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.

中文翻译：

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在溶液中存在聚合物的情况下洞悉氟苯甲酸共晶溶解：从单晶到粉末溶解

聚乙二醇（PEG），聚乙烯吡咯烷酮（PVP）和乙烯基吡咯烷酮/乙酸乙烯酯共聚物（PVP-VA）这三种聚合物对氟苯那酸与茶碱（FFA-TP CO）和烟酰胺（ FFA-NIC CO）已在多个长度尺度上进行了研究。在分子水平上，通过使用原子力显微镜观察蚀刻图案的变化来分析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通过使用光学显微镜测量面的物理后退速度来确定。在本体实验中，在沉和不沉条件下测量在不存在或存在聚合物的情况下溶解介质中的FFA浓度。已经发现，FFA-TP CO的溶解机理由晶体表面的缺陷部位和母体药物FFA作为单个晶体在本体流体中的沉淀来控制。相反，FFA-NIC CO的溶解机理是通过去除表面层和表面沉淀机理来控制的，其中母体药物FFA直接沉淀在溶解共晶体的表面上。通过预溶解聚合物来控制溶解环境，可以证明PVP或PVP-VA可以与晶体表面相互作用以改变其溶解特性，改善了溶解度，并改善了FFA-TP CO和FFA-NIC CO的溶解速率。