Lamotrigine saccharinate | 1094042-17-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻唑类
• 英文名称: Lamotrigine saccharinate
• 英文别名: samotrigine saccharinate；lamotrigine saccarinate；6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine;1,1-dioxo-1,2-benzothiazol-3-one
• CAS: 1094042-17-7
• 化学式: C₇H₅NO₃S*C₉H₇Cl₂N₅
• 分子量: 439.282
• InChiKey: ROPGQSKFVMSTFM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.13
• 重原子数：
  28
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  162
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  糖精 、 那蒙特金 以 乙腈 为溶剂， 生成 Lamotrigine saccharinate
  参考文献：
  名称：

  Multicomponent solids of lamotrigine with some selected coformers and their characterization by thermoanalytical, spectroscopic and X-ray diffraction methods

  摘要：

  本研究探讨了拉莫三嗪（LTG）与一些药学上可接受的共配体（即烟酰胺（1）、乙酰胺（2）、乙酸（3）、4-羟基苯甲酸（4）和糖精（5））的不同多组分结晶形式的结构和药学特性。通过 DSC/TGA、傅立叶变换红外光谱和 XRD（粉末和单晶结构分析）对固态以及溶液相进行了表征。发现形式 1 和 2 分别是共晶水合物和共晶，而在形式 3、4 和 5 中，观察到质子从共形物转移到药物。多组分晶体的形成焓是根据共晶体和各组分的溶解焓分别确定的。分子复合物 3、4 和 5 的形成焓放热值较高，表明它们比 1 和 2 更稳定。在水和不同 pH 值的磷酸盐缓冲液中测量了溶解度。在对小鼠进行的动物活性研究中，观察到 1、3 和 5 显著降低了 LTG 的剂量曲线。

  DOI：

  10.1039/c1ce05458a

文献信息

• [EN] CRYSTALLINE FORMS OF LAMOTRIGINE<br/>[FR] FORMES CRISTALLINES DE LAMOTRIGINE
  申请人：THAR PHARMACEUTICALS

  公开号：WO2009061513A1

  公开（公告）日：2009-05-14

  The invention is directed to novel crystalline forms of lamotrigine. These novel crystalline forms of lamotrigine have improved dissolution and in-vivo absorption profile, as compared to pure lamotrigine. These novel crystalline forms of lamotrigine provide a substantial increase in the blood concentration of lamotrigine, as compared to pure lamotrigine when administered to a subject. These novel crystalline forms of lamotrigine also provide a slower, steady build up of lamotrigine blood concentration suitable for sustained release of lamotrigine in-vivo, as compared to pure lamotrigine.

  该发明涉及拉莫三嗪的新型晶体形式。与纯拉莫三嗪相比，这些新型晶体形式的拉莫三嗪具有改进的溶解性和体内吸收特性。这些新型晶体形式的拉莫三嗪在给予受试者时，与纯拉莫三嗪相比，可以显著提高血液中拉莫三嗪的浓度。这些新型晶体形式的拉莫三嗪还提供了一个较慢、稳定的拉莫三嗪血液浓度逐渐增加的过程，适合体内持续释放拉莫三嗪，与纯拉莫三嗪相比。
• An experimental and theoretical study of the structure of Lamotrigine in its neutral and protonated forms: evidence of Lamotrigine enantiomers
  作者：Ibon Alkorta、José Elguero、Anna Font、Judit Galcera、Ignasi Mata、Elies Molins、Albert Virgili

  DOI：10.1016/j.tet.2014.02.075

  日期：2014.4

  The energies, geometries, and NMR chemical shifts have been calculated at the B3LYP/6-311++G(d,p) level for 17 structures of the anticonvulsant drug Lamotrigine and 29 structures of protonated Lamotrigine, including tautomers and E/Z isomers of the imino groups. The calculations were compared with solid state (X-ray and CPMAS NMR) and solution experimental results both reported in the literature and determined in this work. The conclusion is that Lamotrigine exists as the diamino tautomer and that its protonation takes place on the N2 atom. Using ABTE and/or deuterated ABTE as chiral solvating agent, it has been demonstrated for the first time by NMR in solution that Lamotrigine is a racemate of rapidly interconverting enantiomers. The crystal structure of two new solvated salts of Lamotrigine, both saccharinates, has been determined. Both salts present the same arrangement in chains of Lamotrigine and saccharinate joined by hydrogen bonds and stacking interactions. No isostructurality is present because of the different arrangement of the chains in both crystal structures. (C) 2014 Elsevier Ltd. All rights reserved.
• Effects of Crystal Form on Solubility and Pharmacokinetics: A Crystal Engineering Case Study of Lamotrigine
  作者：Miranda L. Cheney、Ning Shan、Elisabeth R. Healey、Mazen Hanna、Lukasz Wojtas、Michael J. Zaworotko、Vasyl Sava、Shijie Song、Juan R. Sanchez-Ramos

  DOI：10.1021/cg901010v

  日期：2010.1.6

  In this contribution. we describe how the supramolecular synthon approach call be used for discovery of novel crystal forms and For enhancing the relevant preclinical properties Of 1 IOW solubility antiepileptic drug, lamotrigine (6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine). Ten novel crystal forms are reported: lamotrigine methylparaben cocrystal form I (1:1) (1), lamotrigine methylparaben cocrystal form II (1:1) (2), lamotrigine nicotinamide cocrystal (1:1) (3), lamotrigine nicotinamide cocrystal monohydrate (1:1:1) (4), lamotrigine saccharin salt (1:1) (5), lamotrigine adipate salt (2:1) (6), lamotrigine malate salt (2:1) (7), lamotrigine nicotinate dimethanol solvate (1:1:2) (8), lamotrigine dimethanol solvate (1:2) (9), ad lamotrigine ethanol monohydrate (1:1:1) (10). A selected set of the reported crystal forms Were studied to determine their dissolution rate, solubility, and pharmacokinetic behavior. The solubilities were measured in aqueous media and in acidified aqueous media (pH = 1). It was observed that 5 and 2 exhibited the highest concentration in the aqueous media and acidified aqueous media, respectively. In the pharmacokinetic study, the serum concentration of lamotrigine, measured in Sprague-Dawley rats, reached the highest level after a single-dose oral administration of 5.
• Multicomponent solids of lamotrigine with some selected coformers and their characterization by thermoanalytical, spectroscopic and X-ray diffraction methods
  作者：Renu Chadha、Anupam Saini、Poonam Arora、Dharamvir Singh Jain、Archi Dasgupta、T. N. Guru Row

  DOI：10.1039/c1ce05458a

  日期：——

  The present study investigates the structural and pharmaceutical properties of different multicomponent crystalline forms of lamotrigine (LTG) with some pharmaceutically acceptable coformers viz.nicotinamide (1), acetamide (2), acetic acid (3), 4-hydroxy-benzoic acid (4) and saccharin (5). The structurally homogeneous phases were characterized in the solid state by DSC/TGA, FT-IR and XRD (powder and single crystal structure analysis) as well as in the solution phase. Forms 1 and 2 were found to be cocrystal hydrate and cocrystal, respectively, while in forms 3, 4 and 5, proton transfer was observed from coformer to drug. The enthalpy of formation of multicomponent crystals from their components was determined from the enthalpy of solution of the cocrystals and the components separately. Higher exothermic values of the enthalpy of formation for molecular complexes 3, 4 and 5 suggest these to be more stable than 1 and 2. The solubility was measured in water as well as in phosphate buffers of varying pH. The salt solvate 3 exhibited the highest solubility of the drug in water as well as in buffers over the pH range 7–3 while the cocrystal hydrate 1 showed the maximum solubility in a buffer of pH 2. A significant lowering of the dosage profile of LTG was observed for 1, 3 and 5 in the animal activity studies on mice.

  本研究探讨了拉莫三嗪（LTG）与一些药学上可接受的共配体（即烟酰胺（1）、乙酰胺（2）、乙酸（3）、4-羟基苯甲酸（4）和糖精（5））的不同多组分结晶形式的结构和药学特性。通过 DSC/TGA、傅立叶变换红外光谱和 XRD（粉末和单晶结构分析）对固态以及溶液相进行了表征。发现形式 1 和 2 分别是共晶水合物和共晶，而在形式 3、4 和 5 中，观察到质子从共形物转移到药物。多组分晶体的形成焓是根据共晶体和各组分的溶解焓分别确定的。分子复合物 3、4 和 5 的形成焓放热值较高，表明它们比 1 和 2 更稳定。在水和不同 pH 值的磷酸盐缓冲液中测量了溶解度。在对小鼠进行的动物活性研究中，观察到 1、3 和 5 显著降低了 LTG 的剂量曲线。