Insight into Flufenamic Acid Cocrystal Dissolution in the Presence of a Polymer in Solution: from Single Crystal to Powder Dissolution
Insight into Flufenamic Acid Cocrystal Dissolution in the Presence of a Polymer in Solution: from Single Crystal to Powder Dissolution
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DOI：
10.1021/acs.molpharmaceut.7b00712
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发表时间：
2017-12-01
影响因子：
4.9
通讯作者：
Li, Mingzhong
中科院分区：
文献类型：
--
作者：
Guo, Minshan;Wang, Ke;Li, Mingzhong
研究了聚乙二醇（PEG）、聚乙烯吡咯烷酮（PVP）和聚乙烯吡咯烷酮/醋酸乙烯酯共聚物（PVP- va）三种聚合物在多长度尺度下对氟芬酸与茶碱（FFA-TP CO）和烟酰胺（FFA-NIC CO）共晶溶解行为的影响。在分子水平上，通过原子力显微镜观察蚀刻模式的变化，分析了晶体表面与聚合物的相互作用。在宏观尺度上，单晶特定面的溶解速率是通过光学显微镜测量面的物理后退速度来确定的。在整体实验中，在没有或存在聚合物的溶解介质中，在沉降和非沉降条件下测量了FFA浓度。发现FFA- tp CO的溶解机制受晶体表面缺陷位点和母体药物FFA作为单个晶体在散装流体中析出的控制。相比之下，FFA- nic CO的溶解机制受表面层去除和表面沉淀机制控制，其中母体药物FFA直接沉淀到溶解的共晶表面。通过预溶聚合物来控制溶解环境，PVP或PVP- va可以与晶体表面相互作用，改变其溶解性能，从而提高了FFA-TP CO和FFA-NIC CO的溶解度和溶解速率。
Effects of three polymers, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and copolymer of vinylpyrrolidone/vinyl acetate (PVP-VA), on the dissolution behavior of the cocrystals of flufenamic acid with theophylline (FFA-TP CO) and nicotinamide (FFA-NIC CO) were investigated at multiple length scales. At the molecular level, the interactions of crystal surfaces with a polymer were analyzed by observing etching pattern changes using atomic force microscopy. At the macroscopic scale, dissolution rates of particular faces of a single crystal were determined by measurement of the physical retreat velocities of the faces using optical light microscopy. In the bulk experiments, the FFA concentration in a dissolution medium in the absence or presence of a polymer was measured under both sink and nonsink conditions. It has been found that the dissolution mechanisms of FFA-TP CO are controlled by the defect sites of the crystal surface and by precipitation of the parent drug FFA as individual crystals in the bulk fluid. In contrast, the dissolution mechanisms of FFA-NIC CO are controlled by surface layer removal and by a surface precipitation mechanism, where the parent drug FFA precipitates directly onto the surface of the dissolving cocrystals. Through controlling the dissolution environment by predissolving a polymer, PVP or PVP-VA, which, can interact with the crystal surface to alter its dissolution properties, improved solubility, and dissolution rates of FFA-TP CO and FFA-NIC CO have been demonstrated.