ABSTRACT
A semi-automated chemical stability system was developed, validated, and implemented to assess the chemical and physical stability (24 h) of intravenous and oral solution based formulations in support of preliminary in vivo drug discovery studies. The system utilizes a single Agilent 1100 LC and Xterra column with multiple UV wavelength monitoring. Mobile phase selection, either basic or acidic, is selected base upon on the physico-chemical properties of the test compound. The system was validated against 14 new chemical entities across multiple therapeutic areas. The results indicated that drug discovery compounds could be accurately quantified (<2% R.S.D.) in a wide range of formulation vehicles in greater than 90% of the test cases. This method can be used as a quantitative tool for triaging formulation variables and packaging configurations to quickly develop stable solutions for dosing.
Subject(s)
Chromatography, Liquid/methods , Drug Stability , Pharmaceutical Preparations/chemistry , Spectrophotometry, Ultraviolet/methods , Technology, Pharmaceutical/methods , Autoanalysis/methods , Chemistry, Pharmaceutical , Linear Models , Pharmaceutical Preparations/analysis , Reproducibility of Results , Solutions , Solvents/chemistry , Time FactorsABSTRACT
Optimisation of oral bioavailability is a continuing challenge for the pharmaceutical and biotechnology industries. The number of potential drug candidates requiring in vivo evaluation has significantly increased with the advent of combinatorial chemistry. In addition, drug discovery programmes are increasingly forced into more lipophilic and lower solubility chemical space. To aid in the use of in vitro and in silico tools as well as reduce the number of in vivo studies required, a team-based discussion tool is proposed that provides a 'road map' to guide the selection of profiling assays that should be considered when optimising oral bioavailability. This road map divides the factors that contribute to poor oral bioavailability into two interrelated categories: absorption and metabolism. This road map provides an interface for cross discipline discussions and a systematic approach to the experimentation that drives the drug discovery process towards a common goal - acceptable oral bioavailability using minimal resources in an acceptable time frame.
