| 1392401-13-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• CAS: 1392401-13-6
• 化学式: C₆H₆N₂O*C₁₃H₈Cl₂N₂O₄
• 分子量: 449.25
• InChiKey: NRGAJGOCRFCVIR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.04
• 重原子数：
  30.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  148.45
• 氢给体数：
  3.0
• 氢受体数：
  6.0

反应信息

• 作为产物：
  描述：

  4-吡啶甲酰胺 、 氯硝柳胺 以 乙醇 为溶剂， 反应 0.25h， 生成
  参考文献：
  名称：

  Crystal Engineering of Pharmaceutical Co-crystals: “NMR Crystallography” of Niclosamide Co-crystals

  摘要：

  尼可刹米是一种生物制药分类系统（BCS）二级噻吩酰胺，目前正被重新考虑用于治疗类风湿性关节炎、预防神经退行性疾病中的蛋白质变性，甚至用于癌症和癌症干细胞的多靶点治疗。然而，由于其溶解性或生物利用度不足，其在医学治疗中的功效目前受到限制。因此，我们分别从 "公认安全"（GRAS）或美国食品和药物管理局（U.S. FDA）的 "美国食品添加物"（EAFUS）清单中挑选了合适的共形物，进一步探索了氢键介导的尼古丁酰胺共晶体形成的潜力。溶剂辅助固体研磨和/或缓慢溶剂蒸发产生了四种新的共晶体：(i)烟酰胺-2-氨基噻唑（NCL-AT）、(ii)烟酰胺-苯甲酰胺（NCL-BA）、(iii)烟酰胺-异嗪（NCL-IN）和(iv)烟酰胺-乙酰胺 I 和 II（NCL-AA-I/NCL-AA-II）。在综合应用粉末 X 射线衍射（PXRD）、固态 NMR 和密度泛函理论（DFT）化学位移计算的基础上，从白色微晶粉末样品中解析了 NCL-AA-I/II 和 NCL-AT 的晶体结构。此外，还重新考虑了一水合物 NCL-HA 的晶体结构，以便进行比较。最后，可以确定 1:1 共晶体 NCL-AT 的平衡溶解度有所提高（是原始 NCL 的 2.8 倍，是 NCL-UREA 共晶体的 1.4 倍），这表明 NCL-AT 是未来医疗的候选物质。

  DOI：

  10.1021/acs.cgd.5b01619

文献信息

• Pharmaceutical Cocrystals of Niclosamide
  作者：Palash Sanphui、S. Sudalai Kumar、Ashwini Nangia

  DOI：10.1021/cg300784v

  日期：2012.9.5

  Niclosamide (NCL) is an anthelmintic BCS class II drug of low solubility and high permeability. Pharmaceutical cocrystals of NCL were prepared with GRAS molecules, such as caffeine (CAF), urea (URE), p-aminobenzoic acid (PABA), theophylline (THPH), nicotinamide (NCT), and isonicotinamide (INA), to improve drug solubility. Neat grinding, wet granulation, and slow evaporation methods were successful to make niclosamide cocrystals. All new crystalline forms were characterized by X-ray diffraction, differential scanning calorimetry, and IR-Raman spectroscopy to confirm their purity and homogeneity. X-ray crystal structures provided details of hydrogen bonding, molecular packing, and drug...coformer interactions. The intermolecular O-H center dot center dot center dot O hydrogen bond from the hydroxyl donor to the carbonyl acceptor in the niclosamide crystal structure was replaced by an acceptor atom of the coformer in cocrystal structures. Cocrystals with nicotinamide and isonicotinamide were characterized by C-13 ss-NMR spectroscopy because their single crystals could not be obtained. All cocrystals, except NCL-PABA, showed a faster powder dissolution rate than the reference active pharmaceutical ingredient (API). Niclosamide theophylline acetonitrile solvate showed the highest solubility (6 times compared to the API) among all the crystalline forms. NCL-THPH cocrystals showed comparably good dissolution (5 times faster than the drug) up to 90 min. The solubility advantage of the cocrystal was diminished by transformation to insoluble niclosamide monohydrate within 1 h of the dissolution experiment in 40% i-PrOH-water. Equilibrium solubility experiments showed that all cocrystals as well as the pure API transformed to NCL monohydrate within 24 h in 40% i-PrOH-water slurry medium. Among the cocrystals studied, NCL-NCT and NCL-INA exhibited better stability under accelerated humidity conditions (75% RH, 40 degrees C), but they did not have the same solubility advantage as the fast dissolving species NCL THPH.