Vicatos Alexios I, Hoossen Zakiena, Caira Mino R
Centre for Supramolecular Chemistry Research (CSCR), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
Beilstein J Org Chem. 2022 Dec 22;18:1749-1762. doi: 10.3762/bjoc.18.184. eCollection 2022.
Overcoming the challenges of poor aqueous solubility of active pharmaceutical ingredients (APIs) is necessary to render them bioavailable. This study addresses the poor solubility of two potent steroid hormones, 17β-estradiol (BES) and progesterone (PRO), via their complexation with two water-soluble native cyclodextrins (CDs) namely β-CD and γ-CD. The hydrated inclusion complexes β-CD·BES, β-CD·PRO, γ-CD·BES and γ-CD·PRO were prepared via kneading and co-precipitation, and H NMR spectroscopic analysis of solutions of their pure complex crystals yielded the host-guest stoichiometries 2:1, 2:1, 1:1 and 3:2, respectively. Both powder X-ray diffraction (PXRD) and single-crystal X-ray diffraction (SCXRD) were employed for focused studies of the isostructurality of the CD complexes with known complexes and structural elucidation of the new complexes, respectively. SCXRD analyses of β-CD·BES, β-CD·PRO and γ-CD·PRO at 100(2) K yielded the first crystal structures of CD complexes containing the hormones BES and PRO, while the complex γ-CD·BES was readily shown to be isostructural with γ-CD·PRO by PXRD. Severe disorder of the encapsulated steroid molecules in the respective channels of the CD molecular assemblies was evident, however, preventing their modelling, but combination of the host-guest stoichiometries and water contents of the four hydrated inclusion complexes enabled accurate assignment of the chemical formulae of these ternary systems. Predicted electron counts for the complexed molecules BES and PRO correlated reasonably well with the complex compositions indicated by H NMR spectroscopy. Subsequent measurements of the aqueous solubilities of the four complexes confirmed significant solubility improvements effected by encapsulation of the steroids within the CDs, yielding solubility enhancement factors for BES and PRO in the approximate range 5-20.
克服活性药物成分（API）水溶性差的挑战对于使其具有生物利用度至关重要。本研究通过将两种强效甾体激素17β-雌二醇（BES）和孕酮（PRO）与两种水溶性天然环糊精（CDs）即β-环糊精和γ-环糊精络合，来解决它们的低溶解度问题。通过捏合和共沉淀制备了水合包合物β-CD·BES、β-CD·PRO、γ-CD·BES和γ-CD·PRO，对其纯复合晶体溶液的1H NMR光谱分析分别得到主客体化学计量比为2:1、2:1、1:1和3:2。粉末X射线衍射（PXRD）和单晶X射线衍射（SCXRD）分别用于重点研究CD络合物与已知络合物的同构性以及新络合物的结构解析。在100(2) K下对β-CD·BES、β-CD·PRO和γ-CD·PRO进行的SCXRD分析得到了含有激素BES和PRO的CD络合物的首个晶体结构，而通过PXRD很容易证明络合物γ-CD·BES与γ-CD·PRO同构。然而，在CD分子组装体的各个通道中封装的甾体分子存在严重无序，妨碍了对它们的建模，但四种水合包合物的主客体化学计量比和水含量的结合使得能够准确确定这些三元体系的化学式。对络合分子BES和PRO的预测电子数与1H NMR光谱表明的络合组成相当吻合。随后对四种络合物的水溶性进行的测量证实，通过将甾体封装在CDs中显著提高了溶解度，BES和PRO的溶解度增强因子在大约5-20的范围内。
