Stillhart Cordula, Dürr Désirée, Kuentz Martin
University of Basel, Department of Pharmaceutical Sciences, 4056 Basel, Switzerland; University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Institute of Pharma Technology, 4132 Muttenz, Switzerland.
J Pharm Sci. 2014 Apr;103(4):1194-203. doi: 10.1002/jps.23892. Epub 2014 Feb 11.
The aim of the present study was to analyze the impact of lipid-based formulation (LBF) dispersion and digestion on the precipitation behavior of weakly basic drugs. Loratadine and carvedilol were formulated in a range of LBFs and drug solubilization was analyzed under simulated dispersive and digestive conditions (fasted state). The extent of supersaturation and drug precipitation as well as the solid-state properties and redissolution behavior of precipitated drugs were assessed. X-ray powder diffraction indicated that carvedilol precipitated in a crystalline form upon dispersion, but interestingly, this drug gave an amorphous precipitate during lipolysis. In contrast, loratadine precipitated as crystalline material during both formulation dispersion and digestion. No influence of the formulation composition on the type of precipitation was observed. These results suggested that in vitro conditions (dispersive versus digestive) largely influenced the solid-state properties of precipitating weak bases. Solid-state characterization of precipitated drugs under different experimental conditions should be routinely performed in formulation screening to better understand the biopharmaceutical behavior of LBFs. Hence, these findings are of high practical importance for the pharmaceutical development and in vitro assessment of LBFs using weakly basic drugs.
本研究的目的是分析脂质体制剂（LBF）的分散和消化对弱碱性药物沉淀行为的影响。将氯雷他定和卡维地洛制成一系列脂质体制剂，并在模拟分散和消化条件（禁食状态）下分析药物的溶解情况。评估了过饱和度和药物沉淀的程度以及沉淀药物的固态性质和再溶解行为。X射线粉末衍射表明，卡维地洛在分散时以结晶形式沉淀，但有趣的是，该药物在脂解过程中产生无定形沉淀。相比之下，氯雷他定在制剂分散和消化过程中均以结晶物质形式沉淀。未观察到制剂组成对沉淀类型的影响。这些结果表明，体外条件（分散与消化）在很大程度上影响了沉淀弱碱的固态性质。在制剂筛选过程中应常规进行不同实验条件下沉淀药物的固态表征，以更好地了解脂质体制剂的生物药剂学行为。因此，这些发现对于使用弱碱性药物的脂质体制剂的药物开发和体外评估具有很高的实际重要性。
