State of the art of nanocrystals – special features, production, nanotoxicology aspects and intracellular delivery

Drug nanocrystals are the latest, broadly introduced nanoparticulate carrier to the pharmaceutical market from the year 2000 onwards. The special features of nanocrystals for the delivery of poorly soluble drugs are briefly reviewed (saturation solubility, dissolution velocity, adhesiveness). The industrially relevant bottom up (precipitation) and top down production technologies (pearl milling, high pressure homogenization, combination technologies) are presented. As nanotoxicological aspects, the effect of size, degradability versus biopersistency and intracellular uptake are discussed, classifying the nanocrystals in the low/non-risk group. Intracellular uptake plays a minor or no role for dermal and oral nanocrystals, but it plays a key role for intravenously injected nanocrystals (e.g. nevirapine, paclitaxel, itraconazole). Uptake by the macrophages of the mononuclear phagocytic system (MPS, liver spleen) can modify/optimize blood profiles via prolonged release from the MPS (itraconazole), but also target toxicity by too high organ concentrations and thus cause nanotoxicity. The balance in the competitive intracellular uptake by MPS and the target cells (e.g. blood–brain barrier) decides about therapeutic efficiency. The concept of “differential protein adsorption” to modulate this balance is shown for its applicability to nanocrystals for intracellular delivery to the cells of the blood–brain barrier (atovaquone)

Long-term stability of quercetin nanocrystals prepared by different methods

Objectives  This study aimed to examine the long-term physical stability of quercetin nanocrystals produced by three methods. Methods  Quercetin nanocrystals were prepared by high pressure homogenization, bead milling and cavi-precipitation. The nanocrystals produced by these methods were compared for particle size, saturation solubility and dissolution of the drug particles, and were subjected to stability testing. Key findings  The X-ray diffraction study and microscopic pictures taken under polarized light indicated the crystalline nature of the nanocrystals produced by the three methods. As the crystalline state is relatively more stable than the amorphous state, a good physical stability was expected from the quercetin nanocrystals prepared. The high-pressure homogenized and bead-milled quercetin nanocrystals showed excellent physical stability when stored under refrigeration (4 ± 2°C) and at room temperature (25 ± 2°C) for 180 days. The dissolution properties were not significantly affected on storage at room temperature. However, increase in the storage temperature to 40 ± 2°C led to physical instability. On the other hand, the cavi-precipitated quercetin nanocrystals exhibited a lower stability than the bead-milled and homogenized formulations and did not show the optimum zeta potential values as well. In the case of cavi-precipitated nanocrystals, recrystallization and agglomeration were responsible for the increasing particle size besides the Ostwald ripening phenomenon. The solvents used during cavi-precipitation might have competed with the surfactant for hydration leading to a partial dehydration of the surfactant, which subsequently affected the stability of the quercetin nanocrystals. Conclusions  High-pressure homogenized and bead-milled quercetin nanocrystals showed better physical stability than the cavi-precipitated ones. Freeze drying immediately after nanocrystal production can help to prevent their agglomeration and thus improve physical stability