Skolnik, Suzanne, Geraci, Gina and Dodd, Stephanie (2017) AUTOMATED SUPERATURATION STABILITY ASSAY TO DIFFERENTIATE POORLY SOLUBLE COMPOUNDS IN DRUG DISCOVERY. Journal of pharmaceutical sciences. ISSN 1520-6017

Abstract

Increasingly, in vitro assays are described to evaluate a compound’s tendency to maintain supersaturation towards improving oral absorption. Throughput remains a challenge and only small sets of compounds are evaluated in reported studies. The present work describes an automated workflow and data analysis approach to determine supersaturation stability after 16 minutes. Eight increasing concentrations were targeted and supernatant concentration was measured following solvent-shift in FaSSIF. The effect of DMSO on both equilibrium solubility and on induced supersaturation was addressed, while the change in concentration was evaluated over time. Our sample set included 24 commercial compounds, along with a comparison to literature results. To demonstrate in vivo relevance of in vitro supersaturation, classification of supersaturation stability was proposed based on the target concentration achieved and the percentage of area under the curve (AUC) dose-proportionality in 42 preclinical and clinical studies. Eighty-one percent of low supersaturation stability compounds (target concentrations ≤50 uM) had proportionality <0.8, while 100% of high supersaturation stability compounds (target concentrations ≥200 uM) demonstrated proportionality ≥0.8. The robust, automated assay and its impact on dose proportionality downstream makes this approach applicable in drug discovery where low soluble compounds with otherwise attractive properties may be differentiated on the basis of supersaturation stability.

Item Type:	Article
Date Deposited:	08 Jul 2017 00:45
Last Modified:	08 Jul 2017 00:45
URI:	https://oak.novartis.com/id/eprint/31834