Screening of Organic Small Molecule Excipients on Ternary Solid Dispersions Based on Miscibility and Hydrogen Bonding Analysis: Experiments and Molecular Simulation.

The preparation of solid dispersions by mixing insoluble drugs with polymers is the main way to improve the aqueous solubility of drugs. The introduction of organic small molecule excipients into binary solid dispersions is expected to further enhance drug solubility by regulating intermolecular hydrogen bonding within the system at the microscopic level. In this study, we used carbamazepine (CBZ) as the target drug and polyvinylpyrrolidone as the solid dispersion matrix and screened the third component from 13 organic small molecules with good miscibility in the solid dispersion based on the principle of similarity of solubility parameters. The hydrogen bonding parameters and dissociation Gibbs free energy of the 13 organic small molecule-CBZ dimer were calculated by quantum mechanical simulation, and the tryptophan (Try) was identified as the optimal third component of organic small molecule. The migration of CBZ in binary and ternary systems was also analyzed by molecular dynamics simulation. On this theoretical basis, the corresponding solid dispersions were prepared, characterized, and tested for solubility analysis, which verified that the drug solubility was stronger for the system with the addition of polar fractions and the Try was indeed the best third component of organic small molecule compound, which was consistent with the simulation predictions. This screening method may provide theoretical guidance for drug modification design and clinical studies.

Hydrogen Bonding Principle-Based Molecular Design of a Polymer Excipient and Impacts on Hydrophobic Drug Properties: Molecular Simulation and Experiment.

Although some commercial excipients for improving the solubility of highly crystalline drugs are widely used, they still cannot cover all types of hydrophobic drugs. In this regard, with phenytoin as the target drug, related molecular structures of polymer excipients were designed. The optimal repeating units of NiPAm and HEAm were screened out through quantum mechanical simulation and Monte Carlo simulation methods, and the copolymerization ratio was also determined. Using molecular dynamics simulation technology, it was confirmed that the dispersibility and intermolecular hydrogen bonds of phenytoin in the designed copolymer were better than those in the commercial PVP materials. At the same time, the designed copolymers and solid dispersions were also prepared during the experiment, and the improvement of their solubility was confirmed, which is in accordance with the simulation predictions. The new ideas and simulation technology may be used for drug modification and development.

Study on the Effect of Polymer Excipients on the Dispersibility, Interaction, Solubility, and Scavenging Reactive Oxygen Species of Myricetin Solid Dispersion: Experiment and Molecular Simulation.

Although the preparation of amorphous solid dispersions can improve the solubility of crystalline drugs, there is still a lack of guidance on the micromechanism in the screening and evaluation of polymer excipients. In this study, a particular method of experimental characterization combined with molecular simulation was attempted on solubilization of myricetin (MYR) by solid dispersion. According to the analysis of the dispersibility and hydrogen-bond interaction, the effectiveness of the solid dispersion and the predicted sequence of poly(vinyl pyrrolidone) (PVP) > hypromellose (HPMC) > poly(ethylene glycol) (PEG) as the polymer excipient were verified. Through the dissolution, cell viability, and reactive oxygen species (ROS)-level detection, the reliability of simulation and micromechanism analysis was further confirmed. This work not only provided the theoretical guidance and screening basis for the miscibility of solid dispersions from the microscopic level but also served as a reference for the modification of new drugs.

Insight into the anti-aging mechanisms of natural phenolic antioxidants in natural rubber composites using a screening strategy based on molecular simulation.

The failure of materials upon aging has led to the accumulation of waste and environmental pollution. Adding antioxidants (AOs) to the composites is one of the most effective ways to retard aging. However, traditional synthetic AOs are always detrimental to the environment and human health. The selection of antioxidants from streams by experiments will also definitely cost a lot of time and money. In addition, the complexity of thermo-oxidative aging factors along with the lack of quantitative tools significantly hampers its applications. So, building a screening strategy to quickly and easily find an appropriate and eco-friendly AO is imperative. In this study, we chose natural rubber (NR) as a matrix and provided a screening strategy based on diverse natural phenolic antioxidants to evaluate their ability in protecting NR composites. Thymol, α-tocopherol, and lipid-soluble epigallocatechin gallate (lsEGCG) were chosen from 18 natural phenolic antioxidants as potential alternative candidates. They were proved, indeed, to enhance the oxidative time in NR from experiments. Our results emphasized that thymol, α-tocopherol, and lsEGCG were promising alternatives for AOs in NR, and the in vitro toxicity test suggested that they are biocompatible. This study may develop a new strategy preference for screening the antioxidants by combining molecular simulation with the validation of experimental approaches, and therefore guide the AO molecular design with a more accurate theoretical prediction.