Molecular salts of quinine: a crystal engineering route to enhance the aqueous solubility

The antimalarial drug quinine (QUN) has poor aqueous solubility and belongs to Biopharmaceutical Classification System (BCS) Class-II. We report 12 novel molecular salts of QUN with alpha,omega-aliphatic dicarboxylic acids and aromatic coformers. The high basicity of QUN and Delta pK(a) of similar to 5 make the complexes ionic, and most of them are hydrates. The solid forms showed enhanced aqueous solubility compared to the pristine QUN. The single-crystal and powder X-ray diffraction, thermal, and microscopy data provide structural, compositional, and stability profiles of the salts. The calculated Full Interaction Maps (FIMs) provide statistical insights into the salt formation and high probability of hydration in QUN. Though with prospective torsional freedom, QUN in most complexes adopts a unique conformation; this indicates that the structure class has a higher statistical probability and belongs to a relatively deep potential energy trough in the vast crystal landscape.

Automated summary

The study reports 12 novel molecular salts of quinine with alpha,omega-aliphatic dicarboxylic acids and aromatic coformers, which show enhanced aqueous solubility and are mostly hydrates. The structural, compositional, and stability profiles of the salts were analyzed using various methods, providing insights into salt formation and hydration probabilities in quinine. Despite potential torsional freedom, quinine in most complexes adopts a unique conformation, indicating a higher statistical probability and deeper potential energy trough in the crystal landscape.