University of Applied Sciences and Arts Northwestern Switzerland , Institute of Pharma Technology, Gründenstrasse 40, 4132 Muttenz, Switzerland.
University of Basel , Institute of Pharmaceutical Technology, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Mol Pharm. 2018 Jan 2;15(1):186-192. doi: 10.1021/acs.molpharmaceut.7b00804. Epub 2017 Dec 6.
The methacrylate copolymer Eudragit EPO (EPO) has previously shown to greatly enhance solubilization of acidic drugs via ionic interactions and by multiple hydrophobic contacts with polymeric side chains. The latter type of interaction could also play a role for solubilization of other compounds than acids. The aim of this study was therefore to investigate the solubility of six poorly soluble bases in presence and absence of EPO by quantitative ultrapressure liquid chromatography with concomitant X-ray powder diffraction analysis of the solid state. For a better mechanistic understanding, spectra and diffusion data were obtained by H nuclear magnetic resonance (NMR) spectroscopy. Unexpected high solubility enhancement (up to 360-fold) was evidenced in the presence of EPO despite the fact that bases and polymer were both carrying positive charges. This exceptional and unexpected solubilization was not due to a change in the crystalline solid state. NMR spectra and measured diffusion coefficients indicated both strong drug-polymer interactions in the bulk solution, and diffusion data suggested conformational changes of the polymer in solution. Such conformational changes may have increased the accessibility and extent of hydrophobic contacts thereby leading to increased overall molecular interactions. These initially surprising solubilization results demonstrate that excipient selection should not be based solely on simple considerations of, for example, opposite charges of drug and excipient, but it requires a more refined molecular view. Different solution NMR techniques are especially promising tools to gain such mechanistic insights.
甲基丙烯酸共聚物 Eudragit EPO（EPO）先前已被证明通过离子相互作用和与聚合物侧链的多个疏水接触极大地提高了酸性药物的溶解度。后一种相互作用类型对于溶解其他化合物也可能起作用。因此，本研究的目的是通过定量超压液相色谱法，同时对固体状态进行伴随的 X 射线粉末衍射分析，研究在存在和不存在 EPO 的情况下，六种难溶性碱的溶解度。为了更好地理解其机制，还通过 H 核磁共振（NMR）光谱获得了光谱和扩散数据。尽管碱和聚合物都带有正电荷，但在存在 EPO 的情况下，溶解度仍出人意料地提高了（高达 360 倍）。这种特殊而意外的增溶并非由于结晶固体状态的改变所致。NMR 光谱和测量的扩散系数表明，在本体溶液中存在强烈的药物-聚合物相互作用，并且扩散数据表明聚合物在溶液中发生构象变化。这种构象变化可能增加了疏水性接触的可及性和程度，从而导致整体分子相互作用增加。这些最初令人惊讶的增溶结果表明，赋形剂的选择不应仅基于药物和赋形剂的简单电荷考虑，而需要更精细的分子观点。不同的溶液 NMR 技术是获得这种机制见解的特别有前途的工具。
