurotransmitters and utilizing microfluidic devices to study ectopeptidase activity using electroosmotic perfusion and LC-MS.