Pharmaceutical novel solid forms of Milrinone with advanced physicochemical properties

Milrinone (MLN) is a second-generation bipyridine phosphodiesterase (PDE) inhibitor developed by mod-ifying amrinone chemically. It is a PDE-III antagonist that promotes cardiac function and systemic va-sodilator in chronic decongested cardiovascular disease by increasing cAMP levels. It is classified under Biopharmaceutics Classification System (BCS) class II, which implies, high permeability and low water solubility. Using mechanochemical and solution crystallization, five novel molecular solids of the cardio-protective drug (MLN) with Generally Recognized As Safe (GRAS) co-formers, namely 2-hydroxybenzoic acid (2-HBA), 2,3-dihydroxybenzoic acid (2,3-DHBA), 2,4-dihydroxybenzoic acid (2,4-DHBA), fumaric acid (FA), and adipic acid (AA) were successfully synthesized. All the solid forms were characterized by PXRD, SCXRD, and thermal analysis (TGA and DSC). The structural analysis of the complexes reveals that the dimeric interaction of MLN itself remains intact in all the structures. Molecular assemblies made with AA and 2,3-DHBA produced channel structures, whereas the remaining formed various forms of sheet struc-tures. A physicochemical property analysis revealed that the synthesized molecular solid exhibits higher solubility than the parent form. Furthermore, the theoretical analyses corroborate well with the solu-bility of molecular complexes. We believe that the novel solid forms for MLN are promising candidates for addressing poor solubility difficulties while also providing a new avenue for further improving the material's physicochemical properties. (c) 2022 Elsevier B.V. All rights reserved.

Automated summary

Milrinone (MLN) is a cardiovascular drug that has been successfully synthesized into novel molecular solids with greater solubility and improved physicochemical properties using various co-formers.