Controlled Suspensions Enable Rapid Determinations of Intrinsic Dissolution Rate and Apparent Solubility of Poorly Water-Soluble Compounds
Controlled Suspensions Enable Rapid Determinations of Intrinsic Dissolution Rate and Apparent Solubility of Poorly Water-Soluble Compounds
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DOI：
10.1007/s11095-017-2188-1
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发表时间：
2017-09-01
影响因子：
3.7
通讯作者：
Bergstrom, Christel A. S.
中科院分区：
文献类型：
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作者：
Andersson, Sara B. E.;Alvebratt, Caroline;Bergstrom, Christel A. S.
目的建立一种快速、准确测定难溶化合物的本征溶出度和表观溶解度的小型装置。方法采用湿式研磨控制悬浮液(1.0%(w/w)PVP和0.2%(w/w)十二烷基硫酸钠)和Mu diss Profiler测定6种模型化合物在禁食状态模拟肠液中的本征溶出度和表观溶解度(S-APP)。用Zetasizer测量了颗粒大小分布，并利用化合物的密度计算了总表面积。结果控制混悬液的IDR值与圆盘法测定的IDR值吻合较好。该方法使用少量化合物(µg标度)，实验在几分钟内完成。IDR值为0.20~70.6ug/min/cm(2)，IDR/S-APP比值为0.015~0.23。结论所建立的方法是一种新的、理想的方法，为快速、高精度地测定生物悬浮溶出介质中的IDR和表观溶解度提供了手段。当可能发生显著增溶时，IDR/S-APP被建议作为衡量颗粒大小敏感性的指标。
Purpose To develop a small-scale set-up to rapidly and accurately determine the intrinsic dissolution rate (IDR) and apparent solubility of poorly water-soluble compounds.Methods The IDR and apparent solubility (S-app) were measured in fasted state simulated intestinal fluid (FaSSIF) for six model compounds using wet-milled controlled suspensions (1.0% (w/w) PVP and 0.2% (w/w) SDS) and the mu DISS Profiler. Particle size distribution was measured using a Zetasizer and the total surface area was calculated making use of the density of the compound. Powder and disc dissolution were performed and compared to the IDR of the controlled suspensions.Results The IDR values obtained from the controlled suspensions were in excellent agreement with IDR from disc measurements. The method used low amount of compound (mu g-scale) and the experiments were completed within a few minutes. The IDR values ranged from 0.2-70.6 mu g/min/cm(2) and the IDR/S-app ratio ranged from 0.015 to 0.23. This ratio was used to indicate particle size sensitivity on intestinal concentrations reached for poorly water-soluble compounds.Conclusions The established method is a new, desirable tool that provides the means for rapid and highly accurate measurements of the IDR and apparent solubility in biorelevant dissolution media. The IDR/S-app is proposed as a measure of particle size sensitivity when significant solubilization may occur.