离子液体在药物研究中的应用
|
摘要
离子液体因其高度可调性而具备优良的物理化学性质和独特的生物活性,已不再局限于作为溶剂的传统应用。随着对其毒性与生物相容性的深入了解,由于阴阳离子组合的多样性与可设计性,离子液体已经能够弥补市售药物在溶解度、生物利用度和药物输送等方面的不足,在药物开发中潜力巨大。本文通过对离子液体在药物合成、输送作用,以及作为药物活性成分和剂型改良方面的研究与应用进行阐述,并对离子液体药物的未来发展作出展望。
Ionic liquids are not limited to the traditional use of solvents because of their high permeability and excellent physicochemical and unique biological properties. Nowadays, with the deep understanding of their toxicity and biocompatibility, ionic liquids have been tailored as novel solutions to address potential problems of marketed drugs. Based on the research and development of modified new drugs, ionic liquids have been incorporated into drug synthesis and emerged as attractive environmental-friendly reaction media with milder reaction conditions, higher yields and easier reaction workups and drug delivery systems. In addition, they have been designed for effective drug carriers removing undesirable properties of solid drugs. Further, ionic liquids forming active pharmaceutical ingredients dedicated to the liquefaction of drugs for promising clinical applications.
Ionic liquids are not limited to the traditional use of solvents because of their high permeability and excellent physicochemical and unique biological properties. Nowadays, with the deep understanding of their toxicity and biocompatibility, ionic liquids have been tailored as novel solutions to address potential problems of marketed drugs. Based on the research and development of modified new drugs, ionic liquids have been incorporated into drug synthesis and emerged as attractive environmental-friendly reaction media with milder reaction conditions, higher yields and easier reaction workups and drug delivery systems. In addition, they have been designed for effective drug carriers removing undesirable properties of solid drugs. Further, ionic liquids forming active pharmaceutical ingredients dedicated to the liquefaction of drugs for promising clinical applications.
引文
[1]China Food and Drug Administration:announcement on the publication of the work plan for the registration of chemical drugs[EB/OL].Beijing:China Food and Drug Administration,2016-03-04.http://www.sda.gov.cn/WS01/CL0087/146140.html.
[2]Smietana K,Siatkowski M,M?ller M.Trends in clinical success rates[J].Nat Rev Drug Discov,2016,15:379-380.
[3]Yang Y,Zhao J,Zheng AP,et al.Characteristics and future development of modified new drugs in China[J].J Int Pharm Res(国际药学研究杂志),2017,44:522-526.
[4]Stoimenovski J,MacFarlane DR,Bica K,et al.Crystalline vs ionic liquid salt forms of active pharmaceutical ingredients:a position paper[J].Pharm Res,2010,27:521-526.
[5]Shamshina JL,Kelley SP,Gurau G,et al.Chemistry:develop ionic liquid drugs[J].Nature,2015,528:188-189.
[6]Rodríguez H,Bica K,Rogers RD.Ionic liquid technology:a potential new platform for the pharmaceutical industry[J].Trop J Pharm Res,2008,7:1011-1012.
[7]Heinrich SP,Wermuth CG.Handbook of Pharmaceutical Salts;Properties,Selection,and Use[M].2nd ed.Weinheim:WileyVCH,2011:1-446.
[8]Shadid M,Gurau G,Shamshina JL,et al.Sulfasalazine in ionic liquid form with improved solubility and exposure[J].Med Chem Commun,2015,6:1837-1841.
[9]Szánti-Pintér E,Skoda-F?ldes R.Application of ionic liquids in synthetic procedures leading to pharmaceutically active organic compounds[J].Curr Green Chem,2018,5:4-21.
[10]Tian P,Kang YH,Song XM.Green Solvent:Phase Equilibrium and Microstructure of Ionic Liquids(绿色溶剂:离子液体的相平衡和微观结构)[M].Beijing:Science Press,2009:1-2.
[11]Hough WL,Smiglak M,Rodríguez H,et al.The third evolution of ionic liquids:active pharmaceutical ingredients[J].New JChem,2007,31:1429-1436.
[12]Das RN,Roy K.Advances in QSPR/QSTR models of ionic liquids for the design of greener solvents of the future[J].Mol Divers,2013,17:151-196.
[13]Malhotra SV.Ionic Liquid Applications:Pharmaceuticals,Thera‐peutics,and Biotechnology[M].Washington DC:American Chemical Society,2010:1-12.
[14]Smiglak M,Metlen A,Rogers RD.The second evolution of ionic liquids:from solvents and separations to advanced materials en‐ergetic examples from the ionic liquid cookbook[J].Acc Chem Res,2007,40:1182-1192.
[15]Song Z,Yu Q,Cai M,et al.Green ionic liquid lubricants prepared from anti-inflammatory drug[J].Tribol Lett,2015,60:38.
[16]Plechkova NV,Seddon KR.Applications of ionic liquids in the chemical industry[J].Chem Soc Rev,2008,37:123-150.
[17]Marrucho IM,Branco LC,Rebelo LP.Ionic liquids in pharma‐ceutical applications[J].Annu Rev Chem Biomol Eng,2014,5:527-546.
[18]Egorova KS,Gordeev EG,Ananikov VP.Biological activity of ionic liquids and their application in pharmaceutics and medicine[J].Chem Rev,2017,117:7132-7189.
[19]Claus J,Sommer FO,Kragl U.Ionic liquids in biotechnology and beyond[J].Solid State Ionics,2018,314:119-128.
[20]Hijo AAC,Maximo GJ,Costa MC,et al.Applications of ionic liquids in the food and bioproducts industries[J].ACSSustainable Chem Eng,2016,4:5347-5369.
[21]Shamshina JL,Berton P,Wang H,et al.Ionic liquids in pharma‐ceutical industry[M]//Zhang W,Cue BW.Green Techniques for Organic Synthesis and Medicinal Chemistry.2nd ed.Hoboken:John Wiley&Sons,2018:539-577.
[22]Larson A,O'Brien K,Anderson A.Pfizer pharmaceuticals:green chemistry innovation and business strategy[R].Economics Research Network,2017.
[23]Carr R,Ciccone F,Gabel R,et al.Streamlined process for the esterification and ketalization of shikimic acid en route to the key precursor for oseltamivir phosphate(TamifluTM)[J].Green Chem,2008,10:743-745.
[24]Montalbán MG,Víllora G,Licence P.Ecotoxicity assessment of dicationic versus monocationic ionic liquids as a more environ‐mentally friendly alternative[J].Ecotoxicol Environ Saf,2018,150:129-135.
[25]Vrane?M,Tot A,?anta J,et al.Toxicity reduction of imidazoliumbased ionic liquids by the oxygenation of the alkyl substituent[J].RSC Adv,2016,6:96289-96295.
[26]Chen XP,Lu JJ,Guo JJ,et al.Inspirations from natural products based drug research and development for Chinese medicine research-analysis of natural products recoded in TTD[J].Acta Pharm Sin(药学学报),2012,47:1423-1427.
[27]Cull SG,Holbrey JD,Mora VV,et al.Room-temperature ionic liquids as replacements for organic solvents in multiphase bioprocess operations[J].Biotechnol Bioeng,2000,69:227-233.
[28]Du FY,Xiao XH,Xu PP,et al.Ionic liquid-based microwaveassisted extraction and HPLC analysis of dehydrocavidine in corydalis saxicola bunting[J].Acta Chromatogr,2010,22:459-471.
[29]Freire MG,Neves CM,Marrucho IM,et al.High-performance extraction of alkaloids using aqueous two-phase systems with ionic liquids[J].Green Chem,2010,12:1715-1718.
[30]Bi W,Tian M,Row KH.Ultrasonication-assisted extraction and preconcentration of medicinal products from herb by ionic liquids[J].Talanta,2011,85:701-706.
[31]Grodowska K,Parczewski A.Organic solvents in the phar‐maceutical industry[J].Acta Pol Pharm,2010,67:3-12.
[32]Earle MJ,McCormac PB,Seddon KR.The first high yield green route to a pharmaceutical in a room temperature ionic liquid[J].Green Chem,2000,2:261-262.
[33]Mizuuchi H,Jaitely V,Murdan S,et al.Room temperature ionic liquids and their mixtures:potential pharmaceutical solvents[J].Eur J Pharm Sci,2008,33:326-331.
[34]Ventura SP,Silva FAE,Quental MV,et al.Ionic-liquid-mediated extraction and separation processes for bioactive compounds:past,present,and future trends[J].Chem Rev,2017,117:6984-7052.
[35]Albertsson PA.Partitioning of Cell Particles and Macromole‐cules[M].3rd ed.New York:Wiley,1986:273-274.
[36]Gutowski KE,Broker GA,Willauer HD,et al.Controlling the aqueous miscibility of ionic liquids:aqueous biphasic systems of water-miscible ionic liquids and water-structuring salts for recy‐cle,metathesis,and separations[J].J Am Chem Soc,2003,125:6632-6633.
[37]Han J,Wang Y,Chen C,et al.(Liquid+liquid)equilibria and extraction capacity of(imidazolium ionic liquids+potassium tartrate)aqueous two-phase systems[J].J Mol Liq,2014,193:23-28.
[38]Gómez E,Domínguez I,Dominguez.,et al.Ionic liquids-based aqueous biphasic systems with citrate biodegradable salts[J].JChem Eng Data,2018,63:1103-1108.
[39]Hines CC,Reichert M,Griffin S,et al.Crystallization of new and interesting crystal structures in ionic liquids:complex sys‐tems with complex results[C].Proceedings of the 210th ECSMeeting.Cancun,Mexico:ECS,2006.
[40]Koradia V,Chawla G,Bansal AK.Qualitative and quantitative analysis of clopidogrel bisulphate polymorphs[J].Acta Pharm,2004,54:193-204.
[41]Kim HJ,Kim K.Quantitative study on polymorphic form in solution crystallization of clopidogrel hydrogen sulfate[J].Ind Eng Chem Res,2009,48:11133-11139.
[42]An JH,Jin F,Kim HS,et al.Investigation of the polymorphic transformation of the active pharmaceutical ingredient clopi‐dogrel bisulfate using the ionic liquid AEImBF4[J].Cryst Growth Des,2016,16:1829-1836.
[43]Weber CC,Kulkarni SA,Kunovkruse AJ,et al.The use of cooling crystallization in an ionic liquid system for the purifica‐tion of pharmaceuticals[J].Cryst Growth Des,2015,15:4946-4951.
[44]Zhang D,Wang CX,Li L,et al.Application and development of ionic liquids as pharmaceutical ingredients[J].Chin J Hops Pharm(中国医院药学杂志),2014,34:1399-1403.
[45]Hao TY,Wei YF,Qian S,et al.Advances in strategies of improving solubility and permeability of taxanes[J].Acta Pharm Sin(药学学报),2018,53:54-61.
[46]Khmelnitsky YL,Budde C,Arnold JM,et al.Synthesis of watersoluble paclitaxel derivatives by enzymatic acylation[J].J Am Chem Soc,1997,119:11554-11555.
[47]Kim S,Hwang JY,Seo JW,et al.Production of CNT-Taxolembedded PCL microspheres using an ammonium-based room temperature ionic liquid:as a sustained drug delivery system[J].J Colloid Interface Sci,2015,442:147-153.
[48]Chowdhury MR,Moshikur RM,Wakabayashi R,et al.Ionicliquid-based paclitaxel preparation:a new potential formulation for cancer treatment[J].Mol Pharm,2018,15:2484-2488.
[49]Kandasamy S,Moniruzzaman M,Sivapragasam M,et al.Formu‐lation and characterization of acetate based ionic liquid in oil microemulsion as a carrier for acyclovir and methotrexate[J].Sep Purif Technol,2018,196:149-156.
[50]McCrary PD,Beasley PA,Gurau G,et al.Drug specific,tuning of an ionic liquid's hydrophilic-lipophilic balance to improve water solubility of poorly soluble active pharmaceutical ingre‐dients[J].New J Chem,2013,37:2196-2202.
[51]Lim GS,Jaenicke S,Kl?hn M.How the spontaneous insertion of amphiphilic imidazolium-based cations changes biological mem‐branes:a molecular simulation study[J].Phys Chem Chem Phys,2015,17:29171-29183.
[52]Banerjee A,Ibsen K,Brown T,et al.Ionic liquids for oral insulin delivery[J].Proc Natl Acad Sci USA,2018,115:7296-7301.
[53]Weissig V,Pettinger TK,Murdock N.Nanopharmaceuticals(part1):products on the market[J].Int J Nanomedicine,2014,9:4357-4373.
[54]Li Q,Mahendra S,Lyon DY,et al.Antimicrobial nanomaterials for water disinfection and microbial control:potential applica‐tions and implications[J].Water Res,2008,42:4591-4602.
[55]Chang HC,Chang TC,Chang SC,et al.Interactions of silica nanoparticles and ionic liquids probed by high pressure vibra‐tional spectroscopy[J].J Phys Chem C,2011,115:11962-11967.
[56]Aditya A,Chattopadhyay S,Jha D,et al.Zinc oxide nanoparti‐cles dispersed in ionic liquids show high antimicrobial efficacy to skin-specific bacteria[J].ACS Appl Mater Interfaces,2018,10:15401-15411.
[57]?epin M,Jovanovski V,Podlogar M,et al.Amino-and ionic liquid-functionalised nanocrystalline ZnO via silane anchoringan antimicrobial synergy[J].J Mater Chem B,2015,3:1059-1067.
[58]Zakrewsky M,Lovejoy KS,Kern TL,et al.Ionic liquids as a class of materials for transdermal delivery and pathogen neutral‐ization[J].Proc Natl Acad Sci USA,2014,111:13313-13318.
[59]Healy AM,Worku ZA,Kumar D,et al.Pharmaceutical solvates,hydrates and amorphous forms:a special emphasis on cocrystals[J].Adv Drug Deliv Rev,2017,117:25-46.
[60]Tandon R,Tandon N,Thapar RK.Patenting of polymorphs[J].Pharm Pat Anal,2018,7:59-63.
[61]Shamshina JL,Barber PS,Rogers RD.Ionic liquids in drug delivery[J].Expert Opin Drug Deliv,2013,10:1367-1381.
[62]Chemburkar SR,Bauer J,Deming K,et al.Dealing with the impact of ritonavir polymorphs on the late stages of bulk drug process development[J].Org Proc Res Dev,2000,4:413-417.
[63]Bauer J,Spanton S,Henry R,et al.Ritonavir:an extraordinary example of conformational polymorphism[J].Pharm Res,2001,18:859-866.
[64]Hancock BC,Dalton CR.The effect of temperature on water vapor sorption by some amorphous pharmaceutical sugars[J].Pharm Dev Technol,1999,4:125-131.
[65]He Y,Ho C.Amorphous solid dispersions:utilization and challenges in drug discovery and development[J].J Pharm Sci,2015,104:3237-3258.
[66]Shamshina JL,Cojocaru OA,Kelley SP,et al.Acyclovir as an ionic liquid cation or anion can improve aqueous solubility[J].ACS Omega,2017,2:3483-3493.
[67]Bica K,Shamshina J,Hough WL,et al.Liquid forms of pharma‐ceutical co-crystals:exploring the boundaries of salt formation[J].Chem Commun,2011,47:2267-2269.
[68]Egorova KS,Seitkalieva MM,Posvyatenko AV,et al.Cytotoxic activity of salicylic acid-containing drug models with ionic and covalent binding[J].ACS Med Chem Lett,2015,6:1099-1104.
[69]Zakrewsky M,Mitragotri S.Therapeutic RNAi robed with ionic liquid moieties as a simple,scalable prodrug platform for treat‐ing skin disease[J].J Control Release,2016,242:80-88.
[70]Rogers RD.Nucleoside analog salts with improved solubility and methods of forming same:US,2014145464[P].2014-09-18.
[71]Dean PM,Turanjanin J,Fujita MY,et al.Exploring an anticrystal engineering approach to the preparation of pharmaceuti‐cally active ionic liquids[J].Cryst Growth Des,2009,9:1137-1145.
[72]Hough-Troutman WL,Smiglak M,Griffin S,et al.Ionic liquids with dual biological function:sweet and anti-microbial,hydro‐phobic quaternary ammonium-based salts[J].New J Chem,2009,33:26-33.
[73]Gao Y,Zu H,Zhang JJ.Pharmaceutical cocrystals[J].Prog Chem(化学进展),2010,22:829-836.
[74]Bevill MJ,Vlahova PI,Smit JP.Polymorphic cocrystals of nutraceutical compound p-coumaric acid with nicotinamide:characterization,relative solid-state stability,and conversion to alternate stoichiometries[J].Cryst Growth Des,2014,14:1438-1448.
[75]Schultheiss N,Bethune S,Henck JO.Nutraceutical cocrystals:utilizing pterostilbene as a cocrystal former[J].CrystEngComm,2010,12:2436-2442.
[76]Banerjee A,Ibsen K,Iwao Y,et al.Transdermal protein delivery using choline and geranate(CAGE)deep eutectic solvent[J].Adv Healthc Mater,2017,6:1601411.
[77]Zakrewsky M,Banerjee A,Apte S,et al.Choline and geranate deep eutectic solvent as a broad-spectrum antiseptic agent for preventive and therapeutic applications[J].Adv Healthcare Mater,2016,5:1282-1289.
[78]Tanner EE,Ibsen KN,Mitragotri S.Transdermal insulin delivery using choline-based ionic liquids(CAGE)[J].J Control Release,2018,286:137-144.
[79]Abbott AP,Capper G,Davies DL,et al.Ionic liquids based up‐on metal halide/substituted quaternary ammonium salt mixtures[J].Inorg Chem,2004,43:3447-3452.
[80]Shekaari H,Moattar MT,Shayanfar A,et al.Effect of choline chloride/ethylene glycol or glycerol as deep eutectic solvents on the solubility and thermodynamic properties of acetaminophen[J].J Mol Liq,2018,249:1222-1235.
[81]Jiang JF,Li XL,Chen XY,et al.Role of human liver and intestine esterases in drug design and development[J].Acta Pharm Sin(药学学报),2018,53:177-185.
[82]Cojocaru O,Bica K,Gurau G,et al.Prodrug ionic liquids:functionalizing neutral active pharmaceutical ingredients to take advantage of the ionic liquid form[J].MedChemComm,2013,4:559-563.
[83]Smith DJ,Shah JK,Maginn EJ.Molecular dynamics simulation study of the association of lidocainium docusate and its deriva‐tives in aqueous solution[J].Mol Pharm,2015,12:1893-1901.
[84]Pernak J,Branicka M.The properties of 1-alkoxymethyl-3-hydroxypyridinium and 1-alkoxymethyl-3-dimethylaminopyri‐dinium chlorides[J].J Surfact Deterg,2003,6:119-123.
[85]Ferraz R,Teixeira V,Rodrigues D,et al.Antibacterial activity of ionic liquids based on ampicillin against resistant bacteria[J].RSC Adv,2014,4:4301-4307.
[86]Trapp S,Franco A,Mackay D.Activity-based concept for trans‐port and partitioning of ionizing organics[J].Environ Sci Tech‐nol,2010,44:6123-6129.
[87]Scheit K,Bauer G.Direct and indirect inactivation of tumor cell protective catalase by salicylic acid and anthocyanidins reacti‐vates intercellular ROS signaling and allows for synergistic ef‐fects[J].Carcinogenesis,2015,36:400-411.
[88]Cojocaru OA,Bica K,Gurau G,et al.Prodrug ionic liquids combining the prodrug and ionic liquid strategies to active pharmaceutical ingredients[J].Chim Oggi,2013,31:24-29.
[89]Hussan KPS,Thayyil MS,Deshpande SK,et al.Synthesis and molecular dynamics of double active pharmaceutical ingredientbenzalkonium ibuprofenate[J].J Mol Liq,2016,223:1333-1339.
[90]Hussan KPS,Thayyil MS,Rajan VK,et al.Experimental and density functional theory studies on benzalkonium ibuprofenate,a double active pharmaceutical ingredient[J].Comput Biol Chem,2018,72:113-121.
[91]Hawley SA,Fullerton MD,Ross FA,et al.The ancient drug salicylate directly activates AMP-activated protein kinase[J].Science,2012,336:918-922.
[92]Moshikur RM,Chowdhury MR,Wakabayashi R,et al.Charac‐terization and cytotoxicity evaluation of biocompatible amino acid esters used to convert salicylic acid into ionic liquids[J].Int J Pharm,2018,546:31-38.
[93]Hamamoto H,Miwa Y.Tape preparation comprising etodolac in ionic liquid form:US,2233138[P].2014-7-23.
[94]Ziggiotti A,Schiena MD.Salt of diclofenac with a pyrrolidine compound and pharmaceutical compositions which contain it:US,4948805[P].1990-8-14.
[95]Miwa Y,Hamamoto H,Hikake S,et al.A phase I,randomized,open-label,cross-over study of the pharmacokinetics,dermal tolerability,and safety of MRX-7EAT etodolac-lidocaine topical patch in healthy volunteers[J].J Pain,2013,14:S72.
[96]Kuwabara Y,Hamamoto H,Hikake S,et al.A randomized,multicenter,double-blind,placebo-controlled phase II/III trial to eval‐uate the efficacy,tolerability and safety of MRX-7EAT etodolaclidocaine topical patch in the treatment of pain[J].J Pain,2013,14:S73.
[97]Okamura Y.Although the clinical trials of ETOREAT ended with failure,several promising pipelines for the U.S.are moving ahead[R].Magical Pocket Corp,2016.
[98]Li XL,Jin YP.Irreversible profound symptomatic bradycardia requiring pacemaker after tizanidine/loxoprofen combination therapy:a case report[J].J Int Med Res,2018,46:2466-2469.
[99]Xu JZ,Yi LG,Mou YX,et al.Effect of a molecule of imidaz‐olium bromide ionic liquid on the structure and properties of cytosine by density functional theory[J].Chem Phys Lett,2018,708:109-116.
[100]Xu JZ,Mou YX,Cao JP,et al.A density functional theory study on effects of imidazolium bromide ionic liquids on the structure and properties of cytosine[J].Acta Sci Circumst(环境科学学报),2018,38:4113-4123.
[2]Smietana K,Siatkowski M,M?ller M.Trends in clinical success rates[J].Nat Rev Drug Discov,2016,15:379-380.
[3]Yang Y,Zhao J,Zheng AP,et al.Characteristics and future development of modified new drugs in China[J].J Int Pharm Res(国际药学研究杂志),2017,44:522-526.
[4]Stoimenovski J,MacFarlane DR,Bica K,et al.Crystalline vs ionic liquid salt forms of active pharmaceutical ingredients:a position paper[J].Pharm Res,2010,27:521-526.
[5]Shamshina JL,Kelley SP,Gurau G,et al.Chemistry:develop ionic liquid drugs[J].Nature,2015,528:188-189.
[6]Rodríguez H,Bica K,Rogers RD.Ionic liquid technology:a potential new platform for the pharmaceutical industry[J].Trop J Pharm Res,2008,7:1011-1012.
[7]Heinrich SP,Wermuth CG.Handbook of Pharmaceutical Salts;Properties,Selection,and Use[M].2nd ed.Weinheim:WileyVCH,2011:1-446.
[8]Shadid M,Gurau G,Shamshina JL,et al.Sulfasalazine in ionic liquid form with improved solubility and exposure[J].Med Chem Commun,2015,6:1837-1841.
[9]Szánti-Pintér E,Skoda-F?ldes R.Application of ionic liquids in synthetic procedures leading to pharmaceutically active organic compounds[J].Curr Green Chem,2018,5:4-21.
[10]Tian P,Kang YH,Song XM.Green Solvent:Phase Equilibrium and Microstructure of Ionic Liquids(绿色溶剂:离子液体的相平衡和微观结构)[M].Beijing:Science Press,2009:1-2.
[11]Hough WL,Smiglak M,Rodríguez H,et al.The third evolution of ionic liquids:active pharmaceutical ingredients[J].New JChem,2007,31:1429-1436.
[12]Das RN,Roy K.Advances in QSPR/QSTR models of ionic liquids for the design of greener solvents of the future[J].Mol Divers,2013,17:151-196.
[13]Malhotra SV.Ionic Liquid Applications:Pharmaceuticals,Thera‐peutics,and Biotechnology[M].Washington DC:American Chemical Society,2010:1-12.
[14]Smiglak M,Metlen A,Rogers RD.The second evolution of ionic liquids:from solvents and separations to advanced materials en‐ergetic examples from the ionic liquid cookbook[J].Acc Chem Res,2007,40:1182-1192.
[15]Song Z,Yu Q,Cai M,et al.Green ionic liquid lubricants prepared from anti-inflammatory drug[J].Tribol Lett,2015,60:38.
[16]Plechkova NV,Seddon KR.Applications of ionic liquids in the chemical industry[J].Chem Soc Rev,2008,37:123-150.
[17]Marrucho IM,Branco LC,Rebelo LP.Ionic liquids in pharma‐ceutical applications[J].Annu Rev Chem Biomol Eng,2014,5:527-546.
[18]Egorova KS,Gordeev EG,Ananikov VP.Biological activity of ionic liquids and their application in pharmaceutics and medicine[J].Chem Rev,2017,117:7132-7189.
[19]Claus J,Sommer FO,Kragl U.Ionic liquids in biotechnology and beyond[J].Solid State Ionics,2018,314:119-128.
[20]Hijo AAC,Maximo GJ,Costa MC,et al.Applications of ionic liquids in the food and bioproducts industries[J].ACSSustainable Chem Eng,2016,4:5347-5369.
[21]Shamshina JL,Berton P,Wang H,et al.Ionic liquids in pharma‐ceutical industry[M]//Zhang W,Cue BW.Green Techniques for Organic Synthesis and Medicinal Chemistry.2nd ed.Hoboken:John Wiley&Sons,2018:539-577.
[22]Larson A,O'Brien K,Anderson A.Pfizer pharmaceuticals:green chemistry innovation and business strategy[R].Economics Research Network,2017.
[23]Carr R,Ciccone F,Gabel R,et al.Streamlined process for the esterification and ketalization of shikimic acid en route to the key precursor for oseltamivir phosphate(TamifluTM)[J].Green Chem,2008,10:743-745.
[24]Montalbán MG,Víllora G,Licence P.Ecotoxicity assessment of dicationic versus monocationic ionic liquids as a more environ‐mentally friendly alternative[J].Ecotoxicol Environ Saf,2018,150:129-135.
[25]Vrane?M,Tot A,?anta J,et al.Toxicity reduction of imidazoliumbased ionic liquids by the oxygenation of the alkyl substituent[J].RSC Adv,2016,6:96289-96295.
[26]Chen XP,Lu JJ,Guo JJ,et al.Inspirations from natural products based drug research and development for Chinese medicine research-analysis of natural products recoded in TTD[J].Acta Pharm Sin(药学学报),2012,47:1423-1427.
[27]Cull SG,Holbrey JD,Mora VV,et al.Room-temperature ionic liquids as replacements for organic solvents in multiphase bioprocess operations[J].Biotechnol Bioeng,2000,69:227-233.
[28]Du FY,Xiao XH,Xu PP,et al.Ionic liquid-based microwaveassisted extraction and HPLC analysis of dehydrocavidine in corydalis saxicola bunting[J].Acta Chromatogr,2010,22:459-471.
[29]Freire MG,Neves CM,Marrucho IM,et al.High-performance extraction of alkaloids using aqueous two-phase systems with ionic liquids[J].Green Chem,2010,12:1715-1718.
[30]Bi W,Tian M,Row KH.Ultrasonication-assisted extraction and preconcentration of medicinal products from herb by ionic liquids[J].Talanta,2011,85:701-706.
[31]Grodowska K,Parczewski A.Organic solvents in the phar‐maceutical industry[J].Acta Pol Pharm,2010,67:3-12.
[32]Earle MJ,McCormac PB,Seddon KR.The first high yield green route to a pharmaceutical in a room temperature ionic liquid[J].Green Chem,2000,2:261-262.
[33]Mizuuchi H,Jaitely V,Murdan S,et al.Room temperature ionic liquids and their mixtures:potential pharmaceutical solvents[J].Eur J Pharm Sci,2008,33:326-331.
[34]Ventura SP,Silva FAE,Quental MV,et al.Ionic-liquid-mediated extraction and separation processes for bioactive compounds:past,present,and future trends[J].Chem Rev,2017,117:6984-7052.
[35]Albertsson PA.Partitioning of Cell Particles and Macromole‐cules[M].3rd ed.New York:Wiley,1986:273-274.
[36]Gutowski KE,Broker GA,Willauer HD,et al.Controlling the aqueous miscibility of ionic liquids:aqueous biphasic systems of water-miscible ionic liquids and water-structuring salts for recy‐cle,metathesis,and separations[J].J Am Chem Soc,2003,125:6632-6633.
[37]Han J,Wang Y,Chen C,et al.(Liquid+liquid)equilibria and extraction capacity of(imidazolium ionic liquids+potassium tartrate)aqueous two-phase systems[J].J Mol Liq,2014,193:23-28.
[38]Gómez E,Domínguez I,Dominguez.,et al.Ionic liquids-based aqueous biphasic systems with citrate biodegradable salts[J].JChem Eng Data,2018,63:1103-1108.
[39]Hines CC,Reichert M,Griffin S,et al.Crystallization of new and interesting crystal structures in ionic liquids:complex sys‐tems with complex results[C].Proceedings of the 210th ECSMeeting.Cancun,Mexico:ECS,2006.
[40]Koradia V,Chawla G,Bansal AK.Qualitative and quantitative analysis of clopidogrel bisulphate polymorphs[J].Acta Pharm,2004,54:193-204.
[41]Kim HJ,Kim K.Quantitative study on polymorphic form in solution crystallization of clopidogrel hydrogen sulfate[J].Ind Eng Chem Res,2009,48:11133-11139.
[42]An JH,Jin F,Kim HS,et al.Investigation of the polymorphic transformation of the active pharmaceutical ingredient clopi‐dogrel bisulfate using the ionic liquid AEImBF4[J].Cryst Growth Des,2016,16:1829-1836.
[43]Weber CC,Kulkarni SA,Kunovkruse AJ,et al.The use of cooling crystallization in an ionic liquid system for the purifica‐tion of pharmaceuticals[J].Cryst Growth Des,2015,15:4946-4951.
[44]Zhang D,Wang CX,Li L,et al.Application and development of ionic liquids as pharmaceutical ingredients[J].Chin J Hops Pharm(中国医院药学杂志),2014,34:1399-1403.
[45]Hao TY,Wei YF,Qian S,et al.Advances in strategies of improving solubility and permeability of taxanes[J].Acta Pharm Sin(药学学报),2018,53:54-61.
[46]Khmelnitsky YL,Budde C,Arnold JM,et al.Synthesis of watersoluble paclitaxel derivatives by enzymatic acylation[J].J Am Chem Soc,1997,119:11554-11555.
[47]Kim S,Hwang JY,Seo JW,et al.Production of CNT-Taxolembedded PCL microspheres using an ammonium-based room temperature ionic liquid:as a sustained drug delivery system[J].J Colloid Interface Sci,2015,442:147-153.
[48]Chowdhury MR,Moshikur RM,Wakabayashi R,et al.Ionicliquid-based paclitaxel preparation:a new potential formulation for cancer treatment[J].Mol Pharm,2018,15:2484-2488.
[49]Kandasamy S,Moniruzzaman M,Sivapragasam M,et al.Formu‐lation and characterization of acetate based ionic liquid in oil microemulsion as a carrier for acyclovir and methotrexate[J].Sep Purif Technol,2018,196:149-156.
[50]McCrary PD,Beasley PA,Gurau G,et al.Drug specific,tuning of an ionic liquid's hydrophilic-lipophilic balance to improve water solubility of poorly soluble active pharmaceutical ingre‐dients[J].New J Chem,2013,37:2196-2202.
[51]Lim GS,Jaenicke S,Kl?hn M.How the spontaneous insertion of amphiphilic imidazolium-based cations changes biological mem‐branes:a molecular simulation study[J].Phys Chem Chem Phys,2015,17:29171-29183.
[52]Banerjee A,Ibsen K,Brown T,et al.Ionic liquids for oral insulin delivery[J].Proc Natl Acad Sci USA,2018,115:7296-7301.
[53]Weissig V,Pettinger TK,Murdock N.Nanopharmaceuticals(part1):products on the market[J].Int J Nanomedicine,2014,9:4357-4373.
[54]Li Q,Mahendra S,Lyon DY,et al.Antimicrobial nanomaterials for water disinfection and microbial control:potential applica‐tions and implications[J].Water Res,2008,42:4591-4602.
[55]Chang HC,Chang TC,Chang SC,et al.Interactions of silica nanoparticles and ionic liquids probed by high pressure vibra‐tional spectroscopy[J].J Phys Chem C,2011,115:11962-11967.
[56]Aditya A,Chattopadhyay S,Jha D,et al.Zinc oxide nanoparti‐cles dispersed in ionic liquids show high antimicrobial efficacy to skin-specific bacteria[J].ACS Appl Mater Interfaces,2018,10:15401-15411.
[57]?epin M,Jovanovski V,Podlogar M,et al.Amino-and ionic liquid-functionalised nanocrystalline ZnO via silane anchoringan antimicrobial synergy[J].J Mater Chem B,2015,3:1059-1067.
[58]Zakrewsky M,Lovejoy KS,Kern TL,et al.Ionic liquids as a class of materials for transdermal delivery and pathogen neutral‐ization[J].Proc Natl Acad Sci USA,2014,111:13313-13318.
[59]Healy AM,Worku ZA,Kumar D,et al.Pharmaceutical solvates,hydrates and amorphous forms:a special emphasis on cocrystals[J].Adv Drug Deliv Rev,2017,117:25-46.
[60]Tandon R,Tandon N,Thapar RK.Patenting of polymorphs[J].Pharm Pat Anal,2018,7:59-63.
[61]Shamshina JL,Barber PS,Rogers RD.Ionic liquids in drug delivery[J].Expert Opin Drug Deliv,2013,10:1367-1381.
[62]Chemburkar SR,Bauer J,Deming K,et al.Dealing with the impact of ritonavir polymorphs on the late stages of bulk drug process development[J].Org Proc Res Dev,2000,4:413-417.
[63]Bauer J,Spanton S,Henry R,et al.Ritonavir:an extraordinary example of conformational polymorphism[J].Pharm Res,2001,18:859-866.
[64]Hancock BC,Dalton CR.The effect of temperature on water vapor sorption by some amorphous pharmaceutical sugars[J].Pharm Dev Technol,1999,4:125-131.
[65]He Y,Ho C.Amorphous solid dispersions:utilization and challenges in drug discovery and development[J].J Pharm Sci,2015,104:3237-3258.
[66]Shamshina JL,Cojocaru OA,Kelley SP,et al.Acyclovir as an ionic liquid cation or anion can improve aqueous solubility[J].ACS Omega,2017,2:3483-3493.
[67]Bica K,Shamshina J,Hough WL,et al.Liquid forms of pharma‐ceutical co-crystals:exploring the boundaries of salt formation[J].Chem Commun,2011,47:2267-2269.
[68]Egorova KS,Seitkalieva MM,Posvyatenko AV,et al.Cytotoxic activity of salicylic acid-containing drug models with ionic and covalent binding[J].ACS Med Chem Lett,2015,6:1099-1104.
[69]Zakrewsky M,Mitragotri S.Therapeutic RNAi robed with ionic liquid moieties as a simple,scalable prodrug platform for treat‐ing skin disease[J].J Control Release,2016,242:80-88.
[70]Rogers RD.Nucleoside analog salts with improved solubility and methods of forming same:US,2014145464[P].2014-09-18.
[71]Dean PM,Turanjanin J,Fujita MY,et al.Exploring an anticrystal engineering approach to the preparation of pharmaceuti‐cally active ionic liquids[J].Cryst Growth Des,2009,9:1137-1145.
[72]Hough-Troutman WL,Smiglak M,Griffin S,et al.Ionic liquids with dual biological function:sweet and anti-microbial,hydro‐phobic quaternary ammonium-based salts[J].New J Chem,2009,33:26-33.
[73]Gao Y,Zu H,Zhang JJ.Pharmaceutical cocrystals[J].Prog Chem(化学进展),2010,22:829-836.
[74]Bevill MJ,Vlahova PI,Smit JP.Polymorphic cocrystals of nutraceutical compound p-coumaric acid with nicotinamide:characterization,relative solid-state stability,and conversion to alternate stoichiometries[J].Cryst Growth Des,2014,14:1438-1448.
[75]Schultheiss N,Bethune S,Henck JO.Nutraceutical cocrystals:utilizing pterostilbene as a cocrystal former[J].CrystEngComm,2010,12:2436-2442.
[76]Banerjee A,Ibsen K,Iwao Y,et al.Transdermal protein delivery using choline and geranate(CAGE)deep eutectic solvent[J].Adv Healthc Mater,2017,6:1601411.
[77]Zakrewsky M,Banerjee A,Apte S,et al.Choline and geranate deep eutectic solvent as a broad-spectrum antiseptic agent for preventive and therapeutic applications[J].Adv Healthcare Mater,2016,5:1282-1289.
[78]Tanner EE,Ibsen KN,Mitragotri S.Transdermal insulin delivery using choline-based ionic liquids(CAGE)[J].J Control Release,2018,286:137-144.
[79]Abbott AP,Capper G,Davies DL,et al.Ionic liquids based up‐on metal halide/substituted quaternary ammonium salt mixtures[J].Inorg Chem,2004,43:3447-3452.
[80]Shekaari H,Moattar MT,Shayanfar A,et al.Effect of choline chloride/ethylene glycol or glycerol as deep eutectic solvents on the solubility and thermodynamic properties of acetaminophen[J].J Mol Liq,2018,249:1222-1235.
[81]Jiang JF,Li XL,Chen XY,et al.Role of human liver and intestine esterases in drug design and development[J].Acta Pharm Sin(药学学报),2018,53:177-185.
[82]Cojocaru O,Bica K,Gurau G,et al.Prodrug ionic liquids:functionalizing neutral active pharmaceutical ingredients to take advantage of the ionic liquid form[J].MedChemComm,2013,4:559-563.
[83]Smith DJ,Shah JK,Maginn EJ.Molecular dynamics simulation study of the association of lidocainium docusate and its deriva‐tives in aqueous solution[J].Mol Pharm,2015,12:1893-1901.
[84]Pernak J,Branicka M.The properties of 1-alkoxymethyl-3-hydroxypyridinium and 1-alkoxymethyl-3-dimethylaminopyri‐dinium chlorides[J].J Surfact Deterg,2003,6:119-123.
[85]Ferraz R,Teixeira V,Rodrigues D,et al.Antibacterial activity of ionic liquids based on ampicillin against resistant bacteria[J].RSC Adv,2014,4:4301-4307.
[86]Trapp S,Franco A,Mackay D.Activity-based concept for trans‐port and partitioning of ionizing organics[J].Environ Sci Tech‐nol,2010,44:6123-6129.
[87]Scheit K,Bauer G.Direct and indirect inactivation of tumor cell protective catalase by salicylic acid and anthocyanidins reacti‐vates intercellular ROS signaling and allows for synergistic ef‐fects[J].Carcinogenesis,2015,36:400-411.
[88]Cojocaru OA,Bica K,Gurau G,et al.Prodrug ionic liquids combining the prodrug and ionic liquid strategies to active pharmaceutical ingredients[J].Chim Oggi,2013,31:24-29.
[89]Hussan KPS,Thayyil MS,Deshpande SK,et al.Synthesis and molecular dynamics of double active pharmaceutical ingredientbenzalkonium ibuprofenate[J].J Mol Liq,2016,223:1333-1339.
[90]Hussan KPS,Thayyil MS,Rajan VK,et al.Experimental and density functional theory studies on benzalkonium ibuprofenate,a double active pharmaceutical ingredient[J].Comput Biol Chem,2018,72:113-121.
[91]Hawley SA,Fullerton MD,Ross FA,et al.The ancient drug salicylate directly activates AMP-activated protein kinase[J].Science,2012,336:918-922.
[92]Moshikur RM,Chowdhury MR,Wakabayashi R,et al.Charac‐terization and cytotoxicity evaluation of biocompatible amino acid esters used to convert salicylic acid into ionic liquids[J].Int J Pharm,2018,546:31-38.
[93]Hamamoto H,Miwa Y.Tape preparation comprising etodolac in ionic liquid form:US,2233138[P].2014-7-23.
[94]Ziggiotti A,Schiena MD.Salt of diclofenac with a pyrrolidine compound and pharmaceutical compositions which contain it:US,4948805[P].1990-8-14.
[95]Miwa Y,Hamamoto H,Hikake S,et al.A phase I,randomized,open-label,cross-over study of the pharmacokinetics,dermal tolerability,and safety of MRX-7EAT etodolac-lidocaine topical patch in healthy volunteers[J].J Pain,2013,14:S72.
[96]Kuwabara Y,Hamamoto H,Hikake S,et al.A randomized,multicenter,double-blind,placebo-controlled phase II/III trial to eval‐uate the efficacy,tolerability and safety of MRX-7EAT etodolaclidocaine topical patch in the treatment of pain[J].J Pain,2013,14:S73.
[97]Okamura Y.Although the clinical trials of ETOREAT ended with failure,several promising pipelines for the U.S.are moving ahead[R].Magical Pocket Corp,2016.
[98]Li XL,Jin YP.Irreversible profound symptomatic bradycardia requiring pacemaker after tizanidine/loxoprofen combination therapy:a case report[J].J Int Med Res,2018,46:2466-2469.
[99]Xu JZ,Yi LG,Mou YX,et al.Effect of a molecule of imidaz‐olium bromide ionic liquid on the structure and properties of cytosine by density functional theory[J].Chem Phys Lett,2018,708:109-116.
[100]Xu JZ,Mou YX,Cao JP,et al.A density functional theory study on effects of imidazolium bromide ionic liquids on the structure and properties of cytosine[J].Acta Sci Circumst(环境科学学报),2018,38:4113-4123.