Nanocrystal Preparation: Low-Energy Precipitation Method Revisited

• Published in: Crystal growth & design 2013-07, Vol.13 (7), p.2766-2777
• Main Authors: Khan, Shahzeb, Matas, Marcel de, Zhang, Jiwen, Anwar, Jamshed
• Format: Article
• Language: English
• Subjects: Condensed matter: structure, mechanical and thermal properties; Cross-disciplinary physics: materials science; rheology; Equations of state, phase equilibria, and phase transitions; Exact sciences and technology; Materials science; Nanoscale materials and structures: fabrication and characterization; Other topics in nanoscale materials and structures; Phase diagrams and microstructures developed by solidification and solid-solid phase transformations; Physics; Precipitation; Solubility, segregation, and mixing; phase separation; Structure of solids and liquids; crystallography; Structure of specific crystalline solids
• ISSN: 1528-7483; 1528-7505
• DOI: 10.1021/cg4000473

Nanocrystals have the potential to address the challenges of delivering drugs with low aqueous solubility. In this study, the use of low energy anti-solvent precipitation for producing nanocrystals has been investigated. Stable nanocrystals with uniform particle size were prepared for the three model compounds, glyburide, ibuprofen, and artemisinin, which are all practically insoluble in water and have diverse molecular structures and crystal packings. The choice of crystal growth inhibitors/stabilizers was found to be critical and specific for each drug. The effect of the process variables, temperature, stirring rate, and the solute solution infusion rate into the antisolvent, was rationalized in terms of how these factors influence the local supersaturation attained at the earliest stages of precipitation. The dissolution of the nanocrystals in aqueous media under physiological conditions was shown in all cases to occur almost instantaneously, being markedly more rapid than that observed for micronized suspensions of the model drugs and their marketed tablet formulations. Rationalization of the choice of optimum stabilizers in terms of molecular interaction with the exposed crystal surfaces proved to be difficult. The study demonstrates that standard crystallization technology is effective in producing nanocrystals with the primary challenge being physicochemical (rather than mechanical), involving the identification of molecule-specific crystal growth inhibitors and/or stabilizers.