Abstract：
This study focuses on the dry milling of biopharmaceutical classification system (BCS) class II molecules. These molecules have a limited bioavailability because of their low aqueous solubility, poor water wettability and low dissolution rate. In order to improve these properties, indomethacin (IND) and niflumic acid (NIF) were milled using two different types of equipment: Pulverisette 0® and CryoMill®. Milled samples were characterized and compared to commercial molecules. IND shows a modified solid state, like surface crystallinity reduction and an increase in water vapor adsorption from to 2- up to 5-fold due to milling processes. The obtained solubility data resulted in an improvement in solubility up to 1.2-fold and an increase in initial dissolution kinetics: 2% of dissolved drug for original crystals against 25% for milled samples. For NIF no crystallinity reduction, no change of surface properties and no solubility improvement after milling were noticed. In addition, milled particles seemed more agglomerated resulting in no changes in dissolution rate compared to the original drug. IND solubility and dissolution enhancement can be attributed to the modification of surface area, drug crystallinity reduction, and water sorption increase due to specific behavior related to the drug crystal disorder induced by milling process.
摘要：
本研究的重点是生物制药分类系统（BCS）II类分子的干磨。这些分子具有有限的生物利用度，因为它们的水溶性低，水润湿性差，溶解速率低。为了改善这些性能，使用两种不同类型的设备:Pulverisett0®和CryoMill®研磨吲哚美辛(IND)和尼氟灭酸(NIF)。对研磨的样品进行表征并与商业分子进行比较。IND显示改良的固态，例如，由于研磨过程，表面结晶度降低和水蒸气吸附从2倍增加到5倍。获得的溶解度数据导致溶解度提高高达1.2倍，并且初始溶解动力学增加：原始晶体的溶解药物为2％，而研磨样品的溶解药物为25％。对于没有结晶度降低的NIF，在研磨后没有观察到表面性质的变化和溶解度的改善。此外,与原始药物相比,研磨的颗粒似乎更团聚,导致溶出速率没有变化。IND溶解度和溶解增强可归因于表面积的改性，药物结晶度降低，由于与研磨过程引起的药物晶体紊乱相关的特定行为，吸水率增加。
