The First Cocrystallization of Milrinone with Nutraceuticals: The Adjusting Effects of Hydrophilicity/Hydrophobicity in Cavities on the In Vitro/In Vivo Properties of the Cocrystals

• Published in: Crystal growth & design Vol. 22; no. 3; pp. 1623 - 1637
• Main Authors: Liu, Lu, Yu, Yue-Ming, Bu, Fan-Zhi, Li, Yan-Tuan, Yan, Cui-Wei, Wu, Zhi-Yong
• Format: Journal Article
• Language: English
• Published: American Chemical Society 02-03-2022
• ISSN: 1528-7483; 1528-7505
• DOI: 10.1021/acs.cgd.1c01143

To give full prominence to the superiority of phenolic acid nutraceuticals syringic acid (SYRA) and gallic acid (GALA) in perfection of in vitro and in vivo performances for cardiotonic drug milrinone (MLN), and ulteriorly attain novice insights in the development of cardiotonic drug-nutraceutical cocrystals, two new solid forms of MLN including one cocrystal with SYRA, and one cocrystal hydrate with GALAnamely, MLN-SYRA (1) and MLN-GALA- H2O (2)are first assembled and thoroughly characterized. The single-crystal X-ray diffraction showcases that both cocrystal 1 and cocrystal hydrate 2 have three-dimensional supramolecular structures controlled by hydrogen-bonding and aromatic packing interactions, where the hydrogen-bonding dimers of MLN itself still remain in 1 but are broken in 2, forming hydrophobic cavities in the former and hydrophilic ones in the latter. Such structural characteristics and aggregation motifs, because of the introduction of different phenolic acids in the crystalline lattices, have important influence on the improvements of dissolvability and permeability for the two crystalline forms, and in accordance with the theoretical studies. Intriguingly, the optimized in vitro biopharmaceutical properties can be effectually transformed to satisfactory in vivo pharmacokinetic peculiarity, performing the increased bioavailability and extended half-life. Thus, the current research not only offers promising solid-state forms for MLN with development foregrounds, but opens up new applications for nutraceutical phenolic acids in cardiotonic pharmaceutical cocrystals.