Colombo Miriam, Staufenbiel Sven, Rühl Eckart, Bodmeier Roland
College of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, Germany.
Physical Chemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany.
Int J Pharm. 2017 Apr 15;521(1-2):156-166. doi: 10.1016/j.ijpharm.2017.02.030. Epub 2017 Feb 20.
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).
本研究的目的是在原位条件下测定三种难溶性皮肤用药物纳米晶体的饱和溶解度和溶解速率。纳米晶体通过湿珠磨法制备。其尺寸可通过各种工艺参数进行控制。基于原位紫外-可见光谱，使用Sirius inForm在32°C下于水或表面活性剂存在的情况下测量饱和溶解度。与未研磨的药物粉末相比，尺寸约为300nm的纳米晶体的每种药物的饱和溶解度均有所增加，增加因子在1.3至2.8范围内。用比药物粉末溶解度高4倍和10倍的过量纳米晶体量进一步分析他克莫司的溶解度。相应的溶解度增加分别为2.8和6.6，因此取决于过量纳米晶体的量。较高的增加是由于存在较大比例的小尺寸颗粒，并且只有远低于1μm的晶体显示出过饱和。原位测定的纳米晶体的溶解度增加明显低于先前使用非原位方法报道的增加。纳米研磨提高了药物溶解速率：布洛芬的增加最高（速率增加约30）。
