Solid-state compatibility studies using a high-throughput and automated forced degradation system

Abstract As the number of pharmaceutical candidate compounds increases, so does the need for development workflow that is capable of handling more compounds in shorter times. In this paper, the establishment of a high-throughput automated powder compatibility testing system is reported. The integrated robotic system automatically dispenses, weighs, and stores powder samples, and extracts and analyses drug substance using ultra-performance liquid chromatography (UPLC). Although automation of powder testing systems is generally accompanied by difficulties in accuracy and precision, mass tracking at every unit operation allowed the system to be validated. In a standard procedure, drug substance and an excipient were dispensed 1:1 (w/w), stored at 70 °C for 9 days, dissolved in solvents, and analyzed to examine the degradation of drug substance and the increases in related substances. The robot quantitatively discriminate between initial conditions of the incompatible powder mixtures of aspirin and magnesium stearate (Mg-St) prepared with or without the use of a whisk and shaker system, demonstrating the capability for evaluating powder mixtures with varying degrees of homogeneity where the contact area between excipient and drug substance differs. Differential scanning calorimetry (DSC), however, did not clearly distinguish between those powder samples, indicating that DSC is less sensitive to powder conditions. The incompatibility results of aspirin and Mg-St were comparable to those reported previously, demonstrating that the automated testing system is reliable. The robot reduced manual work to one sixth and cut down on the costs of outsourcing. An extensive impact is anticipated on development workflows because this system is applicable not only to compatibility testing but also to analytical method development for drug products.