Automated Supersaturation Stability Assay to Differentiate Poorly Soluble Compounds in Drug Discovery
| Autor: | Gina Geraci, Stephanie Kay Dodd, Suzanne Skolnik |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Drug Compounding
Pharmaceutical Science Administration Oral 02 engineering and technology Absorption (skin) 030226 pharmacology & pharmacy 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Drug Stability In vivo Drug Discovery Solubility Supersaturation Chromatography Dimethyl sulfoxide In vitro toxicology Area under the curve 021001 nanoscience & nanotechnology Solvent chemistry Intestinal Absorption Pharmaceutical Preparations Biological Assay 0210 nano-technology |
| Zdroj: | Journal of pharmaceutical sciences. 107(1) |
| ISSN: | 1520-6017 |
| Popis: | Increasingly, in vitro assays evaluate a compound's tendency to maintain supersaturation toward 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 min. Eight increasing concentrations were targeted and supernatant concentration was measured following solvent shift in fasted-state simulated intestinal fluid. The effect of dimethyl sulfoxide both on equilibrium solubility and on induced supersaturation was addressed, whereas the change in concentration was evaluated over time. Our sample set included 24 commercial compounds, along with 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 dose proportionality in 42 preclinical and clinical studies. Eighty-one percent of low supersaturation stability compounds (target concentrations ≤50 μM) had proportionality |
| Databáze: | OpenAIRE |
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