Bottom-Up Preparation Techniques for Nanocrystals of Lipophilic Drugs

Modern drug discovery techniques result in the development of an increasing number of highly lipophilic drug candidates. Their lipophilicity results in a slow dissolution of these drugs in the aqueous gastro-intestinal fluids, resulting in a poor bioavailability. Over the past few decades, many strategies have been developed to increase the dissolution rate of these types of drugs. The application of drug nanocrystals is one technique. The dissolution rate of drugs from nanocrystals is increased due to an increase of the saturation concentration around these particles (Kelvin law) and an increase of the surface area available for dissolution. Preparation techniques for drug nanocrystals can be divided into top-down and bottom-up techniques. Top-down techniques are based on size reduction of relatively large particles into smaller particles, whereas bottom-up techniques consist of the growth of small particles from individual molecules. The driving force for the growth of a crystal from individual molecules is supersaturation. Supersaturation of a drug in a solution can be obtained by decreasing the temperature or addition of an anti-solvent. The size of crystals formed from supersaturated pure drug solutions depends on the balance between the nucleation rate and crystal growth. This balance between nucleation and growth is determined by the extent of supersaturation. At a higher extent of supersaturation, the nucleation rate increases, and, hence, the crystal size decreases, whereas at a lower extent of supersaturation, the growth rate increases, and, hence, the crystal size increases. Therefore, process conditions, such as temperature or the ratio between solvent and anti-solvent and their mixing rate, can be used to control the drug crystal size. When drug crystals are formed in drug composites, the size of the crystals is also determined by the interstitial spaces between matrix molecules. While there are many excellent reviews on top-down techniques (e.g. (1,2)), bottom-up techniques are usually just referred to as “precipitation techniques.” Bottom-up techniques can be considered as the oldest techniques to prepare drug nanocrystals. However, recently, interesting new developments in the field of bottom-up preparation of drug nanocrystals have evolved. This commentary focuses on these techniques. First, an overview of bottom-up preparation techniques of crystalline drug nanoparticles will be given (Table I). Second, the process-related barriers for products prepared by these techniques to reach the market will be discussed. For an introduction on top-down methods to prepare drug nanocrystals and the application thereof, the reader is referred to an excellent recently published review (2). Table 1 Overview of Bottom-Up Techniques to Prepare Drug Nanocrystals