• 中国精品科技期刊
  • 中国高校百佳科技期刊
  • 中国中文核心期刊
  • 中国科学引文数据库核心期刊
Advanced Search
RUAN Xiaoling, ZHENG Xiangyuan, XU Jie, DING Li, ZHENG Feng. Advances in analytical techniques for the determination of genotoxic impurities in pharmaceuticals[J]. Journal of China Pharmaceutical University, 2016, 47(3): 267-274. DOI: 10.11665/j.issn.1000-5048.20160303
Citation: RUAN Xiaoling, ZHENG Xiangyuan, XU Jie, DING Li, ZHENG Feng. Advances in analytical techniques for the determination of genotoxic impurities in pharmaceuticals[J]. Journal of China Pharmaceutical University, 2016, 47(3): 267-274. DOI: 10.11665/j.issn.1000-5048.20160303

Advances in analytical techniques for the determination of genotoxic impurities in pharmaceuticals

More Information
  • Genotoxic or potentially genotoxic impurities seriously threaten people′s health, therefore, it is necessary to identify and quantify these impurities in pharmaceutical materials even at trace levels. Due to the special requirements on the sensitivity, selectivity, analyte stability and matrix effect, development of analytical methods is a challenge for the determination of genotoxic impurities. This paper reviews the recent advances in analytical methods for trace levels of commonly encountered genotoxic or potentially genotoxic impurities, including alkyl halides, alkyl sulfonates, hydrazines, epoxides and acyl halides, which would be helpful to control these impurities.
  • [1]
    Bouder F.Regulating impurities in pharmaceutical products:a tolerability of risk approach[J].Expert Rev Clin Pharmacol,2008,1(2):241-250.
    [2]
    Mueller L,Mauthe RJ,Riley CM,et al.A rationale for determining,testing,and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity[J].Regul Toxicol Pharmacol,2006,44(3):198-211.
    [3]
    Committee for Medicinal Products for Human Use(CHMP).Guidelines on the limits of genotoxic impurities(CPMP/SWP/5199/02)[S].London:European Medicines Agency Evaluation of Medicines for Human Use(EMEA),2006.
    [4]
    U.S.Food and Drug Administration,Department of Health and Human Services,Center for Drug Evaluation and Research(CDER).Guidance for industry:genotoxic and carcinogenic impurities in drug substances and products:recommended approaches(draft)[S].Silver Spring:U.S.Food and Drug Administration,2008.
    [5]
    Benigni R,Bossa C,Tcheremenskaia O,et al.Development of structural alerts for the in vivo micronucleus assay in rodents,EUR 23844 EN[R].Luxenbourg:Office for the Official Publications of the European Communities,2009.
    [6]
    Benigni R,Bossa C.Mechanisms of chemical carcinogenicity and mutagenicity:a review with implications for predictive toxicology[J].Chem Rev,2011,111(4):2507-2536.
    [7]
    Skett PW,Smith RJ,Webb ML.Low level measurement of potent toxins[M]//Smith RJ,Webb ML.Analysis of Drug Impurities.Oxford:Blackwell Publishing,2007:82-123.
    [8]
    Wang Y.Determination of organic volatile impurities in azasetron hydrochloride[J].Chin J Pharm Anal(药物分析杂志),2004,24(3):293-295.
    [9]
    Liu DQ,Sun M,Kord AS.Recent advances in trace analysis of pharmaceutical genotoxic impurities[J].J Pharm Biomed Anal,2010,51(5):999-1014.
    [10]
    Frost RP,Hussain MS,Raghani AR.Determination of pharmaceutical process impurities by solid phase microextraction gas chromatography[J].J Sep Sci,2003,26(12/13):1097-1103.
    [11]
    Ho TD,Yehl PM,Chetwyn NP,et al.Determination of trace level genotoxic impurities in small molecule drug substances using conventional headspace gas chromatography with contemporary ionic liquid diluents and electron capture detection[J].J Chromatogr A,2014,1361:217-228.
    [12]
    Lee KC,Cheuk MW,Chan W,et al.Determination of glucosinolates in traditional Chinese herbs by high-performance liquid chromatography and electrospray ionization mass spectrometry[J].Anal Bioanal Chem,2007,386(7/8):2225-2232.
    [13]
    Venugopal N,Reddy AVB,Madhavi G,et al.Trace level quantification of 1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine HCl genotoxic impurity in trazodone using LC-MS/MS[J].Arab J Chem,2014,575:1-8.
    [14]
    Cappiello A,Famiglini G,Palma P,et al.A new liquid chromatography-mass spectrometry approach for generic screening and quantitation of potential genotoxic alkylation compounds without derivatization[J].J Pharm Biomed Anal,2012,1255(17):286-290.
    [15]
    van Wijk AM,Niederländer HA,Siebum AH,et al.A new derivatization reagent for LC-MS/MS screening of potential genotoxic alkylation compounds[J].J Pharm Biomed Anal,2013,74(4):133-140.
    [16]
    van Wijk AM,Niederländer HA,van Ogten MD,et al.Sensitive CE-MS analysis of potentially genotoxic alkylation compounds using derivatization and electrokinetic injection[J].Anal Chimi Acta,2015,874:75-83.
    [17]
    Raman NV,Prasad AV,Reddy KR,et al.Sensitive derivatization methods for the determination of genotoxic impurities in drug substances using hyphenated techniques[J].J Pharm Biomed Anal,2014,89:276-281.
    [18]
    Harigaya K,Yamada H,Yaku K,et al.Novel sensitive determination method for a genotoxic alkylating agent,4-chloro-1-butanol,in active pharmaceutical ingredients by LC-ICP-MS employing iodo derivatization[J].Anal Sci,2014,30(3):377-382.
    [19]
    Li W.Trace analysis of residual methyl methanesulfonate,ethyl methanesulfonate and isopropyl methanesulfonate in pharmaceuticals by capillary gas chromatography with flame ionization detection[J].J Chromatogr A,2004,1046(1/2):297-301.
    [20]
    Wollein U, Schramek N. Simultaneous determination of alkyl mesilates and alkyl besilates in finished drug products by direct injection GC/MS[J].Eur J Pharm Sci,2012,45(1/2):201-204.
    [21]
    Ramakrishna K,Raman NV,Rao KM,et al.Developmentand validation of GC-MS method for the determination of methyl methanesulfonate and ethyl methanesulfonate in imatinib mesylate[J].J Pharm Biomed Anal,2008,46(4):780-783.
    [22]
    Raman NV,Prasad AV,Reddy KR,et al.Determination of genotoxic alkyl methane sulfonates and alkyl paratoluene sulfonates in lamivudine using hyphenated techniques[J].J Pharm Anal,2012,2(4):314-318.
    [23]
    Raman NV,Reddy KR,Prasad AV,et al.Development and validation of RP-HPLC method for the determination of genotoxic alkyl benzenesulfonates in amlodipine besylate[J].J Pharm Biomed Anal,2008,48(1):227-230.
    [24]
    García A,Rupérez FJ,Ceppa F,et al.Development of chromatographic methods for the determination of genotoxic impurities in cloperastine fendizoate[J].J Pharm Biomed Anal,2012,61(5):230-236.
    [25]
    Kakadiya PR,Reddy BP,Singh V,et al.Low level determinations of methyl methanesulfonate and ethyl methanesulfonate impurities in lopinavir and ritonavir active pharmaceutical ingredients by LC/MS/MS using electrospray ionization[J].J Pharm Biomed Anal,2011,55(2):379-384.
    [26]
    Guo T,Shi YY,Zheng L,et al.Rapid and simultaneous determination of sulfonate ester genotoxic impurities in drug substance by liquid chromatography coupled to tandem mass spectrometry:comparison of different ionization modes[J].J Chromatogr A,2014,1355:73-79.
    [27]
    European Directorate for Quality and Medicines&HealthCare(EDQM).Methyl,ethyl and isopropyl methanesulfonate in methanesulfonic acid[S]//European Pharmacopoeia 8.0.Strasbourg:Council of Europe,2011.
    [28]
    Colon I,Richoll SM.Determination of methyl and ethyl esters of methanesulfonic,benzenesulfonic and p-toluenesulfonic acids in active pharmaceutical ingredients by solid-phase microextraction(SPME)coupled to GC/SIM-MS [J].J Pharm Biomed Anal,2005,39(3/4):477-485.
    [29]
    Lee CR,Guivarch F,Van Dau CN,et al.Determination of polar alkylating agents as thiocyanate/isothiocyanate derivatives by reaction headspace gas chromatography[J].Analyst,2003,128(7):857-863.
    [30]
    Alzaga R,Ryan RW,Taylor-Worth K,et al.A generic approach for the determination of residues of alkylating agents in active pharmaceutical ingredients by in situ derivatization-headspace-gas chromatography-mass spectrometry[J].J Pharm Biomed Anal,2007,45(3):472-479.
    [31]
    European Directorate for Quality and Medicines&HealthCare(EDQM).Methyl,ethyl and isopropyl methanesulfonate in active substances[S]//European Pharmacopoeia 8.0.Strasbourg:Council of Europe,2012.
    [32]
    An JG,Sun MJ,Bai L,et al.A practical derivatization LC/MS approach for determination of trace level alkyl sulfonates and dialkyl sulfates genotoxic impurities in drug substances[J].J Pharm Biomed Anal,2008,48(3):1006-1010.
    [33]
    Reddy VB,Venugopal N,Madhavi G.A selective and sensitive LC-MS/MS method for the simultaneous determination of two potential genotoxic impurities in celecoxib[J].J Anal Sci Technol,2014,5(1):1-8.
    [34]
    Lakshmi KJ,Devi PR,Mukkanti K.Quantitative determination of residual hydrazine content in cilazapril by ion chromatography[J].Orient J Chem,2010,26(3):1001-1006.
    [35]
    Kean T, Miller JH, Skellern GG, et al. Acceptance criteria for levels of hydrazine in substances for pharmaceutical use and analytical methods for its determination[J].Pharmeur Sci Notes,2006(2):23-33.
    [36]
    Liu M,Ostovic J,Chen EX,et al.Hydrophilic interaction liquid chromatography with alcohol as a weak eluent[J].J Chromatogr A,2009,1216(12):2362-2370.
    [37]
    Matsui F,Robertson DL,Lovering EG.Determination of hydrazine in pharmaceuticals III:hydralazine and isoniazid using glc[J].J Pharm Sci,1983,72(8):948-951.
    [38]
    Sun M,Bai L,Terfloth GJ,et al.Matrix deactivation:a general approach to improve stability of unstable and reactive pharmaceutical genotoxic impurities for trace analysis[J].J Pharm Biomed Anal,2010,52(1),30-36.
    [39]
    Oh JA,Park JH,Shin HS.Sensitive determination of hydrazine in water by gas chromatography-mass spectrometry after derivatization with ortho-phthalaldehyde[J].Anal Chim Acta,2013,769(6):79-83.
    [40]
    Oh JA,Shin HS.Simple and sensitive determination of hydrazine in drinking water by ultra-high-performance liquid chromatography-tandem mass spectrometry after derivatization with naphthalene-2,3-dialdehyde[J].J Chromatogr A,2015,1395:73-78.
    [41]
    Klick S.Evaluation of different injection techniques in the gas chromatographic determination of thermo labile trace impurities in a drug substance[J].J Pharm Biomed Anal,1995,13(4/5):563-566.
    [42]
    Xiao KP,Xiong Y,Liu FZ,et al.Efficient method development strategy for challenging separation of pharmaceutical molecules using advanced chromatographic techniques[J].J Chromatogr A,2007,1163(1/2):145-156.
    [43]
    Rao RN,Raju AN,Narshima R.Isolation and characterization of process related impurities an degradation products of bicalutamide and development of RP-HPLC method for impurity profile study[J].J Pharm Biomed Anal,2008,46(3):505-519.
    [44]
    Spangler M,Mularz E.A validated,stability-indicating method for the assay of dexamethasone in drug substance and drug product analyses,and the assay of preservatives in drug product[J].Chromatographia,2001,54(5):329-334.
    [45]
    Petkovska R,Cornett C,Dimitrovska A.Development and validation of rapid resolution RP-HPLC method for simultaneous determination of atorvastatin and related compounds by use of chemometrics[J].Anal Lett,2008,41(6):992-1009.
    [46]
    Bai L,Sun M,An J,et al.Enhancing the detection sensitivity of trace analysis of pharmaceutical genotoxic impurities by chemical derivatization and coordination ion spray-mass spectrometry[J].J Chromatogr A,2010,1217(3):302-306.
    [47]
    Wu L,Liu DQ,Vogt FG,et al.Gas-phase derivatization via the Meerwein reaction for selective and sensitive LC-MS analysis of epoxides in active pharmaceutical ingredients[J].J Pharm Biomed Anal,2011,56(5):1106-1111.
    [48]
    Khan SJ,Weinberg HS,Bedford EC.Aqueous-phase aminolysis:approach for the analysis of epoxides in water[J].Anal Chem,2006,78(8):2608-2616.
    [49]
    Khan M,Jayasree K,Reddy KV,et al.A validated CE method for determining dimethylsulfate a carcinogen and chloroacetyl chloride a potential genotoxin at trace levels in drug substances[J].J Pharm Biomed Anal,2012,58(2):27-33.
    [50]
    Fu M,Lu Q,Hewitt E,et al.Ultra high performance liquid chromatography coupled with high resolution quantitation mass spectrometry method development and validation for determining genotoxic 2,5-dichlorobenzoyl chloride in MLN9708 drug substance[J].J Pharm Biomed Anal,2014,89(4):233-239.
    [51]
    Tang L,Kim A,Miller SA,et al.Development and validation of a specific and sensitive GC-FID method for the determination of impurities in 5-chlorovaleroyl chloride[J].J Pharm Biomed Anal,2010,53(3):309-314.
  • Related Articles

    [1]HU Linlin, GUO Nan, ZHANG Xueli, SHAO Hua. Determination of daptomycin by UPLC-MS/MS and its pharmacokinetic eva-luation in critically ill patients[J]. Journal of China Pharmaceutical University, 2015, 46(6): 700-706. DOI: 10.11665/j.issn.1000-5048.20150611
    [2]HAO Kun, YU Dan, WANG Guangji. Pharmacokinetic translational research from bench to bedside[J]. Journal of China Pharmaceutical University, 2015, 46(1): 50-57. DOI: 10.11665/j.issn.1000-5048.20150105
    [3]LIANG Yan, XING Rong, LIU Jiali, MAO Yong, FU Hanxu, XIE Lin, WANG Guangji. Advances of novel technologies and theories in pharmacokinetic research[J]. Journal of China Pharmaceutical University, 2014, 45(6): 607-616. DOI: 10.11665/j.issn.1000-5048.20140601
    [4]Application of pharmacometrics in drug development and therapeutic drug monitoring[J]. Journal of China Pharmaceutical University, 2010, 41(1): 91-96.
    [5]Pharmacokinetics Studies of 99mTc-BM[J]. Journal of China Pharmaceutical University, 2004, (3): 57-59.
    [6]Pharmacokinetics of 0325k1-1 in Dogs[J]. Journal of China Pharmaceutical University, 2003, (4): 79-81.
    [7]Pharmacokinetics of Aceclofenac in Rats[J]. Journal of China Pharmaceutical University, 1998, (4): 68-70.
    [8]Pharmacokinetics and Pharmacodynamics of Sophocarpine and Oxysophocarpine[J]. Journal of China Pharmaceutical University, 1992, (3): 161-164.
    [9]PHARMACOKINETICS OF MATRINR IN RABBITS[J]. Journal of China Pharmaceutical University, 1986, (4): 309-311.
    [10]PHARMACOKINETICS OF OCTANOYLPRIMAQUINE IN RABBITS[J]. Journal of China Pharmaceutical University, 1986, (2): 125-128.

Catalog

    Article views (2721) PDF downloads (9647) Cited by()

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return