Nanosizing is a suitable method to enhance the dissolution rate and therefore the bioavailability of poorly soluble drugs. The success of the particle size reduction processes depends on critical factors such as the employed technology, equipment, and drug physicochemical properties. High pressure homogenization and wet bead milling are standard comminution techniques that have been already employed to successfully formulate poorly soluble drugs and bring them to market. However, these techniques have limitations in their particle size reduction performance, such as long production times and the necessity of employing a micronized drug as the starting material. This review article discusses the development of combinative methods, such as the NANOEDGE, H 96, H 69, H 42, and CT technologies. These processes were developed to improve the particle size reduction effectiveness of the standard techniques. These novel technologies can combine bottom-up and/or top-down techniques in a two-step process. The combinative processes lead in general to improved particle size reduction effectiveness. Faster production of drug nanocrystals and smaller final mean particle sizes are among the main advantages. The combinative particle size reduction technologies are very useful formulation tools, and they will continue acquiring importance for the production of drug nanocrystals. 1. Introduction Standard techniques employed for the production of drug nanocrystals are high pressure homogenization and wet bead milling. These processes have been already employed to successfully formulate poorly soluble compounds [1]. However, they have drawbacks, such as long processing times and the necessity of employing a micronized drug as the starting material [2]. Next-generation technologies involve combinative particle size reduction methods to improve the particle size reduction effectiveness of the standard techniques [3]. There are basically two approaches to produce drug nanocrystals, with a third one (the combinative approach) being a combination of the first two techniques. The first process type produces drug nanocrystals by precipitating dissolved molecules. This approach is called bottom-up, as the size of the particles is increased. This group involves processes such as microprecipitation and chemical synthesis. The second process type involves particle size reduction or comminution. This approach is called top-down, as the size of already existing particles is decreased [4]. The third approach involves combinations of bottom-up and/or top-down steps to improve the particle
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