An automated screening assay for determination of aqueous equilibrium solubility enabling SPR study during drug lead optimization.
Aqueous solubility is one of the most critical physicochemical properties to be determined in the process of drug lead optimization. Particularly, an equilibrium solubility method is highly valuable to the study of structure property relationship (SPR), while meeting the needs of analytical sensitiv...
| Publicado en: | JALA: Journal of the Association for Laboratory Automation Vol. 10; no. 6; pp. 364 - 374 |
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| Autores principales: | , , , |
| Formato: | research tables/charts Journal Article |
| Publicado: |
Elsevier B.V.
Dec2005
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=106330271&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 106330271 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 15355535 YU9 jtl: JALA: Journal of the Association for Laboratory Automation issn: 15355535 maglogo: N pubinfo: dt: Dec2005 vid: 10 iid: 6 pid: 467 pub: Elsevier B.V. place: New York, New York artinfo: ui: 106330271 2009266046 10.1016/j.jala.2005.06.003 106330271 ppf: 364 ppct: 10 formats: tig: atl: An automated screening assay for determination of aqueous equilibrium solubility enabling SPR study during drug lead optimization. aug: au: Tan H Semin D Wacker M Cheetham J affil: Discovery Analytical Sciences, Molecular Structure, Amgen, One Amgen Center Drive, Mail Stop 29--2-B, Thousand Oaks, CA 91320; helmingt@amgen.com sug: subj: Drug Design Solubility Evaluation Chemistry, Analytical Chromatography, High Pressure Liquid Automation Validation Studies Human ab: Aqueous solubility is one of the most critical physicochemical properties to be determined in the process of drug lead optimization. Particularly, an equilibrium solubility method is highly valuable to the study of structure property relationship (SPR), while meeting the needs of analytical sensitivity, reproducibility, and throughput. In this report, an automated solubility assay in a 96-well library format was designed and developed by means of robotic liquid handling, centrifugal separation, and HPLC-UV quantification. Requiring 1 mg of solid compound, this assay was used to determine the equilibrium solubility in three user-selected media, that is, 0.01 N HCI, phosphate buffer saline (PBS), and fasted state simulated intestinal fluid (SIF), with a throughput of up to 192 compounds a week. The assay parameters, including the equilibration time and the separation technique, were optimized to ensure that the thermodynamic solubility was measured at the presence of excess solid compound. A fast gradient HPLC method was developed with single-point on-plate calibration for each compound, followed by a customized 96-well chromatographic data analysis. The reporting solubility range was 1--200 micorog/mL, appropriate for oral drug candidate selection at the stage of discovery lead optimization. Based on the test results obtained on the commercially available drugs and Amgen research compounds, this assay was considered to be equivalent to the conventional shake-flask methods. Examples were given to demonstrate that the thermodynamic solubility determined by this assay enabled the SPR study to support drug lead optimization. pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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