Interactions Of Amino Acids/Dipeptides With Active Pharmaceutical Ingredient Ionic Liquids In Aqueous Solution:Volumetric,Conductometric And Spectroscopy Study

Ionic liquids are recognized as green solvents and new materials attribute to their excellent physical and chemical properties,especially the tunable and designable structure and performance.With a further research,the active pharmaceutical ingredient ionic liquids(API-ILs)have been synthesized continuously in recent years.The researches demonstrated that the API-ILs have the biological activity of pharmaceutical ingredient and the outstanding properties of ionic liquids.Compared with the traditional solid pharmaceuticals,this API-ILs can provide the possibility of improved performance such as the elimination of polymorphic conversion,the controlled solubility and new delivery options,which are deserved high attention in pharmaceutical industry,forming the third generation of ionic liquids.The researchs of the interactions between API-ILs and protein model molecules are very necessary for the understanding of the interactions between API-ILs with biological molecules under physiological environments.And these investigations also have very important practical significance on the exploition,selection or the application of new API-ILs.In this paper,we synthesized three API-ILs;benzethonium chloride-L-proline(BT-PL),benzethonium chloride-DL-mandelic acid(BT-MAN),benzalkonium chloride-salicylic acid(BK-SAL).The density,conductivity,fluorescence spectrum and UV absorption spectrum measurement have been carried out to obtain information on the molecular interactions between API-ILs and amino acids/glycyl dipeptides with different alkyl chain length(glycine,DL-alanine,L-valine,L-leucine,glycylglycine,glycyl-L-valine,glycyl-L-leucine).The major contents and conclusions of the paper are as follows:(1)The Anton Paar density meter has been used to measure the density of the ternary systems(API-ILs +amino acids/dipeptides + water).The volume parameters of amino acids/dipeptides in different concentrations of API-ILs at different temperature have been calculated.What can be found is that with the increase of temperature,the standard partial molar volume V2o,?,standard partial molar transfer volumes ?tVo,standard partial molar expansibilities E?o of amino acids and dipeptides gradually increase but the hydration number NH is gradually decrease.At the studied four temperatures,the standard partial molar volume V2o,? of amino acids and dipeptides in aqueous BT-PL?BK-SAL solution is bigger than that in water.The standard partial molar transfer volume AtVo is positive,The hydration number NH is smaller than that in water.But in aqueous BT-MAN solution this results are opposite.It suggests that in the BT-PL and BK-SAL aqueous solutions,the interactions of the polar groups and charged groups of amino acids/dipeptides with the ions of API-ILs is stronger,but in the BT-MAN aqueous solution,the interactions of the hydrophobic groups of amino acids/dipeptides with the ions and hydrophobic groups of API-ILs is predominante.The Hepler's factors are positive which indicates that the amino acids/dipeptides are structure makers in aqueous API-ILs solutions.(2)The standard partial molar volume V(2,?)o of amino acids has been successfully used to estimates the standard partial molar volumes V(2,?)o of glycyl dipeptide.There is very good linear relationship between the standard partial molar volume of amino acid and the number of carbon atoms on its hydrophobic alkyl chain,as well as the standard partial molar volume of glycyl dipeptide V(2,?)o(Gly-X)and the standard partial molar volume of the corresponding amino acid Vo(2,?)(X).Based on the groups contribution principle,the contribution of zwitterionic end groups(NH3+,COO-)?methylene group(CH2)?alky side chain?glycyl dipeptide(CH2CONH)to Vo(2,?)have been obtained.The result confirmed the two trends of the V(2,?)o and ?tVo in the API-ILs aqueous solution.(3)The conductometry is used to measure the conductivities of API-ILs in different concentration of amino acid/dipeptide solutions.Then we obtain the critical micelle concentration CMC of BT-PL?BT-MAN and the limiting molar conductivity Ao of BK-SAL.The CMC of BK-SAL was measured by UV absorption spectrum.The results show that the CMC of API-ILs was affected by temperature,the concentration and the length of alky chain of amino acid/dipeptide,as well as the molecular structure of API-ILs.At a certain concentration of amino acid/dipeptide,the CMC of API-ILs have different change trend with the increase of temperature.This is attribution to the different strength of the hydrophilic and hydrophobic effect.At a certain temperature,the CMC of API-ILs and the limiting molar conductivity of BK-SAL decrease with the increase of the alky chain length of amino acid/dipeptide.(4)Thermodynamic parameters of micellization of API-ILs in aqueous amino acids/dipeptides solutions indicate that the micellization process is a spontaneous process.It is an entropy driven process at low temperature,but at high temperature it is an enthalpy driven process,and the enthalpy-entropy compensation effect is very good in the ternary solutions.(5)The intensity ratio I1/I3 of the pyrene fluorescence spectrum and aggregation number of BT-PL and BT-MAN in the ternary systems were calculated by the pyrene fluorescence spectra.The aggregation number of BK-SAL was calculated by the conductivity.The consequence show that while the amino acids/dipeptides were added,the polarity of solution and the aggregation number of API-ILs decrease,which result in the decrease of CMC.With the increase in the length of amino acids/dipeptides,the polarity of solution and the aggregation number decrease.(6)The binding constants of amino acids and dipeptides with API-ILs have been determined by UV-vis absorption spectrum.What can be found is that the binding constant is gradually increasing while the alky chain length of amino acids/dipeptides is increasing.It is reveal that the interaction between amino acids/dipeptides and API-ILs is stronger.