Lee Tu, Wang Yeh Wen
Department of Chemical and Materials Engineering, National Central University, Jhong-Li City, Taiwan, Republic of China.
Drug Dev Ind Pharm. 2009 May;35(5):555-67. doi: 10.1080/03639040802459452.
The aim of this paper is to design initial salt screening procedures for manufacturing ibuprofen. Salt forms of a pharmaceutical acid racemic (R,S)-(+/-)-ibuprofen and their "developable" synthetic routes were ferreted out simultaneously through the screening of seven bases of sodium hydroxide, potassium hydroxide, L-arginine, L-histidine, L-lysine, diethanolamine, and tris(hydroxymethyl)aminomethane (THAM), and the match with the use of nine organic solvents of methanol, dimethyl sulfoxide, ethanol, N, N-dimethylformamide, acetonitrile, isopropyl alcohol, 1,4-dioxane, acetone, and tetrahydrofuran mainly in the presence of water in 20 mL scintillation vials. Racemic (R,S)-(+/-)-sodium ibuprofen dihydrate, a well-known ibuprofen salt and the newly discovered racemic (R,S)-(+/-)-THAM ibuprofen, appeared as white-squared powders with a molecular weight of 327.42 g/mol, a melting point of 160.17 degrees C, and the apparent solubility product, K'(sp), of 6.0 x 10(-4) M(2) at 25 degrees C were successfully synthesized by the initial salt screening methods. The new amine salt of ibuprofen was monoclinic and had a space group of P2(1)/c and lattice parameters of a = 17.578(8) degrees, b = 10.428(4) degrees, c = 9.991(4) A, alpha = 90.00 degrees , beta = 97.17(1) degrees, gamma = 90.00 degrees, and V = 1,817.05(244) A(3). The aspect ratio of the amine salt crystals of ibuprofen of approximately 1.0 implied that the crystals had a better flowability than the sodium salt counterparts. This amine salt of ibuprofen was more stable in moist or dried atmospheres and was more hydrophobic than the sodium salt of ibuprofen. Moreover, the slow dissolution of this amine salt of ibuprofen might have made it less bitter and more suitable as a sustained release drug than the sodium salt of ibuprofen. The future work is to search for the different polymorphs of this amine salt of ibuprofen and to extend the initial salt screening working logics to the formation of co-crystals.
本文旨在设计布洛芬生产的初始盐筛选程序。通过筛选氢氧化钠、氢氧化钾、L-精氨酸、L-组氨酸、L-赖氨酸、二乙醇胺和三（羟甲基）氨基甲烷（THAM）七种碱，并在20 mL闪烁瓶中主要在水存在的情况下与甲醇、二甲基亚砜、乙醇、N，N-二甲基甲酰胺、乙腈、异丙醇、1,4-二氧六环、丙酮和四氢呋喃九种有机溶剂配合使用，同时找出了药物酸外消旋体（R，S）-（±）-布洛芬的盐形式及其“可开发”的合成路线。外消旋体（R，S）-（±）-布洛芬二水合钠，一种著名的布洛芬盐，以及新发现的外消旋体（R，S）-（±）-THAM布洛芬，呈现为白色方形粉末，分子量为327.42 g/mol，熔点为160.17℃，在25℃时的表观溶度积K'(sp)为6.0×10⁻⁴ M²，通过初始盐筛选方法成功合成。布洛芬的新胺盐为单斜晶系，空间群为P2(1)/c，晶格参数为a = 17.578(8)°，b = 10.428(4)°，c = 9.991(4) Å，α = 90.00°，β = 97.17(1)°，γ = 90.00°，V = 1,817.05(244) ų。布洛芬胺盐晶体的长径比约为1.0，这意味着该晶体的流动性比钠盐晶体更好。这种布洛芬胺盐在潮湿或干燥气氛中更稳定，并且比布洛芬钠盐更疏水。此外，这种布洛芬胺盐的缓慢溶解可能使其苦味减轻，比布洛芬钠盐更适合作为缓释药物。未来的工作是寻找这种布洛芬胺盐的不同多晶型物，并将初始盐筛选工作逻辑扩展到共晶体的形成。
