(T1430-10-56) High-Throughput Analytical: Development of New High-Throughput Experimentation and Analytics Capabilities

Purpose: Throughout the stages of process development, new reactions, work-ups, and crystallizations need to be invented and optimized. This work, along with the measurement of compound physical properties, can be significantly accelerated using High-Throughput Experimentation (HTE). The mission of the HTE Community of Practice (CoP) is to enhance and augment the way in which our small molecule Chemical Process Development department conducts HTE (I.e., screening/surveying) where appropriate, by raising the collective capability of knowledge capture and execution by an end-user to make informed decisions. The effective management of intentionally added elemental impurities (EI's), such as metal catalysts, is of utmost importance during the process development of active pharmaceutical ingredients (API's). Traditionally, efforts to address metal removal strategies have involved conducting routine experiments, focusing on one variable at a time (OVAT). However, we are currently dedicated to advancing the field by developing pre-weighed high-throughput experimentation platforms. These platforms enable the screening of multi-dimensional, large, arrayed treatment regimens, resulting in significantly larger sample sets for EI analysis. In this abstract, we present a novel high-throughput EI analysis platform that allows for the direct analysis of common processing solvents through a parallel sample preparation procedure. By measuring elemental impurities in organic matrices directly, the need for acid digestion prior to analysis is eliminated. This not only reduces the turnaround time for obtaining results but also enhances the efficiency of the drug development process.

Methods: Calibration Curve Preparation: A 10 ppm metal standard solution of palladium (Pd), copper (Cu), cobalt (Co), nickel (Ni), iron (Fe), iridium (Ir), ruthenium (Ru) and rhodium (Rh) was prepared by diluting ICP standards in 2% nitric acid. The prepFAST 2DX auto dilution system (Elemental Scientific) then prepared a 0.3 - 10 ppm calibration curve for each metal by diluting the metal standard stock solution with the sample diluent. Sample Preparation and Analysis: The Pd pre-catalyst (Pd-172, Johnson Matthey) was spiked into solutions containing typical process solvents (e.g., formic acid, methyl tert-butyl ether and isopropyl acetate) and an organic process product to achieve final metal concentrations of 3, 10, and 100 ppm. These samples were then diluted 1:10 in the sample diluent and transferred to metal free conical tubes for analysis. The concentration of Pd in the diluted samples was determined by direct infusion into an ICP-OES 5110. An internal standard solution of yttrium was combined with the sample prior infusion into the conical nebulizer. Metal concentrations in the samples were derived from the prepared calibration curve utilizing Agilent’s ICP Expert data analysis software.

Results: The Pd pre-catalyst (Pd-172, Johnson Matthey) was chosen as a recovery test subject as it is a commonly added catalyst for organic transformations. The Pd levels (3 - 100 ppm) in process mimicking samples were quantified using ICP-OES. The results for the PD recovery are seen in Table 1.

Conclusion: The table above demonstrates the capability of our high-throughput EI analysis platform to accurately quantify the concentration of Pd Catalyst in various reaction solvent streams. This successful proof of concept experiment paves the way for further investigations into other commonly used metal catalysts. By applying these methods to future pharmaceutical samples, we can achieve rapid turnaround times and facilitate efficient decision-making, ultimately accelerating the drug development process.

Table 1: Pd Recovery Results (n=3 at each level)