殘留溶(rong)劑是指在(zai)原料或輔(fu)料的生產中， 以及在(zai)溶劑制備過程中使用或產生而又未能*去(qu)除的有機溶(rong)劑，由于在(zai)(zai)生(sheng)產過程中未(wei)能被(bei)全部清除,服用(yong)后對人體有毒性和致(zhi)癌(ai)作(zuo)用(yong),近(jin)年來(lai)(lai)日益引(yin)起(qi)各方面的(de)重視,在(zai)(zai)新藥研究中要(yao)求越來(lai)(lai)越嚴格。根據(ju)化學品安(an)全性綱要，以及美國環境(jing)保(bao)護機構、世界(jie)衛生組織(zhi)等公布的(de)研究結果表明，很多有(you)機溶(rong)劑對(dui)環境(jing)、人體都有(you)一定的(de)危(wei)害。因此，為保(bao)障藥物的(de)質(zhi)量和(he)用藥安(an)全以及保(bao)護環境(jing)，需(xu)要對(dui)殘留溶(rong)劑進(jin)行研究和(he)控制。我國在1995年(nian)藥(yao)(yao)典(dian)也規定(ding)7種(zhong)限制溶劑(ji)殘留項2,在2000年(nian)藥(yao)(yao)典(dian)中(zhong)3,根(gen)據ICH的(de)(de)(de)限度要(yao)(yao)求(qiu)對(dui)(dui)這7種(zhong)溶劑(ji)殘留*進(jin)行調整。ICH要(yao)(yao)求(qiu)檢測的(de)(de)(de)溶劑(ji)就有(you)69種(zhong),雖然我國藥(yao)(yao)典(dian)并未要(yao)(yao)求(qiu)按ICH的(de)(de)(de)規定(ding)實(shi)施,但(dan)在新藥(yao)(yao)研究中(zhong)對(dui)(dui)于殘留溶劑(ji)的(de)(de)(de)要(yao)(yao)求(qiu)事(shi)實(shi)上(shang)是(shi)參照ICH的(de)(de)(de)規定(ding)執行的(de)(de)(de)。這是(shi)SDA對(dui)(dui)新藥(yao)(yao)研究從嚴從高要(yao)(yao)求(qiu)的(de)(de)(de)體現,也是(shi)與接軌,適應WTO規則的(de)(de)(de)需要(yao)(yao)。在實(shi)際(ji)工(gong)作(zuo)中(zhong),藥(yao)(yao)品(pin)的(de)(de)(de)合成、制劑(ji)、消(xiao)毒工(gong)作(zuo)涉及到的(de)(de)(de)有(you)機溶劑(ji)有(you)上(shang)百(bai)種(zhong),(氣是中國藥典對有(you)機殘(can)留(liu)溶(rong)劑(ji)測(ce)定的法定檢(jian)測(ce)方法,也是檢(jian)測(ce)有(you)機溶(rong)劑(ji)的zui常用、zui適用的方法之一。

1、(氣相色譜儀SP7800)氣相色譜法(fa)

       1、1一般是將(jiang)樣(yang)(yang)品(pin)溶(rong)(rong)(rong)(rong)(rong)于(yu)適(shi)當的(de)(de)溶(rong)(rong)(rong)(rong)(rong)劑(ji)(ji)(ji)(ji)中(zhong)(zhong)(zhong),能達到的(de)(de)濃度越高越好,以利于(yu)殘留量極微(wei)溶(rong)(rong)(rong)(rong)(rong)劑(ji)(ji)(ji)(ji)的(de)(de)測定(ding)。由(you)于(yu)樣(yang)(yang)品(pin)復雜多樣(yang)(yang),為(wei)提(ti)高樣(yang)(yang)品(pin)濃度,所用(yong)(yong)溶(rong)(rong)(rong)(rong)(rong)劑(ji)(ji)(ji)(ji)也(ye)是多種多樣(yang)(yang)。一般常(chang)用(yong)(yong)溶(rong)(rong)(rong)(rong)(rong)劑(ji)(ji)(ji)(ji)為(wei)水、二(er)(er)甲(jia)(jia)基甲(jia)(jia)酰胺(an)(DMF)、二(er)(er)甲(jia)(jia)亞(ya)砜(feng)(DMSO),也(ye)有用(yong)(yong)二(er)(er)甲(jia)(jia)基乙(yi)酰胺(an)、乙(yi)醇5、正己烷、二(er)(er)氧(yang)六環、乙(yi)酸(suan)、甲(jia)(jia)氧(yang)基乙(yi)醇6、氫氧(yang)化鈉溶(rong)(rong)(rong)(rong)(rong)液(ye)7、十二(er)(er)烷基磺酸(suan)鈉溶(rong)(rong)(rong)(rong)(rong)液(ye)8等的(de)(de),不一而足。大(da)部(bu)分(fen)(fen)為(wei)單獨使用(yong)(yong),也(ye)有的(de)(de)混合使用(yong)(yong),主要目的(de)(de)就(jiu)是增加樣(yang)(yang)品(pin)溶(rong)(rong)(rong)(rong)(rong)解度。所用(yong)(yong)溶(rong)(rong)(rong)(rong)(rong)劑(ji)(ji)(ji)(ji)與所測溶(rong)(rong)(rong)(rong)(rong)劑(ji)(ji)(ji)(ji)應達到較好的(de)(de)分(fen)(fen)離(li)。其(qi)中(zhong)(zhong)(zhong)二(er)(er)甲(jia)(jia)基甲(jia)(jia)酰胺(an)、二(er)(er)甲(jia)(jia)亞(ya)砜(feng)因其(qi)溶(rong)(rong)(rong)(rong)(rong)解范(fan)圍(wei)廣,溶(rong)(rong)(rong)(rong)(rong)解性(xing)好,素(su)有“能溶(rong)(rong)(rong)(rong)(rong)劑(ji)(ji)(ji)(ji)"之稱,是zui常(chang)用(yong)(yong)的(de)(de)溶(rong)(rong)(rong)(rong)(rong)劑(ji)(ji)(ji)(ji)。需要注(zhu)意的(de)(de)是,樣(yang)(yang)品(pin)一定(ding)要溶(rong)(rong)(rong)(rong)(rong)清,保證(zheng)所測組(zu)分(fen)(fen)都(dou)溶(rong)(rong)(rong)(rong)(rong)解在溶(rong)(rong)(rong)(rong)(rong)劑(ji)(ji)(ji)(ji)中(zhong)(zhong)(zhong)。在一段時間里,曾將(jiang)不溶(rong)(rong)(rong)(rong)(rong)性(xing)樣(yang)(yang)品(pin)用(yong)(yong)水等溶(rong)(rong)(rong)(rong)(rong)劑(ji)(ji)(ji)(ji)超聲提(ti)取、離(li)心,取上清液(ye)進樣(yang)(yang)

1.2定量方法

    用色譜峰定量(liang)(liang)的(de)(de)(de)標(biao)(biao)(biao)(biao)準技(ji)術分為(wei)(wei)四種15,分別為(wei)(wei)面積歸(gui)一(yi)化法(fa)(fa)、標(biao)(biao)(biao)(biao)準物(wu)(wu)添加法(fa)(fa)、外標(biao)(biao)(biao)(biao)法(fa)(fa)、內(nei)(nei)標(biao)(biao)(biao)(biao)法(fa)(fa)。前兩種方(fang)法(fa)(fa)很(hen)少見到(dao),一(yi)般用后兩種方(fang)法(fa)(fa)。中(zhong)國藥(yao)典2000年(nian)版(ban)規定兩種方(fang)法(fa)(fa)均(jun)(jun)可,美國藥(yao)典24版(ban)(US2PXXIV)16、英國藥(yao)典2000年(nian)版(ban)(BP2000)17均(jun)(jun)要(yao)求(qiu)用外標(biao)(biao)(biao)(biao)法(fa)(fa)。內(nei)(nei)標(biao)(biao)(biao)(biao)法(fa)(fa)不要(yao)求(qiu)所有組(zu)分都*分離、流(liu)(liu)出(chu)和檢測出(chu)來(lai)。它只需(xu)(xu)將要(yao)分析的(de)(de)(de)峰與內(nei)(nei)標(biao)(biao)(biao)(biao)物(wu)(wu)*分離即可。內(nei)(nei)標(biao)(biao)(biao)(biao)物(wu)(wu)必須符合(he)下列要(yao)求(qiu):在(zai)樣(yang)品中(zhong)原來(lai)沒有內(nei)(nei)標(biao)(biao)(biao)(biao)物(wu)(wu)的(de)(de)(de)存在(zai);內(nei)(nei)標(biao)(biao)(biao)(biao)物(wu)(wu)必須與所有樣(yang)品組(zu)分*分離;內(nei)(nei)標(biao)(biao)(biao)(biao)物(wu)(wu)的(de)(de)(de)流(liu)(liu)出(chu)時間(jian)應盡(jin)量(liang)(liang)接近(jin)待分析組(zu)分;內(nei)(nei)標(biao)(biao)(biao)(biao)物(wu)(wu)應與待分離的(de)(de)(de)物(wu)(wu)質具有相近(jin)的(de)(de)(de)濃度、物(wu)(wu)化特性(xing)和檢測器的(de)(de)(de)響應值(zhi);內(nei)(nei)標(biao)(biao)(biao)(biao)物(wu)(wu)必需(xu)(xu)穩定、不起化學(xue)反應、純度高、揮發性(xing)應很(hen)低以允(yun)許長(chang)期保存并且(qie)在(zai)注樣(yang)過程中(zhong)損失zui小。待測樣(yang)品可以是一(yi)個(ge)或一(yi)個(ge)以上(shang)。

1.3進樣方式

     固體頂(ding)空不受樣(yang)品溶(rong)(rong)解度影響,適(shi)(shi)合蒸汽壓高、沸點低、含量(liang)低的殘(can)(can)留溶(rong)(rong)劑且(qie)不易溶(rong)(rong)解的樣(yang)品。在用(yong)毛細管柱(zhu)時,一般(ban)又選擇分(fen)(fen)(fen)流法(fa)進(jin)樣(yang)。分(fen)(fen)(fen)流法(fa)是(shi)指在氣化室出口分(fen)(fen)(fen)兩(liang)路,絕大(da)部(bu)分(fen)(fen)(fen)放空,極(ji)小部(bu)分(fen)(fen)(fen)進(jin)柱(zhu)子。這兩(liang)部(bu)分(fen)(fen)(fen)比例(li)叫分(fen)(fen)(fen)流比。又分(fen)(fen)(fen)為動(dong)態進(jin)樣(yang)和(he)靜態進(jin)樣(yang),一般(ban)應用(yong)較多的是(shi)動(dong)態進(jin)樣(yang)24。溶(rong)(rong)液(ye)直接進(jin)樣(yang)是(shi)指將樣(yang)品定(ding)量(liang)溶(rong)(rong)解于適(shi)(shi)當(dang)溶(rong)(rong)劑中,準確量(liang)取適(shi)(shi)量(liang)注入氣相色譜儀測定(ding)溶(rong)(rong)劑殘(can)(can)留量(liang)的進(jin)樣(yang)方法(fa)。

1.4檢(jian)測器的選擇

      一般選用(yong)(yong)FID檢(jian)(jian)(jian)測(ce)(ce)器(qi),也有選用(yong)(yong)MS為(wei)檢(jian)(jian)(jian)測(ce)(ce)器(qi)的(de),多為(wei)GC-MS聯(lian)用(yong)(yong)儀13,34。對于含氯(lv)元素的(de)溶劑,選用(yong)(yong)ECD檢(jian)(jian)(jian)測(ce)(ce)器(qi)專屬性(xing)強,可排除雜質干擾(rao)。中國藥典(dian)2000年(nian)版、美國藥典(dian)24版(USPXXIV)均選用(yong)(yong)FID檢(jian)(jian)(jian)測(ce)(ce)器(qi),英國藥典(dian)2000年(nian)版(BP2000)則上述三種檢(jian)(jian)(jian)測(ce)(ce)器(qi)均有應(ying)用(yong)(yong)。

很(hen)多(duo)有機溶劑對(dui)環境、人體都有一定的(de)危(wei)害。因此，為保(bao)障(zhang)藥(yao)物的(de)質量(liang)和用(yong)藥(yao)安全(quan)以(yi)及保(bao)護(hu)環境，需要(yao)對(dui)殘留溶劑進行研究和控制。由(you)于通常要(yao)同時檢(jian)測多(duo)種溶劑，為了(le)操作的(de)可(ke)行性(xing)和簡(jian)便(bian)性(xing)， 應采用(yong)同樣(yang)的(de)檢(jian)測條件(jian)以(yi)控制盡量(liang)多(duo)種類(lei)的(de)殘留溶劑。該研究采用(yong)氣相色譜法對(dui)藥(yao)物中(zhong)的(de)甲(jia)醇、丙酮(tong)、甲(jia)苯、二甲(jia)苯等(deng)溶劑殘留的(de)含量(liang)進行測定，方法簡(jian)單、快速、回收率(lv)高，為藥(yao)物中(zhong)的(de)殘留溶劑提(ti)供了(le)檢(jian)測依據(ju)。