SOLUBILITY (a physicochemical property) - 1

What kind of data set you get to see during a medicinal chemistry project?  Let us try to understand what information you get by profiling ADME properties and the implication of such data.

Starts with in vitro biological activity data followed by (a) clogP (b) solubility (c) PAMPA (d) caco-2 (e) plasma protein binding (f) microsomal stability (g) toxicity (h) CYP inhibition (i) hERG etc.

Solubility: In earlier post it was mentioned that only soluble compounds can be absorbed from the gastrointestinal tract. Therefore one should make sure that the solubility of compounds is good.  Compounds with low solubility sometimes might end-up providing inaccurate in vitro biological data as well. 

The ability of a compound to dissolve in a solvent to give a homogenous system is one of the important parameters to achieve a desired concentration of drug in systemic circulation for the desired (anticipated) pharmacological response.

Especially for oral dosing, solubility is important.  It is challenging for poorly soluble drugs, as it limits the absorption of compound from the gastrointestinal tract.

Compounds with solubility between 1 - 100 mM (micromolar) range can be termed as partially soluble and >100 micromolar can be termed soluble compounds.     

Sometimes poorly soluble compounds can also be forwarded.  For example, if a compound has extremely high potency in vivo - then low solubility should not be a problem provided this compound has good permeability.  In such cases, high dose can be administered if this compound has least side effects.    

But, just the solubility data is not going to limit the compound chance for progressing to the next stage.  There are several ways to get away from the solubility issue, one such example includes all sorts of structural changes to improve solubility, and in very late stage drug discovery programs by choosing relevant formulation etc.