Nucleation of Supersaturated Flufenamic Acid Cocrystal Solutions in the Presence of a Polymer
Nucleation of Supersaturated Flufenamic Acid Cocrystal Solutions in the Presence of a Polymer
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DOI：
10.1021/acs.cgd.2c00323
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发表时间：
2022-08-12
影响因子：
3.8
通讯作者：
Li, Mingzhong
中科院分区：
文献类型：
--
作者：
Alinda, Peace;Shi, Kejing;Li, Mingzhong
研究了氟灭酸两种共晶溶液的成核动力学和热力学，研究了氟芬那酸和茶碱（FFA-TP）和氟芬那酸和烟酰胺（FFA-NIC）在不存在和存在聚合物聚乙烯吡咯烷酮（PVP）或乙烯基吡咯烷酮（60%）/乙酸乙烯酯（40%）共聚物（PVP-VA）的情况下的反应，并与纯FFA溶液进行了比较。在27 ℃下，在5个相等的母体药物过饱和水平下收集诱导时间，对于每个过饱和水平，在1 mL溶液中进行至少80次重复实验。成核率，提取的诱导时间分布占核生长时间，已被用来确定的界面能和指前因子的经典成核理论（CNT）的框架内。结果表明，共晶共形成物在诱导共晶或母体药物沉淀中起重要作用。由于与母体药物FFA相比，FFA-TP共晶体的溶解度较低，因此可以在FFA-TP共晶体溶液中形成FFA-TP复合物，导致FFA-TP共晶体的溶液成核延迟。FFA-NIC共晶与纯化合物FFA溶液的成核没有显着差异，其中仅FFA III晶体在成核诱导时间相当的情况下沉淀。虽然PVP或PVP-VA是FFA共晶的有效表面沉淀抑制剂，但其在将FFA保持在过饱和溶液中的有效性相当有限。PVP或PVP-VA对过饱和FFA共晶溶液成核时间的影响取决于其浓度和溶液中的组成成分。从碳纳米管的角度来看，它表明，FFA-TP核的动力学运动被改变的聚合物，导致促进或阻碍的成核。相比之下，在FFA-NIC溶液体系中的NIC与聚合物PVP或PVP-VA相互作用，使得较少量的NIC被吸收在核的表面上，导致增加的界面能以延迟成核。研究表明，一个良好的表面沉淀抑制剂，如PVP或PVP-VA，不能保证是一个有效的本体溶液沉淀抑制剂。此外，需要优化聚合物的类型及其浓度以开发有效的共晶制剂。
The nucleation kinetics and thermodynamics of two flufenamic acid cocrystal solutions, i.e., flufenamic acid and theophylline (FFA-TP) and flufenamic acid and nicotinamide (FFA-NIC), in the absence and presence of the polymer polyvinylpyrrolidone (PVP) or the copolymer vinylpyrrolidone (60%)/vinyl acetate (40%) (PVP-VA) have been investigated and compared with the pure FFA solution. Induction times have been collected under five equal parent drug supersaturation levels at 27 degrees C with at least 80 repetitive experiments in 1 mL solutions for each supersaturation level. Nucleation rates, extracted from the induction time distributions by accounting for a nucleus growth time, have been used to determine the interfacial energy and the pre-exponential factor within the framework of classical nucleation theory (CNT). It is shown that the cocrystal coformer played a significant role in inducing the precipitation of the cocrystal or the parent drug. Due to a lower solubility of the FFA-TP cocrystal in comparison with the parent drug FFA, FFA-TP complexes can be formed in the FFA-TP cocrystal solution, resulting in a delay in the solution nucleation of FFA-TP cocrystals. There was no significant difference in the nucleations of the FFA-NIC cocrystal and the pure compound FFA solutions, in which only FFA III crystals were precipitated with comparable nucleation induction times. Although PVP or PVP-VA is an effective surface precipitation inhibitor of the FFA cocrystals, its effectiveness in maintaining FFA in a supersaturated solution is rather limited. The influence of PVP or PVP-VA on the nucleation time of a supersaturated FFA cocrystal solution depends on both its concentration and constituent components in the solution. From a CNT perspective, it was revealed that the kinetic movement of the FFA-TP nucleus was altered by the polymer, leading to the promotion or hindrance of the nucleation. In contrast, NIC in the FFA-NIC solution system interacted with the polymer PVP or PVP-VA so that a lesser amount of NIC was absorbed on the surfaces of the nuclei, resulting in increased interfacial energy to delay the nucleation. The study has indicated that a good surface precipitation inhibitor, such as PVP or PVP-VA, is not guaranteed to be an effective bulk solution precipitation inhibitor. Additionally, optimization of both the type of polymer and its concentration is needed for the development of an effective cocrystal formulation.