Effect of PVP and HPMC on production of indomethacin amorphous nanoparticles: experiments and molecular dynamics simulations

OBJECTIVE: This study investigated the effect of molecular interactions between drug and polymers on preparation of nanoamorphous indomethacin (IND) through milling of solid dispersions (SDs). SIGNIFICANCE: The polymer selection (molecular interaction) emerged as a critical factor in the dynamic milling process for achieving nanoamorphous drug. METHODS: Polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) were selected as models. Amorphous dispersions were used to prepare nanoamorphous drugs by applying wet milling. Molecular simulations were employed to elucidate the molecular mechanisms of drug-polymer miscibility, interaction energy, and molecular migration. RESULTS: Both PVP and HPMC related SDs could be nanosized after milling. The rate of size reduction might be related to the solid state of the dispersions. The combination of amorphous PVP SDs with reduced particle size significantly improved the dissolution rate of IND. However, HPMC-based samples exhibited recrystallization during milling. Molecular simulation indicated that PVP formed strong molecular interaction with the drug to maintain the amorphous form, which contributed to avoid recrystallization induced by the external milling forces. The radial distribution function of hydrated IND/HPMC amorphous cells demonstrated the absence of hydrogen bonding interactions between IND and HPMC. CONCLUSION: PVP contributed to maintain the amorphous state during the milling process, which resulted from the higher molecular binding energy compared to HPMC. Controlled milling of amorphous SD with optimized polymer selection could simultaneously achieve nanoamorphous particle and enhanced dissolution rate.