In this work, it is shown that the common toxicity indicator, MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide), will fail to predict the toxicity of porous silicon (PSi) microparticles. This is due to the spontaneous redox reactions where the MTT is reduced and the PSi particle surfaces are oxidized simultaneously. MTT was shown to even react with thermally oxidized and carbonized forms of PSi particles, although the treatment did give an enhanced protection against the unwanted reactions as compared to as-anodized PSi particles. The observed levels of cellular viability with the MTT assay were much higher than expected in the presence of Caco-2 cells, even considering the spontaneous reduction of MTT at PSi surfaces. The results indicate that the redox reaction is further enhanced inside living cells. Thus, we recommend that MTT should not be used to test the cytotoxicity of drug formulations containing PSi microparticles. The study also shows that since PSi particles are capable of reducing the MTT, they will also be able to reduce other species as well. This should be taken into account when considering future applications for the porous silicon particles. The completely oxidized SiO2 particles (MCM-41 and SBA-15) were shown to work as expected with the MTT assay and showed no inherent oxidation/reduction.
Sink conditions used in dissolution tests lead to rapid dissolution rates for nanosuspensions, causing difficulties in discriminating dissolution profiles between different formulations. Here, non-sink conditions were studied for the dissolution testing of poorly water-soluble drug nanosuspensions. A mathematical model for polydispersed particles was established to clarify dissolution mechanisms. The dissolution of nanosuspensions with either a monomodal or bimodal size distribution was simulated. In the experimental part, three different particle sizes of indomethacin nanosuspensions were prepared by the wet milling technique. The effects of the dissolution medium pH and agitation speed on dissolution rate were investigated. The dissolution profiles in sink and non-sink conditions were obtained by changing the ratio of sample amount to the saturation solubility. The results of the simulations and experiments indicated that when the sample amount was increased to the saturation solubility of drug, the slowest dissolution rate and the best discriminating dissolution profiles were obtained. Using sink conditions or too high amount of the sample will increase the dissolution rate and weaken the discrimination between dissolution profiles. Furthermore, the low solubility by choosing a proper pH of the dissolution medium was helpful in getting discriminating dissolution profiles, whereas the agitation speed appeared to have little influence on the dissolution profiles. This discriminatory method is simple to perform and can be potentially used in any nanoproduct development and quality control studies.
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