Mitali Kakran (1), Nanda Gopal Sahoo (1), Lin Li (1), Rainer H. Müller (2)
A number of newly developed drugs exhibit poor water-solubility as well as poor bioavailability and one of the most challenging tasks in drug development is to improve the solubility and oral bioavailability of these drugs. Various methods to enhance solubility of such drugs include formation of complexes (e.g. with β-cyclodextrin), solid dispersions, liposomes, microemulsions etc. However, these methods are successful in some instances and are specific to drug candidates. An alternative universal approach, which can be applied to any drug, is to increase the particle surface area by reducing the particle size to nanoscale. Nanocrystals exhibit advantages like increased saturation solubility, dissolution velocity attributed to their larger surface area, and excellent adhesion to biological surfaces. This results in not only an improved bioavailability but also in reduction of variation in bioavailability. There are two key approaches to achieve nano-dimension namely, ‘top down’ and ‘bottom up’. The aim of this study is to compare production of nanocrystals of a poorly water-soluble antioxidant, quercetin, by top-down and bottom-up methods. The top-down method used was high pressure homogenization (HPH) and bottom-up method was evaporative precipitation of nanosuspension (EPN) and the products from these methods were compared.
Quercetin nanosuspensions (2-10% w/w) in water using Tween 80 as a stabilizer (0.5-2% w/w) were homogenized at 500-1500 bar. Quercetin nanosuspensions were later lyophilized. For EPN method, quercetin was dissolved in a good solvent (ethanol) and nanocrystals were formed by quickly adding an antisolvent (hexane), followed by quick evaporation and vacuum drying. Different quercetin concentrations in ethanol used were 5-15 mg/ml and ethanol to hexane ratios were varied from 1:5 to 1:25 (v/v).
Particle size of the commercial drug was about 34 μm. Its particle size was reduced after HPH to 330 nm, and after EPN to 340 nm. The solubility and dissolution rate of the quercetin nanocrystals prepared by both methods enhanced 8-10 times compared to the commercial quercetin.
This study demonstrated that both the methods can successfully prepare quercetin nanocrystals with enhanced solubility and dissolution. On one hand, HPH has no specific solvent requirement but is energy intensive and costly. However, EPN is a simple process and cost effective but the drug should be soluble in at least one solvent. For quercetin, as the solvent criteria is fulfilled, therefore, EPN is a suitable method. But for drugs which cannot dissolve in any solvent, HPH is more applicable.
1) School of Mechanical and Aerospace Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798
2) Free University of Berlin, Department of Pharmacy, Biopharmaceutics and Nutricosmetics, Kelchstrass 31, Berlin, Germany