药物多晶型的过程控制和工程技术进展
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摘要
多晶型现象在药物结晶领域普遍存在。同一种药物的不同晶型尽管化学组分相同,却具有不同的理化性质,因此晶型是药品研究和开发的一个重要内容。从药物质量控制角度来看,药物晶型的不同可能会引起生物利用度的差异,不仅会影响到药物的稳定性和后续加工(过滤、干燥、制剂等)过程,而且会影响到药物的临床效果。本文从药物晶型的筛选与控制、结晶过程分析以及工程技术进展等方面对近年来药物结晶工业的发展情况进行总结和分析,并从连续结晶技术和数值模拟等方面展望了药物结晶工业未来的发展方向。
Polymorphism is a prevalent phenomenon for drugs. Polymorphs of one drug are chemically identical, however, their physical and chemical properties are different. Therefore, polymorphism is an important part of research content for drugs. In terms of drug quality control, bioavailability of various polymorphs may be different. Polymorphism is an important factor for the clinic effect of drugs, and has strong influence on the stability of drug crystallization and the post processing(filtration, drying, preparation, et al). Progresses on the screening and control of polymorphism, process analysis of crystallization, and engineering were summarized and analyzed in this article. Perspectives of development of continuous crystallization and the numerical simulation for industrial crystallization in the future were also given.
Polymorphism is a prevalent phenomenon for drugs. Polymorphs of one drug are chemically identical, however, their physical and chemical properties are different. Therefore, polymorphism is an important part of research content for drugs. In terms of drug quality control, bioavailability of various polymorphs may be different. Polymorphism is an important factor for the clinic effect of drugs, and has strong influence on the stability of drug crystallization and the post processing(filtration, drying, preparation, et al). Progresses on the screening and control of polymorphism, process analysis of crystallization, and engineering were summarized and analyzed in this article. Perspectives of development of continuous crystallization and the numerical simulation for industrial crystallization in the future were also given.
引文
[1]周肖寅,刘峥,冯小珍.药物多晶型现象研究进展[J].化学与生物工程,2010,27(10):1-5.
[2]Chieng N,Rades T,Aaltonen J.An overview of recent studies on the analysis of pharmaceutical polymorphs[J].J Pharm Biomed Anal,2011,55(4):618-644.
[3]杜冠华,吕扬.仿制药一致性评价相关药物晶型的问题分析[J].医药导报,2017,36(6):593-596.
[4]应剑,吕扬,杜冠华.固体药物无定型状态的研究进展[J].药学学报,2009,44(5):443-448.
[5]黄耀辉,尹秋响,张霞,等.药物共晶的合成和结构分析[J].化工学报,2017,68(2):509-518.
[6]王义成,冯成亮,杨素勤,等.药物共晶的最新研究进展[J].药学进展,2013,37(3):120-130.
[7]Lee AY,Erdemir D,Myerson AS.Crystal polymorphism in chemical process development[J].Annu Rev Chem Biomol Eng,2011,2:259-280.
[8]Singhal D,Curatolo W.Drug polymorphism and dosage form design:a practical perspective[J].Adv Drug Deliv Rev,2004,56(3):335-347.
[9]杜冠华,吕扬.固体化学药物的优势药物晶型[J].中国药学杂志,2010,45(1):5-10.
[10]Ostwald W.The formation and changes of solids[J].Z Phys Chem,1987,22:289-330.
[11]Erdemir D,Lee AY,Myerson AS.Polymorph selection:the role of nucleation,crystal growth and molecular modeling[J].Curr Opin DrugDiscov Devel,2007,10(6):746-755.
[12]Mullin JW.Crystallization[M].Oxford:ButterworthHeinemann,2001.
[13]Cote A,Zhou G,Stanik M.A novel crystallization methodology to ensure isolation of the most stable crystal form[J].Org Process Res Dev,2009,13(6):1276-1283.
[14]Hansen TB,Taris A,Rong BG,et al.Polymorphic behavior of isonicotinamide in cooling crystallization from various solvents[J].J Cryst Growth,2016,450:81-90.
[15]Parambil JV,Poornachary SK,Tan RBH,et al.Influence of solvent polarity and supersaturation on template-induced nucleation of carbamazepine crystal polymorphs[J].J Cryst Growth,2017,469:84-90.
[16]Hamad S,Moon C,Catlow CRA,et al.Kinetic insights into the role of the solvent in the polymorphism of 5-fluorouracil from molecular dynamics simulations[J].J Phys Chem B,2006,110(7):3323-3329.
[17]Myerson AS,Trout BL.Nucleation from solution[J].Science,2013,341(6148):855-856.
[18]Di Profio G,Caridi A,Caliandro R,et al.Fine dosage of antisolvent in the crystallization of L-histidine:effect on polymorphism[J].Cryst Growth Des,2010,10(1):449-455.
[19]刘玉敏,杜世超,王海生,等.头孢菌素类抗生素溶剂化物研究进展[J].中国抗生素杂志,2016,41(3):1 16-165.
[20]Lee AY,Lee IS,Dettet SS,et al.Crystallization on confined engineered surfaces:a method to control crystal size and generate different polymorphs[J].J Am Chem Soc,2005,127(43):14982-14983.
[21]Kitamura M.Controlling factor of polymorphism in crystallization process[J].J Cryst Growth,2002,237:2205-2214.
[22]Yu L,Nucleation of one polymorph by another[J].J Am Chem Soc,2003,125(21):6380-6381.
[23]龚俊波,王琦,董伟兵,等.药物晶型转化与控制的研究进展[J].化工学报,2013,64(2):385-392.
[24]Zhang GGZ,Law D,Schmitt EA,et al.Phase transformation considerations during process development and manufacture of solid oral dosage forms[J].Adv Drug Deliv Rev,2004,56(3):371-390.
[25]葛纪龙,董秀忠,孙柏旺,等.盐酸文拉法辛多晶型现象的研究[J].中国医药工业杂志,2009,40(5):361-364.
[26]Fischer F,Greiser S,Pfeifer D,et al.Mechanochemicallyinduced conversion of crystalline benzamide polymorphs by seeding[J].Angew Chem Int Ed Engl,2016,55(46):14281-14285.
[27]Zhou G,Moment A,Cuff J,et al.Process development and control with recent new FBRM,PVM,and IR[J].Org Process Res Dev,2015,19(1):227-235.
[28]Barrett P,Smith B,Worlitschek J,et al.A review of the use of process analytical technology for the understanding and optimization of production batch crystallization processes[J].Org Process Res Dev,2005,9(3):348-355.
[29]Yu LX,Lionberger RA,Raw AS,et al.Applications of process analytical technology to crystallization processes[J].Adv Drug Deliv Rev,2004,56(3):349-369.
[30]Ruf A,Worlitschek J,Mazzotti M.Modeling and experimental analysis of PSD measurements through FBRM[J].Part Part Syst Char,2000,17(4):167-179.
[31]Heath AR,Fawell PD,Bahri PA,et al.Estimating average particle size by focused beam reflectance measurement(FBRM)[J].Part Part Syst Char,2002,19(2):84-95.
[32]Barrett P,Glennon B.In-line FBRM monitoring of particle size in dilute agitated suspensions[J].Part Part Syst Char,1999,16(5):207-211.
[33]Barrett P,Glennon B.Characterizing the metastable zone width and solubility curve using lasentec FBRM and PVM[J].Chem Eng Res Des,2002,80(7):799-805.
[34]Nagy ZK,Fujiwara M,Woo XY,et al.Determination of the kinetic parameters for the crystallization of paracetamol from water using metastable zone width experiments[J].Ind Eng Chem Res,2008,47(4):1245-1252.
[35]何元.在线监测化合物结晶的先进技术——在线颗粒度监测[J].中国医药工业杂志,2006,37(4):317.
[36]Zhang FK,Liu T,Wang XZ,et al.Comparative study on ATR-FTIR calibration models for monitoring solution concentration in cooling crystallization[J].J Cryst Growth,2017,459:50-55.
[37]Cornel J,Lindenberg C,Mazzotti M.Quantitative application of in situ ATR-FTIR and Raman spectroscopy in crystallization processes[J].Ind Eng Chem Res,2008,47(14):4870-4882.
[38]Duffy D,Barrett M,Glennon B.Novel,calibrationfree strategies for supersaturation control in antisolvent crystallization processes[J].Cryst Growth Des,2013,13(8):3321-3332.
[39]Wu HQ,Dong ZD,Li HT,et al.An integrated process analytical technology(PAT)approach for pharmaceutical crystallization process understanding to ensure product quality and safety:FDA scientist's perspective[J].Org Process Res Dev,2015,19(1):89-101.
[40]叶晓霞,刘茜,耿志旺,等.拉曼光谱法检测拉米夫定晶型Ⅰ[J].中国医药工业杂志,2013,44(01):60-63.
[41]Pienack N,Bensch W.In-situ monitoring of the formation of crystalline solids[J].Angew Chem Int Ed Engl,2011,50(9):2014-2034.
[42]Griffen JA,Owen AW,Matousek P.Development of transmission raman spectroscopy towards the in line,high throughput and non-destructive quantitative analysis of pharmaceutical solid oral dose[J].Analyst,2015,140(1):107-112.
[43]Zhang J,Wang D,Zhang DM,et al.In situ investigation of BaBP05 crystal growth mechanism by high-temperature Raman spectroscopy[J].J Mol Struct,2017,1138:50-54.
[44]Lin SY.Simultaneous screening and detection of pharmaceutical co-crystals by the one-step DSC-FTIR microspectroscpic technique[J].Drug Discov Today,2017,22(4):718-728.
[45]Scholl J,Bonalumi D,Vicum AL,et al.In situ monitoring and modeling of the solvent-mediated polymorphic transformation of L-glutamic acid[J].Cryst Growth Des,2006,6(4):881-891.
[46]Wong SY,Chen J,Forte LE,et al.Compact crystallization,filtration,and drying for the production of active pharmaceutical ingredients[J].Org Process Res Dev,2013,17(4):684-692.
[47]Yang C,Wang X,Yong Y,et al.Passive spiral micromixer and its applications:US,8894966B2[P].2014-11-25.
[48]Duan XX,Feng X,Yang C,et al.Numerical simulation of micro-mixing in stirred reactors using the engulfment model coupled with CFD[J].Chem Eng Sci,2016,140:179-188.
[49]Feng X,Li XY,Cheng JC,et al.Numerical simulation of solid-liquid turbulent flow in a stirred tank with a two-phase explicit algebraic stress model[J].Chem Eng Sci,2012,82:272-284.
[50]Feng X,Cheng JC,Li XY,et al.Numerical simulation of turbulent flow in a baffled stirred tank with an explicit algebraic stress model[J].Chem Eng Sci,2012,69(1):30-44.
[51]Cheng JC,Yang C,Mao ZS.CFD-PBE simulation of premixed continuous precipitation incorporating nucleation,growth and aggregation in a stirred tank with multi-class method[J].Chem Eng Sci,2012,68(1):469-480.
[52]Cheng JC,Yang C,Mao ZS,et al.CFD modeling of nucleation,growth,aggregation,and breakage in continuous precipitation of barium sulfate in a stirred tank[J].Ind Eng Chem Res,2009,48(15):6992-7003.
[53]Cheng JC,Yang C,Jiang M,et al.Simulation of antisolvent crystallization in impinging jets with coupled multiphase flow-micromixing-PBE[J].Chem Eng Sci,2017,171:500-512.
[54]李涛,任国宾.蛋氨酸的连续结晶过程[J].中国医药工业杂志,2014,45(10):973-977.
[55]Wong SY,Tatusko AP,Trout BL,et al.Development of continuous crystallization processes using a single-stage mixed-suspension,mixed-product removal crystallizer with recycle[J].Cryst Growth Des,2012,12(11):5701-5707.
[56]李涛,任国宾,王尚君.连续结晶在医药工业中的应用[J].中国医药指南,2013,11(34):605-607.
[57]Wang DG,Li ZB.Gas-liquid reactive crystallization kinetics of hydromagnesite in the MgCl_2-CO_2-NH3-H_2O system:its potential in CO_2 sequestration[J].Ind Eng Chem Res,2012,51(50):16299-16310.
[58]Su QL,Powell KA,Rielly CD,et al.Mathematical modelling and experimental validation of a novel periodic flow crystallization using MSMPR crystallizers[J].AIChE J,2017,63(4):1313-1327.
[59]Alvarez AJ,Singh A,Myerson AS.Crystallization of cyclosporine in a multistage continuous MSMPR crystallizer[J].Cryst Growth Des,2011,11(10):4392-4400.
[60]黄青山,张伟鹏,杨超,等.环流反应器的流动、混合与传递特性[J].化工学报,2014,65(7):2465-2473.
[61]Myerson AS,Anderson SR,Bennett RC,et al.Handbook of industrial crystallization[M].Oxford:ButterworthHeinemann,2001.
[62]尹秋响,王静康,王永莉.MSMPR连续结晶器的多定态[J].化工学报,1997,48(6):692-697.
[63]武首香,沙作良.不同操作条件下连续结晶过程的CFD模拟[J].化学工程,2013,41(6):13-17.
[64]张梦华,李小松,罗妍,等.工业结晶器内流体流动过程的数值模拟[J].华东理工大学学报(自然科学版),2010,36(1):14-19.
[65]王先恒,许巧珊,赵长阔.基于专利分析的我国药物晶型进展研究[J].中国新药杂志,2017,26(8):845-850.
[2]Chieng N,Rades T,Aaltonen J.An overview of recent studies on the analysis of pharmaceutical polymorphs[J].J Pharm Biomed Anal,2011,55(4):618-644.
[3]杜冠华,吕扬.仿制药一致性评价相关药物晶型的问题分析[J].医药导报,2017,36(6):593-596.
[4]应剑,吕扬,杜冠华.固体药物无定型状态的研究进展[J].药学学报,2009,44(5):443-448.
[5]黄耀辉,尹秋响,张霞,等.药物共晶的合成和结构分析[J].化工学报,2017,68(2):509-518.
[6]王义成,冯成亮,杨素勤,等.药物共晶的最新研究进展[J].药学进展,2013,37(3):120-130.
[7]Lee AY,Erdemir D,Myerson AS.Crystal polymorphism in chemical process development[J].Annu Rev Chem Biomol Eng,2011,2:259-280.
[8]Singhal D,Curatolo W.Drug polymorphism and dosage form design:a practical perspective[J].Adv Drug Deliv Rev,2004,56(3):335-347.
[9]杜冠华,吕扬.固体化学药物的优势药物晶型[J].中国药学杂志,2010,45(1):5-10.
[10]Ostwald W.The formation and changes of solids[J].Z Phys Chem,1987,22:289-330.
[11]Erdemir D,Lee AY,Myerson AS.Polymorph selection:the role of nucleation,crystal growth and molecular modeling[J].Curr Opin DrugDiscov Devel,2007,10(6):746-755.
[12]Mullin JW.Crystallization[M].Oxford:ButterworthHeinemann,2001.
[13]Cote A,Zhou G,Stanik M.A novel crystallization methodology to ensure isolation of the most stable crystal form[J].Org Process Res Dev,2009,13(6):1276-1283.
[14]Hansen TB,Taris A,Rong BG,et al.Polymorphic behavior of isonicotinamide in cooling crystallization from various solvents[J].J Cryst Growth,2016,450:81-90.
[15]Parambil JV,Poornachary SK,Tan RBH,et al.Influence of solvent polarity and supersaturation on template-induced nucleation of carbamazepine crystal polymorphs[J].J Cryst Growth,2017,469:84-90.
[16]Hamad S,Moon C,Catlow CRA,et al.Kinetic insights into the role of the solvent in the polymorphism of 5-fluorouracil from molecular dynamics simulations[J].J Phys Chem B,2006,110(7):3323-3329.
[17]Myerson AS,Trout BL.Nucleation from solution[J].Science,2013,341(6148):855-856.
[18]Di Profio G,Caridi A,Caliandro R,et al.Fine dosage of antisolvent in the crystallization of L-histidine:effect on polymorphism[J].Cryst Growth Des,2010,10(1):449-455.
[19]刘玉敏,杜世超,王海生,等.头孢菌素类抗生素溶剂化物研究进展[J].中国抗生素杂志,2016,41(3):1 16-165.
[20]Lee AY,Lee IS,Dettet SS,et al.Crystallization on confined engineered surfaces:a method to control crystal size and generate different polymorphs[J].J Am Chem Soc,2005,127(43):14982-14983.
[21]Kitamura M.Controlling factor of polymorphism in crystallization process[J].J Cryst Growth,2002,237:2205-2214.
[22]Yu L,Nucleation of one polymorph by another[J].J Am Chem Soc,2003,125(21):6380-6381.
[23]龚俊波,王琦,董伟兵,等.药物晶型转化与控制的研究进展[J].化工学报,2013,64(2):385-392.
[24]Zhang GGZ,Law D,Schmitt EA,et al.Phase transformation considerations during process development and manufacture of solid oral dosage forms[J].Adv Drug Deliv Rev,2004,56(3):371-390.
[25]葛纪龙,董秀忠,孙柏旺,等.盐酸文拉法辛多晶型现象的研究[J].中国医药工业杂志,2009,40(5):361-364.
[26]Fischer F,Greiser S,Pfeifer D,et al.Mechanochemicallyinduced conversion of crystalline benzamide polymorphs by seeding[J].Angew Chem Int Ed Engl,2016,55(46):14281-14285.
[27]Zhou G,Moment A,Cuff J,et al.Process development and control with recent new FBRM,PVM,and IR[J].Org Process Res Dev,2015,19(1):227-235.
[28]Barrett P,Smith B,Worlitschek J,et al.A review of the use of process analytical technology for the understanding and optimization of production batch crystallization processes[J].Org Process Res Dev,2005,9(3):348-355.
[29]Yu LX,Lionberger RA,Raw AS,et al.Applications of process analytical technology to crystallization processes[J].Adv Drug Deliv Rev,2004,56(3):349-369.
[30]Ruf A,Worlitschek J,Mazzotti M.Modeling and experimental analysis of PSD measurements through FBRM[J].Part Part Syst Char,2000,17(4):167-179.
[31]Heath AR,Fawell PD,Bahri PA,et al.Estimating average particle size by focused beam reflectance measurement(FBRM)[J].Part Part Syst Char,2002,19(2):84-95.
[32]Barrett P,Glennon B.In-line FBRM monitoring of particle size in dilute agitated suspensions[J].Part Part Syst Char,1999,16(5):207-211.
[33]Barrett P,Glennon B.Characterizing the metastable zone width and solubility curve using lasentec FBRM and PVM[J].Chem Eng Res Des,2002,80(7):799-805.
[34]Nagy ZK,Fujiwara M,Woo XY,et al.Determination of the kinetic parameters for the crystallization of paracetamol from water using metastable zone width experiments[J].Ind Eng Chem Res,2008,47(4):1245-1252.
[35]何元.在线监测化合物结晶的先进技术——在线颗粒度监测[J].中国医药工业杂志,2006,37(4):317.
[36]Zhang FK,Liu T,Wang XZ,et al.Comparative study on ATR-FTIR calibration models for monitoring solution concentration in cooling crystallization[J].J Cryst Growth,2017,459:50-55.
[37]Cornel J,Lindenberg C,Mazzotti M.Quantitative application of in situ ATR-FTIR and Raman spectroscopy in crystallization processes[J].Ind Eng Chem Res,2008,47(14):4870-4882.
[38]Duffy D,Barrett M,Glennon B.Novel,calibrationfree strategies for supersaturation control in antisolvent crystallization processes[J].Cryst Growth Des,2013,13(8):3321-3332.
[39]Wu HQ,Dong ZD,Li HT,et al.An integrated process analytical technology(PAT)approach for pharmaceutical crystallization process understanding to ensure product quality and safety:FDA scientist's perspective[J].Org Process Res Dev,2015,19(1):89-101.
[40]叶晓霞,刘茜,耿志旺,等.拉曼光谱法检测拉米夫定晶型Ⅰ[J].中国医药工业杂志,2013,44(01):60-63.
[41]Pienack N,Bensch W.In-situ monitoring of the formation of crystalline solids[J].Angew Chem Int Ed Engl,2011,50(9):2014-2034.
[42]Griffen JA,Owen AW,Matousek P.Development of transmission raman spectroscopy towards the in line,high throughput and non-destructive quantitative analysis of pharmaceutical solid oral dose[J].Analyst,2015,140(1):107-112.
[43]Zhang J,Wang D,Zhang DM,et al.In situ investigation of BaBP05 crystal growth mechanism by high-temperature Raman spectroscopy[J].J Mol Struct,2017,1138:50-54.
[44]Lin SY.Simultaneous screening and detection of pharmaceutical co-crystals by the one-step DSC-FTIR microspectroscpic technique[J].Drug Discov Today,2017,22(4):718-728.
[45]Scholl J,Bonalumi D,Vicum AL,et al.In situ monitoring and modeling of the solvent-mediated polymorphic transformation of L-glutamic acid[J].Cryst Growth Des,2006,6(4):881-891.
[46]Wong SY,Chen J,Forte LE,et al.Compact crystallization,filtration,and drying for the production of active pharmaceutical ingredients[J].Org Process Res Dev,2013,17(4):684-692.
[47]Yang C,Wang X,Yong Y,et al.Passive spiral micromixer and its applications:US,8894966B2[P].2014-11-25.
[48]Duan XX,Feng X,Yang C,et al.Numerical simulation of micro-mixing in stirred reactors using the engulfment model coupled with CFD[J].Chem Eng Sci,2016,140:179-188.
[49]Feng X,Li XY,Cheng JC,et al.Numerical simulation of solid-liquid turbulent flow in a stirred tank with a two-phase explicit algebraic stress model[J].Chem Eng Sci,2012,82:272-284.
[50]Feng X,Cheng JC,Li XY,et al.Numerical simulation of turbulent flow in a baffled stirred tank with an explicit algebraic stress model[J].Chem Eng Sci,2012,69(1):30-44.
[51]Cheng JC,Yang C,Mao ZS.CFD-PBE simulation of premixed continuous precipitation incorporating nucleation,growth and aggregation in a stirred tank with multi-class method[J].Chem Eng Sci,2012,68(1):469-480.
[52]Cheng JC,Yang C,Mao ZS,et al.CFD modeling of nucleation,growth,aggregation,and breakage in continuous precipitation of barium sulfate in a stirred tank[J].Ind Eng Chem Res,2009,48(15):6992-7003.
[53]Cheng JC,Yang C,Jiang M,et al.Simulation of antisolvent crystallization in impinging jets with coupled multiphase flow-micromixing-PBE[J].Chem Eng Sci,2017,171:500-512.
[54]李涛,任国宾.蛋氨酸的连续结晶过程[J].中国医药工业杂志,2014,45(10):973-977.
[55]Wong SY,Tatusko AP,Trout BL,et al.Development of continuous crystallization processes using a single-stage mixed-suspension,mixed-product removal crystallizer with recycle[J].Cryst Growth Des,2012,12(11):5701-5707.
[56]李涛,任国宾,王尚君.连续结晶在医药工业中的应用[J].中国医药指南,2013,11(34):605-607.
[57]Wang DG,Li ZB.Gas-liquid reactive crystallization kinetics of hydromagnesite in the MgCl_2-CO_2-NH3-H_2O system:its potential in CO_2 sequestration[J].Ind Eng Chem Res,2012,51(50):16299-16310.
[58]Su QL,Powell KA,Rielly CD,et al.Mathematical modelling and experimental validation of a novel periodic flow crystallization using MSMPR crystallizers[J].AIChE J,2017,63(4):1313-1327.
[59]Alvarez AJ,Singh A,Myerson AS.Crystallization of cyclosporine in a multistage continuous MSMPR crystallizer[J].Cryst Growth Des,2011,11(10):4392-4400.
[60]黄青山,张伟鹏,杨超,等.环流反应器的流动、混合与传递特性[J].化工学报,2014,65(7):2465-2473.
[61]Myerson AS,Anderson SR,Bennett RC,et al.Handbook of industrial crystallization[M].Oxford:ButterworthHeinemann,2001.
[62]尹秋响,王静康,王永莉.MSMPR连续结晶器的多定态[J].化工学报,1997,48(6):692-697.
[63]武首香,沙作良.不同操作条件下连续结晶过程的CFD模拟[J].化学工程,2013,41(6):13-17.
[64]张梦华,李小松,罗妍,等.工业结晶器内流体流动过程的数值模拟[J].华东理工大学学报(自然科学版),2010,36(1):14-19.
[65]王先恒,许巧珊,赵长阔.基于专利分析的我国药物晶型进展研究[J].中国新药杂志,2017,26(8):845-850.