(S)-carvedilol phosphate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (S)-carvedilol phosphate
• 英文别名: (2S)-1-(9H-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]propan-2-ol;phosphoric acid
• 化学式: C₂₄H₂₆N₂O₄*H₃O₄P
• 分子量: 504.477
• InChiKey: XCPXNPBILMXKNX-LMOVPXPDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.81
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  154
• 氢给体数：
  6
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  (S)-(-)-卡维地洛 在 磷酸 作用下， 以 丙酮 为溶剂， 反应 2.0h， 生成 (S)-carvedilol phosphate
  参考文献：
  名称：

  用于开发缓释制剂的 (S)-卡维地洛盐的最佳形式的制备、表征和选择

  摘要：

  (S)-卡维地洛 (S-CAR) 是卡维地洛的主要药效学构象，但由于其溶解性差，限制了其进一步开发缓释制剂。本研究旨在制备和筛选可用于提高溶解度并允许延长释放的 S-CAR 盐。具有众所周知的酸反离子的 S-CAR 的五种盐（即、磷酸盐、盐酸盐、硫酸盐、富马酸盐和酒石酸盐）使用类似的工艺生产。然而，这些盐的含水量为 1.60-12.28%，它们的理化性质不同。磷酸盐、盐酸盐和酒石酸盐的熔点比游离碱高 1.1-1.5 倍。在 pH 5.0-8.0 时，S-CAR 盐的溶解度比游离碱高约 3-32 倍。在 S-CAR 盐中明显观察到典型的 pH 依赖性溶解度，但观察到这些盐之间溶解度特性的显着差异。S-CAR磷酸盐和盐酸盐具有高熔点、可观的溶解性以及优异的化学和晶体稳定性。因此，选择 S-CAR 磷酸盐和盐酸盐进行进一步的药代动力学实验和药物研究。以 HPMC K15 为基质制备 S-CAR

  DOI：

  10.1021/acs.molpharmaceut.1c00100

文献信息

• Isomorphism, Disorder, and Hydration in the Crystal Structures of Racemic and Single-Enantiomer Carvedilol Phosphate
  作者：Frederick G. Vogt、Royston C. B. Copley、Ronald L. Mueller、Grant P. Spoors、Thomas N. Cacchio、Robert A. Carlton、Lee M. Katrincic、James M. Kennady、Simon Parsons、Olga V. Chetina

  DOI：10.1021/cg100209v

  日期：2010.6.2

  Understanding the crystalline structure of racemic carvedilol phosphate hemihydrate presents several challenges that were overcome using a combination of single-crystal X-ray diffraction, solid-state NMR (SSNMR), and other analytical techniques. Initial attempts to obtain a crystal structure were hampered by difficulties with twinning and problematic disorder in the final refinements. Multinuclear SSNMR analysis localized the disorder to portions of the molecule near the chiral center. As a result, single-enantiomer carvedilol phosphate was prepared and was found to crystallize in a phase that was isomorphous with the racemate, while SSNMR spectra of the single enantiomers did not contain the disorder observed in the racemate. The single-crystal X-ray structure of the (R)-enantiomer was solved and used as a starting point to successfully progress the solution of the disordered racemic crystal structure. Thermal analysis and construction of a phase diagram, along with crystallographic and spectroscopic analysis, found the crystal structure of the racemate to be a solid solution of (R)- and (S)-enantiomers, with the conformation of the molecule adjusting to fit. The crystal structures show the stoichiometry of the both the racemate and (R)-enantiomer to be a hemihydrate. The phase isomorphically dehydrates below relative humidity values of 1% and above temperatures of 125 degrees C as assessed by water vapor sorption studies, powder X-ray diffraction, and SSNMR. Single-crystal diffraction detected significant changes in the unit cell dimensions as the phase dehydrated, which was related to the visual appearance of opacity in a single crystal of the (R)-enantiomer. The mechanism of water incorporation was further probed spectroscopically via exchange with deuterium, O-17-, and O-18-labeled water; the results suggest that dehydration and rehydration likely proceed via narrow tunnels in the crystal structure, combined with the formation of fissures in the crystal. H-2 SSNMR experiments showed that the water does not engage in solid-state jump motion even at higher temperatures.
• Preparation, Characterization, and Selection of Optimal Forms of (S)-Carvedilol Salts for the Development of Extended-Release Formulation
  作者：Qi Zhang、Baolin Huang、Hongjiao Xue、Zimin Lin、Jie Zhao、Zheng Cai

  DOI：10.1021/acs.molpharmaceut.1c00100

  日期：2021.6.7

  differed. The melting points of phosphate, hydrochloride, and tartrate were 1.1–1.5 times higher than that of the free base. The solubility of S-CAR salts was promoted to approximately 3–32 times higher than that of the free base at pH 5.0–8.0. Typical pH-dependent solubilities were evidently observed in S-CAR salts, but considerable differences in solubility properties among these salts were observed

  (S)-卡维地洛 (S-CAR) 是卡维地洛的主要药效学构象，但由于其溶解性差，限制了其进一步开发缓释制剂。本研究旨在制备和筛选可用于提高溶解度并允许延长释放的 S-CAR 盐。具有众所周知的酸反离子的 S-CAR 的五种盐（即、磷酸盐、盐酸盐、硫酸盐、富马酸盐和酒石酸盐）使用类似的工艺生产。然而，这些盐的含水量为 1.60-12.28%，它们的理化性质不同。磷酸盐、盐酸盐和酒石酸盐的熔点比游离碱高 1.1-1.5 倍。在 pH 5.0-8.0 时，S-CAR 盐的溶解度比游离碱高约 3-32 倍。在 S-CAR 盐中明显观察到典型的 pH 依赖性溶解度，但观察到这些盐之间溶解度特性的显着差异。S-CAR磷酸盐和盐酸盐具有高熔点、可观的溶解性以及优异的化学和晶体稳定性。因此，选择 S-CAR 磷酸盐和盐酸盐进行进一步的药代动力学实验和药物研究。以 HPMC K15 为基质制备 S-CAR