Conformational and Synthon Polymorphism in Furosemide (Lasix)
Conformational and Synthon Polymorphism in Furosemide (Lasix)
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DOI：
10.1021/cg100098z
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发表时间：
2010-04-01
影响因子：
3.8
通讯作者：
Nangia, Ashwini
中科院分区：
文献类型：
--
作者：
Babu, N. Jagadeesh;Cherukuvada, Suryanarayan;Nangia, Ashwini
著名利尿剂 Lasix（通用名呋塞米）的两种多晶型物通过单晶 X 射线衍射进行表征，得到多晶型物的三晶型簇：已知晶型 1 位于条形空间群上的 P (1) 中，新晶形 2 和 3 位于条形空间群上的 P2(1)/n 和 P(1) 中。构象灵活的分子4-氯-2-[(2-呋喃基甲基)氨基]-5-氨磺酰基苯甲酸在位于6 kcal mol(-1)能量窗口的构象异构体中的磺酰胺和呋喃环部分具有可变的扭转。计算构象异构体表面图显示，晶型1中的两种构象与4.5 kcal mol(-1)相似，但稳定性低于晶型2和3中存在的构象异构体(0.7、0.0 kcal mol(-1))。根据吸引性分子内N-H中心点CI氢键和排斥性S=O中心点CI相互作用的最小化来分析分子构象的稳定性。相稳定性关系通过 X 射线粉末衍射和红外光谱证实了研磨和浆料实验中 1 型的热力学性质。尽管分子构象能量差异较大，但多晶型物1-3的晶格能量非常接近（-41.65、41.78、41.53 kcal mol(-1)）。这些结果表明，在结晶实验中得出的呋塞米多晶型物1的热力学稳定性不可能通过计算来预测。此外，稳定晶体结构中亚稳态构象异构体的存在再次强调多晶型系统中的实验验证是无可替代的。多晶型物I的更高稳定性归因于其更有效的晶体堆积、更高的密度以及R-4(2)(8)磺酰胺N-H中心点中心点O二聚体合成子的存在。由于多晶型物1-3中扭转角和氢键的差异，它们更适合分类为构象多晶型物和合成子多晶型物。
Two polymorphs of the well-known diuretic drug Lasix, generic name furosemide, are characterized by single crystal X-ray diffraction to give a trimorphic cluster of polymorphs: known form 1 in P (1) over bar space group, and novel forms 2 and 3 in P2(1)/n and P (1) over bar space groups. The conformationall, flexible molecule 4-chloro-2-[(2-furanylmethyl)amino]-5-sulfamoylbenzoic acid has variable torsions at the sulfonamide and furyl ring portions in conformers which lie in a 6 kcal mol(-1) energy window. A conformer surface map was calculated to show that the two conformations in crystal form 1 are similar to 4.5 kcal mol(-1) less stable than conformers present in forms 2 and 3 (0.7, 0.0 kcal mol(-1)). The stabilization of molecular conformations is analyzed in terms of attractive intramolecular N-H center dot center dot center dot CI hydrogen bonds and minimization of repulsive S=O center dot center dot center dot CI interactions. Phase stability relationships confirm the thermodynamic nature of form 1 in grinding and slurry experiments by X-ray powder diffraction and infrared spectroscopy. Despite the large difference in molecular conformer energies, crystal lattice energies of polymorphs 1-3 are very close (-41.65, 41.78, 41.53 kcal mol(-1)). These results show that the thermodynamic stability of polymorph 1 of furosemide concluded in crystallization experiments is not possible to predict through computations. Moreover, the presence of metastable conformers in the stable crystal structure reemphasizes that there is no substitute for experimental validation in polymorphic systems. The greater stability of polymorph I is ascribed to its more efficient crystal packing, higher density, and the presence of R-4(2)(8) sulfonamide N-H center dot center dot center dot O dimer synthon. Because of the differences in torsion angles and hydrogen bonding in polymorphs 1-3, they are more appropriately classified as conformational and synthon polymorphs.