title: In situ determination of the saturation solubility of nanocrystals of poorly soluble drugs for dermal application.
abstract: The aim of this study was to determine, in situ, the saturation solubility and dissolution rate of nanocrystals of three poorly water-soluble drugs for dermal application. The nanocrystals were prepared by wet bead milling. Their size could be controlled by various process parameters. The saturation solubility was measured in water or in the presence of surfactant at 32°C with a Sirius®inForm based on in situ UV-vis spectroscopy. The saturation solubility of nanocrystals with sizes of ∼300nm increased for each drug in comparison to non-milled drug powders, with factors of increase in the range 1.3-2.8. The tacrolimus solubility was further analyzed with excess nanocrystal amounts four and ten times higher than the drug powder solubility. The corresponding solubility increases were 2.8 and 6.6 and thus dependent on the amount of excess nanocrystals. The higher increase was due to the presence of a larger fraction of small size particles, and only crystals far below 1μm showed supersaturation. The solubility increase for nanocrystals determined in situ was remarkably lower than the one previously reported with the use of non in situ methods. Nanomilling increased the drug dissolution rates: the highest increase was obtained with ibuprofen (rate increase ∼30).
authors.affiliation: College of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Colombo
authors.affiliation: College of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Staufenbiel
authors.affiliation: Physical Chemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany.
authors.forename: Eckart
authors.initials: E
authors.lastname: Rühl
authors.affiliation: College of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, Germany. Electronic address: roland.bodmeier@fu-berlin.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Bodmeier
mesh_terms: D000279:Administration, Cutaneous; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003879:Dermatologic Agents / Q000737:chemistry*; D003907:Dexamethasone / Q000737:chemistry; D007052:Ibuprofen / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry*; D012995:Solubility; D014961:X-Ray Diffraction
chemical_list: D003879:Dermatologic Agents; D003907:Dexamethasone; D007052:Ibuprofen
keywords: Dermal nanocarrier; Dissolution rate; In situ methods; Nanocrystals; Saturation solubility; Wet bead milling