Nanosizing is a suitable method to enhance the dissolution rate and therefore the bioavailability of poorly soluble drugs. The\r\nsuccess of the particle size reduction processes depends on critical factors such as the employed technology, equipment, and drug\r\nphysicochemical properties. High pressure homogenization and wet bead milling are standard comminution techniques that have\r\nbeen already employed to successfully formulate poorly soluble drugs and bring them to market. However, these techniques have\r\nlimitations in their particle size reduction performance, such as long production times and the necessity of employing a micronized\r\ndrug as the starting material. This review article discusses the development of combinative methods, such as the NANOEDGE, H\r\n96, H 69, H 42, and CT technologies. These processes were developed to improve the particle size reduction effectiveness of the\r\nstandard techniques. These novel technologies can combine bottom-up and/or top-down techniques in a two-step process. The\r\ncombinative processes lead in general to improved particle size reduction effectiveness. Faster production of drug nanocrystals and\r\nsmaller final mean particle sizes are among the main advantages. The combinative particle size reduction technologies are very\r\nuseful formulation tools, and they will continue acquiring importance for the production of drug nanocrystals.
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