Cocrystals of Propylthiouracil and Nutraceuticals toward Sustained-Release: Design, Structure Analysis, and Solid-State Characterization

Propylthiouracil (PTU) is a clinically preferred drug to treat hyperthyroidism effectively. The sustained release of PTU is necessary because of the shortcomings of rapid release and hepatotoxicity. In this study, cocrystals of PTU with nutritional coformers were screened, and four new cocrystals of PTU with cinnamic acid (CA), gentistic acid (GA), ellagic acid (EA), and kaempferol (KA) were discovered. The cocrystals were characterized by single-crystal and powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and scanning electron microscopy. The Hirshfeld surface analysis and reduced density gradient analysis reveal that the weak van der Waals interactions play an essential role in the crystal packing. The stability test indicates that all four cocrystals show excellent stability under accelerated storage conditions (40 degrees C and 75% RH) over 12 weeks. Moreover, PTU-CA, PTU-EA, and PTU-KA cocrystals all exhibit decreased solubility and decelerated intrinsic dissolution rate (IDR). Among them, the PTU-KA cocrystal shows the best performance. Specifically, the solubility decrease is up to 77.32% in pH 1.2 buffer and 85.15% in pH 6.8 buffer, and the lowest IDR is 12.0% and 20.8% of that of PTU in pH 1.2 and 6.8 buffers. According to the calculation result, the sustained-release effect could be attributed to the enhanced lattice energies and hydrophobic interaction. This work may be useful to design a sustained-release system via cocrystallization of APIs that have significant hepatotoxicity.

Automated summary

This study discovered four new cocrystals of propylthiouracil (PTU) with nutritional coformers, showing excellent stability and sustained-release effects, especially the PTU-KA cocrystal. The sustained-release effect may be attributed to enhanced lattice energies and hydrophobic interactions.