4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide maleic acid (1:1) | 1174325-93-9

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 英文名称: 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide maleic acid (1:1)
• 英文别名: meloxicam maleic acid；meloxicam maleic acid (1:1)；meloxicam:maleic acid；(Z)-but-2-enedioic acid;4-hydroxy-2-methyl-N-(5-methyl-1,3-thiazol-2-yl)-1,1-dioxo-1lambda6,2-benzothiazine-3-carboxamide；(Z)-but-2-enedioic acid;4-hydroxy-2-methyl-N-(5-methyl-1,3-thiazol-2-yl)-1,1-dioxo-1λ6,2-benzothiazine-3-carboxamide
• CAS: 1174325-93-9
• 化学式: C₄H₄O₄*C₁₄H₁₃N₃O₄S₂
• 分子量: 467.48
• InChiKey: NOKHWVHYBXWWHB-BTJKTKAUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.66
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  211
• 氢给体数：
  4
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  美洛昔康 、 顺丁烯二酸 以 丙酮 为溶剂， 反应 0.25h， 生成 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide maleic acid (1:1)
  参考文献：
  名称：

  Preparation and studies of the co-crystals of meloxicam with carboxylic acids

  摘要：

  在制备 4-羟基-2-甲基-N-(5-甲基噻唑-2-基)-2H-1,2-苯并噻嗪-3-甲酰胺 1,1-二氧化物（美洛昔康）与羧酸的共晶体时，采用了添加一些液体的机械处理法、从溶液中结晶法和加热初步经过机械处理的混合物组分法。研究表明，初步机械处理对合成起着重要作用，而添加少量溶剂则可加速合成过程。17 种美洛昔康与羧酸的混合物都获得了共晶体。研究发现，美洛昔康与羧酸的共晶体的溶解速率和溶解度均高于美洛昔康本身，因此在改良药剂配方中使用美洛昔康共晶体大有可为。

  DOI：

  10.1007/s11172-012-0248-6

文献信息

• In vivo studies of crystalline forms of meloxicam
  申请人：Hanna Mazen

  公开号：US20090203680A1

  公开（公告）日：2009-08-13

  The invention is directed to novel crystalline forms of meloxicam. These novel crystalline forms of meloxicam have improved bioavailability, an enhanced rate of dissolution and shorter time to C max in blood, as compared to pure meloxicam.

  本发明涉及美洛昔康的新晶体形式。这些新晶体形式的美洛昔康具有比纯美洛昔康更好的生物利用度，更快的溶解速度和更短的达到血浆Cmax的时间。
• [EN] MELOXICAM CO-CRYSTALS<br/>[FR] CO-CRISTAUX DE MÉLOXICAM
  申请人：MYLAN LABORATORIES LTD

  公开号：WO2020095316A1

  公开（公告）日：2020-05-14

  Co-crystals of meloxicam co-formers can be prepared by co-crystallization from a polar solvent, such as aqueous dimethyl sulfoxide; or by slurry processes, such as with ethyl acetate. Such co-crystals have improved purities and are physically stable under storage for several months.

  美洛昔康辅基的共晶可以通过在极性溶剂中共结晶制备，例如水溶性二甲基亚砜；或者通过浆状过程，例如乙酸乙酯。这种共晶具有提高的纯度，并且在存储数月后仍然具有物理稳定性。
• Supramolecular Architectures of Meloxicam Carboxylic Acid Cocrystals, a Crystal Engineering Case Study
  作者：Miranda L. Cheney、David R. Weyna、Ning Shan、Mazen Hanna、Lukasz Wojtas、Michael J. Zaworotko

  DOI：10.1021/cg100514g

  日期：2010.10.6

  Meloxicam is a nonsteroidal anti-inflammatory drug with low aqueous solubility and high permeability prescribed for indications of arthritis, primary dysmenorrhea, fever, and pain, in this contribution, we apply crystal engineering and the supramolecular synthon approach to prepare novel meloxicam cocrystal forms with various pharmaceutically acceptable or toxicologically qualified carboxylic acids. As a result, 19 pharmaceutical cocrystals including one cocrystal of a salt are synthesized by solid-state and solution methods. All resulting cocrystals are characterized by X-ray diffraction. infrared. and thermal analyses. In particular, crystal structures of six rneloxicam cocrystals are determined and reported, namely. meloxicam . 1-hydroxy-2-naphthoic acid cocrystal (1), meloxicam . glutaric acid cocrystal (2), meloxicam . L-malic acid cocrystal lit salt (3), meloxicam . salicylic acid cocrystal form 111 (4), meloxicam . fumaric acid cocrystal (5), and meloxicam . succinic acid cocrystal (6). The supramolecular assembly of each cocrystal is analyzed and discussed. It is observed that the meloxicam dimer is robust since this motif is observed in five out of six meloxicam cocrystal structures that have been determined. As part of the continuous development, the resulting meloxicam cocrystal forms will be further investigated to explore improved physicochemical and pharmacological properties.
• The role of pH and dose/solubility ratio on cocrystal dissolution, drug supersaturation and precipitation
  作者：Tatiane Cogo Machado、Gislaine Kuminek、Simone Gonçalves Cardoso、Naír Rodríguez-Hornedo

  DOI：10.1016/j.ejps.2020.105422

  日期：2020.9

  Cocrystals that are more soluble than the constituent drug, generate supersaturation levels during dissolution and are predisposed to conversion to the less soluble drug. Drug release studies during cocrystal dissolution generally compare several cocrystals and their crystal structures. However, the influence of drug dose and so-lubility in different dissolution media has been scarcely reported. The present study aims to investigate how drug dose/solubility ratio (Do=C-dose/S-drug), cocrystal solubility advantage over drug (SA=S-cocrystal/S-drug), and dis-solution media affect cocrystal dissolution-drug supersaturation and precipitation (DSP) behavior. SA and Ksp values of 1:1 cocrystals of meloxicam-salicylic acid (MLX-SLC) and meloxicam-maleic acid (MLX-MLE) were determined at cocrystal/drug eutectic points. Results demonstrate that both cocrystals enhance SA by orders of magnitude (20 to 100 times for the SLC and over 300 times for the MLE cocrystal) in the pH range of 1.6 to 6.5. It is shown that during dissolution, cocrystals regulate the interfacial pH (pH(int)) to 1.6 for MLX-MLE and 4.5 for MLX-SLC, therefore diminishing the cocrystal dissolution rate dependence on bulk pH. Do values ranged from 2 (pH 6.5) to 410 (pH 1.6) and were mostly determined by the drug solubility dependence on pH. Drug release profiles show that maximum supersaturation (sigma(max)=C-max/S-drug)and AUC increased with increasing Do as pH decreased. When Do >SA, the cocrystal solubility is not sufficient to dissolve the dose so that a dissolution -precipitation quasi-equilibrium state is able to sustain supersaturation for the extent of the experiment (24 h). When Do<