[Exploring]

Hi!
My question is, how the solvent used for synthesis of a molecule (using the same starting materials) can affect the solubility of that molecule when is completely dried.  I mean, I can synthesise molecule A using CHCl3, and I can synthesise molecule A using supercritical CO2 (works like hexane).
Once A is isolated and dried, I found that molecule A is much more soluble in CDCL3 when prepared using CHCL3 than in supercritical CO2.
If the molecule is the same, how can the solubility be affected so much?

[cpncoop]

This is a good question.  Solubility is very dependent on crystal structure and habit.  Changing solvents can very easily give you a different crystal structure, different crystal habits, and different types of solvates.  All of these differences can be seen by analyzing the solids by either DSC/TGA, or using Raman.  Physical form is a huge problem in drug development... a molecule that is pure can have many different polymorphic forms depending upon how it is isolated, all with different solubilities, melting points, etc...

If the material you are isolating is amorphous (i.e. not crystalline), differences in solubilities are likely due to trapped solvents.

[Exploring]

Thank you very much,
I thought that using CHCl3 this could be trapped within the structure despite not seeing it NMR (for obvious reasons), and this fact could help to the solubility, but I found it so improbable…
Using TGA/DSC I will only see the presence of the remaining solvent, but in my case, it will be so tiny that not sure if I’ll see the difference.
Is Raman going to be the solution? I believe that only ESI will help.

[orgopete]

You could try old school microanalysis. Trapped chloroform should be easily found.

I didn't use chloroform much, but I often found dichloromethane co-crystallizing with compounds. It was usually in ratios other than 1:1.

(My apology for posting in this topic.)

[alphahydroxy]

If it's CHCl₃, you may be able to observe it using NMR - just use a different solvent (i.e. not CDCl₃) - methanol or DMSO perhaps.

If you really need to use chloroform you may still be able to do it. Take a blank sample with 0.7ml of CDCl₃, put a precisely known about of a spike in it, and run an NMR, you will have a spectrum of the spike + residual CHCl₃.

Then add the same amount of the spike to a solution of your compound in 0.7ml, CDCl₃, correlate the integrals of the spike in the two spectra, and see what the chloroform integral is in your sample.

Alternatively, crush your sample (assuming it's a solid) to a fine powder, and gently heat and dry under high vacuum for a while. This may eliminate the observed difference in solubility.

Of course, it may be that your compound actually crystallizes with one or more molecules of choroform, in which case the x-ray crystal structure will show this...