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

Abstract

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.

New Insights into the Solubilization of Multicomponent Crystals: A Case Study of Pipemidic Acid

“…The solubility increase could be attributed to the CCFs of higher solubility involved in the crystal lattice , (The solubility of SAA, GA, PCA, CAA, and SAC are 2.24 mg/mL at 25 °C, 5.00 mg/mL at 5 °C, 18.20 mg/mL at 14 °C, slightly soluble and 4.00 mg/mL at 25 °C, respectively.) However, the solubility of the multicomponent crystals did not follow the same order as the solubility of the CCFs, indicating that the solubility is controlled by multiple factors, such as the strength, position . Particularly, the presence of water molecules in the lattice appears to inhibit the solubility enhancement since all multicomponent crystals in anhydrous form show higher solubility than hydrate, which is similar to property the hydrates of monocomponent crystals. , …”

Drug-nutrient cocrystallization-driven strategy towards self-assembly of milrinone and ferulic acid provides an exemplification in perfecting in vitro/vivo characteristics of anti-heart failure drugs

“…, the melting point of the present cocrystal. Clearly, the observed melting point value is quite distinct from that of either MLN (>300.0 °C) or FEA (172.8 °C), 16,22 which falls in between that of the corresponding raw materials, signifying the emergence of a novel solid phase. The decomposition process of the cocrystal at the same position in the TG curve can be regarded as the proof of new phase formation.…”

“…15 Considering the above facts, giving rein to the advantages of this technique to surmount the major shortcomings for MLN is of considerable value. Nevertheless, for all we know, there are few systematic research studies on MLN cocrystal, 16 which may be attributed to the existence of firm complementary lactam-lactam self-dimers formed by the self-assembly of stable N-HÁ Á ÁO hydrogen bonders synthons. 17 According to the current study status, it is of great reference value to select pharmaceutically acceptable CCFs to achieve the directional assembly with MLN by altering or destroying the intermolecular self-dimerization towards ameliorating its pharmaceutical characteristics.…”

Two Novel Co-Crystals of Naproxen: Comparison of Stability, Solubility and Intermolecular Interaction

“…Moreover, the crystal density affects the solubility of the co-crystals to some extent [ 35 ]. Therefore, this study achieved its purpose and provided a basis for further research on the reduction of adverse reactions by reducing drug doses [ 36 , 37 ].…”