Resveratrol nanosuspensions: interaction of preservatives with nanocrystal production.

The effect of six different preservatives on the production process and stability of resveratrol nanosuspensions was investigated. Nanosuspensions of the anti-oxidant resveratrol were prepared by high pressure homogenization (1,500 bar, 20 homogenization cycles). The preservatives used were: caprylyl glycol (0.75%), Euxyl PE 9010 (1.0%), Hydrolite-5 (2.0), Phenonip (0.75%), Rokonsal PB-5 (0.5%) and MultiEx Naturotics (2.0%). Preservation is essential for oral and dermal nanosuspensions, but can impair the stability. The effect of the preservatives on stability as a function of cycle numbers was determined by size measurements (photon correlation spectroscopy (PCS), laser diffraction (LD) and light microscopy). Zeta potential measurements were performed for determination of the Stern potential (measurements in water) and as stability criterion (measurements in original dispersion medium), to elucidate the mechanism of destabilization. The preservatives could be placed into three groups. Hydrolite-5 did not affect the production process and the short term stability, sizes were practically identical to the preservative-free nanosuspension (e.g. PCS diameters 196 nm and 184 nm, respectively). All other preservatives impaired the stability medium to pronounced, being most pronounced for MultiEx Naturotics. Hydrolite-5 is recommended as preservative of choice. A mechanistic model was developed to explain the absence and the different degrees of destabilization. In general, when screening for suitable preservatives, suspensions are produced, different preservatives added and the size changes are monitored over long-term. The destabilizing effect of the preservatives on nanosuspensions became evident when added in the production process immediately, thus this can be used as a screening tool for optimal, non-destabilizing preservatives, replacing or minimizing time-consuming long-term stability studies.