A novel bottom–up process to produce drug nanocrystals: Controlled crystallization during freeze-drying

To improve the dissolution behavior of lipophilic drugs, a novel bottom-up process based upon freeze drying which allows for the production of nanocrystalline particles was developed: "controlled crystallization during freeze drying". This novel process could strongly increase the dissolution behavior of fenofibrate. For example at a drug load of 30% w/w, 80% of the drug dissolved within 10 min from tablets prepared from the controlled crystallized dispersions, while from tablets prepared from the physical mixture only 50% was dissolved after 120 min. Furthermore it was found that faster freezing or using a solution with a lower water/tertiary butyl alcohol (TBA) ratio resulted in faster dissolution, indicating that the crystalline dispersions contained smaller crystals. Crystallization of the drug could occur during freezing or during drying. When crystallization occurs during freezing, faster freezing or using solutions with a lower water/TBA ratio results in the formation of more nuclei and consequently smaller crystals. When crystallization occurs during drying, faster freezing or using solutions with a higher water/TBA ratio results in the formation of smaller solvent crystals and therefore smaller interstitial spaces which contain the freeze-concentrated fraction. Since crystallization occurs in the freeze-concentrated fraction and the size of the crystals are limited to the size of the interstitial spaces, smaller crystals are formed in these situations.