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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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Physical Chemists by Physical Chemists
