PCERG-1201结晶过程的研究
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摘要
PCERG-1201是世界卫生组织认可的有效的抗癫痫药物之一。该药具有多晶型现象,目前已知的晶型有四种,分别为Ⅰ,Ⅱ,Ⅲ和Ⅳ型,其中在常温下晶型Ⅲ最稳定。针对厂家生产的PCERG-1201存在的晶体粒度较大,易聚结的问题,本文对PCERG-1201的结晶过程进行了系统研究,以得到最佳工艺条件。
本文首先对PCERG-1201的晶习和晶型进行了研究,应用重结晶法和溶析结晶法进行高通量晶型筛选,采用差示扫描量热仪、热重分析仪、扫描电子显微镜及显微镜等仪器进行了其晶习和晶型的研究,结果表明该药晶型和晶习间没有必然的关系；进一步研究了放大实验中产品的晶习,结果表明：以80%乙醇溶液为结晶溶剂、采用冷却结晶获得的产品晶习较好,多呈片状,无聚结现象。用热分析法初步研究了晶体间的转晶过程,结果表明：晶型Ⅲ向晶型Ⅰ的固态熔融转晶为不可逆过程。
采用动态法对PCERG-1201的结晶热力学进行了研究,分别测定了PCERG-1201在不同单溶剂体系及不同配比的水-乙醇二元溶剂中的溶解度并进行了数据关联,结果良好。同时测定了PCERG-1201结晶过程的介稳区,考察了不同降温速率和搅拌速率对介稳区的影响；结果证明介稳区的宽度随降温速率的增大而逐渐变宽,随搅拌速率的增大而变窄。测定了PCERG-1201冷却结晶过程中的成核诱导期并得出了其固液表面张力。
采用间歇动态法测定了PCERG-1201的冷却结晶的动力学,选用粒度相关模型对动力学结果进行分析。采用MJ2模型建立数学模型并进行实验数据的关联。通过对大量的动力学数据进行分析,得到PCERG-1201冷却结晶过程的成核速率方程和生长速率方程,并对影响冷却结晶的动力学因素进行了分析,结果表明搅拌速率和过饱和比是影响成核速率的主要因素。
针对PCERG-1201生产过程中的产品质量要求,本文对比了溶析结晶和冷却结晶两种工艺,确定选用在80%乙醇溶液中的冷却结晶工艺。同时主要考察了结晶液浓度、加不加晶种、搅拌速率、降温速率、结晶终点温度、老化时间等因素对PCERG-1201的粒度和收率的影响,并最终确定了PCERG-1201的最优冷却结晶工艺条件,得到了晶习为片状、晶型单一、粒度均匀的产品。
PCERG-1201is one of the effective anti-epileptic drugs approved by the World Health Organization, and it shows polymorphisms. Four crystalline forms of PCERG-1201, known as Ⅰ, Ⅱ, Ⅲ and Ⅳ, have been identified, of which form IE is the most stable at room temperature. There are some serious problems in the production process of PCERG-1201, such as relatively large crystal size and tendency of aggregation. In this thesis, an optimized process for the recrystallization of PCERG-1201was presented based on a systematic study of the crystallization processes.
First, the crystal habit and polymorphism of PCERG-1201was studied. Recrystallization method and anti-solvent method were used for high-throughput polymorphism screening, where differential scanning calorimetry thermal, thermal gravimetric analysis analyzer, scanning electron microscopy, and optical microscope were used to study the crystal habit and crystal form. The obtained results showed that there was no definitive relationship between the crystal habit and the crystal form of PCERG-1201. The crystal habit of PCERG-1201was further studied in the scaleup experiments. It was found that products obtained using a cooling crystallization method with80%ethanol as the solvent showed a better crystal habit which was characteristic of plate shape and no aggregation. Thermal analysis method was used to study the process of crystal transformation, and irreversible solid-state melting transition from form I to form Ⅲ was observed.
Dynamic method was used to study the thermodynamics of the crystallization of PCERG-1201by measuring its solubility in various single solvent and water-ethanol binary system with various proportions. The solubility data was then analyzed, and a good correlation was obtained. At the same time, the metastable zone of the crystallization process was determined. Specifically, the effect of the cooling rate and stirring rate on the metastable zone was evaluated; the results showed that the metastable zone with the cooling rate increases gradually widened, with the stirring rate increases narrowed. The nucleation induction period during the cooling crystallization process was determined, and the solid-liquid surface tension was calculated.
Batch dynamic method was used to study the cooling crystallization dynamics profile of PCERG-1201. MJ2model, the commonly used model, was used to analyze the experimental data to obtain the nucleation rate equation and the growth rate equation. It turned out that the cooling crystallization kinetics, stirring speed and supersaturation ratio were the main factors which may affect the crystal growth process. The process of crystal growth was under the control of surface reaction.
Aim to obtain the qualified product of PCERG-1201, two crystallization methods including anti-solvent crystallization and cooling crystallization were studied. The results showed that the optimized crystallization process was using80%ethanol as the solvent by the cooling crystallization method. The factors, such as crystallization concentration, plus without seed, stirring rate, cooling rate, crystallization end temperature, aging time, which could affect the particle size and yield of PCERG-1201were also studied. The optimized crystallization conditions were determined, and the products were characteristic of plate shape with uniform size to fulfill the demand of the client.
本文首先对PCERG-1201的晶习和晶型进行了研究,应用重结晶法和溶析结晶法进行高通量晶型筛选,采用差示扫描量热仪、热重分析仪、扫描电子显微镜及显微镜等仪器进行了其晶习和晶型的研究,结果表明该药晶型和晶习间没有必然的关系；进一步研究了放大实验中产品的晶习,结果表明：以80%乙醇溶液为结晶溶剂、采用冷却结晶获得的产品晶习较好,多呈片状,无聚结现象。用热分析法初步研究了晶体间的转晶过程,结果表明：晶型Ⅲ向晶型Ⅰ的固态熔融转晶为不可逆过程。
采用动态法对PCERG-1201的结晶热力学进行了研究,分别测定了PCERG-1201在不同单溶剂体系及不同配比的水-乙醇二元溶剂中的溶解度并进行了数据关联,结果良好。同时测定了PCERG-1201结晶过程的介稳区,考察了不同降温速率和搅拌速率对介稳区的影响；结果证明介稳区的宽度随降温速率的增大而逐渐变宽,随搅拌速率的增大而变窄。测定了PCERG-1201冷却结晶过程中的成核诱导期并得出了其固液表面张力。
采用间歇动态法测定了PCERG-1201的冷却结晶的动力学,选用粒度相关模型对动力学结果进行分析。采用MJ2模型建立数学模型并进行实验数据的关联。通过对大量的动力学数据进行分析,得到PCERG-1201冷却结晶过程的成核速率方程和生长速率方程,并对影响冷却结晶的动力学因素进行了分析,结果表明搅拌速率和过饱和比是影响成核速率的主要因素。
针对PCERG-1201生产过程中的产品质量要求,本文对比了溶析结晶和冷却结晶两种工艺,确定选用在80%乙醇溶液中的冷却结晶工艺。同时主要考察了结晶液浓度、加不加晶种、搅拌速率、降温速率、结晶终点温度、老化时间等因素对PCERG-1201的粒度和收率的影响,并最终确定了PCERG-1201的最优冷却结晶工艺条件,得到了晶习为片状、晶型单一、粒度均匀的产品。
PCERG-1201is one of the effective anti-epileptic drugs approved by the World Health Organization, and it shows polymorphisms. Four crystalline forms of PCERG-1201, known as Ⅰ, Ⅱ, Ⅲ and Ⅳ, have been identified, of which form IE is the most stable at room temperature. There are some serious problems in the production process of PCERG-1201, such as relatively large crystal size and tendency of aggregation. In this thesis, an optimized process for the recrystallization of PCERG-1201was presented based on a systematic study of the crystallization processes.
First, the crystal habit and polymorphism of PCERG-1201was studied. Recrystallization method and anti-solvent method were used for high-throughput polymorphism screening, where differential scanning calorimetry thermal, thermal gravimetric analysis analyzer, scanning electron microscopy, and optical microscope were used to study the crystal habit and crystal form. The obtained results showed that there was no definitive relationship between the crystal habit and the crystal form of PCERG-1201. The crystal habit of PCERG-1201was further studied in the scaleup experiments. It was found that products obtained using a cooling crystallization method with80%ethanol as the solvent showed a better crystal habit which was characteristic of plate shape and no aggregation. Thermal analysis method was used to study the process of crystal transformation, and irreversible solid-state melting transition from form I to form Ⅲ was observed.
Dynamic method was used to study the thermodynamics of the crystallization of PCERG-1201by measuring its solubility in various single solvent and water-ethanol binary system with various proportions. The solubility data was then analyzed, and a good correlation was obtained. At the same time, the metastable zone of the crystallization process was determined. Specifically, the effect of the cooling rate and stirring rate on the metastable zone was evaluated; the results showed that the metastable zone with the cooling rate increases gradually widened, with the stirring rate increases narrowed. The nucleation induction period during the cooling crystallization process was determined, and the solid-liquid surface tension was calculated.
Batch dynamic method was used to study the cooling crystallization dynamics profile of PCERG-1201. MJ2model, the commonly used model, was used to analyze the experimental data to obtain the nucleation rate equation and the growth rate equation. It turned out that the cooling crystallization kinetics, stirring speed and supersaturation ratio were the main factors which may affect the crystal growth process. The process of crystal growth was under the control of surface reaction.
Aim to obtain the qualified product of PCERG-1201, two crystallization methods including anti-solvent crystallization and cooling crystallization were studied. The results showed that the optimized crystallization process was using80%ethanol as the solvent by the cooling crystallization method. The factors, such as crystallization concentration, plus without seed, stirring rate, cooling rate, crystallization end temperature, aging time, which could affect the particle size and yield of PCERG-1201were also studied. The optimized crystallization conditions were determined, and the products were characteristic of plate shape with uniform size to fulfill the demand of the client.
引文
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[9]Mitsutaka Kitamura. Controlling factor of polymorphism in crystallization process[J]. Journal of Crystal Growth,2002:237～239
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[2]王静康.结晶.化学工程手册[M].化学工业出版社,1996
[3]Shekunov BY, York P. Crystallization processes in pharmaceutical technology and drug delivery design[J]. Journal of Crystal Growth,2000,211(1-4):122～136
[4]任国宾,王静康,徐昭.同质多晶现象[J].中国抗生素杂志,2005,30(1)：32～37
[5]赵茜,陈永泉,等.抗生素结晶工艺优化方法[J].国外医药：抗生素分册,2001,22(5)：207～210
[6]王静康,黄向荣,刘秉文等.有机分子晶体晶习预测的研究进展[N].人工晶体学报,2002,31(3)：218～223
[7]Lu XJ, Yang X. Characterization and selective crystallization of famotidine polymorphs[J]. Pharm Sci,2007,96:2457-2468
[8]Lu J, Rohani S. Polymorphism and crystallization of active pharmaceutical ingredients(APIs)[J]. Curr Med Chem,2009,16:884～905
[9]Mitsutaka Kitamura. Controlling factor of polymorphism in crystallization process[J]. Journal of Crystal Growth,2002:237～239
[10]宋彦梅.甘氨酸结晶过程及多晶型现象研究[D].[硕士学位论文].天津：天津大学,2004
[11]王钰莹,刘晓谦,王智民,张启伟,高慧敏.药物多晶型分析方法的研究进展[C].In：第三届中国晶型药物研发技术研讨会暨中国晶体学会药物晶体学专业委员会成立大会论文集,2011
[12]左志辉.热分析法在药学研究中的最新进展[J].中国药品标准,2004,(01)：14～17
[13]王晶,黄荣清,肖炳坤等.药物多晶型研究中的分析技术[J].药物分析杂志,2007,(03)：464～469
[14]David E. Bugay. Characterization of the solid-sate:Spectroscopic techniques[J]. Adv Drug Delivery Rev,2001,48:43～65
[15]王明.甘氨酸多晶型现象与产品结块机理的研究[D].[硕士学位论文].天津：天津大学,2007
[16]Park K. Crystallization:The study of Kinetics, Solubility, Polymorphism and Phase Transitions Using Defferential Scanning Calorimetry[D]. doctor, chemical engineering,2003
[17]武洁花.头孢唑林钠结晶过程研究[D].[博士学位论文].天津：天津大学,2007
[18]Mohan R, H. Lorenz, S. Myerson A. Solubility measurement using differential scanning calorimetry[J]. IndEngChem Res,2002,41:4854～4862
[19]姜萍萍.离子液体诱导溶菌酶结晶及机理研究[D].[硕士学位论文].天津：天津大学,2010
[20]丁绪淮,谈遒.工业结晶[M]：化学工业出版社,1985
[21]张海涛.头孢噻肟钠结晶技术研究[D].[博士学位论文].天津：天津大学,2008
[22]Kim KJ, Mersmann A. Estimation of metastable zone width in different nucleation processes[J]. Chemical Engineering Science.2001,56(7):2315～2324
[23]Mersmann K, Bartosch. How to predict the metastable zone width[J]. Crystal Growth,1998,183(1-2):240～250
[24]Cheng F Q, Bai Y, Liu C. Thermodynamic analysis of temperature dependence of the crystal growth rate of potassium sulfate[J]. Ind Eng Chem Res Date,2006, 45(18):6266～6271
[25]Mullin J. W. Crystalization.3r ded[M]. London:Butterworths,1993
[26]W Mullin J. Crystalization[M]. Butterworrth Heinemannn,2000
[27]Christoph M, Rolf L. Secondary nucleation of sodium chlorate studied with the aid of asymmetric crystallization[J]. ChemEngTechnol,1997,20:63～640
[28]J W Mullin. Crystallization[M]. Oxford:Butterworth-Heinemann,2003
[29]王水.7-氨基头孢烷酸反应结晶过程研究[D].[博士学位论文].天津：天津大学,2005
[30]Larson M A, Garside J. Crystallizer design techniques using the population balance[J].The Chemical Engineer,1973:318
[31]J Garside, Jancic S J. Growth and dissolution of potash alum crystals in the subsieve size range[J]. AIChEJ,1976,22(5):887～894
[32]Mahadevan C, Jegatheesan, C. S. Nucleation studies in supersaturated aqueous solutions of chromate doped potassium phosphate[J]. India Chem. Soc,1999.76: 47-48
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