| With the enhancement of environmental awareness,academia and industry are now encouraging the integration of green chemistry,sustainability and eco-efficiency into the pharmaceutical industry.However,industrial chemical processes or even pharmaceutical manufacturing processes often require large numbers of toxic and environmentally hazardous organic solvents,where a major source of waste in the pharmaceutical industry is organic solvents.In the recent years,ionic liquids（ILs）,with the advanced characteristics of non-volatility,non-flammability and high recyclability,have been proposed as“green solvents”to widely use in the pharmaceutical industry,which has solved the problem of environmental pollution in the pharmaceutical manufacturing processes.At the same time,ILs can not only promote the reaction and improve the product yield in the drug synthesis,but also use its extraordinary solvation capability to solve the problems of polymorph,low solubility and low bioavailability in the drug development.On the other hand,the“hygroscopicity characteristics”of ILs make it enable to mix with green solvent water to form a new green IL/water mixture.Compared with pure ILs solvent,IL/water mixtures have lower viscosity and stronger solvation capacity,which further expands their applications in the separation and mass transfer process in the pharmaceutical industry.However,the number of ILs has reached 1018 and even continues to increase due to due to their outstanding tunable nature,and the physicochemical properties of ILs are greatly affected by water concentration.Therefore,how to select suitable ILs and IL/water mixtures for the pharmaceutical industry is a major challenge.Generally,solubility is often used as an important criterion for screening and designing solvents,because the solubility of drugs in solvents is often used as as the basis for the development of IL-based crystallization and extraction of drugs.Therefore,it is of considerable significance to understand the solvation mechanism of drugs in ILs and IL/water mixtures for the development of new green solvents that are cheaper,greener and more suitable for drug dissolution,separation and purification.Based on this,this paper is mainly divided into two parts:（i）density functional theory（DFT）calculation and molecular dynamics（MD）simulations are used to systematically study the solvation mechanism of poorly water-soluble drugs in pure ILs solvents,and reveal the effect of cationic and anionic structures,ILs types and the complex intermolecular interactions during the drugs solvation process;（ii）Based on the results（i）,ILs with high solvation capacity was selected and combined with water to form a new IL/water mixtures.Then,molecular dynamics simulation was used to study the effect of water concentration on the solvation mechanism of drugs in ILs.The main research content as follows:（1）MD simulations were performed to study the combinations of[Ac O]–,[Tf O]–,[BF4]–and[PF6]–anions paired with imidazolium cations of increasing alkyl chain length to elucidate the roles of anions and cations in solvating ibuprofen.Our simulation results revealed that ILs with strong ibuprofen solvation capacity should possess strong hydrogen bond（HB）interactions from anions and strongπ-πstacking interactions and van der Waals force from cations.However,the simulation results showed that the HB interactions between anion and ibuprofen is the main driving force.It was found that the strong HB acceptability of[Ac O]–can form a strong HB interaction with ibuprofen,resulting in a highest solubility of ibuprofen in this kind of ILs.While the electron withdrawing groups in[Tf O]–,[BF4]–and[PF6]–could weaken the HB interaction between them and ibuprofen,thus reducing the solubility of ibuprofen in these ILs.In terms of imidazolium cations,the longer alkyl chain in the imidazolium cations decrease the polarity,thus increasing the affinity with ibuprofen,which is helpful to improve the solubility of ibuprofen in ILs.Therefore,this study provides the following reference factors for the design of ILs with high-performance dissolved ibuprofen:（i）the heterocyclic structure of imidazolium cation with high polarity and longer alkyl chain are beneficial,（ii）the cations should have strong ability of HB donor to form HB interaction with ibuprofen,（iii）the HB acceptors of anions should have strongly HB acceptability to interact strongly with the hydroxyl proton of ibuprofen,（iv）the negative charge of HB acceptor atom in anions should be larger,（v）the anions should be without any electron-withdrawing groups.（2）Five unsaturated heterocyclic cations including[Amim]+,[C2OHmim]+,[C1OC2mim]+,[C4dmim]+and[C4mpy]+,as well as three unsaturated heterocyclic cations such as[C4mpip]+,[C4mpyr]+,and[Cho]+,were selected as the research solvents.Then,how the cationic structure affected the solvation mechanism of ibuprofen in ILs by using MD simulations and DFT caculation.It was found that the acidic protons in the cationic structure play an important role in ibuprofen solvation in ILs.Compared with saturated heterocyclic cations,acidic hydrogen protons in unsaturated heterocyclic cations can form HB interaction with ibuprofen,so as to improve the solvation ability of ILs for the ibuprofen.In addition,for imidazolium cations,although the three acidic hydrogen protons on the imidazolium ring play an important role in the solvation process of ibuprofen,the hydrogen protons at the C2 position of the imidazolium ring were the major factor.However,when the end of the alkyl side chain of imidazolium cation is connected with hydroxyethyl and methoxyethyl electron donor groups,it can affect the solvation of ibuprofen in ILs by reducing the acidity of hydrogen protons in unsaturated heterocyclic cations,interfering with the formation of HB between ibuprofen and anions,as well as forming a competitive relationship with ibuprofen.Therefore,for the rational design of efficient IL solvents for ibuprofen,cationic backbone with unsaturated heterocycles and strong acidic protons but without high electronegativity atoms（say oxygen atom）and functional groups with electron donating properties in the side chain should give top priority（3）Aspirin and etomidate were selected as model drugs,and then a set of MD simulations and DFT calculations were designed to systematically explore the solvation mechanism of aspirin and etomidate in ILs from the analysis of solvation structure,interaction energy,various molecular-level interaction mechanisms,IGM,and AIM.The results showed that the favorable solvation of aspirin in ILs correlated well with the HB basicity of anions,while the good solubility of etomidate is mainly determined by the HB acidity of cations.This distinct difference was principally caused by different functional groups of these two drugs.The carboxylic acid functional group of aspirin mainly presented strongly HB donating characteristic,whereas etomidate with no active hydrogen protons primarily formed HB interaction with cations.In addition,AIM analysis further revealed that owing to the high HB basicity of[OAc]–anion,the HB between aspirin and[OAc]–anion was strong enough to show covalent feature,thus ILs containing[OAc]–anion was often most effective solvent in solubilizing aspirin.Unlike aspirin,the H-bond interactions between etomidate and cations exhibited an electrostatic dominant,and moderate cation-anion interaction could weakened this HB strength.Accordingly,in terms of etomidate,the best ILs solvent comprised a weakly interacting anion and a cation with strong HB acidity.（4）We extend our research system from pure IL to more complex IL/water mixtures,and then MD simulations was used to study the solvation behavior and phase separation mechanism of ibuprofen in the mixture of 1-butyl-3-methylimizaolium acetate（[Bmim][Ac O]）and water at seven different water concentrations,where the water mole fractions are in turn 0.1,0.2,0.4,0.5,0.7,0.8,and 0.9.The results showed that when the water concentration is low（<0.5）,the ternary system composed of ibuprofen,[Bmim][Ac O]and water formed a homogeneous solution.However,when the mole fraction of water is greater than 0.7,the ternary mixure system was devided into two phases,which were consist of one phase rich in ibuprofen and the other rich in[Bmim][Ac O]and water.The results showed that the solvation process at high water concentration,water was used as an effective antisolvent,so that ibuprofen was precipitated from[Bmim][Ac O]aqueous solution,thus realizing the drug purification.This phenomenon was mainly caused by the fact that when the mole fraction of water was extremely low,ibuprofen was preferentially solvated by[Bmim][Ac O]IL with the[Bmim][Ac O]clusters formed around ibuprofen due to their strong HB interactions.As the water content increased（>0.7）,the interactions between ibuprofen and solvents were weakened and the polarity of solvent increased.This leads to that[Bmim][Ac O]IL around ibuprofen turned to interact with water molecules through strong HB interaction,so that more and more ibuprofen formed aggregates through strong van der Waals interactions between themselves. |
