(598g) Controlled Particle Suspensions for Determination of Intrinsic Dissolution Rate in Simulated Intestinal Fluids at Medium Throughput

The intrinsic dissolution rate (IDR) of active pharmaceutical ingredients (API) is a key property that aids in early drug development. It can guide in the selection of formulation strategies or in the comparison of different polymorphs and salt forms to improve dissolution and thereby drug absorption in the intestine. In industrial settings, it is also an important quality control parameter during API production. A number of small-scale experimental techniques to determine IDR have emerged in the past years that facilitate rapid API screening in biorelevant dissolution media. In this study, we develop a robust method for medium throughput screening of IDR and thereby establish the largest IDR dataset in open literature to date. Dissolution profiles are measured in a small-scale apparatus using in situ fiber optic probes to measure amounts of drug dissolved by UV absorbance spectroscopy. Nineteen compounds with diverse physicochemical properties were studied in both fasted and fed state simulated intestinal fluids. The assays are carried out using either compacted powder discs or stabilized particle suspensions depending on the solubility of the API in the corresponding dissolution medium. IDR measurements were not solely linked to API solubility in either dissolution media. Ionization was weakly correlated to IDR in acids, exhibiting higher IDR compared to bases in both biorelevant media. Multivariate data analysis revealed that IDR strongly depends on compound partitioning into bile salt and phospholipid micelles in the simulated intestinal fluids, a process that in turn is governed by API lipophilicity, hydrophobicity, and ionization. The medium throughput method established here for the determination of IDR in biorelevant media, will be used to establish an extensive IDR database that ultimately can be used to predict IDR in silico based solely on molecular descriptors of the API.