中药混合过程终点在线判定方法研究
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摘要
混合过程是制剂生产过程的关键环节,它直接影响固体制剂质量的均一性和稳定性。随着《工业过程分析技术指南》的发布,在线分析技术在混合过程应用的研究报道越来越多,但对混合终点在线判断算法的研究尚处于起步阶段。该研究以移动块标准偏差法为原型,建立适于在线应用的混合终点判断方法——递增窗口移动块标准偏差,并将其用于中药配方颗粒混合过程终点的判断。通过在线学习调整窗口大小,将混合过程物料状态的变化实时体现在标准差的计算过程中。在3种不同中药饮片提取物和辅料糊精混合过程的应用中表明,与传统的移动块标准偏差法相比,基于递增窗口移动块标准偏差法计算得到的窗口尺寸变化可以更为清晰地反映混合过程物料状态变异,适于在线应用。
Blending process,which is an essential part of the pharmaceutical preparation,has a direct influence on the homogeneity and stability of solid dosage forms. With the official release of Guidance for Industry PAT,online process analysis techniques have been more and more reported in the applications in blending process,but the research on endpoint detection algorithm is still in the initial stage. By progressively increasing the window size of moving block standard deviation(MBSD),a novel endpoint detection algorithm was proposed to extend the plain MBSD from off-line scenario to online scenario and used to determine the endpoint in the blending process of Chinese medicine dispensing granules. By online learning of window size tuning,the status changes of the materials in blending process were reflected in the calculation of standard deviation in a real-time manner. The proposed method was separately tested in the blending processes of dextrin and three other extracts of traditional Chinese medicine. All of the results have shown that as compared with traditional MBSD method,the window size changes according to the proposed MBSD method(progressively increasing the window size) could more clearly reflect the status changes of the materials in blending process,so it is suitable for online application.
Blending process,which is an essential part of the pharmaceutical preparation,has a direct influence on the homogeneity and stability of solid dosage forms. With the official release of Guidance for Industry PAT,online process analysis techniques have been more and more reported in the applications in blending process,but the research on endpoint detection algorithm is still in the initial stage. By progressively increasing the window size of moving block standard deviation(MBSD),a novel endpoint detection algorithm was proposed to extend the plain MBSD from off-line scenario to online scenario and used to determine the endpoint in the blending process of Chinese medicine dispensing granules. By online learning of window size tuning,the status changes of the materials in blending process were reflected in the calculation of standard deviation in a real-time manner. The proposed method was separately tested in the blending processes of dextrin and three other extracts of traditional Chinese medicine. All of the results have shown that as compared with traditional MBSD method,the window size changes according to the proposed MBSD method(progressively increasing the window size) could more clearly reflect the status changes of the materials in blending process,so it is suitable for online application.
引文
[1]FDA.Guidance for industry powder blends and finished dosage units—stratified in-process dosage unit sampling and assessment[EB/OL].[2017-01-08].http://www.fda.gov/OHRMS/DOCKETS/98fr/03d-0493-gdl0001.pdf.
[2]FDA.Guidance for Industry PAT—A framework for innovative pharmaceutical development,manufacturing,and quality assurance[EB/OL].[2017-01-08].http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070305.pdf.
[3]Scheibelhofer O,Balak N,Wahl P R,et al.Monitoring blending of pharmaceutical powders with multipoint NIR spectroscopy[J].AAPS Pharm Sci Tech,2013,14(1):234.
[4]Vanarase A U,AlcalàM,Rozo J I J,et al.Real-time monitoring of drug concentration in a continuous powder mixing process using NIR spectroscopy[J].Chem Eng Sci,2010,65(21):5728.
[5]Sulub Y,Konigsberger M,Cheney J,Blend uniformity end-point determination using near-infrared spectroscopy and multivariate calibration[J].J Pharmaceut Biomed,2011,55(3):429.
[6]金叶,杨凯,陈木洲,等.微型近红外仪用于众生丸粉末混合过程的在线监测研究[J].中国中药杂志,2011,36(21):2963.
[7]Sasic'S,Blackwood D,Liu A,et al.Detailed analysis of the online near-infrared spectra of pharmaceutical blend in a rotary tablet press feed frame[J].J Pharmaceut Biomed,2015,103:73.
[8]Colón Y M,Florian M A,Acevedo D,et al.Near infrared method development for a continuous manufacturing blending process[J].J Pharm Innov,2014,9(4):291.
[9]De B T,Burggraeve A,Fonteyne M,et al.Near infrared and Raman spectroscopy for the in-process monitoring of pharmaceutical production processes[J].Int J Pharm,2011,417(1/2):32.
[10]De Beer T R,Baeyens W R,Ouyang J,et al.Raman spectroscopy as aprocess analytical technology tool for the understanding and the quantitative in-line monitoring of the homogenization process of a pharmaceutical suspension[J].Analyst,2006,131(10):1137.
[11]De Beer T R,Bodson C,Dejaegher B,et al.Raman spectroscopy as a process analytical technology(PAT)tool for the in-line monitoring and understanding of a powder blending process[J].J Pharmaceut Biomed,2008,48(3):772.
[12]Firkala T,Farkas A,Vajna B,et al.Investigation of drug distribution in tablets using surface enhanced Raman chemical imaging[J].J Pharmaceut Biomed,2013,76(6):145.
[13]Carneiro R L,Poppi R J.Homogeneity study of ointment dosage forms by infrared imaging spectroscopy[J].J PharmaceutBiomed,2012,58(1):42.
[14]Wu Z,Tao O,Dai X,et al.Monitoring of a pharmaceutical blending process using near infrared chemical imaging[J].Vib Spectrosc,2012,63(6):371.
[15]Osorio J G,Stuessy G,Kemeny G J,et al.Characterization of pharmaceutical powder blends using in situ near-infrared chemical imaging[J].Chem Eng Sci,2014,108(17):244.
[16]Momose W,Imai K,Yokota S,et al.Process analytical technology applied for end-point detection of pharmaceutical blending by combining two calibration-free methods:simultaneously monitoring specific near-infrared peak intensity and moving block standard deviation[J].Powder Technol,2011,210(2):122.
[17]Moes J J,Ruijken M M,Gout E,et al.Application of process analytical technology in tablet process development using NIR spectroscopy:blend uniformity,content uniformity and coating thickness measurements[J].Int J Pharm,2008,357(1/2):108.
[18]杨婵,徐冰,张志强,等.基于移动窗F检验法的中药配方颗粒混合均匀度近红外分析研究[J].中国中药杂志,2016,41(19):3557.
[19]陈红英,李琼娅,陈佳乐,等.近红外光谱技术用于正天丸混合过程终点的判断[J].中国实验方剂学杂志,2016(12):13.
[20]Hausman D S,Cambron R T,Sakr A.Application of Raman spectroscopy for on-line monitoring of low dose blend uniformity[J].Int J Pharm,2005,298(1):80.
[21]El-Hagrasy A S,Iii J K D.A process analytical technology approach to near-infrared process control of pharmaceutical powder blending.PartⅢ:quantitative near-infrared calibration for prediction of blend homogeneity and characterization of powder mixing kinetics[J].J Pharm Sci US,2006,95(2):422.
[22]Porfire A,Rus L,Vonica A L,et al.High-throughput NIR-chemometric methods for determination of drug content and pharmaceutical properties of indapamide powder blends for tabletting[J].J Pharmaceut Biomed,2012,70(11):301.
[23]Scheibelhofer O,Balak N,Koller D M,et al.Spatially resolved monitoring of powder mixing processes via multiple NIR-probes[J].Powder Technol,2013,243(7):161.
[24]Karande A D,Heng P W,Liew C V.In-line quantification of micronized drug and excipients in tablets by near infrared(NIR)spectroscopy:real time monitoring of tabletting process[J].Int J Pharm,2010,396(1/2):63.
[25]Puchert T,Holzhauer C V,Menezes J C,et al.A new PAT/Qb D approach for the determination of blend homogeneity:combination of on-line NIRS analysis with PC scores distance analysis(PC-SDA)[J].Eur J Pharm Biophar,2011,78(1):173.
[2]FDA.Guidance for Industry PAT—A framework for innovative pharmaceutical development,manufacturing,and quality assurance[EB/OL].[2017-01-08].http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070305.pdf.
[3]Scheibelhofer O,Balak N,Wahl P R,et al.Monitoring blending of pharmaceutical powders with multipoint NIR spectroscopy[J].AAPS Pharm Sci Tech,2013,14(1):234.
[4]Vanarase A U,AlcalàM,Rozo J I J,et al.Real-time monitoring of drug concentration in a continuous powder mixing process using NIR spectroscopy[J].Chem Eng Sci,2010,65(21):5728.
[5]Sulub Y,Konigsberger M,Cheney J,Blend uniformity end-point determination using near-infrared spectroscopy and multivariate calibration[J].J Pharmaceut Biomed,2011,55(3):429.
[6]金叶,杨凯,陈木洲,等.微型近红外仪用于众生丸粉末混合过程的在线监测研究[J].中国中药杂志,2011,36(21):2963.
[7]Sasic'S,Blackwood D,Liu A,et al.Detailed analysis of the online near-infrared spectra of pharmaceutical blend in a rotary tablet press feed frame[J].J Pharmaceut Biomed,2015,103:73.
[8]Colón Y M,Florian M A,Acevedo D,et al.Near infrared method development for a continuous manufacturing blending process[J].J Pharm Innov,2014,9(4):291.
[9]De B T,Burggraeve A,Fonteyne M,et al.Near infrared and Raman spectroscopy for the in-process monitoring of pharmaceutical production processes[J].Int J Pharm,2011,417(1/2):32.
[10]De Beer T R,Baeyens W R,Ouyang J,et al.Raman spectroscopy as aprocess analytical technology tool for the understanding and the quantitative in-line monitoring of the homogenization process of a pharmaceutical suspension[J].Analyst,2006,131(10):1137.
[11]De Beer T R,Bodson C,Dejaegher B,et al.Raman spectroscopy as a process analytical technology(PAT)tool for the in-line monitoring and understanding of a powder blending process[J].J Pharmaceut Biomed,2008,48(3):772.
[12]Firkala T,Farkas A,Vajna B,et al.Investigation of drug distribution in tablets using surface enhanced Raman chemical imaging[J].J Pharmaceut Biomed,2013,76(6):145.
[13]Carneiro R L,Poppi R J.Homogeneity study of ointment dosage forms by infrared imaging spectroscopy[J].J PharmaceutBiomed,2012,58(1):42.
[14]Wu Z,Tao O,Dai X,et al.Monitoring of a pharmaceutical blending process using near infrared chemical imaging[J].Vib Spectrosc,2012,63(6):371.
[15]Osorio J G,Stuessy G,Kemeny G J,et al.Characterization of pharmaceutical powder blends using in situ near-infrared chemical imaging[J].Chem Eng Sci,2014,108(17):244.
[16]Momose W,Imai K,Yokota S,et al.Process analytical technology applied for end-point detection of pharmaceutical blending by combining two calibration-free methods:simultaneously monitoring specific near-infrared peak intensity and moving block standard deviation[J].Powder Technol,2011,210(2):122.
[17]Moes J J,Ruijken M M,Gout E,et al.Application of process analytical technology in tablet process development using NIR spectroscopy:blend uniformity,content uniformity and coating thickness measurements[J].Int J Pharm,2008,357(1/2):108.
[18]杨婵,徐冰,张志强,等.基于移动窗F检验法的中药配方颗粒混合均匀度近红外分析研究[J].中国中药杂志,2016,41(19):3557.
[19]陈红英,李琼娅,陈佳乐,等.近红外光谱技术用于正天丸混合过程终点的判断[J].中国实验方剂学杂志,2016(12):13.
[20]Hausman D S,Cambron R T,Sakr A.Application of Raman spectroscopy for on-line monitoring of low dose blend uniformity[J].Int J Pharm,2005,298(1):80.
[21]El-Hagrasy A S,Iii J K D.A process analytical technology approach to near-infrared process control of pharmaceutical powder blending.PartⅢ:quantitative near-infrared calibration for prediction of blend homogeneity and characterization of powder mixing kinetics[J].J Pharm Sci US,2006,95(2):422.
[22]Porfire A,Rus L,Vonica A L,et al.High-throughput NIR-chemometric methods for determination of drug content and pharmaceutical properties of indapamide powder blends for tabletting[J].J Pharmaceut Biomed,2012,70(11):301.
[23]Scheibelhofer O,Balak N,Koller D M,et al.Spatially resolved monitoring of powder mixing processes via multiple NIR-probes[J].Powder Technol,2013,243(7):161.
[24]Karande A D,Heng P W,Liew C V.In-line quantification of micronized drug and excipients in tablets by near infrared(NIR)spectroscopy:real time monitoring of tabletting process[J].Int J Pharm,2010,396(1/2):63.
[25]Puchert T,Holzhauer C V,Menezes J C,et al.A new PAT/Qb D approach for the determination of blend homogeneity:combination of on-line NIRS analysis with PC scores distance analysis(PC-SDA)[J].Eur J Pharm Biophar,2011,78(1):173.