Department of Pharmaceutics and ‡Department of Natural Products , National Institute of Pharmaceutical Education and Research (NIPER) , SAS Nagar , Punjab - 160 062 , India.
Mol Pharm. 2019 Jan 7;16(1):151-164. doi: 10.1021/acs.molpharmaceut.8b00923. Epub 2018 Dec 11.
Solubility advantage of thermodynamically highly unstable cocrystals, which undergo solution-mediated phase transformation (SMPT) in less than 1 min, does not translate to enhanced dissolution. The present study was aimed to understand the impact of polymeric additives on dissolution of thermodynamically highly unstable cocrystal with specific emphasis on influence of drug-polymer interactions. Exemestane-maleic acid was selected as a model cocrystal with SMPT time of <30 s and eutectic constant ( K) of 75475. Hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polyvinylpyrrolidone (PVP) were selected as polymers for a dissolution study based on measurement of induction time using precipitation study. In the presence of 0.2% w/v of HPC, the cocrystal showed significantly higher drug release (∼3-fold) as compared with the cocrystal in the absence of predissolved polymers. Differential dissolution profiles of the cocrystal were observed with each polymer and the order of increasing dissolution rate was found to be HPC ≈ HPMCAS > PVP. The molecular basis of the differential dissolution performance was investigated using infrared spectroscopy, solution-state nuclear magnetic resonance spectroscopy, and nuclear Overhauser effect spectroscopy (NOESY). The polymers with stronger interactions with drug in the cocrystal (HPMCAS and HPC) displayed higher dissolution rate as compared with that of no intermolecular interaction (PVP). The study also highlighted that, despite no influence of the polymers on the cocrystal SMPT, dissolution enhancement was achieved. This was attributed to small-sized drug crystals (1-3 μm) generated from the supersaturation-mediated crystallization and improved solvation due to drug-polymer interactions. These findings have implications on development of drug products using thermodynamically unstable cocrystals.
热力学上极不稳定的共晶在不到 1 分钟内经历溶液介导的相转变（SMPT），其溶解度优势并没有转化为溶解增强。本研究旨在了解聚合物添加剂对热力学上极不稳定共晶溶解的影响，特别强调药物-聚合物相互作用的影响。依西美坦-马来酸被选为具有 SMPT 时间<30s 和共晶常数（K）为 75475 的模型共晶。根据沉淀研究中诱导时间的测量，选择羟丙基纤维素（HPC）、羟丙基甲基纤维素醋酸琥珀酸酯（HPMCAS）和聚乙烯吡咯烷酮（PVP）作为聚合物进行溶解研究。在 0.2%w/v 的 HPC 存在下，与不存在预溶解聚合物的共晶相比，共晶显示出显著更高的药物释放（约 3 倍）。观察到共晶与每种聚合物的不同溶解曲线，并发现溶解速率增加的顺序为 HPC≈HPMCAS>PVP。使用红外光谱、溶液核磁共振波谱和核奥弗豪瑟效应光谱（NOESY）研究了差异溶解性能的分子基础。与共晶中药物具有更强相互作用的聚合物（HPMCAS 和 HPC）显示出比无分子间相互作用的聚合物（PVP）更高的溶解速率。该研究还强调，尽管聚合物对共晶 SMPT 没有影响，但仍能实现溶解增强。这归因于超饱和介导结晶产生的小尺寸药物晶体（1-3μm）和由于药物-聚合物相互作用而改善的溶剂化。这些发现对使用热力学不稳定共晶开发药物产品具有重要意义。
