Pub Date : 2024-06-28DOI: 10.1021/acs.oprd.4c00143
Nathan B. Bennett, Laurie B. Mlinar, Eric G. Moschetta, Ryan G. Ellis, Ryan Chung, Onkar Manjrekar, Michael Rasmussen, Laura A. McKee, Mark A. Servos, Justin A. Simanis, Bradley D. Gates, Xiaoqiang Shen, Dennie S. Welch, Zhe Wang
The final step in the preparation of the ABBV-154 drug-linker is a global acidic deprotection of three tert-butyl protecting groups that proceeds through several intermediates and is complicated by acetal epimerization, which generates an undesired diastereomer. This complex reaction was initially optimized in a batch setup, but scaling issues prompted the development of a flow process with an impinging jet mixing element. Initial studies utilized commercially available Y-mixers for small-scale experiments; however, clogging of the mixer was difficult to avoid. A three-dimensional (3D) printed Y-mixer impinging jet was created for lab development to avoid this issue and scale down the geometry of the plant-scale jet. The impinging process was executed in the manufacturing environment at kilogram scale, maintaining the desired diastereoselectivity, and reversed-phase chromatography enabled purification of the drug-linker. This paper discusses the key parameters examined to ensure successful scale-up of a mixing-sensitive reaction that demonstrated superior selectivity in flow compared to the batch process.
制备 ABBV-154 药物连接剂的最后一步是对三个叔丁基保护基团进行整体酸性脱保护，这一过程需要经过多个中间体，并因产生非对映异构体的缩醛外延而变得复杂。这种复杂的反应最初是在间歇式装置中进行优化的，但规模问题促使我们开发了一种带有撞击喷射混合元件的流动工艺。最初的研究利用市场上出售的 Y 型混合器进行小规模实验，但很难避免混合器的堵塞。为了避免这一问题并缩小工厂规模喷流的几何尺寸，实验室开发了一种三维（3D）打印的 Y 型混合器撞击喷流。在生产环境中执行公斤级的撞击过程，保持了所需的非对映选择性，并通过反相色谱法纯化了药物连接剂。本文讨论了为确保成功放大对混合敏感的反应而检查的关键参数，与批量工艺相比，该反应在流动过程中表现出更优越的选择性。
{"title":"Use of Impinging Jet to Improve Scalability in the Preparation of the ABBV-154 Drug-Linker","authors":"Nathan B. Bennett, Laurie B. Mlinar, Eric G. Moschetta, Ryan G. Ellis, Ryan Chung, Onkar Manjrekar, Michael Rasmussen, Laura A. McKee, Mark A. Servos, Justin A. Simanis, Bradley D. Gates, Xiaoqiang Shen, Dennie S. Welch, Zhe Wang","doi":"10.1021/acs.oprd.4c00143","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00143","url":null,"abstract":"The final step in the preparation of the ABBV-154 drug-linker is a global acidic deprotection of three <i>tert</i>-butyl protecting groups that proceeds through several intermediates and is complicated by acetal epimerization, which generates an undesired diastereomer. This complex reaction was initially optimized in a batch setup, but scaling issues prompted the development of a flow process with an impinging jet mixing element. Initial studies utilized commercially available Y-mixers for small-scale experiments; however, clogging of the mixer was difficult to avoid. A three-dimensional (3D) printed Y-mixer impinging jet was created for lab development to avoid this issue and scale down the geometry of the plant-scale jet. The impinging process was executed in the manufacturing environment at kilogram scale, maintaining the desired diastereoselectivity, and reversed-phase chromatography enabled purification of the drug-linker. This paper discusses the key parameters examined to ensure successful scale-up of a mixing-sensitive reaction that demonstrated superior selectivity in flow compared to the batch process.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141463975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-28DOI: 10.1021/acs.oprd.4c00197
Xiaoqi Xing, Kangming Zhao, Zhidong Li, Ning Ye, Nan Zhao, Fengfeng Guo, Chunhua Qiao, Guoqiang Xu, Michael Parmentier, Fabrice Gallou, Bin Wu
An environmentally sustainable approach for the Hofmann rearrangement was developed. The presence of nanomicelles allows such a transformation to proceed smoothly in mild conditions with water as the sole reaction medium compared to traditional methods, which use significant amounts of organic solvents. A variety of amides containing functional groups have been constructed under these conditions, affording the compounding amine product in good to excellent yields (up to 99%). The process was scaled up and proven to be robust for its implementation in the synthesis of pharmaceutically relevant compounds.
{"title":"Micelle-Enabled Hofmann Rearrangement in Water","authors":"Xiaoqi Xing, Kangming Zhao, Zhidong Li, Ning Ye, Nan Zhao, Fengfeng Guo, Chunhua Qiao, Guoqiang Xu, Michael Parmentier, Fabrice Gallou, Bin Wu","doi":"10.1021/acs.oprd.4c00197","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00197","url":null,"abstract":"An environmentally sustainable approach for the Hofmann rearrangement was developed. The presence of nanomicelles allows such a transformation to proceed smoothly in mild conditions with water as the sole reaction medium compared to traditional methods, which use significant amounts of organic solvents. A variety of amides containing functional groups have been constructed under these conditions, affording the compounding amine product in good to excellent yields (up to 99%). The process was scaled up and proven to be robust for its implementation in the synthesis of pharmaceutically relevant compounds.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-28DOI: 10.1021/acs.oprd.4c00150
U Bin Kim, Srinivas Samala, Jaehun Jung, Juyoung Song, Kee-Young Lee, Chang-Young Oh, Hyunik Shin
Successful kilogram-scale preparation of the C27–C35 sulfide fragment of Eribulin was presented, which was elaborated with the C14–C26 fragment to produce a proprietary C14–C35 sulfide intermediate. The sulfide group was then oxidized to yield the known C14–C35 sulfone intermediate of Eribulin.
{"title":"Proprietary Synthesis of the C27–C35 Fragment of Eribulin and Its Elaboration toward the C14–C35 Subunit","authors":"U Bin Kim, Srinivas Samala, Jaehun Jung, Juyoung Song, Kee-Young Lee, Chang-Young Oh, Hyunik Shin","doi":"10.1021/acs.oprd.4c00150","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00150","url":null,"abstract":"Successful kilogram-scale preparation of the C27–C35 sulfide fragment of Eribulin was presented, which was elaborated with the C14–C26 fragment to produce a proprietary C14–C35 sulfide intermediate. The sulfide group was then oxidized to yield the known C14–C35 sulfone intermediate of Eribulin.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-27DOI: 10.1021/acs.oprd.4c00160
Georg Wuitschik, Vera Jost, Torsten Schindler, Michal Jakubik
HTE OS is a free, open-source high-throughput experimentation workflow that supports practitioners from experiment submission all the way to results presentation. A core Google Sheet is responsible for reaction planning and execution as well as for communication with users and robots. All generated data are funneled into Spotfire where users analyze it. Tools for parsing of LCMS data and translation of chemical identifiers provide data-wrangling capabilities to complete the workflow.
HTE OS 是一个免费、开源的高通量实验工作流程，可为从业人员提供从实验提交到结果展示的全程支持。一个核心的谷歌工作表负责反应计划和执行，以及与用户和机器人的交流。所有生成的数据都被导入 Spotfire，由用户进行分析。用于解析 LCMS 数据和翻译化学标识符的工具提供了数据整理功能，以完善工作流程。
{"title":"HTE OS: A High-Throughput Experimentation Workflow Built from the Ground Up","authors":"Georg Wuitschik, Vera Jost, Torsten Schindler, Michal Jakubik","doi":"10.1021/acs.oprd.4c00160","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00160","url":null,"abstract":"HTE OS is a free, open-source high-throughput experimentation workflow that supports practitioners from experiment submission all the way to results presentation. A core Google Sheet is responsible for reaction planning and execution as well as for communication with users and robots. All generated data are funneled into Spotfire where users analyze it. Tools for parsing of LCMS data and translation of chemical identifiers provide data-wrangling capabilities to complete the workflow.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-27DOI: 10.1021/acs.oprd.4c00085
Lu Han, Bryan Li, Ke Wang, David B. Damon, Javier Magano, Mark T. Maloney, Jason Mustakis, Ronald J. Post, Ruizhi Li, Truong Nguyen
Danuglipron (PF-06882961), a potent, orally bioavailable small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist, is currently being developed for glycemic control among patients with Type-2 diabetes (J. Med. Chem. 2022, 65, 8208–8226; JAMA Netw. Open. 2023; 6(5): e2314493). The earlier synthesis of danuglipron suffered from chemoselective issues due to the competing nitrile hydrolysis in the final saponification step, which resulted in highly convoluted operations and extensive chromatographic purifications. We found that the methyl ester could be converted to trifluoroethyl ester, and the latter underwent hydrolysis to carboxylic acid in a much cleaner reaction profile. A thorough design of experiments (DOE) was conducted to expand the operating time window of the process to aid the process robustness during manufacturing. The improved process increased the yield by ∼20% and reduced the process mass intensity (PMI) by 86%.
{"title":"Chemoselective Saponification in the Synthesis of Danuglipron Facilitated with Trifluoroethanol","authors":"Lu Han, Bryan Li, Ke Wang, David B. Damon, Javier Magano, Mark T. Maloney, Jason Mustakis, Ronald J. Post, Ruizhi Li, Truong Nguyen","doi":"10.1021/acs.oprd.4c00085","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00085","url":null,"abstract":"Danuglipron (PF-06882961), a potent, orally bioavailable small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist, is currently being developed for glycemic control among patients with Type-2 diabetes (<i>J. Med. Chem. 2022, 65, 8208–8226; JAMA Netw. Open. 2023; 6(5): e2314493</i>). The earlier synthesis of danuglipron suffered from chemoselective issues due to the competing nitrile hydrolysis in the final saponification step, which resulted in highly convoluted operations and extensive chromatographic purifications. We found that the methyl ester could be converted to trifluoroethyl ester, and the latter underwent hydrolysis to carboxylic acid in a much cleaner reaction profile. A thorough design of experiments (DOE) was conducted to expand the operating time window of the process to aid the process robustness during manufacturing. The improved process increased the yield by ∼20% and reduced the process mass intensity (PMI) by 86%.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-25DOI: 10.1021/acs.oprd.4c00142
Nathan B. Bennett, Xiaoqiang Shen, Bradley D. Gates, Dennie S. Welch, Mark A. Servos, Justin A. Simanis, Ryan G. Ellis, Haixiao Qiu, Eric G. Moschetta, Jiajie Feng, Moussa Boukerche, Michael Rasmussen, Laura A. McKee, Laurie B. Mlinar, Shuang Chen, Zhe Wang
Bromoacetamide 1 is a phosphorylated glucocorticoid drug-linker used in conjugation with the monoclonal antibody (mAb) adalimumab to produce the antibody-drug conjugate ABBV-154. A scalable route to drug-linker 1 has been developed that improves upon the first-generation sequence and allows the production of hundreds of grams of material. The new route begins with an acetal formation that incorporates a crystallization eliminating the previous need for reversed-phase chromatography to reject the undesired acetal diastereomer. The dipeptide portion of the linker fragment is then installed in a single transformation. The subsequent product is taken directly into a phosphorylation using a one-pot phosphoramidite displacement and oxidation sequence. Deprotection of a Fmoc group is accompanied by a continuous extraction to remove associated byproducts. The amine is coupled with bromoacetic acid, and a final global deprotection of three t-butyl groups with a reversed-phase purification yields drug-linker.
{"title":"Development and Execution of a Scalable Route to an Immunology ADC Drug-Linker for ABBV-154","authors":"Nathan B. Bennett, Xiaoqiang Shen, Bradley D. Gates, Dennie S. Welch, Mark A. Servos, Justin A. Simanis, Ryan G. Ellis, Haixiao Qiu, Eric G. Moschetta, Jiajie Feng, Moussa Boukerche, Michael Rasmussen, Laura A. McKee, Laurie B. Mlinar, Shuang Chen, Zhe Wang","doi":"10.1021/acs.oprd.4c00142","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00142","url":null,"abstract":"Bromoacetamide <b>1</b> is a phosphorylated glucocorticoid drug-linker used in conjugation with the monoclonal antibody (mAb) adalimumab to produce the antibody-drug conjugate ABBV-154. A scalable route to drug-linker <b>1</b> has been developed that improves upon the first-generation sequence and allows the production of hundreds of grams of material. The new route begins with an acetal formation that incorporates a crystallization eliminating the previous need for reversed-phase chromatography to reject the undesired acetal diastereomer. The dipeptide portion of the linker fragment is then installed in a single transformation. The subsequent product is taken directly into a phosphorylation using a one-pot phosphoramidite displacement and oxidation sequence. Deprotection of a Fmoc group is accompanied by a continuous extraction to remove associated byproducts. The amine is coupled with bromoacetic acid, and a final global deprotection of three <i>t</i>-butyl groups with a reversed-phase purification yields drug-linker.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-25DOI: 10.1021/acs.oprd.4c00155
Hsiao-Wu Hsieh, Daniel J. Griffin, Anirudh M. K. Nambiar, Nandini Sarkar, Hamza Youssef Ismail, Kartik Saigal, Dongying Erin Shen, Nicole Goudas-Salomon, Rasangi Wimalasinghe, Alicia Zeng, Oliver R. Thiel, Matthew G. Beaver
Previously, we reported the development and characterization of an integrated continuous manufacturing (CM) process for the penultimate step in the synthesis of apremilast, the drug substance of Otezla. Herein, we report the application of closed-loop control to this CM process as a case study. A Python-based feedforward closed-loop controller is developed that uses infrared (IR) process analytical technology (PAT) to monitor incoming feed concentrations and then automatically adjusts the downstream feed flow rates in response to disturbances such that near optimal product yield is maintained through the continuous operation. The closed-loop controller was developed and demonstrated on a lab system that replicates the continuous manufacturing skid for apremilast production. In reporting this demonstration, we aim to (1) provide an example of how PAT-based closed-loop control could be beneficially applied to a drug substance CM process and (2) highlight areas where we believe further technical advancement is required to enable such closed-loop control to be successfully deployed in a manufacturing setting.
在此之前，我们曾报道过用于合成 Otezla 药物阿普司特倒数第二步的集成连续制造（CM）工艺的开发和特性分析。在此，我们以案例研究的形式报告了闭环控制在该 CM 过程中的应用。我们开发了一种基于 Python 的前馈闭环控制器，它使用红外（IR）过程分析技术（PAT）来监控进料浓度，然后自动调整下游进料流速以应对干扰，从而在连续操作中保持接近最佳的产品产量。闭环控制器是在实验室系统上开发和演示的，该系统复制了阿普司特生产的连续生产橇。在报告该演示时，我们的目的是：(1) 举例说明如何将基于 PAT 的闭环控制有益地应用于药物 CM 工艺；(2) 强调我们认为需要进一步提高技术的领域，以便在生产环境中成功部署这种闭环控制。
{"title":"PAT-Enabled Automated Feedforward Control: An Application to the Continuous Manufacture of Apremilast","authors":"Hsiao-Wu Hsieh, Daniel J. Griffin, Anirudh M. K. Nambiar, Nandini Sarkar, Hamza Youssef Ismail, Kartik Saigal, Dongying Erin Shen, Nicole Goudas-Salomon, Rasangi Wimalasinghe, Alicia Zeng, Oliver R. Thiel, Matthew G. Beaver","doi":"10.1021/acs.oprd.4c00155","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00155","url":null,"abstract":"Previously, we reported the development and characterization of an integrated continuous manufacturing (CM) process for the penultimate step in the synthesis of apremilast, the drug substance of Otezla. Herein, we report the application of closed-loop control to this CM process as a case study. A Python-based feedforward closed-loop controller is developed that uses infrared (IR) process analytical technology (PAT) to monitor incoming feed concentrations and then automatically adjusts the downstream feed flow rates in response to disturbances such that near optimal product yield is maintained through the continuous operation. The closed-loop controller was developed and demonstrated on a lab system that replicates the continuous manufacturing skid for apremilast production. In reporting this demonstration, we aim to (1) provide an example of how PAT-based closed-loop control could be beneficially applied to a drug substance CM process and (2) highlight areas where we believe further technical advancement is required to enable such closed-loop control to be successfully deployed in a manufacturing setting.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-21DOI: 10.1021/acs.oprd.4c00212
Aaron C. Sather*, and , James J. Douglas*,
{"title":"First Deliveries of API Enabling Early Drug Development","authors":"Aaron C. Sather*, and , James J. Douglas*, ","doi":"10.1021/acs.oprd.4c00212","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00212","url":null,"abstract":"","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141438006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-20DOI: 10.1021/acs.oprd.4c00181
Rojan Parvaresh, Zoltan K. Nagy
Continuous manufacturing can show potential benefits over batch processing in lower turnaround times and smaller footprint in addition to higher productivity, adaptability, and consistent product quality. Although these possible benefits exist, there are also challenges in integrating the various technological steps into a coherent end-to-end continuous system, such as settling, clogging and breakage of particles during transfer, long filtration and drying times and large residence times needed to achieve desired product qualities. This study addresses these difficulties by creating and implementing an end-to-end continuous manufacturing process for atorvastatin calcium (ASC), a statin that is frequently used to treat hypercholesterolemia. The first end-to-end integrated continuous, process involving reaction, crystallization, spherical agglomeration, filtration and drying is presented in this work. This approach uses a novel modular integrated continuous manufacturing system, which is developed to improve control over process parameters for the purpose of producing pharmaceutical compounds. Process intensification is achieved by a holistic integration of novel equipment design such as oscillatory flow crystallizers as well as innovative process development (spherical agglomeration). Both the product quality and the manufacturing efficiency are enhanced as a result. This study aims to ascertain the influence of crucial process parameters on the end product’s quality through an extensive experimental investigation. Process variables, filtration and drying times, were changed, which offered information about how to best optimize the continuous manufacturing process for ASC with and without the spherical agglomeration step. This paper highlights the use of such methodologies in demonstrating the viability and benefits of a novel continuous end-to-end manufacturing process for ASC as it demonstrated significant improvements in cake yield, solvent retention, throughput and productivity and its potential for the future of intensified integrated continuous pharmaceutical manufacturing.
{"title":"Process Intensification via End-to-End Continuous Manufacturing of Atorvastatin Calcium Using an Integrated, Modular Reaction-Crystallization-Spherical Agglomeration-Filtration-Drying Process","authors":"Rojan Parvaresh, Zoltan K. Nagy","doi":"10.1021/acs.oprd.4c00181","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00181","url":null,"abstract":"Continuous manufacturing can show potential benefits over batch processing in lower turnaround times and smaller footprint in addition to higher productivity, adaptability, and consistent product quality. Although these possible benefits exist, there are also challenges in integrating the various technological steps into a coherent end-to-end continuous system, such as settling, clogging and breakage of particles during transfer, long filtration and drying times and large residence times needed to achieve desired product qualities. This study addresses these difficulties by creating and implementing an end-to-end continuous manufacturing process for atorvastatin calcium (ASC), a statin that is frequently used to treat hypercholesterolemia. The first end-to-end integrated continuous, process involving reaction, crystallization, spherical agglomeration, filtration and drying is presented in this work. This approach uses a novel modular integrated continuous manufacturing system, which is developed to improve control over process parameters for the purpose of producing pharmaceutical compounds. Process intensification is achieved by a holistic integration of novel equipment design such as oscillatory flow crystallizers as well as innovative process development (spherical agglomeration). Both the product quality and the manufacturing efficiency are enhanced as a result. This study aims to ascertain the influence of crucial process parameters on the end product’s quality through an extensive experimental investigation. Process variables, filtration and drying times, were changed, which offered information about how to best optimize the continuous manufacturing process for ASC with and without the spherical agglomeration step. This paper highlights the use of such methodologies in demonstrating the viability and benefits of a novel continuous end-to-end manufacturing process for ASC as it demonstrated significant improvements in cake yield, solvent retention, throughput and productivity and its potential for the future of intensified integrated continuous pharmaceutical manufacturing.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141435905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-18DOI: 10.1021/acs.oprd.4c00209
Andrejs Pelšs, Kirill Shubin
Recently, a multitude of modern and short syntheses of various prostanoids were reported, rejuvenating this synthesis field. One such synthesis reported by Aggarwal et al. has good potential for industrialization. Herein, synthesis of bicyclic enal intermediate (Aggarwal enal) was demonstrated on a hectogram scale by finding an appropriate l-proline source which is soluble under overhead stirring conditions in reactor. Kilogram scale synthesis of volatile starting material─succinaldehyde─was achieved in a high yield by finding a suitable isolation method.
{"title":"Scale-Up Investigation of Aggarwal Enal Bicyclic Intermediate Synthesis","authors":"Andrejs Pelšs, Kirill Shubin","doi":"10.1021/acs.oprd.4c00209","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00209","url":null,"abstract":"Recently, a multitude of modern and short syntheses of various prostanoids were reported, rejuvenating this synthesis field. One such synthesis reported by Aggarwal et al. has good potential for industrialization. Herein, synthesis of bicyclic enal intermediate (Aggarwal enal) was demonstrated on a hectogram scale by finding an appropriate <span>l</span>-proline source which is soluble under overhead stirring conditions in reactor. Kilogram scale synthesis of volatile starting material─succinaldehyde─was achieved in a high yield by finding a suitable isolation method.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141334543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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