Reactive Melt Extrusion To Improve the Dissolution Performance and Physical Stability of Naproxen Amorphous Solid Dispersions
Reactive Melt Extrusion To Improve the Dissolution Performance and Physical Stability of Naproxen Amorphous Solid Dispersions
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DOI：
10.1021/acs.molpharmaceut.6b00960
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发表时间：
2017-03-01
影响因子：
4.9
通讯作者：
Zhang, Feng
中科院分区：
文献类型：
--
作者：
Liu, Xu;Zhou, Lin;Zhang, Feng
本研究的目的是研究萘普生（NPX）与葡甲胺（MEG）在高温下的反应，并研究该反应对熔融挤出的萘普生无定形固体分散体（ASD）的物理稳定性和体外释药性能的影响。差示扫描量热法，热台偏振光显微镜，傅里叶变换红外光谱，和X射线光电子能谱分析表明，在原位盐的形成与质子转移NPX和MEG之间发生在高温熔融挤出过程中。当两种组分以1：1摩尔比存在时，无定形NPX MEG盐物理上最稳定。聚合物载体，包括聚维酮、共聚维酮和SOLUPLUS，在熔融挤出过程中不干扰NPX和MEG之间的反应。与仅由NPX和聚合物组成的传统NPX ASD相比，NPX MEG ASD物理上更稳定，并且在40摄氏度和75%RH（相对湿度）下储存四个月后仍保持无定形。基于非漏溶试验和偏光显微镜分析，我们得出结论，传统的NPX ASD的NPX和聚合物组成的未能提高NPX的溶解速率，由于NPX在接触水介质中的快速重结晶。NPX MEG ASD的溶出速率是相应物理混合物和常规NPX ASD的两倍。研究表明，NPX和MEG在熔融挤出过程中发生的酸碱反应显著提高了NPX ASD的物理稳定性和溶出速率。
The purpose of this study was to investigate the reaction between naproxen (NPX) and meglumine (MEG) at elevated temperature and to study the effect of this reaction on the physical stabilities and in vitro drug-release properties of melt-extruded naproxen amorphous solid dispersions (ASDs). Differential scanning calorimetry, hot-stage polarized light microscopy, Fourier transform infrared spectroscopy, and Xray photoelectron spectroscopy analyses demonstrated that in situ salt formation with proton transfer between NPX and MEG occurred at elevated temperature during the melt extrusion process. The amorphous NPX MEG salt was physically most stable when two components were present at a 1:1 molar ratio. Polymeric carriers, including povidone, copovidone, and SOLUPLUS, did not interfere with the reaction between NPX and MEG during melt extrusion. Compared to the traditional NPX ASDs consisting of NPX and polymer only, NPX MEG ASDs were physically more stable and remained amorphous following four months storage at 40 degrees C and 75% RH (relative humidity). Based on nonsink dissolution testing and polarized light microscopy analyses, we concluded that the conventional NPX ASDs composed of NPX and polymers failed to improve the NPX dissolution rate due to the rapid recrystallization of NPX in contact with aqueous medium. The dissolution rate of NPX MEG ASDs was two times greater than the corresponding physical mixtures and conventional NPX ASDs. This study demonstrated that the acid base reaction between NPX and MEG during melt extrusion significantly improved the physical stability and the dissolution rate of NPX ASDs.