There energy processes [28]. Among them, precipitation by liquid

There are two approaches to produce nanocrystals: top-down approaches and bottom-up approaches. In top-down methods large particles are broken down to small ones (e.g. wet milling and high pressure homogenization (HPH)), while bottom-up methods rely on a process of dissolved 6 drug molecules building up to nano-sized particles (e.g. precipitation). Table 2 shows an overview of various technologies for nanocrystal preparations. Table 2 Overview of the technologies utilized in nanocrystal formulations (modified after the reference 26) Technique Nanocrystal Company Precipitation Bottom-up Hydrosol® Sandoz/Novartis Precipitation Bottom-up Nanomorph® Soligs/Abbott Wet milling Top-down Nanocrystal® NanoSystems/élan HPH Top-down IDD-P® SkyePharma Canada Inc. HPH Top-down Dissocubes® SkyePharma HPH Top-down Nanopure® PharmaSol Combination – NanoEdge® Baxter Combination – smartCrystal® PharmaSol Berlin/Abbott 2.2.2.1 Bottom-up techniques The basic idea of bottom-up techniques for preparation of nanosuspensions is that dissolved drug molecules precipitate from the solvent and grow up to nanoparticles. Nucleation and crystal growth are the two main steps for nanocrystal formation. List and Sucker in 1988 first reported the preparation of “hydrosol” by controlled precipitation method, with the intellectual property owned by Novartis (previously Sandoz) 27. Later, Nanomorph® technology as another precipitation method was reported to be able to prepare stable amorphous drug nanoparticles. This technique is owned by the company Soliqs/Abbott (previously Knoll/BASF) 16 (Table 2). Precipitation technologies can be broadly classified into four categories: precipitation by liquid solvent-antisolvent addition, precipitation in presence of supercritical fluid, precipitation by removal of solvent and precipitation in presence of high energy processes 28. Among them, precipitation by liquid solvent-antisolvent addition is the simplest and most common method. The drug compound dissolved in a solvent is mixed with a miscible antisolvent under stirring or sonication. The supersaturated drug in the antisolvent quickly creates a large amount of nuclei, and then the nuclei grow to the nanoparticles. Agitation and ultrasound is a feasible mixing method to accelerate molecular diffusion and mass transfer, which controls the nucleation and crystallization processes 29. Stabilizers should be added in solvent or antisolvent to prevent the molecular association and crystal growth. Many experimental parameters can affect the results of nanocrystals, such as the drug concentration in solvent, volume ratio of antisolvent to drug solution, power input (the stirring speed or ultrasonication time), precipitation temperature and stabilizers 30, 31. The choice of the antisolvent is important since it determines the supersaturation degree of the drug. The high level of supersaturation would lead to a fast nucleation rate and small nucleus size. That large amount of nuclei are created at the same time and that the nuclei grow simultaneously, are preconditions to produce the small crystals with the same size 32. Water is mostly used as the antisolvent for poorly water soluble drugs, but in some cases both the solvent and the antisolvent can be organic in nature 33.