Particle An additional step is needed to reduce

Particle size reduction became an efficient approach applied to a wide range of hydrophobic drugs. The drug micronization process increases the drug surface area with increases the dissolution rate and extent. For very low solubility drug, the micronization fails to increase their dissolution. An additional step is needed to reduce the drug particle size to nanometer size range and it is defined as nanoformulation (Rainer H Müller, Gohla, & Keck, 2011). Various forms of nanoformulations are prepared for drug delivery, as nano-complexes, polymeric micelles, nano-emulsions, polymeric nanoparticles, liposomes, virosomes, and nanosuspensions (Hafner, Lovri?, Lakoš, & Pepi?, 2014). Nanosuspensions is a novel strategy to improve the solubility of hydrophobic drugs with considering the simplicity and efficiency of the technique that is easily scaled-up to the global market (Junghanns & Müller, 2008; Rainer H Müller et al., 2011). Nanosuspensions — also known as nanocrystals­ — are colloidal dispersions of submicron (nanosized) drug particles, stabilized either by surfactants, polymers, or a mixture of both (Chingunpituk, 2011; Yadav & Singh, 2012). The term nanocrystals — despite designating the particles of drug are in a crystalline form — is expanded to define nanosized suspensions of partially crystalline or amorphous drug particles (Lindfors, Skantze, Skantze, Westergren, & Olsson, 2007).

1.1              Nanosuspension Production Methods

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Two basic approaches are used to produce a drug nanosuspension: the bottom-up approach and the top-down approaches. The principle of the bottom-up approach is to dissolve drug molecules then accumulate them to form nanosized particles as in precipitation. While for the top-down approach, large drug particles are broken down into smaller particles as in wet milling and high-pressure homogenization (HPH).  The combination approaches of the bottom-up and the top-down may be applied to produce nanosuspension (Chin, Parmentier, Widzinski, Tan, & Gokhale, 2014).

1.1.1        Bottom-Up Approach

Nucleation and crystal growth are major steps for nanosuspension formation using the bottom-up approach. List and Sucker reported the preparation of first crystalline nanosuspension “hydrosol” by the precipitation method (Sandoz, nowadays known as Novartis company) (List & Sucker, 1988). After that, Nanomorph® technology (Soliqs was known as Abbott company) was developed to prepare amorphous nanosuspension (Junghanns & Müller, 2008).

Precipitation methods are divided into four categories: precipitation using liquid solvent-antisolvent, precipitation using supercritical fluid, precipitation through the elimination of solvent and precipitation in the involvement of high energy procedure (Sinha, Müller, & Möschwitzer, 2013). Precipitation using liquid solvent-antisolvent addition is the most used method due to its simplicity. In this method, the drug is dissolved in a solvent. Then, a miscible antisolvent is added gradually under the influence of stirring or sonication in the presence of a stabilizer. The supersaturated drug instantly generates plenty of nuclei that grow to become nanoparticles. Agitation and ultrasound are applied to stimulate molecular diffusion and mass transfer to manage the nucleation and crystallization procedure (Guo, Zhang, Li, Wang, & Kougoulos, 2005).

Additional bottom-up approaches have been published to prepare the nanosuspension, including that by Mou et al. where an acid-base neutralization reaction to formulate itraconazole nanosuspensions based on drug pH-dependent solubility. Itraconazole was dissolved in a mixture of water-miscible solvents (hydrochloric acid solution and ethanol). Then, sodium hydroxide solution was added to the itraconozole solution under stirring until it was neutralized (Mou, Chen, Wan, Xu, & Yang, 2011). Hydrocortisone nanosuspensions were prepared using a microfluidic nanoprecipitation method. Hydrocortisone was the first drug dissolved in an organic solvent. Then, antisolvent phase with stabilizers has flowed from micro-channels resulting in nucleoli formation (Ali, York, Ali, & Blagden, 2011; Ali, York, & Blagden, 2009). Other methods such as liquid atomization based techniques include spray drying (S. H. Lee, Heng, Ng, Chan, & Tan, 2011), electro-spraying (M. Wang, Rutledge, Myerson, & Trout, 2012) and aerosol flow reactor (Eerikäinen, Watanabe, Kauppinen, & Ahonen, 2003). However, using the bottom-up approach is reduced after the introduction of a top-down approach.

1.1.2        Top-Down Approach

In 1990, the first top-down approach was developed by Liversidge et al that is known as wet pearl milling (Nanocrystal®) (G. G. Liversidge, Cundy, Bishop, & Czekai, 1992). It involves a container with pearls, beads, or balls (Milling chamber); the drug is dispersed with stabilizer and dispersion media (water, buffer or organic solvent). The resulting suspension is poured into a mill; then it is rotated at a very high speed. collision of the particles with high shear forces breaks the crystals into nanosized particles (P. Liu, 2013).

High-pressure homogenization (HPH) is the second technology for drug nanosuspension production. Piston-gap and microfluidizer homogenizer are commonly used technologies of HPH (P. Liu, 2013). The first generation of piston-gap homogenizers using aqueous media was invented by Müller et al. and is known as DissoCubes® Technology (R. H. Muller, Becker, Kruss, & Peters, 1999). The raw drug powder or dispersion is firstly homogenized into micro-size by jet-mill (R. Müller, Jacobs, & Kayser, 2001), basic homogenizer (Hecq, Deleers, Fanara, Vranckx, & Amighi, 2005; P. Sharma, Denny, & Garg, 2009), sonication (Lai et al., 2011) or mortar and pestle (Pardeike et al., 2011) to prevent the blocking of the small homogenization gap. The presence of the lower liquid static pressure compared with a higher vapor pressure at room temperature leads to boiling of the liquid. In the homogenization gap, the implosion of gas bubbles and cavitation generates particle breakage. The cavitation, shear and collision forces collaborate to produce nanocrystals (P. Liu, 2013).

The microfluidizer homogenizer is a technology that uses aqueous media for homogenization and it is operated based on a jet stream. The drug micro-suspension moves within chambers under a high pressure. The liquid streams and extreme speed create turbulence in the channels and hits against each other and toward the chamber wall that result in particle size reduction to the nano-size range (Gruverman, 2003).

The second generation of piston-gap homogenizers uses non-aqueous media known as Nanopure® technology. The Nanopure® technology was invented for specific administration routes where the drug must be dispersed in oils or water-free media e.g. drug nanosuspensions prepared for soft gelatin capsules (C. M. Keck & Müller, 2006).

1.1.3        Combination Approaches

Two techniques are combined to overcome the limitations of each technique. Baxter Healthcare Company has presented a combination technology named NANOEDGE®. This technology is a combination of precipitation then additional high energy step to prevent extra aggregation and crystal growth (Kipp, Wong, Doty, & Rebbeck, 2003). Another combination method is known as melt emulsification where high-pressure homogenization is applied to prepare nanoformulations (Dolenc, Govedarica, Kocbek, Sr?i?, & Kristl, 2010).

The second generation of nanocrystals has been represented and it is known as a SmartCrystal® technology that involves pre-treatment and main treatment. The combinations include precipitation-HPH (H69), lyophilization-HPH (H96), spray drying-HPH (H42), and pearl milling-HPH (CT). The benefits of these combinations are to create faster production processes and smaller nanocrystals with enhanced physical stabilities (C. Keck, Kobierski, Mauludin, & Müller, 2008; Shegokar & Müller, 2010). All approaches are presented in Figure 1.3 with their principles, advantages, disadvantages and patents.