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The feasibility and efficiency of wet-nanogrinding of three drug substances (miconazole, itraconazole, etravirine) with similar elastic and plastic properties proved to depend primarily on the adequate electrostatic and steric stabilization of the nanoparticles and the specific energy input. Particle stabilization was provided by sodium dodecyl sulfate (SDS) and hydroxypropylcellulose. The specific energy input was defined by the grinding time, grinding bead size, and stirrer tip speed. Miconazole and itraconazole exhibited similar milling behavior, whereas etravirine nanosuspensions revealed agglomerates and increasing viscosity with increasing specific energy input. Agglomeration and viscosity increase were successfully counteracted by increasing the SDS concentration in the nanosuspension from 0 to 0.125 %. Under the provision of proper particle stabilization, the three drug substances could be nanosized to a mean size of ∼ 130 nm, with 90 % of all particles being smaller than ∼ 250 nm.

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Nanosuspension technology is an attractive approach for the formulation and solubility enhancement of poorly water-soluble drug compounds. The technology requires adequate excipients for stabilizing the suspensions during nanogrinding and storage. This study aimed at establishing a near-infrared (NIR) method for assaying simultaneously the two nanoparticle stabilizers, sodium dodecyl sulphate (SDS) and hydroxypropylcellulose (HPC), in miconazole nanosuspensions. Second derivative of NIR signals was used to establish calibration curves in concentration ranges of interest of SDS (0.03-0.3%) and HPC (0.75-7.5%). The suitability and applicability of the NIR method was verified by evaluating the linearity, accuracy, precision, and specificity of the obtained data. The method was then used to quantify indirectly the amount of SDS and HPC adsorbed onto miconazole nanoparticles. Within the concentration range of interest, SDS adsorption increased up to 122 µg/m(2) (4.2 × 10(-7) mol/m(2)) with increasing SDS concentration, and HPC adsorption was in the range of 800-1000 µg/m(2) (21-27 × 10(-7) mol/m(2)) for nanosuspensions containing nominally 5% HPC and 12.5% or 20% miconazole. Interestingly, some of the adsorbed HPC was displaced upon increase of SDS concentration and adsorption. The data were also confirmed by surface tension measurements of aqueous solutions of SDS and HPC and nanosuspension supernatants. The availability of a fast and nondestructive method for quantifying simultaneously the adsorption of two stabilizers onto nanoground particles may not only speed up nanosuspension development, but also provide insight into the mechanisms of nanoparticle stabilization regarding competitive adsorption and electrostatic versus steric stabilization.