Co-crystallization experiments of 4-halophenylboronic acid with several pharmaceutical compounds (including aciclovir, caffeine, nitrofurazone, and proline) produced several new molecular complexes. The experiments involved varying the solvent and the molar ratio of boronic acid to a pharmaceutical compound (e.g., 1:1, 2:1, 1:2). The screening process for new crystal phases revealed that the formation of the different molecular complexes was strongly influenced by the molar ratio and the presence or absence of water in the solvent. The new molecular crystals were characterized through single crystal X-ray diffraction and differential scanning calorimetry (DSC) analyses. The single crystal analyses of the molecular complexes revealed an unexpected variety in the hydrogen bonding network interactions that can be produced by the –B(OH)₂ motif.

This study presents a structural screening and molecular electrostatic potential (MEP) computational analysis of various organoboronic acids as effective co-formers in pharmaceutical crystal engineering. The strong predictability of dimeric B(OH)₂ homosynthons allows for precise control of molecular self-assembly within the crystal structure. Concurrently, the presence of the boron atom imparts significant biomedical importance to these systems due to its documented efficacy in boron neutron capture therapy (BNCT) and non-enzymatic diagnostic glucose sensors for diabetes management. By developing multi-component co-crystals, boronic acids play a key role in improving critical pharmaceutical parameters, such as aqueous solubility, bioavailability, and overall drug absorption. In this work, we analyze their binding behavior with a diverse array of active pharmaceutical ingredients (APIs) through the lens of various xanthine derivatives (caffeine and theophylline) and nitrofurazone. The successful co-crystallization with these molecules demonstrates the broad compatibility of boronic structures. Conversely, despite highly favorable theoretical predictions for donor–acceptor compatibility, systematic laboratory screening revealed that co-crystallization with other well-known APIs, such as paracetamol and amikacin, fails, leading exclusively to the isolation of the unreacted starting materials. Therefore, by comparing successful structures and collecting data from the resulting negative outcomes, this study provides a systematic approach for the evaluation and selection of future co-formers.