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Understanding the Effects of a Polymer on the Surface Dissolution of Pharmaceutical Cocrystals Using Combined Experimental and Molecular Dynamics Simulation Approaches.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-01-07 , DOI: 10.1021/acs.molpharmaceut.9b00955 Preyanthiny Kirubakaran 1 , Ke Wang 1 , Ian Rosbottom 2 , Richard Barrie Michael Cross 3 , Mingzhong Li 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-01-07 , DOI: 10.1021/acs.molpharmaceut.9b00955 Preyanthiny Kirubakaran 1 , Ke Wang 1 , Ian Rosbottom 2 , Richard Barrie Michael Cross 3 , Mingzhong Li 1
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The molecular interactions between the surfaces of cocrystals [i.e., flufenamic acid and theophylline (FFA-TP), flufenamic acid and nicotinamide (FFA-NIC), and carbamazepine and nicotinamide (CBZ-NIC)] and the polymers [i.e., polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and copolymer of vinylpyrrolidone (60%)/vinyl acetate (40%) (PVP-VA)] were investigated through combined experimental and molecular dynamics simulation approaches to resolve the mechanisms of cocrystal dissolution and precipitation. It was found that adsorption of the polymers on the surfaces of cocrystals might prevent the precipitation of the parent drug and alter the dissolution rate. The effect of polymers on precipitation could be determined by the cocrystal dissolution rate, the interactions of polymers with the surfaces of cocrystals, the characters of the noncovalent bonds formed between the polymers and the cocrystal surfaces, and the mobility and conformation of the polymers. The etching experiments of single cocrystals revealed that FFA-NIC and CBZ-NIC appeared as surface precipitation cocrystals while FFA-TP could lead to bulk precipitation. Both PVP and PVP-VA were good precipitation inhibitors for FFA-NIC, and they could completely inhibit the recrystallization of FFA III on the surfaces of dissolving cocrystals. In addition, as the adsorption of the polymer was slower than dissolution rate of the cocrystals, PVP and PVP-VA could only partially inhibit the recrystallization of CBZ dihydrate on the surface of CBZ-NIC. While PEG had no inhibitory effect on the surface crystallization of FFA-NIC and CBZ-NIC, due to its weak interactions with the surfaces of the cocrystals, it enhanced the dissolution performance of FFA-TP. In contrast, PVP and PVP-VA reduced the dissolution rate of FFA-TP and subsequently undermined the performance of cocrystals. Taken together, the approach of combining experimental and molecular dynamics simulation provided insights into the mechanisms of cocrystal dissolution as well as the polymers acting as inhibitory excipients for precipitation/recrystallization, making contribution to the development of novel formulations.
中文翻译：
结合实验和分子动力学模拟方法，了解聚合物对药物共晶体表面溶解的影响。
共晶体[即氟苯那酸和茶碱（FFA-TP），氟苯那酸和烟酰胺（FFA-NIC），卡马西平和烟酰胺（CBZ-NIC）]和聚合物[即聚乙二醇（ PEG），聚乙烯吡咯烷酮（PVP）和乙烯基吡咯烷酮（60％）/乙酸乙烯酯（40％）（PVP-VA）的共聚物]通过组合的实验和分子动力学模拟方法进行了研究，以解决共晶溶解和沉淀的机理。已经发现，聚合物在共晶体表面上的吸附可能会阻止母体药物的沉淀并改变溶出速率。聚合物对沉淀的影响可以通过共晶溶解速率，聚合物与共晶表面的相互作用，聚合物与共晶表面之间形成的非共价键的特性，以及聚合物的迁移率和构象。单一共晶的刻蚀实验表明，FFA-NIC和CBZ-NIC表现为表面沉淀共晶，而FFA-TP可能导致大量沉淀。PVP和PVP-VA都是FFA-NIC的良好沉淀抑制剂，它们可以完全抑制FFA III在溶解共晶表面的重结晶。另外，由于聚合物的吸附比共晶体的溶解速率慢，因此PVP和PVP-VA只能部分抑制CBZ-NIC表面CBZ二水合物的重结晶。尽管PEG对FFA-NIC和CBZ-NIC的表面结晶没有抑制作用，但由于其与共晶表面的相互作用较弱，它提高了FFA-TP的溶出性能。相反，PVP和PVP-VA降低了FFA-TP的溶解速率，并随后破坏了共晶的性能。总之，将实验和分子动力学模拟相结合的方法提供了对共晶溶解机理以及作为沉淀/重结晶抑制赋形剂的聚合物的见解，为新型配方的开发做出了贡献。
更新日期：2020-01-07
中文翻译：
结合实验和分子动力学模拟方法，了解聚合物对药物共晶体表面溶解的影响。
共晶体[即氟苯那酸和茶碱（FFA-TP），氟苯那酸和烟酰胺（FFA-NIC），卡马西平和烟酰胺（CBZ-NIC）]和聚合物[即聚乙二醇（ PEG），聚乙烯吡咯烷酮（PVP）和乙烯基吡咯烷酮（60％）/乙酸乙烯酯（40％）（PVP-VA）的共聚物]通过组合的实验和分子动力学模拟方法进行了研究，以解决共晶溶解和沉淀的机理。已经发现，聚合物在共晶体表面上的吸附可能会阻止母体药物的沉淀并改变溶出速率。聚合物对沉淀的影响可以通过共晶溶解速率，聚合物与共晶表面的相互作用，聚合物与共晶表面之间形成的非共价键的特性，以及聚合物的迁移率和构象。单一共晶的刻蚀实验表明，FFA-NIC和CBZ-NIC表现为表面沉淀共晶，而FFA-TP可能导致大量沉淀。PVP和PVP-VA都是FFA-NIC的良好沉淀抑制剂，它们可以完全抑制FFA III在溶解共晶表面的重结晶。另外，由于聚合物的吸附比共晶体的溶解速率慢，因此PVP和PVP-VA只能部分抑制CBZ-NIC表面CBZ二水合物的重结晶。尽管PEG对FFA-NIC和CBZ-NIC的表面结晶没有抑制作用，但由于其与共晶表面的相互作用较弱，它提高了FFA-TP的溶出性能。相反，PVP和PVP-VA降低了FFA-TP的溶解速率，并随后破坏了共晶的性能。总之，将实验和分子动力学模拟相结合的方法提供了对共晶溶解机理以及作为沉淀/重结晶抑制赋形剂的聚合物的见解，为新型配方的开发做出了贡献。
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