Prep LC and solubility issues

[chromeleon]

Let's say I want to use RP for my prep but my sample really dislikes water and will show the beginnings of crashing out...

I would love to dissolve my sample in neat acetonitrile or something that loves my sample just as much - but the chromatogrpahy is a mess because solvent strength of my sample is much greater than that of my mobile phase...

I try increasing solvent strength of the mob phase but now my target molecule flies off the column...

etc etc....

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so what have people tried?
what is the compromise?

the ideal is same solvent composition/pH of sample and mobile phase, but in this case not viable.
so how much "strong" solvent can you get away with before the chromatography suffers?

I might add that we're talking 1ml injection volume on semi-prep (10ml i.d.)... 2ml or higher for prep (21mm i.d.)

[bisnettrj2]

I think what you're asking for is something Uwe Neue described in his paper "At-column dilution for improved loading in preparative chromatography" published in Chromatographia. There's a description on the Waters site, the link is below.

http://www.waters.com/webassets/cms/lib ... pNotes.pdf

[DJ]

Can you tell us more about your compound? Is it neutral or does it have an ionizable group? Any polar groups?

What is its log P, calculated water solubility?
http://www.vcclab.org/lab/alogps/start.html

Often times it can be tricky to dissolve solid directly in mostly aqueous starting mobile phase. Sometimes you can get around this by initially dissolving the material in a minimal amount of solvent "it likes" (THF, DMSO, MeOH, MeCN), then carefully dilute with starting mobile phase (dropwise, with constant stirring/shaking, sonnication can't hurt).

If your sample precipitates upon dilution with starting mobile phase, you definitely have good reason to suspect that it would also precipitate once loaded.