Intermolecular Interactions and Solubility Behavior of Multicomponent Crystal Forms of Orotic Acid: Prediction and Experiments

Multicomponent crystal forms for drugs with poor solubility, such as orotic acid (OA), can potentially promote dissolution behavior and bioavailability. Herein an affinity prediction was carried out to predict the formation of multicomponent crystal forms between OA and 41 coformers. Amino acids were selected as coformers to solve the solid-state solubility problem of OA. Six new multicomponent crystal forms, including five salts and one salt hydrate, were characterized and confirmed by powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. Spectroscopic techniques, such as Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy, were used to validate the cocrystal/salt dichotomy. In the crystal packing, all salts exhibit N+-H center dot center dot center dot O- intermolecular interactions, which is well explained by molecular electrostatic potential surfaces. Finally, a powder dissolution study was conducted. The powder dissolution of all salts presented a higher apparent solubility (1.15-1.32 times) and a faster dissolution rate in comparison to those of OA, which is ascribed to the strength of the crystal lattice and the solvation of components.

Automated summary

The study predicts the possibility of multicomponent crystal forms between OA and various coformers using different techniques, and successfully identifies six new multicomponent crystal forms. All salts exhibit higher solubility and faster dissolution rate compared to OA, attributed to the strength of the crystal lattice and solvation of components.