{"title":"利用集成式模块化反应-结晶-球形造粒-过滤-干燥工艺,通过端到端连续生产阿托伐他汀钙实现工艺强化","authors":"Rojan Parvaresh, and , Zoltan K. Nagy*, ","doi":"10.1021/acs.oprd.4c00181","DOIUrl":null,"url":null,"abstract":"<p >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.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"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, and , Zoltan K. Nagy*, \",\"doi\":\"10.1021/acs.oprd.4c00181\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >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.</p>\",\"PeriodicalId\":55,\"journal\":{\"name\":\"Organic Process Research & Development\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2024-06-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Organic Process Research & Development\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.oprd.4c00181\",\"RegionNum\":3,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, APPLIED\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic Process Research & Development","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.oprd.4c00181","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
Process Intensification via End-to-End Continuous Manufacturing of Atorvastatin Calcium Using an Integrated, Modular Reaction-Crystallization-Spherical Agglomeration-Filtration-Drying Process
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.
期刊介绍:
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools,process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.