A parallel nanoliter microfluidic analysis system based on capillary action, centrifugal force, and hydrophobic barriers is described. The precision of 112 parallel volume definition operations is determined to 0.75% CV at 200 nL using the individual sample introduction structure. For 20 nL, the actual measurement error is the dominating factor, with a combined error of 1.9% CV. Individual dispensing as well as dispensing through a common distribution channel is described. The volume definition precision for the common distribution channel is 1.6% CV for 200 nL. Unlike the dominating forces in microlitersized channel systems, we describe hysteresis effects as exerting a major influence, which needs to be considered in order to control the operation and design of discrete nanoliter fluidics. Hydrophobic patches at the corners of the rectangular channel control corner-enhanced wicking. Excellent flow control of 1 and 2 nL/s is achieved using a predefined spin program.In comparison with conventional analysis systems, µ-TAS (micro total analysis system) have the potential to achieve faster analysis times, improve automation, consume less reagents, gain more information from less sample, and significantly increase throughput by running parallel analyses. 1 The development of µ-TAS-based parallel analysis systems has shown to be demanding. In 2001, Cheng et al. showed six parallel analyses 2 using electroosmotic (EO) flow; however, despite more than a decade of research on electroosmotic (EO) pumping, parallel separation systems have been challenging to develop. Some of the challenges using EO-pumping-based systems have been described earlier. 3,4 With suppressed EO flow, conventional multicapillary DNA electrophoresis was transferred to a chip performing parallel separations on 384 samples. 5 At present, most of the µ-TAS systems use a continuously pumped approach, i.e., liquid is pumped from an inlet reservoir to an outlet reservoir, and in most cases the volumes of sample and reagents needed to interface with the chip are several orders of magnitude higher than the volumes used in the analysis. This is also true of the parallel multilayer elastomeric system proposed by Unger et al.,4 where an additional issue of sample and reagent compatibility with the elastomeric material has to be resolved. Moreover, using a continuous flow system requires reliable liquid connections to the chip; a chip with 100 or more channels requires at least 200 electrodes for the simplest EO case, 6 or hundreds of low dead volume pressure connections for pressure-driven systems. It is difficult to eliminate error in such a system, particularly if a disposable chip format is used. Centrifugal analyzers enable the development of parallel analysis systems without external connections. Miniaturized centrifugal analyzers for microliter volumes were reported in 1973; these used a plastic disc with the same diameter (12 cm) as used in today's compact discs (CD). 7 In another microliter-range centrifugal system, a microfabricated burst valve was i...

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PurposeA versatile methodology is demonstrated for improving dissolution kinetics, gastrointestinal (GI) absorption, and bioavailability of protein kinase inhibitors (PKIs).MethodsThe approach is based on nanoparticle precipitation by sub- or supercritical CO2 together with a matrix-forming polymer, incorporating surfactants either during or after nanoparticle formation. Notably, striking synergistic effects between hybrid PKI/polymer nanoparticles and surfactant added after particle formation is investigated.ResultsThe hybrid nanoparticles, consisting of amorphous PKI embedded in a polymer matrix (also after 12 months), display dramatically increased release rate of nilotinib in both simulated gastric fluid and simulated intestinal fluid, particularly when surfactants are present on the hybrid nanoparticle surface. Similar results indicated flexibility of the approach regarding polymer identity, drug load, and choice of surfactant. The translation of the increased dissolution rate found in vitro into improved GI absorption and bioavalilability in vivo was demonstrated for male beagle dogs, where a 730% increase in the AUC0–24h was observed compared to the benchmark formulation. Finally, the generality of the formulation approach taken was demonstrated for a range of PKIs.ConclusionsHybrid nanoparticles combined with surfactant represent a promising approach for improving PKI dissolution rate, providing increased GI absorption and bioavailability following oral administration.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-013-1191-4) contains supplementary material, which is available to authorized users.

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