[Improvement in Aqueous Solubility of Bioactive Molecules by Decreasing Intermolecular Interaction]

Area of Science:

• Medicinal Chemistry
• Physical Chemistry
• Drug Discovery

Background:

• Aqueous solubility is crucial for small molecule drug candidates.
• Conventional methods like decreasing partition coefficient (Log P) are not always effective.
• Solid-state crystal packing influences solute solubility.

Purpose of the Study:

• To explore alternative strategies for improving aqueous solubility.
• To investigate chemical modifications that weaken intermolecular interactions in the solid state.
• To correlate structural modifications with changes in melting point and solubility.

Main Methods:

• Chemical modification to disrupt molecular planarity (increase dihedral angle).
• Structural modifications to induce molecular bending or asymmetry.
• Introduction of non-flat substituents at meta positions of benzene rings.
• Evaluation of changes in melting point and aqueous solubility.

Main Results:

• Strategies disrupting molecular planarity, symmetry, or planarity increased aqueous solubility.
• These solubility improvements were observed even with concomitant increases in hydrophobicity.
• Disruption of intermolecular interactions proved more effective for solubility enhancement than reducing hydrophobicity in some cases.

Conclusions:

• Chemical modifications weakening intermolecular forces in the solid state offer a viable strategy for enhancing drug solubility.
• Altering molecular geometry (planarity, symmetry, bending) can effectively increase aqueous solubility.
• This approach provides an alternative to traditional hydrophilicity-based strategies for improving drug candidate solubility.