Multi-directionally evaluating the formation mechanism of 1,4-dihydropyridine drug nanosuspensions through experimental validation and computer-aided drug design

The poor aqueous solubility of 1,4-dihydropyridine drugs needs to be solved urgently to improve bioavailability. Nanotechnology can improve drug solubility and dissolution by reducing particle size, but usually, a specific polymer or surfactant is required for stabilization. In this study, Poloxamer-407(P-407) was screened as the optimal stabilize through energy simulation, molecular docking, and particle size. the morphological study, X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, Raman, in vitro dissolution test, and molecular simulation of interactions were utilized to explore the formation mechanisms of four 1,4-dihydropyridine drugs/P-407 nanosuspensions. The result shows that the optimized nanosuspensions had the particle size in the nano-size range and maintained the original crystal state. The in vitro dissolution rate of the nanosuspension was 3-4 times higher than the corresponding API and could reduce the restriction of drug dissolution in different pH environments. Raman spectroscopy, FTIR, and molecular docking simulations provided strong supporting evidence for the formation mechanism of 1,4-dihydropyridine drugs/P-407 nanosuspensions at the molecular level, which confirmed that the stable intermolecular hydrogen bond adsorption and hydrophobic interaction were formed between the drug and P-407. This research will provide practical concepts and technologies, which are helpful to develop nanosuspensions for the same class of drugs.