I am trying to develop a method for a basic polar compound with sample prep. in 100% MeOH. It has to be in MeOH because of the solubility of the excipients in the drugs formulation. I want to use reverse phase and have been able to analyze with various columns using a very high aqueous (low pH) and low organic (usually starting at around 5%). This works fine for injection volumes of 10ul or less, above that I am affected by band broadening. Does anyone have any ideas of how I can increase my retention and inturn increase the organic fraction of my mobile phase to allow for greater injection volumes.

You must increase the polarity of your injection solvent or 10 ul will be the limit on 4.6mm column. The broadening you are seeing is caused by the mismatch in polarity between your injection solvent and the starting mobile phase composition.

I think you may need a buffer to control pH at 8-9 (depend your sample pKa) to make your sample to retain on the reverse phase column longer. or consider ion-pair reagents.

Phenomenex Luna C18(2) column or Merck C18 Purospher worked well ar pH 8-9 giving very symmetrical peaks with basic compounds like pseudoephedrine, diltiazem, pyridine, etc. Retention will be increased and you will need to add a higher propprtion of organic solvent to m.p.

Unless you want to analyse the excipients, why do you care if they precipitate? Just centrifuge the sample and inject the supernatant. The only thing that you need to do is to prove that your analytes are still all there and everything is fine.