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Increasing safety concerns and environmental legislation have mandated the reduction and eventual elimination of chlorinated solvents. Therefore, the Preparative Chromatography Group at Searle is working to eliminate the use of chlorinated solvents. Three areas of investigation to meet this goal are under way: (1) develop replacement solvents, (2) reduce the percentage of chlorinated solvents and (3) develop alternative sample application techniques. This paper demonstrates the progress that has been made in all three areas.

A new technique for the application of insoluble samples in preparative liquid chromatography has been developed. This technique, solid injection, greatly reduces the time and inefficiencies associated with techniques previously developed for this problem. Examples of purifications accomplished with this technique are given for compounds of pharmaceuticals interest.

A contaminant was discovered in the eluate from a preparative liquid chromatographic purification of a research drug. The contaminant was isolated by column chromatography and identified by spectral data as 1,4-dioxan-2-yl hydroperoxide ( p -dioxanyl hydroperoxide). The hydroperoxide was characterized by NMR and IR spectroscopy and thin-layer and high-performance liquid chromatography. The conditions for safe removal and reduction were also investigated.

Preparative liquid chromatographic methods were developed for the chiral resolution of two different cyclopentenone precursors of a synthetic prostaglandin. Various solvent combinations of alcohols and alkanes were investigated to determine the method which has the greatest throughout. The effect of particle size on the chiral resolution was also investigated. In addition, the preparative system was automated to llow for unattended operation for up to 10 h.