Properties Of Bifunctional Pharmaceutically Active Ionic Liquid With Ibuprofen As Anions And Their Interactions With Amino Acid/glycyl Dipeptide

API-ILs has both the excellent properties of ionic liquid and the biological activity of pharmaceutical components,which can be used to solve the bottleneck problems of traditional drugs in terms of poor solubility,polycrystalline conversion and delivery mode.Ibuprofen is a commonly used non-steroidal anti-inflammatory drug,but its low water solubility limits its therapeutic application.This paper combines ibuprofen and counter ion into ionic liquids,the method of synthesis of the four with the anion of ibuprofen dual functional ionic liquid containing drug active component(API-ILs),N-dodecyl-dimethyl-2-phenoxy ethyl ammonium(domiphen)-ibuprofen([DOM][Ibu]),N-decyl-dimethyl-2-phenoxy-ethyl ammonium-ibuprofen([DDPA][Ibu]),benzalkonium chloride,ammonia-ibuprofen([BK][Ibu]),benzethonium chloride-ibuprofen([BTC][Ibu]).Thermal stability,water/simulated body fluids in the solubility and the octanol-water partition coefficient and the water of micellar behavior were determined by using ultraviolet spectrum,fluorescence spectrum,conductance,volume and other methods.API-ILs in aqueous solution is studied and the interaction between small biomolecules and API-ILs the results of the study to understand the physiological environment law of API-ILs to interact with biological molecules and for the development of new API-ILs,screening,and clinical applications has a very important guiding significance.The research contents and results are as follows:(1)Ibuprofen was combined with dumeiphene and its derivatives,benzalkonium chloride and benzylsolonium chloride,and the four bifunctional API-ILs synthesized were characterized by hydrogen spectrum and thermogravimetric analysis,which indicated that the product had high purity.Thermal analysis shows that[DOM][Ibu]and[DDPA][Ibu]have good thermal stability.(2)The solubility of the four API-ILs was measured at two temperatures(T=25℃,37℃)at different pH(=1.2,6.8,7.4)and in water,and it was found that the solubility of the four API-ILs increased with the increase of temperature at each pH.(3)The partition coefficients KO/W of the four API-ILs were measured at two temperatures(T=25℃,37℃)at different pH(=1.2,6.8,7.4)and in the phase of water and n-octanol.It was found that the partition coefficients decreased with the increase of temperature at each pH,which was consistent with the results of solubility.(4)The conductivity and limiting molar conductivity of the four API-ILs in water and biological small molecule aqueous solution were measured by the conductivity method and the critical micelle concentration CMC of API-ILs in the system was obtained,and some thermodynamic data were calculated accordingly.These data indicate that the micellar process of API-ILs is a spontaneous process of entropy increase and heat release.The factors affecting micellar process,such as chain length(API-ILs and small biomolecules),concentration of small biomolecules,temperature and so on,were also discussed.It was found that the critical micelle concentration of ternary system was lower than the critical micelle concentration of ternary system,which indicated that the addition of biological small molecules was beneficial to the aggregation of micelles.(5)The micropolarity I1/I3 and aggregation number Nagg of four API-ILs in water(binary system)and glycine,glycine and glycine glycine solutions(ternary system)were determined by fluorescence spectrum.The numerical value of micropolarity can play an explanatory relationship with CMC of critical micelle concentration.The experimental results are in good agreement.It is found that the aggregation number of ternary system is smaller than that of water.(6)The density of biological small molecules in two API-ILs:[DOM][Ibu]and[DDPA][Ibu]aqueous solution(ternaries system)was measured by volume method and a series of relevant thermodynamic values were calculated.The influencing factors of the interaction about the system,such as the increase of temperature,will lead to a raise on the standard partial molar volume.It is also found that the standard partial molar transfer volume is negative,indicating that the interaction between hydrophobic group and ion-hydrophobic group is dominant in the system.Hepler’s constant is positive,indicating that[DOM][Ibu]and[DDPA][Ibu]belong to the structure-promoting solute.(7)The contribution of some groups of small biological molecules,such as amphoteric terminal group(NH3+,COO-),CH2,alkyl side chain,(CH2CONH)to the standard partial molar volume of amino acids/dipeptides in API-ILs aqueous solution was obtained by group contribution method.The standard partial molar volumes of amino acids and their corresponding dipeptides were plotted,and there was a good linear relationship between them.(8)The binding constants of four API-ILs in amino acid/glycyl dipeptide were calculated by ultraviolet spectrum,and it was found that the four drugs had red shift at 195 nm.The size of the binding constant reflects the strength of the interaction between drugs and small biological molecules.It is found that the binding constant increases with the increase of the chain length of API-ILs and small biological molecules.