The chemical modifications led to higher solubility for three of the derivatives of ciprofloxacin (Figure 3). (3) The underlying molecular reason(s) for poor solubility can hence inform the medicinal chemists upon strategies to improve the aqueous solubility. Typically these are highly lipophilic, small, and rigid molecules with a strong hydrogen bond capacity within the crystal lattice. (2a) In addition there are intermediate compounds that have both a strong crystal lattice and a poor solvation. In comparison, the solvation limited compounds are larger, flexible, and lipophilic. (2c) These structural features allow the molecules to pack densely in the crystal and provide strong intermolecular bonds through van der Waals interaction, π–π stacking, and hydrogen bond formation. The molecules that are solid state limited in their solubility, are smaller, rigid, and often flat molecules. (1) We have investigated molecular features of importance for poor solubility (2) and identified structural differences between compounds that are poorly soluble because of strong crystal lattice and those that are poorly hydrated in the aqueous environment. Poor aqueous solubility is a main hurdle to overcome in current discovery programs with 40–70% of all new hits estimated to have too low solubility to allow complete absorption from the GI tract.
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