Organic Process Research & Development最新文献_第2页

Use of Population Balance Modelling to Derisk Scale-Up of an Integrated Crystallization–Wet Milling Process

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-12-16 DOI: 10.1021/acs.oprd.4c00390

Tamar Rosenbaum, Andrew Werneth, Shasad Sharif, Troy Wilkens, Benjamin Cohen, Joshua D. Engstrom, Antonio C. Ferretti, Yash Melkeri

{"title":"Use of Population Balance Modelling to Derisk Scale-Up of an Integrated Crystallization–Wet Milling Process","authors":"Tamar Rosenbaum, Andrew Werneth, Shasad Sharif, Troy Wilkens, Benjamin Cohen, Joshua D. Engstrom, Antonio C. Ferretti, Yash Melkeri","doi":"10.1021/acs.oprd.4c00390","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00390","url":null,"abstract":"Control over the particle size distribution (PSD) of the active pharmaceutical ingredient in the crystallization process is of key importance. Sometimes, it can be challenging to control the PSD to the target value via optimization of the crystallization process alone; in these scenarios, high shear wet milling is often utilized to reduce PSD. Much work has been done developing scaling parameters to be able to robustly scale-up wet milling processes and consistently achieve target PSD at the plant/commercial scale. While different scaling parameters have had good success with guiding scale-up of terminal wet milling processes, wet milling while crystallization is ongoing (i.e., integrated crystallization and wet milling; iCWM) introduces additional complexity to the system, as it couples scale-independent growth with scale-dependent milling and is therefore more difficult to scale-up in a reproducible manner. Herein, we present how population balance modeling of an iCWM process indicated that mill size and batch size, in addition to wet mill tip speed, had a large impact on final PSD. The model predictions can be used to guide selection of wet mill tip speed in order to maintain consistent PSD across different batch sizes and mill sizes.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"6 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833007","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}

引用次数: 0

Overview and Recent Advances in the Purification and Isolation of Therapeutic Oligonucleotides

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-12-16 DOI: 10.1021/acs.oprd.4c00382

Aljaž Abe, Zdenko Časar

引用次数: 0

Synthesis, Characterization, and Control Strategies for Cabazitaxel-Related Substances at Scale

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-12-16 DOI: 10.1021/acs.oprd.4c00414

Amarendhar Manda, Shravan Kumar Komati, Debjit Basu, Gopal Chandru Senadi, Arthanareeswari Maruthapillai, Rakeshwar Bandichhor

引用次数: 0

High-Throughput Experimentation Reveals Scope and Limitations of Selective Phosphine Reductants and Enables One-Pot mAb Reduction/Conjugation

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-12-13 DOI: 10.1021/acs.oprd.4c00343

Marion H. Emmert, Cuixian Yang, Eugene E. Kwan, Rebecca Chmielowski, Bruce Kilgore, Zachary L. VanAernum, Cecilia Bottecchia, Rodell C. Barrientos, Monica Haley, Kelly Raymond, Michael Rauscher, Zachary D. Dunn, Jay Desai

{"title":"High-Throughput Experimentation Reveals Scope and Limitations of Selective Phosphine Reductants and Enables One-Pot mAb Reduction/Conjugation","authors":"Marion H. Emmert, Cuixian Yang, Eugene E. Kwan, Rebecca Chmielowski, Bruce Kilgore, Zachary L. VanAernum, Cecilia Bottecchia, Rodell C. Barrientos, Monica Haley, Kelly Raymond, Michael Rauscher, Zachary D. Dunn, Jay Desai","doi":"10.1021/acs.oprd.4c00343","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00343","url":null,"abstract":"This manuscript describes the detailed evaluation of more than 40 phosphine reductants via automated and nonautomated high-throughput experimentation approaches with the goal of identifying selective reductants for cleaving the disulfide bonds of capped, engineered cysteines in a proprietary monoclonal antibody (mAb). As a point of reference, this study included phosphines that have previously been documented in the literature [4-diphenylphosphino benzoic acid (DPPBA), tris(3-sulfophenyl)phosphine (TSPP), and 3-(diphenylphosphino)benzenesulfonate (diPPBS)]; however, all known reductants showed the formation of undesired side products upon reduction (detectable by IEX), especially at higher phosphine loadings. The high-throughput study also revealed several phosphines with potential for selective reduction that had not been previously studied for this type of transformation. These initial hits were further evaluated with regard to the phosphine/mAb ratio, solubility in aqueous media, and air oxidation behavior. The best phosphine identified (1-(4-(diphenylphosphanyl)benzyl)-1-methylpyrrolidin-1-ium bromide (P10)) was then employed in a sequence of high-throughput studies that established efficient one-pot reduction/conjugation reaction conditions. Overall, the work detailed herein demonstrates how high-throughput experimental design enables rapid and resource-sparing insights into mAb reduction and conjugation reactivity with phosphine-based reductants.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"14 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816362","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}

引用次数: 0

Development of an Inherently Safe and Scalable Nickel-Catalyzed Borylation Process of an Aryl Sulfamate

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-12-12 DOI: 10.1021/acs.oprd.4c00454

Matthew V. Joannou, Christopher Y. Bemis, Geoffrey E. Purdum, Candice L. Joe, Kyle Eckenroad, Sharla L. Wood, Shasha Zhang, Amy A. Sarjeant, Rebecca A. Green, Jeffrey Nye, Steven R. Wisniewski, Scott A. Savage

{"title":"Development of an Inherently Safe and Scalable Nickel-Catalyzed Borylation Process of an Aryl Sulfamate","authors":"Matthew V. Joannou, Christopher Y. Bemis, Geoffrey E. Purdum, Candice L. Joe, Kyle Eckenroad, Sharla L. Wood, Shasha Zhang, Amy A. Sarjeant, Rebecca A. Green, Jeffrey Nye, Steven R. Wisniewski, Scott A. Savage","doi":"10.1021/acs.oprd.4c00454","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00454","url":null,"abstract":"A safe and scalable synthesis of A, a key aryl boronate ester intermediate toward an immunology asset udifitimod, via a Ni-catalyzed Miyaura borylation is reported. High-throughput experimentation, design of experiment, and reagent stability/compatibility studies were used to optimize the reaction conditions and furnish the borylation of aryl sulfamate B in 80–85% yield and >98% purity/potency. Significant hydrogen off-gassing was observed during the reaction, metal remediation, and crystallization steps of the first-generation process, and efforts were made to quantify, understand, and mitigate this off-gassing to ensure a safe and reliable scale-up. Two multikilogram batches of the process were successfully run to afford A in an average 85% yield, >99% potency, and ≤28 ppm residual Ni. Using the mechanistic learnings from this work, a second-generation process was developed which significantly reduced hydrogen off-gassing at all steps of the process, as well as increasing final yield and reducing process mass intensity. This second-generation process was demonstrated on a 1 kg scale to afford the product in 90% yield, >99% purity/potency, and 50 ppm residual Ni.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"4 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142810039","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}

引用次数: 0

Development of an Inherently Safe and Scalable Nickel-Catalyzed Borylation Process of an Aryl Sulfamate

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-12-12 DOI: 10.1021/acs.oprd.4c0045410.1021/acs.oprd.4c00454

Matthew V. Joannou*, Christopher Y. Bemis, Geoffrey E. Purdum, Candice L. Joe, Kyle Eckenroad, Sharla L. Wood, Shasha Zhang, Amy A. Sarjeant, Rebecca A. Green, Jeffrey Nye, Steven R. Wisniewski and Scott A. Savage,

{"title":"Development of an Inherently Safe and Scalable Nickel-Catalyzed Borylation Process of an Aryl Sulfamate","authors":"Matthew V. Joannou*, Christopher Y. Bemis, Geoffrey E. Purdum, Candice L. Joe, Kyle Eckenroad, Sharla L. Wood, Shasha Zhang, Amy A. Sarjeant, Rebecca A. Green, Jeffrey Nye, Steven R. Wisniewski and Scott A. Savage, ","doi":"10.1021/acs.oprd.4c0045410.1021/acs.oprd.4c00454","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00454https://doi.org/10.1021/acs.oprd.4c00454","url":null,"abstract":"A safe and scalable synthesis of A, a key aryl boronate ester intermediate toward an immunology asset udifitimod, via a Ni-catalyzed Miyaura borylation is reported. High-throughput experimentation, design of experiment, and reagent stability/compatibility studies were used to optimize the reaction conditions and furnish the borylation of aryl sulfamate B in 80–85% yield and >98% purity/potency. Significant hydrogen off-gassing was observed during the reaction, metal remediation, and crystallization steps of the first-generation process, and efforts were made to quantify, understand, and mitigate this off-gassing to ensure a safe and reliable scale-up. Two multikilogram batches of the process were successfully run to afford A in an average 85% yield, >99% potency, and ≤28 ppm residual Ni. Using the mechanistic learnings from this work, a second-generation process was developed which significantly reduced hydrogen off-gassing at all steps of the process, as well as increasing final yield and reducing process mass intensity. This second-generation process was demonstrated on a 1 kg scale to afford the product in 90% yield, >99% purity/potency, and 50 ppm residual Ni.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4513–4533 4513–4533"},"PeriodicalIF":3.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867914","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}

引用次数: 0

Exploration for Chemical Filter Cartridges that Can Reduce Nitrogen Oxides, a Common Factor in the Formation of Nitrosamines

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-12-12 DOI: 10.1021/acs.oprd.4c00301

Ryota Nomura, Takahiko Taniguchi, Kazuya Suzuoki, Rintaro Yokoi, Kanenao Akasaki, Kyoko Hirai, Osamu Uchikawa

引用次数: 0

Robust Liquid Chromatography–Mass Spectrometry Determination of Deuterium Isotopologues for Quality Control of Deucravacitinib Using Nominal Mass Instrumentation

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-12-11 DOI: 10.1021/acs.oprd.4c00361

Cong Bi, Yueer Shi, Wei Ding, James Chadwick, Yan Zha, Su Pan, Paul Foy, Nicola Hulme, Brent Kleintop

{"title":"Robust Liquid Chromatography–Mass Spectrometry Determination of Deuterium Isotopologues for Quality Control of Deucravacitinib Using Nominal Mass Instrumentation","authors":"Cong Bi, Yueer Shi, Wei Ding, James Chadwick, Yan Zha, Su Pan, Paul Foy, Nicola Hulme, Brent Kleintop","doi":"10.1021/acs.oprd.4c00361","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00361","url":null,"abstract":"Deuterated drug molecules are a growing area of interest in the pharmaceutical industry, and controlling isotopologue impurities can be vital due to potential toxicity and efficacy concerns. The limited number of analytical approaches reported for this purpose often relies on high-end instrumentation that is not readily available in quality control (QC) laboratories. We developed and validated a robust liquid chromatography–mass spectrometry (LC–MS) method for the determination of isotopologue impurities in the deuterated drug SOTYKTU (deucravacitinib) using QC-friendly nominal mass LC–MS instruments. The method conditions were systematically evaluated and optimized to ensure key performance attributes, and the method was extended to assess isotopologue impurities in the input material d3-methylamine hydrochloride via an efficient derivatization procedure. The established conditions demonstrated excellent robustness and reproducibility, facilitating successful transfer from development laboratories to commercial QC laboratories. The successful implementation in the release testing of both input reagent and the final drug substance highlights the practical application of nominal mass LC–MS for the determination of the isotopic purity in pharmaceutical development.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"118 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142810040","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}

引用次数: 0

Robust Liquid Chromatography–Mass Spectrometry Determination of Deuterium Isotopologues for Quality Control of Deucravacitinib Using Nominal Mass Instrumentation

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-12-11 DOI: 10.1021/acs.oprd.4c0036110.1021/acs.oprd.4c00361

Cong Bi*, Yueer Shi, Wei Ding, James Chadwick, Yan Zha, Su Pan, Paul Foy, Nicola Hulme and Brent Kleintop,

{"title":"Robust Liquid Chromatography–Mass Spectrometry Determination of Deuterium Isotopologues for Quality Control of Deucravacitinib Using Nominal Mass Instrumentation","authors":"Cong Bi*, Yueer Shi, Wei Ding, James Chadwick, Yan Zha, Su Pan, Paul Foy, Nicola Hulme and Brent Kleintop, ","doi":"10.1021/acs.oprd.4c0036110.1021/acs.oprd.4c00361","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00361https://doi.org/10.1021/acs.oprd.4c00361","url":null,"abstract":"Deuterated drug molecules are a growing area of interest in the pharmaceutical industry, and controlling isotopologue impurities can be vital due to potential toxicity and efficacy concerns. The limited number of analytical approaches reported for this purpose often relies on high-end instrumentation that is not readily available in quality control (QC) laboratories. We developed and validated a robust liquid chromatography–mass spectrometry (LC–MS) method for the determination of isotopologue impurities in the deuterated drug SOTYKTU (deucravacitinib) using QC-friendly nominal mass LC–MS instruments. The method conditions were systematically evaluated and optimized to ensure key performance attributes, and the method was extended to assess isotopologue impurities in the input material d3-methylamine hydrochloride via an efficient derivatization procedure. The established conditions demonstrated excellent robustness and reproducibility, facilitating successful transfer from development laboratories to commercial QC laboratories. The successful implementation in the release testing of both input reagent and the final drug substance highlights the practical application of nominal mass LC–MS for the determination of the isotopic purity in pharmaceutical development.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4380–4391 4380–4391"},"PeriodicalIF":3.1,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858701","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}

引用次数: 0

Optimizing Industrial Solid-Phase Peptide Synthesis: Integration of Raman Spectroscopy as Process Analytical Technology

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-12-10 DOI: 10.1021/acs.oprd.4c00432

Michael A. Stager, Carlos Peroza, Julien Villaumie, Christopher Bilham, Cameron Desmond, Marcus Harris, Ramya Sambasivan, Gary Rowe, Lin Chen, Charles Tucker

{"title":"Optimizing Industrial Solid-Phase Peptide Synthesis: Integration of Raman Spectroscopy as Process Analytical Technology","authors":"Michael A. Stager, Carlos Peroza, Julien Villaumie, Christopher Bilham, Cameron Desmond, Marcus Harris, Ramya Sambasivan, Gary Rowe, Lin Chen, Charles Tucker","doi":"10.1021/acs.oprd.4c00432","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00432","url":null,"abstract":"Peptide therapeutics have exploded in popularity in recent years, motivating the need for advanced manufacturing methods which can be applied across the solid-phase peptide synthesis (SPPS) process. The Food and Drug Administration’s Process Analytical Technology (PAT) initiative offers a platform to implement advanced methods to improve the efficiency and understanding of pharmaceutical manufacturing processes and shows great promise in application toward industrial SPPS. In this work, Raman spectroscopy was used as the main PAT tool to implement methods for on-line and real-time monitoring of the entire SPPS process, from Fmoc removal, to coupling, and through the extensive solvent-washing steps. Raman spectroscopy is a rapid, specific, and nondestructive technique that can provide rich real-time information for SPPS processes and can be used to improve efficiency in solvent use and save process time. Specifically, this work reports on the development of PAT methods for monitoring of amino acid coupling during the coupling stage and residual piperidine concentration during the post-deprotection washing stage of SPPS, to help reduce solvent use and better understand the coupling reaction and its time frame. We show a significant reduction in solvent use is possible by employing Raman spectroscopy along with a partial least squares model to predict the piperidine concentration in real time during continuous wash. In addition, Raman spectroscopy offers a greater understanding of coupling reaction kinetics during SPPS, which could lead to significant improvements in total SPPS process time.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"21 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797807","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}

引用次数: 0