氨噻肟酸结晶过程研究
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摘要
受头孢菌素巨大市场的刺激和推动,国内药物中间体产量得到迅速发展,我国已逐渐成为世界上最主要的头孢菌素医药中间体供应国。目前国内产量比较大的抗生素侧链中间体主要有氨噻肟酸、三嗪环、D-对羟基苯甘氨酸及其邓钾盐等。氨噻肟酸作为多个第三、四代头孢菌素的7位氨基侧链中间体,普遍采用以乙酰乙酸乙酯为原料经过肟化、醚化、溴化、蒸馏、环合、水解、结晶生成含水氨噻肟酸,再经过脱水、过滤、干燥得到无水氨噻肟酸,才可用于合成AE-活性酯或直接用于头孢类药物的合成。
GMP规范认为药物合成过程中中间体的质量对最终产品的质量具有重要的影响,因此对中间体的质量也不断提出更高的要求。近年来,国内氨噻肟酸的生产能力增加十分迅速,但在生产工艺和产品质量等方面仍然存在一些问题。因此,从实验及理论的角度对氨噻肟酸生产过程中的关键工艺步骤进行研究,对于进一步提高氨噻肟酸的产品质量和降低生产成本具有十分重要意义。
虽然国内外的研究人员已经对于氨噻肟酸的合成工艺进行了比较充分的研究,但是对其反应结晶过程和脱水重结晶过程还没有见到相关的文献报道。而结晶工艺水平直接影响了最终产品的质量和收率,在整个氨噻肟酸的生产过程中具有非常重要的地位。为使氨噻肟酸在生产过程中质量和收率保持稳定并减低成本,本文针对氨噻肟酸的反应结晶和脱水重结晶过程进行了系统的实验和理论研究,获得了较好的结果。
首先,对氨噻肟酸的水解反应结晶工艺进行了优化研究,确定了最佳的工艺条件。通过对氨噻肟酸的脱水重结晶过程分析,提出了一种共沸脱水新工艺并进行了实验研究。新脱水工艺得到的氨噻肟酸为立方晶体,平均粒径比原工艺的大,分布也更好。新脱水工艺获得的氨噻肟酸可直接用于下一步的合成,省去原工艺的过滤和烘干工序。这不但减少了过滤和烘干过程造成的氨噻肟酸的损失,提高了产品收率,而且节省设备投资,简化生产过程。
氨噻肟酸通常以含水晶型(晶型-Ⅰ)和无水晶型的方式存在。实验发现,新脱水工艺获得的氨噻肟酸晶型(晶型-Ⅲ)与原工艺获得的氨噻肟酸晶型(晶型-Ⅱ)明显不同。通过使用SEM、TG、DSC、红外光谱、拉曼光谱、X-射线衍射等分析测试方法对氨噻肟酸的晶体结构情况进行表征,确定了三个不同晶型的晶体结构和晶胞参数。晶型Ⅰ(含水晶体)属于单斜晶系,空间群为C2,晶胞参数为a=11.14,b:15.63,c=11.80,α=γ=90.00°,β=96.59°。晶型Ⅱ(原工艺获得的无水晶体)属于正交晶系,空间群为Pbcn,晶胞参数为a=10.86,b=22.29,c=6.54,α=γ=β=90.00°。晶型Ⅲ(新工艺获得的无水晶体)属于正交晶系,空间群为Pbcn,晶胞参数为a=6.65,b=9.89,c:19.03,α=γ=β=90.00°。结果表明氨噻肟酸晶体Ⅲ是一种新晶型,在以往的文献中未见报道。
结晶过程中溶液体系对于产品的晶体晶型和收率具有很大的影响,固液相平衡数据是结晶过程设计与工艺优化的重要依据。为了探索对氨噻肟酸结晶溶液体系进行改进的可能性,本文采用激光法对氨噻肟酸在不同的纯溶剂和混合溶剂(水与甲醇、乙醇、乙二醇)中的结晶固液平衡数据进行了测定。为将氨噻肟酸的溶解度和温度及混合溶剂的初始浓度同时进行关联,本文基于改进的Apelblat方程和Jouyban-Acree模型提出一个新的混合溶剂中溶解度模型。新的混合溶剂模型只是温度和混合溶液的组成的函数,可以不用纯溶剂里的溶解度,直接对药物在不同温度下任意组成的混合溶液中的溶解度进行关联和预测。研究表明,新的混合溶剂模型不仅适用于氨噻肟酸,也可以用于三嗪环、D-对羟基苯甘氨酸及其邓钾盐等药物中间体溶解度数据的关联。
结晶动力学是结晶操作和结晶器设计的基础,本文在间歇的MSMPR结晶器中对氨噻肟酸的反应结晶动力学进行了研究。依据体积无关模型,采用矩量变换法对结晶过程的粒数衡算方程进行了求解,得到了氨噻肟酸成核速率方程和生长速率方程。结果表明,随着过饱和度的增加,晶体生长速率大于成核速率。在一定的范围内,较大的过饱和度和搅拌强度有利于氨噻肟酸晶体的生长。
在氨噻肟酸结晶热力学及结晶动力学实验研究的基础上,建立了氨噻肟酸反应结晶过程的数学模型。以结晶热力学和结晶动力学实验数据为依据对该模型进行了求解。结果表明随着反应结晶温度的升高,氨噻肟酸的初始收率迅速增加,在达到一定时间后,收率趋于稳定,因此继续增加停留时间对于收率没有明显的影响。另外,随着反应结晶温度的升高,氨噻肟酸的晶体粒径增大,但收率降低。在一定的温度和搅拌转速下,盐酸的滴加速率对于氨噻肟酸晶体的粒度和粒度分布几乎没有影响。该模型与实验结果基本一致,可以用于优化氨噻肟酸反应结晶过程的参数,对工业生产具有一定的指导意义。
With the production of pharmaceutical intermediates promoted by the huge market of cephalosporin rapidly development, China has become the world's leading producer of pharmaceutical intermediates. (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (ATMAA), Thiotriazinone (TTZ) and D(-)-p-Hydroxyphenylglycine Dane Salt (D-HPG) etc are among the largest domestic production of the antibiotic side-chain intermediates. ATMAA, is a side-chain intermediate of the third and fourth generation of cephalosporin. ATMAA is generally synthesized from ethyl acetoacetate via a process which includes the following steps:oximation, methylation, bromination, distillation, cyclization, filtration, hydrolysis and reactive crystallization. Finally, anhydrous ATMAA used for the synthesis the AE-active ester or cephalosporin is re-crystallized from the aqueous methanol or ethanol mixtures through dehydration, filtration and drying.
In GMP criterion, the awareness of the effect of the quality of intermediates on the quality of the final products in drug synthesis imposes higher requirements on the quality of intermediates. In recent years, although the production capacity of ATMAA rapidly increasing, there are still some technological and quality problems in its production processes. Therefore, optimzation of the key steps involved in the ATMAA production process based on experimental and theoretical study is necessary and importance for improving the quality of ATMAA and reducing the production cost.
Although there are a number of research reports about the synthesis of ATMAA, the data concerning the reactive crystallization and re-crystallization of ATMAA are scare in the open literature. In fact, the crystallization process is very important in the production of ATMAA since it directly accociated with the quality and yield of ATMAA. Therefore, in this paper experimental and theoretical investigations about the reaction crystallization and dehydration re-crystallization process of ATMAA have been systematically carried out.
The optimal conditions for the hydrolysis reactive crystallization of ATMAA was firstly determined based on experimental studies. Starting from the analysis of the process of the dehydration re-crystallization of ATMAA, a new technology was proposed and was experimentally investigated. The ATMAA crystals obtained using the new technology of dehydration re-crystallization are in the form of cubic, which diameters are larger than that of the ATMAA crystals obtaioned via the original process and. narrowly distributed. Thus obtained dehydrated ATMAA can be directly used for the next step of synthesis, eliminating the filtration and drying steps that are required in the original process. Therefore, the loss of ATMAA in the filtration equipment can be saved, the production process is significantly simplified. As a whole, the production efficiency can be markedly improved.
The crystals of ATMAA can be water-containing (PM-Ⅰ) or water-free polymorph. It has been found that the water-free polymorph obtained with the new dehydration re-crystallization technique (PM-Ⅲ) was totally defferent fron that obtained using the original technique (PM-Ⅱ). It is a new water-free polymorph of ATMAA. The crystalline structure of the three polymorphs of ATMAA has been characterized in terms of SEM, TG, DSC, IR, Raman and XRD techniques. For each polymorph, a crystal system has been assigned and its cell parameters have been determined. PM-Ⅰis monoclinic, with a space group of C2. Its cell parameters are as following:a=11.14, b=15.63, c= 11.80,α=γ=90.00°,β=96.59°. PM-Ⅱis orthorhombic, with a space group of Pbcn. Its cell parameters are as following:a=10.86, b=22.29, c=6.54,α=γ=β= 90.00°. PM-Ⅲis orthorhombic, with a space group of Pbcn, Its cell parameters are as following:a=6.65, b=9.89, c=19.03,α=γ=β= 90.00°.
The solvent system used for crystallization singnificantly influences the form and yield of the product crystals. The data of solid-liquid equilibrium of crystallization systems are the foundamentals for the design and optimaization of crystallization process. In order to probe the possibility of improving the solvent systems of ATMAA crystallization, in this paper, the solid-liquid phase equilibrium data of ATMAA in various solvents and solvent mixture systems (H2O with methanol, ethanol and glycol) have been measured in terms of a laser monitoring observation technique. To regress the solubility data with a medel that involing temperature and initio composition of the solvent mixture, a hybrid model was propose based on Apelblat equation and Jouyban-Acree model. In the hybrid model, the solubility of a solute was represented as a function of the system temperature and the initial composition of a binary solvent mixture. Unlike the Jouyban-Acree model, the hybrid model does not invole the the solubility data of the solute in the corresponding pure solvents. The validity of this model has been verified with the experimental data of ATMAA, and excellent agreement between the experimental and simulated results has been observed. At the same time, this model has been verified with the other drug intermediates like (TTZ) and (D-HPG), excellent agreement between the experimental and simulated results was also obtained.
The reactive crystallization kinetics of ATMAA has been experimentally investigated in a batch dynamic crystallizer. The particle population conservation equation of crystallization process was simplified based on the assumption of particle size independent growth and was solved using moment transformation method. Equations of nucleation rate and crystal growth rate were obtained via regression of the experimental data of ATMAA dynamic crystallization using least square method. The results indicate that with increase of degree of the supersaturation, the rate of crystal growth will exceed the rate of nucleation. As a consequence, higher degree of the supersaturation and higher stirring strength will facilitate the crystal growth of ATMAA.
Based on the analysis of the crystallization process and the thermodynamic as well as the kinetic experimental results, a model that describes the reactive crystallization process of ATMAA in aqueous solution was established. With this model, the reactive crystallization process of ATMAA in aqueous solution has been successfully simulated. The results showed, in the initio period the yield of ATMAA will rapidly increase with increasing time, after a while, it gradually reaches a constant value; further increase of time will not have significant influence on the yield. Increasing temperature will result in an increase of the particle size, but a decrease of the ATMAA yield. The rate of adding HCl solution has basically no effect on the particle size and its distribution. It is expected that the model can be used to optimize the operation parameters of the crystallization process of ATMAA, which provides a guideline for the production of ATMAA.
GMP规范认为药物合成过程中中间体的质量对最终产品的质量具有重要的影响,因此对中间体的质量也不断提出更高的要求。近年来,国内氨噻肟酸的生产能力增加十分迅速,但在生产工艺和产品质量等方面仍然存在一些问题。因此,从实验及理论的角度对氨噻肟酸生产过程中的关键工艺步骤进行研究,对于进一步提高氨噻肟酸的产品质量和降低生产成本具有十分重要意义。
虽然国内外的研究人员已经对于氨噻肟酸的合成工艺进行了比较充分的研究,但是对其反应结晶过程和脱水重结晶过程还没有见到相关的文献报道。而结晶工艺水平直接影响了最终产品的质量和收率,在整个氨噻肟酸的生产过程中具有非常重要的地位。为使氨噻肟酸在生产过程中质量和收率保持稳定并减低成本,本文针对氨噻肟酸的反应结晶和脱水重结晶过程进行了系统的实验和理论研究,获得了较好的结果。
首先,对氨噻肟酸的水解反应结晶工艺进行了优化研究,确定了最佳的工艺条件。通过对氨噻肟酸的脱水重结晶过程分析,提出了一种共沸脱水新工艺并进行了实验研究。新脱水工艺得到的氨噻肟酸为立方晶体,平均粒径比原工艺的大,分布也更好。新脱水工艺获得的氨噻肟酸可直接用于下一步的合成,省去原工艺的过滤和烘干工序。这不但减少了过滤和烘干过程造成的氨噻肟酸的损失,提高了产品收率,而且节省设备投资,简化生产过程。
氨噻肟酸通常以含水晶型(晶型-Ⅰ)和无水晶型的方式存在。实验发现,新脱水工艺获得的氨噻肟酸晶型(晶型-Ⅲ)与原工艺获得的氨噻肟酸晶型(晶型-Ⅱ)明显不同。通过使用SEM、TG、DSC、红外光谱、拉曼光谱、X-射线衍射等分析测试方法对氨噻肟酸的晶体结构情况进行表征,确定了三个不同晶型的晶体结构和晶胞参数。晶型Ⅰ(含水晶体)属于单斜晶系,空间群为C2,晶胞参数为a=11.14,b:15.63,c=11.80,α=γ=90.00°,β=96.59°。晶型Ⅱ(原工艺获得的无水晶体)属于正交晶系,空间群为Pbcn,晶胞参数为a=10.86,b=22.29,c=6.54,α=γ=β=90.00°。晶型Ⅲ(新工艺获得的无水晶体)属于正交晶系,空间群为Pbcn,晶胞参数为a=6.65,b=9.89,c:19.03,α=γ=β=90.00°。结果表明氨噻肟酸晶体Ⅲ是一种新晶型,在以往的文献中未见报道。
结晶过程中溶液体系对于产品的晶体晶型和收率具有很大的影响,固液相平衡数据是结晶过程设计与工艺优化的重要依据。为了探索对氨噻肟酸结晶溶液体系进行改进的可能性,本文采用激光法对氨噻肟酸在不同的纯溶剂和混合溶剂(水与甲醇、乙醇、乙二醇)中的结晶固液平衡数据进行了测定。为将氨噻肟酸的溶解度和温度及混合溶剂的初始浓度同时进行关联,本文基于改进的Apelblat方程和Jouyban-Acree模型提出一个新的混合溶剂中溶解度模型。新的混合溶剂模型只是温度和混合溶液的组成的函数,可以不用纯溶剂里的溶解度,直接对药物在不同温度下任意组成的混合溶液中的溶解度进行关联和预测。研究表明,新的混合溶剂模型不仅适用于氨噻肟酸,也可以用于三嗪环、D-对羟基苯甘氨酸及其邓钾盐等药物中间体溶解度数据的关联。
结晶动力学是结晶操作和结晶器设计的基础,本文在间歇的MSMPR结晶器中对氨噻肟酸的反应结晶动力学进行了研究。依据体积无关模型,采用矩量变换法对结晶过程的粒数衡算方程进行了求解,得到了氨噻肟酸成核速率方程和生长速率方程。结果表明,随着过饱和度的增加,晶体生长速率大于成核速率。在一定的范围内,较大的过饱和度和搅拌强度有利于氨噻肟酸晶体的生长。
在氨噻肟酸结晶热力学及结晶动力学实验研究的基础上,建立了氨噻肟酸反应结晶过程的数学模型。以结晶热力学和结晶动力学实验数据为依据对该模型进行了求解。结果表明随着反应结晶温度的升高,氨噻肟酸的初始收率迅速增加,在达到一定时间后,收率趋于稳定,因此继续增加停留时间对于收率没有明显的影响。另外,随着反应结晶温度的升高,氨噻肟酸的晶体粒径增大,但收率降低。在一定的温度和搅拌转速下,盐酸的滴加速率对于氨噻肟酸晶体的粒度和粒度分布几乎没有影响。该模型与实验结果基本一致,可以用于优化氨噻肟酸反应结晶过程的参数,对工业生产具有一定的指导意义。
With the production of pharmaceutical intermediates promoted by the huge market of cephalosporin rapidly development, China has become the world's leading producer of pharmaceutical intermediates. (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (ATMAA), Thiotriazinone (TTZ) and D(-)-p-Hydroxyphenylglycine Dane Salt (D-HPG) etc are among the largest domestic production of the antibiotic side-chain intermediates. ATMAA, is a side-chain intermediate of the third and fourth generation of cephalosporin. ATMAA is generally synthesized from ethyl acetoacetate via a process which includes the following steps:oximation, methylation, bromination, distillation, cyclization, filtration, hydrolysis and reactive crystallization. Finally, anhydrous ATMAA used for the synthesis the AE-active ester or cephalosporin is re-crystallized from the aqueous methanol or ethanol mixtures through dehydration, filtration and drying.
In GMP criterion, the awareness of the effect of the quality of intermediates on the quality of the final products in drug synthesis imposes higher requirements on the quality of intermediates. In recent years, although the production capacity of ATMAA rapidly increasing, there are still some technological and quality problems in its production processes. Therefore, optimzation of the key steps involved in the ATMAA production process based on experimental and theoretical study is necessary and importance for improving the quality of ATMAA and reducing the production cost.
Although there are a number of research reports about the synthesis of ATMAA, the data concerning the reactive crystallization and re-crystallization of ATMAA are scare in the open literature. In fact, the crystallization process is very important in the production of ATMAA since it directly accociated with the quality and yield of ATMAA. Therefore, in this paper experimental and theoretical investigations about the reaction crystallization and dehydration re-crystallization process of ATMAA have been systematically carried out.
The optimal conditions for the hydrolysis reactive crystallization of ATMAA was firstly determined based on experimental studies. Starting from the analysis of the process of the dehydration re-crystallization of ATMAA, a new technology was proposed and was experimentally investigated. The ATMAA crystals obtained using the new technology of dehydration re-crystallization are in the form of cubic, which diameters are larger than that of the ATMAA crystals obtaioned via the original process and. narrowly distributed. Thus obtained dehydrated ATMAA can be directly used for the next step of synthesis, eliminating the filtration and drying steps that are required in the original process. Therefore, the loss of ATMAA in the filtration equipment can be saved, the production process is significantly simplified. As a whole, the production efficiency can be markedly improved.
The crystals of ATMAA can be water-containing (PM-Ⅰ) or water-free polymorph. It has been found that the water-free polymorph obtained with the new dehydration re-crystallization technique (PM-Ⅲ) was totally defferent fron that obtained using the original technique (PM-Ⅱ). It is a new water-free polymorph of ATMAA. The crystalline structure of the three polymorphs of ATMAA has been characterized in terms of SEM, TG, DSC, IR, Raman and XRD techniques. For each polymorph, a crystal system has been assigned and its cell parameters have been determined. PM-Ⅰis monoclinic, with a space group of C2. Its cell parameters are as following:a=11.14, b=15.63, c= 11.80,α=γ=90.00°,β=96.59°. PM-Ⅱis orthorhombic, with a space group of Pbcn. Its cell parameters are as following:a=10.86, b=22.29, c=6.54,α=γ=β= 90.00°. PM-Ⅲis orthorhombic, with a space group of Pbcn, Its cell parameters are as following:a=6.65, b=9.89, c=19.03,α=γ=β= 90.00°.
The solvent system used for crystallization singnificantly influences the form and yield of the product crystals. The data of solid-liquid equilibrium of crystallization systems are the foundamentals for the design and optimaization of crystallization process. In order to probe the possibility of improving the solvent systems of ATMAA crystallization, in this paper, the solid-liquid phase equilibrium data of ATMAA in various solvents and solvent mixture systems (H2O with methanol, ethanol and glycol) have been measured in terms of a laser monitoring observation technique. To regress the solubility data with a medel that involing temperature and initio composition of the solvent mixture, a hybrid model was propose based on Apelblat equation and Jouyban-Acree model. In the hybrid model, the solubility of a solute was represented as a function of the system temperature and the initial composition of a binary solvent mixture. Unlike the Jouyban-Acree model, the hybrid model does not invole the the solubility data of the solute in the corresponding pure solvents. The validity of this model has been verified with the experimental data of ATMAA, and excellent agreement between the experimental and simulated results has been observed. At the same time, this model has been verified with the other drug intermediates like (TTZ) and (D-HPG), excellent agreement between the experimental and simulated results was also obtained.
The reactive crystallization kinetics of ATMAA has been experimentally investigated in a batch dynamic crystallizer. The particle population conservation equation of crystallization process was simplified based on the assumption of particle size independent growth and was solved using moment transformation method. Equations of nucleation rate and crystal growth rate were obtained via regression of the experimental data of ATMAA dynamic crystallization using least square method. The results indicate that with increase of degree of the supersaturation, the rate of crystal growth will exceed the rate of nucleation. As a consequence, higher degree of the supersaturation and higher stirring strength will facilitate the crystal growth of ATMAA.
Based on the analysis of the crystallization process and the thermodynamic as well as the kinetic experimental results, a model that describes the reactive crystallization process of ATMAA in aqueous solution was established. With this model, the reactive crystallization process of ATMAA in aqueous solution has been successfully simulated. The results showed, in the initio period the yield of ATMAA will rapidly increase with increasing time, after a while, it gradually reaches a constant value; further increase of time will not have significant influence on the yield. Increasing temperature will result in an increase of the particle size, but a decrease of the ATMAA yield. The rate of adding HCl solution has basically no effect on the particle size and its distribution. It is expected that the model can be used to optimize the operation parameters of the crystallization process of ATMAA, which provides a guideline for the production of ATMAA.
引文
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