School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin D02 PN40, Ireland.
SSPC, the Science Foundation Ireland Research Centre for Pharmaceuticals, Trinity College Dublin, Dublin D02 PN40, Ireland.
Mol Pharm. 2023 Sep 4;20(9):4770-4785. doi: 10.1021/acs.molpharmaceut.3c00564. Epub 2023 Aug 18.
The aim of the present study was to investigate how different polymers affect the dissociation of cocrystals prepared by co-spray-drying active pharmaceutical ingredient (API), coformer, and polymer. Diclofenac acid-l-proline cocrystal (DPCC) was selected in this study as a model cocrystal due to its previously reported poor physical stability in a high-humidity environment. Polymers investigated include polyvinylpyrrolidone (PVP), poly(1-vinylpyrrolidone--vinyl acetate) (PVPVA), hydroxypropyl methyl cellulose, hydroxypropylmethylcellulose acetate succinate, ethyl cellulose, and Eudragit L-100. Terahertz Raman spectroscopy (THz Raman) and powder X-ray diffraction (PXRD) were used to monitor the cocrystal dissociation rate in a high-humidity environment. A Raman probe was used to monitor the extent of the dissociation of DPCC and DPCC in crystalline solid dispersions (CSDs) with polymer when exposed to pH 6.8 phosphate buffer and water. The solubility of DPCC and solid dispersions of DPCC in pH 6.8 phosphate buffer and water was also measured. The dissociation of DPCC was water-mediated, and more than 60% of DPCC dissociated in 18 h at 40 °C and 95% RH. Interestingly, the physical stability of the cocrystal was effectively improved by producing CSDs with polymers. The inclusion of just 1 wt % polymer in a CSD with DPCC protected the cocrystal from dissociation over 18 h under the same conditions. Furthermore, the CSD with PVPVA was still partially stable, and the CSD with PVP was stable (undissociated) after 7 days. The superior stability of DPCC in CSDs with PVP and PVPVA was also demonstrated when systems were exposed to water or pH 6.8 phosphate buffer and resulted in higher dynamic solubility of the CSDs compared to DPCC alone. The improvement in physical stability of the cocrystal in CSDs was thought to be due to an efficient mixing between polymer and cocrystal at the molecular level provided by spray drying and gelling of polymer. It is hypothesized that polymer chains could undergo gelling and form a physical barrier, preventing cocrystal interaction with water, which contributes to slowing down the water-mediated dissociation.
本研究旨在探讨不同聚合物如何影响通过共喷雾干燥活性药物成分（API）、共晶形成剂和聚合物制备的共晶的解离。由于先前报道的二氯芬酸-脯氨酸共晶（DPCC）在高湿度环境中物理稳定性差，因此选择 DPCC 作为模型共晶。研究中使用的聚合物包括聚乙烯吡咯烷酮（PVP）、聚（1-乙烯基吡咯烷酮-醋酸乙烯酯）（PVPVA）、羟丙基甲基纤维素、羟丙基甲基纤维素醋酸琥珀酸酯、乙基纤维素和 Eudragit L-100。太赫兹拉曼光谱（THz Raman）和粉末 X 射线衍射（PXRD）用于监测高湿度环境中共晶的解离速率。拉曼探针用于监测 DPCC 和 DPCC 在与聚合物形成的结晶固体分散体（CSD）中在暴露于 pH 6.8 磷酸盐缓冲液和水时的解离程度。还测量了 DPCC 在 pH 6.8 磷酸盐缓冲液和水中的溶解度以及 DPCC 的固体分散体的溶解度。DPCC 的解离是水介导的，在 40°C 和 95% RH 下 18 小时后超过 60%的 DPCC 解离。有趣的是，通过与聚合物一起制备 CSD，可以有效提高共晶的物理稳定性。在相同条件下，CSD 中仅包含 1wt%的聚合物即可保护共晶在 18 小时内不发生解离。此外，PVPVA 的 CSD 仍部分稳定，PVP 的 CSD 在 7 天后仍稳定（未解离）。当系统暴露于水或 pH 6.8 磷酸盐缓冲液时，DPCC 在 PVP 和 PVPVA 的 CSD 中的稳定性也得到了证明，与单独的 DPCC 相比，CSD 的动态溶解度更高。CSD 中共晶物理稳定性的提高被认为是由于喷雾干燥和聚合物胶凝在分子水平上提供的聚合物和共晶之间的有效混合。据推测，聚合物链可以胶凝并形成物理屏障，防止共晶与水相互作用，从而减缓水介导的解离。
