Molecular mechanism of polymer-assisting supersaturation of poorly water-soluble loratadine based on experimental observations and molecular dynamic simulations.

Polymers have been usually used to retard nucleation and crystal growth in order to maintain supersaturation, yet their roles in inhibition of nucleation and crystal growth are poorly understood. In our work, the polymer-based supersaturation performances and molecular mechanisms of poorly aqueous soluble loratadine were investigated. Two common hydrophilic polymers (hydroxylpropylmethyl cellulose acetate succinate (HPMC-AS) and poly(vinylpyrrolidone-co-vinyl-acetate) (PVP-VA)) were used. It was found that HPMC-AS was a better polymer to prevent drug molecules from aggregation and to maintain the supersaturated state in solution than PVP-VA. The in vitro dissolution experiments showed that HPMC-AS solid dispersions had more rapid release at pH 4.5 and 6.8 media than PVP-VA solid dispersions under the un-sink condition. Moreover, molecular dynamic simulation results showed that HPMC-AS was more firmly absorbed onto a surface of the drug nanoparticles than PVP-VA due to bigger hydrophobic areas of HPMC-AS. Thereby, crystallization process of loratadine was inhibited in the presence of water to provide prolonged stability of the supersaturated state. In conclusion, polymers played a key role in maintaining supersaturation state of loratadine solid dispersions by strong drug-polymer interactions and the hydrophobic characteristic of polymers.