Essentially every drug on the market or being developed is analyzed by high-performance liquid chromatography (HPLC). Although rugged and robust, HPLC is often criticized as being the rate limiting step in drug development where high-throughput analysis and high efficiency separations are in demand. Reducing the particle diameter (dp) of the packing material in liquid chromatography is the time proven method to achieve increased separation power through faster analysis times and higher separation efficiency. Recently, advances in instrument and column technology have made it feasible to perform very high-pressure liquid chromatography (VHPLC) utilizing small particle (< 2µm) columns for routine analysis. The increased efficiency and resolution from the small particles will ultimately yield faster method development and higher throughput, and provide further cost reduction through standardization of analytical methodologies. This could potentially lead to a truly generic separation system where only small selectivity values will be required to separate structurally similar compounds.

We have investigated VHPLC-MS for routine use in pharmaceutical analysis. We have investigated the performance of chromatographic columns tailored for VHPLC as well as characterized instrument performance. Our presentation will focus on the performance of the instrument for routine method development and discussion of practical considerations for widespread implementation of VHPLC-MS.