中圖分類號(hào):TB9 文獻(xiàn)標(biāo)志碼:A文章編號(hào):1674-5124(2025)07-0095-09
Abstract: Based on the synthetic process route,the impurities in the raw material of Manidipine hydrochloride were separated, confirmed structure and content determination. Agilent ZORBAX SB-C18( 4.6m×250 mm, 5 μm) was used as a column. The detection wavelength was set at 229nm ,the column temperature was 40°C , and the sample size was 20μL .Flow rate was 1mL/min ,mobile phase A was 0.01mol/L ammonium acetate solution,mobile phase B was acetonitrile, gradient elution.The experimental results showed that the byproduct of the synthesis process of Manidipine hydrochloride produced the impurity 5-(3-nitrophenyl)-3-methyl-2-cyclohexene-1-one under acidic conditions, and the impurity dehydromanidipine was produced under light irradiation. The linear relationships of Manidipine hydrochloride impurities were all good (r2?0.9997) in the concentration range. The RSDs of precision and solution stability tests were all less than 3.0%(n=6) .The average recoveries of the three impurities ranged from 97.47% to 102.56% ,and the RSDs were all less than 2.0%(n=9) . The study of these impurities is of great significance for the quality control of Manidipine hydrochloride.
Keywords: Manidipine hydrochloride; impurities; structural confirmation; content determination
0 引言
鹽酸馬尼地平是第三代二氫吡啶類鈣離子拮抗劑,能夠抑制L型和T型雙通道鈣離子,高選擇抑制血管平滑肌中細(xì)胞電壓,擴(kuò)張動(dòng)脈血管平滑肌,從而降低了血管外周阻力,起到降低血壓作用[1-3]。目前,鹽酸馬尼地平的研究內(nèi)容為本品療效和安全性評(píng)價(jià)[4-12],藥動(dòng)學(xué)[13-14],合成和劑型工藝[15-22],質(zhì)量研究主要有原料和片劑主成分含量測(cè)定,殘留溶劑檢測(cè),片劑溶出度測(cè)定[23-31]等。有關(guān)物質(zhì)檢查研究很少,僅有日本藥典[32]收載,且只有一篇文獻(xiàn)[33]報(bào)道了光降解雜質(zhì)的質(zhì)譜圖和光降解動(dòng)力學(xué)。
藥品中的雜質(zhì)主要是指生產(chǎn)過程中帶入的工藝雜質(zhì)和貯藏過程中新增或含量出現(xiàn)增長的降解雜質(zhì),作為質(zhì)量研究中的重點(diǎn)內(nèi)容,它們對(duì)藥品的質(zhì)量和安全有重要的影響[34-35]。該研究有利于藥品質(zhì)量控制和工藝改進(jìn)?;诖?,參照中國藥典藥品雜質(zhì)分析指導(dǎo)原則,依據(jù)合成鹽酸馬尼地平的合成路線(圖1)。對(duì)其雜質(zhì)分離并進(jìn)行結(jié)構(gòu)確證,建立鹽酸馬尼地平有關(guān)物質(zhì)測(cè)定方法。為提高鹽酸馬尼地平質(zhì)量控制標(biāo)準(zhǔn)、確保其臨床使用的有效性和安全性提供技術(shù)支持。
1儀器、試藥與試劑
1.1儀器
PerkinEmpower高效液相色譜儀(PDA檢測(cè)器、Empower工作站);BrukerARX-600核磁共振儀(德國布魯克有限公司);LC-MS/Q-TOF四級(jí)桿飛行時(shí)間液質(zhì)聯(lián)用儀(6545Q-TOF,Agilent);超聲波清洗機(jī)(KQ-400KDE),昆山市超聲儀器有限公司)。
1.2試藥
鹽酸馬尼地平粗品(批號(hào)230401),鹽酸馬尼地平(批號(hào)230405、230510、230515),間硝苯地平(批號(hào)230412),5-(3-硝基苯基)-3-甲基-2-環(huán)已烯-1-酮(批號(hào)230420),脫氫馬尼地平(批號(hào)230425)。
1.3試劑
乙腈、甲醇(色譜純,成都市科隆化學(xué)品有限公司);乙酸乙酯、甲醇、石油醚、磷酸二氫鉀、乙酸銨、鹽酸、氫氧化鈉(分析純,成都市科隆化學(xué)品有限公司);過氧化氫(分析純,國藥集團(tuán)化學(xué)試劑有限公司);氘代甲醇(Cambridge IsotopeLaboratories)。
2 方法與結(jié)果
2.1HPLC色譜條件及測(cè)定方法
以 Agilent ZORBAX SB-C18( 4.6m×250mm 5μm) 為色譜柱,檢測(cè)波長為 229nm ,柱溫為 40% 進(jìn)樣量為 20μL ,流量為 1mL/min ,流動(dòng)相A為0.01mol/L 乙酸銨溶液,流動(dòng)相B為乙腈,梯度洗脫按照表1所示進(jìn)行梯度洗脫。
精密量取對(duì)照溶液 20μL 注入液相色譜儀,記錄色譜圖,調(diào)節(jié)縱坐標(biāo),使主成分色譜峰的峰高約為滿量程的 10% 。再精密量取供試品溶液和對(duì)照溶液各 20μL ,分別注入液相色譜儀,記錄色譜圖。供試品溶液色譜圖中如有雜質(zhì)峰,按加校正因子自身對(duì)照法以峰面積計(jì)算,間硝苯地平和脫氫馬尼地平分別乘以校正因子4.52和4.55,任一單個(gè)雜質(zhì)不得過 0.2% ,各雜質(zhì)的總和不得過 0.6% 。
2.2 專屬性試驗(yàn)
2.2.1 溶液的配制
溶劑為水-乙晴(1:1)。分別精密稱取鹽酸馬尼地平、鹽酸馬尼地平粗品、鹽酸馬尼地平 120qC 下放置 4h 樣品、鹽酸馬尼地平光照放置10天樣品適量,加溶劑制成 0.5mg/mL 的鹽酸馬尼地平供試品、粗品、高溫和光照降解溶液[36]。取鹽酸馬尼地平適量,加人 1mLlmolL 的HCl或NaOH溶液,于 90qC 下放置 4h ,放至室溫,加入 1mol/L 的NaOH或HCl溶液 1mL ,中和后加溶劑制成 0.5mg/mL 的酸、堿降解溶液。取鹽酸馬尼地平適量,加入 1mL 10% 的 H2O2 溶液,放置 4h ,加溶劑制成 0.5mg/mL 的氧化降解溶液,再精密量取鹽酸馬尼地平供試品溶液適量,加溶劑稀釋制成 0.1% 的對(duì)照溶液。
2.2.2 測(cè)定結(jié)果
取\"2.2.1\"項(xiàng)下方法制成的溶液,按照 lt;2.1gt; 項(xiàng)下色譜條件進(jìn)樣測(cè)定,液相色譜圖如圖2~8所示。與圖2相比較,高溫降解圖4和堿降解圖5均未見明顯雜質(zhì)增加;粗品圖3、酸降解圖6、光降解圖7和氧化降解圖8出現(xiàn)明顯雜質(zhì),按加校正因子自身對(duì)照法計(jì)算這些雜質(zhì)的含量,均超過 0.1% ;故對(duì)鹽酸馬尼地平的粗品、酸降解、光降解和氧化降解做進(jìn)一步研究,經(jīng)測(cè)定,圖3保留時(shí)間為 9.321min 的雜峰為中間體。分離制備得到雜質(zhì)I、雜質(zhì)ⅡI和雜質(zhì)Ⅲ單體,而圖8中氧化降解得到的雜質(zhì)比較復(fù)雜且不穩(wěn)定,提純困難,未能制備出雜質(zhì)單體。
2.3.1 雜質(zhì)的制備
取鹽酸馬尼地平粗品適量溶于甲醇,用高效薄層層析硅膠板-厚制備板進(jìn)行分離,在乙酸乙酯-甲醇 (10:1,ν/ν) 中展開,收集雜質(zhì)I的條帶、加甲醇浸泡、清洗、減壓濃縮得到白色粉末狀的雜質(zhì)I。
按 lt;2.2.1 項(xiàng)下酸降解溶液的配制方法,延長降解時(shí)間至 48h ,增大雜質(zhì)的量,并通過制備液相提取純化酸降解雜質(zhì)及對(duì)照溶液,如圖9所示,色譜條件:色譜柱為AgilentZORBAXSB-C18( 9.4m× 250mm,5μm ),檢測(cè)波長 229nm ,柱溫 40% ,流量為 3.0mL/min ,進(jìn)樣量 100μL ,流動(dòng)相為水-甲醇 40:60? ),等度洗脫。收集雜質(zhì)Ⅱ餾分,并在 60°C 下減壓濃縮、干燥,得到淡黃色粉末狀雜質(zhì)II。
取“2.2.1\"項(xiàng)下強(qiáng)光降解30天的樣品,用甲醇溶解后將其均勻點(diǎn)在薄層層析硅膠板厚制備板上,用展開劑石油醚-乙酸乙酯 展開后,在紫外燈下觀察,刮下雜質(zhì)的條帶,用甲醇浸泡、清洗,在50qC 下減壓濃縮[37],干燥,得到白色粉末狀雜質(zhì)IⅢI。
按照\"2.1\"項(xiàng)下色譜條件進(jìn)樣測(cè)定,三個(gè)雜質(zhì)的保留時(shí)間與 ∞2.2.2° 項(xiàng)下圖譜中雜質(zhì)的保留時(shí)間一致,其中雜質(zhì)I、雜質(zhì)ⅡI和雜質(zhì)IⅢ的純度分別為 97.64% 、96.08% 和 94.51% ,如圖10~圖12所示。
2.3.2 雜質(zhì)的結(jié)構(gòu)確證
LC-MS分析:以WatersXBridgeC18( 3.5μm
4.6m×50mm , 3.5μm )為色譜柱;流量為2.0mL/min ;進(jìn)樣體積為 1μL ,流動(dòng)相A為 0.01moL/L 碳酸氫銨溶液,流動(dòng)相B為乙腈;梯度洗脫,流動(dòng)相B在 1.6min 內(nèi)從 5% 上升到 95% ,并保持95%1.4min 。采用ES-API離子源,質(zhì)譜掃描范圍為 105~1000m/z ,正離子模式。取分離得到雜質(zhì)適量溶于甲醇,在正離子模式下獲得其離子色譜圖。雜質(zhì)I、Ⅱ和IⅢ的質(zhì)譜數(shù)據(jù)分別與間硝苯地平、5-(3-硝基苯基)-3-甲基-2-環(huán)己烯-1-酮和脫氫馬尼地的分子量一致。 NMR(1H,13C) 解析 (400MHz Methanol- :雜質(zhì)I、ⅡI和IⅢ的核磁共振譜分別與文獻(xiàn)[38-40]報(bào)道的結(jié)果吻合,確定雜質(zhì)I為間硝苯地平;雜質(zhì)ⅡI為5-(3-硝基苯基)-3-甲基-2-環(huán)己烯-1-酮;雜質(zhì)IⅢ為脫氫馬尼地平。如圖13所示
2.4 系統(tǒng)適用性試驗(yàn)
精密稱取鹽酸馬尼地平適量,加溶劑(水:乙晴 =1:1 )超聲溶解,制得濃度為 1.0mg/mL 的貯備液。分別精密稱取雜質(zhì)I、雜質(zhì)ⅡI和雜質(zhì)IⅢ適量于量瓶中,加入溶劑超聲溶解,制成濃度為0.1mg/mL 的雜質(zhì)貯備液。精密量取供試品貯備液5mL 、各雜質(zhì)貯備液分別 1mL 于 10mL 量瓶中,加入溶劑稀釋至刻度,搖勻,制得系統(tǒng)適應(yīng)性溶液。理論塔板數(shù)按照鹽酸馬尼地平計(jì)算不低于5000,與相鄰的雜峰分離度不低于1.5,記錄色譜圖見圖14。
2.5 線性關(guān)系考察
精密量取“2.4\"項(xiàng)下的供試品貯備液和雜質(zhì)貯備液適量,加溶劑稀釋、定容、搖勻,制得濃度為10μg/mL 混合線性母液。取線性母液加溶劑稀釋制得濃度為 2,1.5,1,0.75,0.5,0.25μg/mL 系列線性溶液。取各線性溶液 20μL ,按 lt;2.1: 項(xiàng)下的色譜條件進(jìn)樣,記錄色譜圖。以濃度 (μg/mL) 為橫坐標(biāo),相應(yīng)的峰面積為縱坐標(biāo)繪制標(biāo)準(zhǔn)曲線,結(jié)果如表2所示。校正因子為鹽酸馬尼地平線性方程的斜率與雜質(zhì)線性方程的斜率之比,計(jì)算結(jié)果在 0.2~5.0 的范圍內(nèi),因此可用加校正因子的主成分自身對(duì)照法計(jì)算各雜質(zhì)的含量。
2.6定量限和檢出限考察
取\"2.4\"項(xiàng)的供試品貯備液和雜質(zhì)貯備液,加溶劑逐級(jí)稀釋制得系列溶液,按 ÷2.1 項(xiàng)下色譜條件進(jìn)樣測(cè)定。以信噪比3:1計(jì)算檢測(cè)限,信噪比10:1計(jì)算定量限,結(jié)果見表2。
2.7 精密度試驗(yàn)
按\"2.1\"項(xiàng)下方法,取同一批鹽酸馬尼地平樣品(批號(hào)230405)平行制備六份供試品溶液進(jìn)樣測(cè)定,計(jì)算重復(fù)性RSD;取其中一份供試品溶液連續(xù)進(jìn)樣6次,計(jì)算進(jìn)樣精密度的 RSD 。經(jīng)試驗(yàn),進(jìn)樣精密度試驗(yàn)的RSD為 2.37% ,重復(fù)性的RSD為 2.64% 表明方法精密度和重復(fù)性良好。
2.8溶液穩(wěn)定性試驗(yàn)
取\"2.2.1\"項(xiàng)下鹽酸馬尼地平供試品溶液,于室溫下避光放置 0.2、4、6、8、12h, 按 ?2.1 \"項(xiàng)下色譜條件進(jìn)樣測(cè)定,記錄峰面積。結(jié)果顯示,供試品溶液中檢出雜質(zhì)的RSD為 2.61% ,表明供試品溶液避光放置 12h 內(nèi)較穩(wěn)定。
2.9 加樣回收率實(shí)驗(yàn)
精密量取 s2.4, 項(xiàng)稱取各雜質(zhì)貯備液適量,并配置成濃度為 4μg/mL 的混合雜質(zhì)對(duì)照品溶液,精密量取供試品貯備液 5mL ,分別置于9個(gè) 10mL 容量瓶中,將樣品分為3組,在每組樣品中平行加入2mL, 2.5mL , 3mL 混合雜質(zhì)對(duì)照品溶液,加人溶劑超聲溶解、定容,制得 80% 、 100% 7 120% 的混合雜質(zhì)對(duì)照回收率溶液。記錄峰面積,計(jì)算加樣回收率。結(jié)果顯示,各雜質(zhì)的平均回收率為 97.47%~102.56% RSD均不大于 2.0%(n=9) ,表明方法準(zhǔn)確度良好。
2.10 雜質(zhì)含量測(cè)定
取鹽酸馬尼地平(批號(hào)230405、230510、230515)按照\"2.2.1\"項(xiàng)下的條件進(jìn)行光照試驗(yàn),分別于第0天、5天、10天、30天取樣,并按照2.2.1\"項(xiàng)下方法制備光降解供試品溶液和對(duì)照溶液,按 ?2.1? P項(xiàng)下色譜條件分別進(jìn)樣測(cè)定,記錄峰面積,計(jì)算得到雜質(zhì)的含量分別為 0.080%0.106%0.135% 和0.228% 結(jié)果如下表所示。其中,雜質(zhì)Ⅰ含量變化不明顯,雜質(zhì)ⅡI未檢出,雜質(zhì)IⅢ的含量隨光照時(shí)間延長而明顯增加,結(jié)果如表3所示。
表3雜質(zhì)含量測(cè)定結(jié)果
%
3討論
3.1 色譜條件篩選
采用日本藥典鹽酸馬尼地平有關(guān)物質(zhì)檢查方法對(duì)雜質(zhì)進(jìn)行測(cè)定,進(jìn)樣濃度從 0.1mg/mL 增加到0.5mg/mL 時(shí),雜質(zhì)脫氫馬尼地平仍未檢出,且其定位色譜圖中雜質(zhì)峰峰型嚴(yán)重拖尾且扁平。因此,本試驗(yàn)采用 0.01mol/L 乙酸銨-乙腈梯度洗脫方法,并將進(jìn)樣濃度改為 0.5mg/mL ,該方法使雜質(zhì)脫氫馬尼地平的色譜峰峰型得到改善,增加測(cè)定的靈敏度,保證雜質(zhì)含量測(cè)定的準(zhǔn)確性,便于本品雜質(zhì)研究。
3.2 雜質(zhì)的生成途徑分析
查閱文獻(xiàn)并結(jié)合合成工藝路線,推測(cè)雜質(zhì)I是由間硝基苯甲醛與3-氨基巴豆酸甲酯發(fā)生Hantzsch反應(yīng)[41-43]而生成,其反應(yīng)機(jī)理如圖15所示。
鹽酸馬尼地平在強(qiáng)酸性條件下不穩(wěn)定,主要降解產(chǎn)物為5-(3-硝基苯基)-3-甲基-2-環(huán)已烯-1-酮,即雜質(zhì)ⅡI。參考文獻(xiàn)[44推測(cè)其降解機(jī)理如圖16所示。
根據(jù)文獻(xiàn)[45]報(bào)道,二氫吡啶類藥物對(duì)光不穩(wěn)定,鹽酸馬尼地平在光照射下,發(fā)生歧化反應(yīng),生成光降解雜質(zhì)脫氫馬尼地平,即雜質(zhì)IⅢI,產(chǎn)生該雜質(zhì)的途徑如圖17所示。
4結(jié)束語
本研究基于鹽酸馬尼地平原料藥的合成工藝和強(qiáng)降解試驗(yàn)結(jié)果,采用制備液相法和薄層層析法,分離得到三個(gè)雜質(zhì)單體,確證雜質(zhì)Ⅰ為工藝雜質(zhì)間硝苯地平;雜質(zhì)ⅡI為酸降解雜質(zhì)5-(3-硝基苯基)-3-甲基-2-環(huán)己烯-1-酮,雜質(zhì)IⅢI為光降解雜質(zhì)脫氫馬尼地平。目前尚未見鹽酸馬尼地平雜質(zhì)Ⅰ和雜質(zhì)Ⅱ的相關(guān)報(bào)道,雜質(zhì)IⅢ僅有質(zhì)譜數(shù)據(jù)及降解動(dòng)力學(xué)的報(bào)道。建立梯度法測(cè)定鹽酸馬尼地平原料藥的有關(guān)物質(zhì),采用加校正因子主成分自身對(duì)照法計(jì)算雜質(zhì)的含量,能有效地控制鹽酸馬尼地平中的各種雜質(zhì)。本研究探討雜質(zhì)產(chǎn)生的機(jī)理,能夠指導(dǎo)改進(jìn)產(chǎn)品的生產(chǎn)工藝和貯存條件。通過強(qiáng)降解試驗(yàn)表明,光降解產(chǎn)生的雜質(zhì)Ⅲ隨存放時(shí)間延長其含量不斷增加,提示鹽酸馬尼地平原料藥在貯存過程中應(yīng)避光保存。
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(編輯:徐柳)