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Darren Edwards
Christine Prosser Paula Garcia John Comer Shenaz Nunhuck Darren Edwards Toni Llinās


Solubility Screening at Organon Scotland: Methodology, validation and observations

Darren Edwards, Physicochemical Sciences, Organon Laboratories Ltd , Lanarkshire, Scotland

Solubility is a key parameter for in-vivo absorption processes in the gastrointestinal tract. It is well known that poor biopharmaceutical properties, e.g. bioavailability due to poor solubility, are one of the main causes of new drugs failing at later stages in development. It is therefore beneficial to measure solubility at an early stage of drug discovery, so that compounds with undesirable properties can be screened out.

An in-house developed solubility screening method, termed “SolKin” will be described. SolKin uses conventional HPLC methodology, and is based upon a miniaturized shake-flask procedure. The compound of interest is dissolved in DMSO (10 mM) and added to an aliquot of phosphate buffered saline in a microtitre plate. The compound/DMSO/buffer mixture is then shaken for a period of time (24 hours) and any un-dissolved material filtered off using a 96-well filter plate. The concentration of dissolved material in the filtrate (and hence the solubility) is then determined using a gradient HPLC method with external standardization from the diluted DMSO stock.

Validation data is presented where SolKin results on a range of neutral marketed drug compounds are compared to those from literature and an in-house shake-flask assay. Recovery data is also presented, where solutions of water soluble drugs of known concentration were assayed using the SolKin method. Descriptions of routine quality control procedures are also described.

The method is a medium throughput technique (25 samples in duplicate over two days), sensitive (solubilities of < 1 mg/L can be determined) and robust. Since its implementation at Organon Scotland over 5000 new chemical entities have had their solubility screened using the SolKin method. The use of the assay as a preliminary indicator of aqueous stability will also be discussed.

Work on the development, validation and implementation of the SolKin methodology raised several issues, and these will also be described; they include validation of methods (how and to what extent), literature solubility data, purity criteria and conditions for testing (e.g. ionic strength). These issues will be presented to the meeting for discussion.

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Last modified: 28 April 2008