A Combination Turbidity and Supernatant Microplate Assay to Rank‐Order the Supersaturation Limits of Early Drug Candidates. Issue 10 (28th July 2014)

• Record Type: Journal Article
• Authors: Morrison, John S.; Nophsker, Michelle J.; Haskell, Roy J.
• Is Part Of: Journal of pharmaceutical sciences. Volume 103:Issue 10(2014:Oct.)
• Page Start: 3022
• Page End: 3032
• Publication Date: 2014-07-28
• Subjects: Pharmacy -- Periodicals; 615.1
• DOI: 10.1002/jps.24090
• Languages: English
• ISSNs: 0022-3549

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>A unique opportunity exists at the drug discovery stage to overcome inherently poor solubility by selecting drug candidates with superior supersaturation propensity. Existing supersaturation assays compare either precipitation‐resistant or precipitation‐inhibiting excipients, or higher‐energy polymorphic forms, but not multiple compounds or multiple concentrations. Furthermore, these assays lack sufficient throughput and compound conservation necessary for implementation in the discovery environment. A microplate‐based combination turbidity and supernatant concentration assay was therefore developed to determine the extent to which different compounds remain in solution as a function of applied concentration in biorelevant media over a specific period of time. Dimethyl sulfoxide stock solutions at multiple concentrations of four poorly soluble, weak base compounds (Dipyridamole, Ketoconazole, Albendazole, and Cinnarizine) were diluted with pH 6.5 buffer as well as FaSSIF. All samples were monitored for precipitation by turbidity at 600 nm over 1 h and the final supernatant concentrations were measured. The maximum supersaturation ratio was calculated from the supersaturation limit and the equilibrium solubility in each media. Compounds were rank‐ordered by supersaturation ratio: Ketoconazole > Dipyridamole > Cinnarizine ∼ Albendazole. These <italic>in vitro</italic> results correlated well with oral AUC ratios from published <italic>in vivo</italic> pH effect studies, thereby confirming the validity of this approach. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3022–3032, 2014</p> </abstract>