**2.3 Nanocrystals**

Nanocrystals are perhaps the simplest forms of nanomedicine, i.e., nanoparticles made up of 100% of the drug. The large surface/area ratio offered by the nanometric scale increases the dissolution rate, allowing improved pharmacokinetic profiles. The small size of the nanoparticles increases the penetration of the nanocrystals to biological barriers such as the digestive tract, thus increasing the bioavailability of insoluble drugs. The production of crystalline nanoparticles has been applied to both organic drugs and inorganic materials [41–43]. Although the inorganic crystalline nanoparticles approved by the FDA (year 2016) are limited to hydroxyapatite and calcium phosphate for use as substitutes for bone grafts and iron oxide, iron oxide nanoparticles have been used for the treatment of glioblastoma and anemia, due to iron deficiency in kidney diseases [15]. Solubility problems associated with several pharmacological compounds have been improved by conversion to nanocrystals and are marketed for a variety of indications [43]. The pearl mill developed by Elan Nanosystems was used to produce the first three FDA-approved nanocrystals: Rapamune®, Tricor® and Emend®, and is expected to be almost universally applicable to a variety of drugs with low solubility, estimated to be 70–90% of potential drug compounds [41].

## **2.4 Polymeric nanoparticles**

Polymeric nanoparticles are colloidal particles of solid nature that, depending on the preparation method, can form two types of structures: nanospheres or nanocapsules [44]. Nanospheres consist of a matrix system in which the drug can be adsorbed on the surface or co-precipitated with the polymer [45], while in nanocapsules the drug is contained in an internal cavity surrounded by a polymeric membrane [46]. Natural polymers like carbohydrates and proteins vary in their properties between hydrophilic, hydrophobic and even amphiphilic. On the other hand, synthetic polymers are mostly hydrophilic in nature and can be present in a prepolymerized form or be polymerized during the nanoparticle synthesis process. Synthetic polymers, in turn, can be subdivided into two classes, biodegradable and non-biodegradable. Polylactic-co-glycolic acid (PLGA) is a biodegradable polymer widely used for drug delivery [47, 48]. On the other hand, polyacrylates are nonbiodegradable polymers that have also been studied for drug delivery [49, 50], although to a lesser extent compared to biodegradable polymers for clear biocompatibility reasons [51].

Polymeric nanoparticles have immense potential as drug carriers, since they can deliver them in different organs, they protect drugs against degradation in vitro and in vivo, they release the drug in a controlled manner and also offer the possibility of passively targeting drugs to tumors or other tissues actively [44]. The use of polymeric nanoparticles for drug delivery is a universal approach to increase the therapeutic performance of those that are poorly soluble in any route of administration.
