Organic Process Research & Development最新文献

Application of an Interdisciplinary Approach to Form Selection in Drug Development

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-01-25 DOI: 10.1021/acs.oprd.4c00320

Darren L. Reid, Margaret M. Faul, Vilmalí López-Mejías, Prashant Agarwal, Markus Bergauer, Laura E. Blue, Mary K. Chaves, John Chung, Melanie Cooke, Robert P. Farrell, James E. Huckle, Ron C. Kelly, Y.-H. Kiang, Weikun Li, Adrian Ortiz, Qiong Wu

{"title":"Application of an Interdisciplinary Approach to Form Selection in Drug Development","authors":"Darren L. Reid, Margaret M. Faul, Vilmalí López-Mejías, Prashant Agarwal, Markus Bergauer, Laura E. Blue, Mary K. Chaves, John Chung, Melanie Cooke, Robert P. Farrell, James E. Huckle, Ron C. Kelly, Y.-H. Kiang, Weikun Li, Adrian Ortiz, Qiong Wu","doi":"10.1021/acs.oprd.4c00320","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00320","url":null,"abstract":"Selecting the development form of an active pharmaceutical ingredient (API) in drug development is key to determining the final performance of the drug substance and drug product. Form selection requires an interdisciplinary approach involving a complex process to discover, monitor, and evaluate the solid-state characteristics, biopharmaceutical properties, stability, and processability of numerous forms. This Perspective discusses the importance of aligning critical material attributes with the desired quality target product profile to ensure drug safety and efficacy. It discusses how the form selection strategy is dependent on factors related to the administration route, dosage form, and therapeutic indication and provides an interdisciplinary framework with four prioritized sets of target attributes for oral delivery: solid-state properties, biopharmaceutical performance, stability, and processability. A classification system to guide form selection, particularly for immediate-release oral medications, is reviewed. The benefits of crystalline forms in terms of stability and processability are highlighted, emphasizing the role of solution crystallization in controlling their development. The interdisciplinary form selection process will be demonstrated through case studies highlighting how each set of target attributes were evaluated leading to the selection of ideal forms for development.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"58 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030888","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

A Confined Impinging Jet Reactor for High-Throughput Continuous Flow Mononitration of Salicylic Acid 用于水杨酸高通量连续流单硝的密闭冲击射流反应器

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-01-23 DOI: 10.1021/acs.oprd.4c00467

Muzammilanwar S. Khan, Tabrez R. Shaikh, Sphurti P. Kulkarni, Abhishek A. Patil, Amol A. Kulkarni

{"title":"A Confined Impinging Jet Reactor for High-Throughput Continuous Flow Mononitration of Salicylic Acid","authors":"Muzammilanwar S. Khan, Tabrez R. Shaikh, Sphurti P. Kulkarni, Abhishek A. Patil, Amol A. Kulkarni","doi":"10.1021/acs.oprd.4c00467","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00467","url":null,"abstract":"Novel approach is reported for highly efficient continuous mononitration of salicylic acid using confined impinging jet reactor (CIJR) with a vent. Initially, controlled semibatch reactions are optimized to achieve complete conversion and formation of mononitro products with very high selectivity for 5-nitrosalicylic acid (5-NSA). Further, the combination of computational fluid dynamics simulations and experiments is employed to optimize CIJR design and operating flow conditions, suitable to yield only mononitro products with excellent control over mixing, heat transfer, and liberation of fumes during continuous flow reaction. Detailed analysis of internal flow patterns, rate of heat generation, and concentration distribution inside the CIJR facilitated the optimization of present exothermic reaction in a safe manner. In less than a minute, complete salicylic acid (SA) conversion with good yield and better selectivity for 5-NSA is achieved using the CIJR. Safety and clogging issues are addressed effectively, even at a relatively lower mole ratio (1:5) of SA:acetic acid (AcOH). The present approach is quite scalable using the numbering-up strategy, with advantages viz. nonfouling, high throughput, and the small footprint of CIJR.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"74 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021130","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

Applicability of Fluidized Bed Crystallization for Separation of Enantiomers Forming Needle-Shaped Crystals

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-01-23 DOI: 10.1021/acs.oprd.4c00444

Jonathan Gänsch, Igor Gamm, Andreas Seidel-Morgenstern, Heike Lorenz

引用次数: 0

Process Analytical Technology for Real-Time Monitoring of Pharmaceutical Bioconjugation Reactions 药物生物偶联反应实时监测的过程分析技术

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-01-22 DOI: 10.1021/acs.oprd.4c00399

Nicole M. Ralbovsky, Gunjan Dixit, Justin P. Lomont, Jay Desai, Cristina Butu, Anumita Saha-Shah, Emily Costello, Janelle Lukens, Michael Mazur, Patrick M. McHugh, Rodell C. Barrientos, Andrew Semple, Gregory J. Hughes, Rebecca Chmielowski, Sheng-Ching Wang, Bhumit A. Patel, Joseph P. Smith

{"title":"Process Analytical Technology for Real-Time Monitoring of Pharmaceutical Bioconjugation Reactions","authors":"Nicole M. Ralbovsky, Gunjan Dixit, Justin P. Lomont, Jay Desai, Cristina Butu, Anumita Saha-Shah, Emily Costello, Janelle Lukens, Michael Mazur, Patrick M. McHugh, Rodell C. Barrientos, Andrew Semple, Gregory J. Hughes, Rebecca Chmielowski, Sheng-Ching Wang, Bhumit A. Patel, Joseph P. Smith","doi":"10.1021/acs.oprd.4c00399","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00399","url":null,"abstract":"Process analytical technology (PAT) is increasingly being explored within pharmaceutical production and process development, with a particular emphasis in the vaccine and biologics space. PAT aims to provide increased process understanding and control through real-time monitoring of critical quality attributes and key process parameters as well as detection of process deviations. Downstream purification in pharmaceutical manufacturing processes can be complex and requires copious analytical characterization. Herein, we showcase the successful implementation of PAT for monitoring bioconjugation reactions related to both vaccine and biologic pharmaceutical manufacturing processes. Specifically, we explore a variety of PAT-based techniques and their utility for monitoring polysaccharide–protein and protein–small molecule bioconjugation reactions. PAT applications using at-line multiangle light scattering, in situ fluorescence spectroscopy, in situ viscosity, and at-line hydrophobic interaction chromatography are shown to each provide distinct, real-time analytical information to enhance the understanding and characterization of bioconjugation reactions.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"27 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992290","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

Quality Control for Incoming Raw Materials Beyond Identity and Purity: Case Studies from Recent Merck API Manufacturing Processes 入厂原材料的质量控制不仅限于特性和纯度：默克近期原料药生产工艺案例研究

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-01-19 DOI: 10.1021/acs.oprd.4c00423

Nelo R. Rivera, Rekha Gangam, Rebecca Arvary, Taylor Behre, Zhiwei Chen, Erik D. Guetschow, Nadine Kuhl, Mingxiang Lin, Nastaran Salehi Marzijarani, Erin McCarthy, Ji Qi, Ben W. H. Turnbull, Tao Wang, Wenjun Liu

引用次数: 0

Leveraging Supercritical Fluid Chromatography for Monitoring the Formation of Methanol Adducts of AR-LDD Antagonist BMS-986409 in Spray-Dried Dispersion Materials 利用超临界液相色谱法监测AR-LDD拮抗剂BMS-986409在喷雾干燥分散材料中甲醇加合物的形成

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-01-17 DOI: 10.1021/acs.oprd.4c00448

Brian Lingfeng He, Xuejun Xu, Leon Liang

{"title":"Leveraging Supercritical Fluid Chromatography for Monitoring the Formation of Methanol Adducts of AR-LDD Antagonist BMS-986409 in Spray-Dried Dispersion Materials","authors":"Brian Lingfeng He, Xuejun Xu, Leon Liang","doi":"10.1021/acs.oprd.4c00448","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00448","url":null,"abstract":"BMS-986409 is a novel ligand-directed degrader of the androgen receptor developed by Bristol Myers Squibb Company for the treatment of metastable castration-resistant prostate cancer (mCRPC). The active pharmaceutical ingredient (API) has an (R,R) configuration and three minor stereoisomers, including (R,S), (S,R), and (S,S) isomers. During pharmaceutical formulation development, methanol adducts were found in spray-dried dispersion (SDD) materials at alarming levels. To investigate the formation mechanism of methanol adducts, we successfully developed an ultrahigh performance liquid chromatography achiral method and a supercritical fluid chromatography chiral method to separate all potential methanol adducts and stereoisomers of BMS-986409. It is concluded that ring-opening at the 2-position of the gluarimide moiety (Pathway 1) is the favored formation mechanism of methanol adducts during the BMS-986409 SDD manufacturing process and epimerization can be neglected. However, under basic conditions, ring-opening at the 6-position of the gluarimide moiety (Pathway 2) becomes dominant and, in the meantime, epimerization is promoted to a great extent. The knowledge collected by leveraging the SFC chiral method gives us the needed confidence in the analytical impurity control strategy that solely relies on the achiral method for monitoring methanol adduct impurities in SDD materials and sample release in future pharmaceutical development.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"21 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989451","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

Synergizing Process Conditions, Water Sensitivity, and Kinetic Mechanisms to Optimize Sodium Salicylate Yield in Sodium Phenol Carboxylation 苯酚钠羧化水杨酸钠收率优化的协同工艺条件、水敏感性及动力学机制

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-01-17 DOI: 10.1021/acs.oprd.4c00383

Haodong Zhang, Junmei Zhang, Jingjing Ma, Maoqian Wu, Linbo Hu, Hongfu Chen, Zhenya Duan

{"title":"Synergizing Process Conditions, Water Sensitivity, and Kinetic Mechanisms to Optimize Sodium Salicylate Yield in Sodium Phenol Carboxylation","authors":"Haodong Zhang, Junmei Zhang, Jingjing Ma, Maoqian Wu, Linbo Hu, Hongfu Chen, Zhenya Duan","doi":"10.1021/acs.oprd.4c00383","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00383","url":null,"abstract":"Sodium salicylate can be formed by carboxylation of solid sodium phenol particles with carbon dioxide gas under certain conditions. Single-factor experiments were carried out with self-made dried sodium phenol particles in a batch high-pressure reactor. It was determined that the carboxylation reaction of sodium phenol particles was more suitable under the conditions of a reaction temperature of 160 °C, a reaction pressure of 0.55 MPa, a reaction time of about 40 min, and a stirring speed of 50 rpm. Besides that, the water content of the material also had important effects on the yield. Through the establishment of the kinetic model of the carboxylation reaction between solid sodium phenol particles and carbon dioxide gas, the control step of the reaction temperature at 150 and 160 °C was determined as ash layer diffusion, and the kinetic equation was further calculated. The research results can provide the basic technological conditions and kinetic data of the carboxylation reaction of sodium phenol particles and provide a reference for the development of a continuous and efficient production process of sodium phenol carboxylation.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"49 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987655","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

OPR&D: An Exceptional Legacy and Exciting Opportunities for the Future of Process Chemistry OPR&D：过程化学未来的杰出遗产和激动人心的机遇

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-01-17 DOI: 10.1021/acs.oprd.4c00537

Margaret M. Faul

引用次数: 0

Development of the Crystallization Process for Rivaroxaban–Oxalic Acid Cocrystal Preparation Using a Combination of Phase Diagrams and In Situ Measurements 用相图和原位测量相结合的方法研究利伐沙班-草酸共晶制备的结晶工艺

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-01-15 DOI: 10.1021/acs.oprd.4c00509

Erika Hriňová, Igor Čerňa, Eliška Zmeškalová, Luděk Ridvan, Miroslav Šoóš

{"title":"Development of the Crystallization Process for Rivaroxaban–Oxalic Acid Cocrystal Preparation Using a Combination of Phase Diagrams and In Situ Measurements","authors":"Erika Hriňová, Igor Čerňa, Eliška Zmeškalová, Luděk Ridvan, Miroslav Šoóš","doi":"10.1021/acs.oprd.4c00509","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00509","url":null,"abstract":"This study presents the development of the crystallization process for the rivaroxaban–oxalic acid cocrystal. The solvent screening was conducted by means of the crystallization of the cocrystal from a saturated solution of acetone, ethanol, isopropanol, acetonitrile, ethyl acetate, and ethyl formate. Two selected solvents, namely, ethyl formate and acetone, were subjected to ternary phase diagram construction in order to ascertain the system equilibrium and identify the boundaries for pure cocrystal crystallization. The crystallization process was subsequently examined through the utilization of an in situ Raman spectroscopy probe. It was observed that the rate of transformation decreased at higher temperatures, which is most probably due to lower saturation in terms of the cocrystal. The reaction mechanism was observed by an in situ imaging probe, showing that new crystals were growing directly from the solution instead of growing from the surface of existing crystals. These findings were employed in the development of a crystallization process for both solvents, resulting in enhanced time and cost efficiency. A notable difference in particle size was observed between solvents, with acetone producing larger crystals. Consequently, ethyl formate was selected as the optimal solvent for further scale-up of the process, given its favorable impact on dissolution enhancement.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987097","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

Correction to “Development of an Optimized Process for 2,4-Dichloro-5-fluoroacetophenone: A Key Intermediate of Ciprofloxacin” 对“环丙沙星关键中间体2,4-二氯-5-氟苯乙酮优化工艺的开发”的更正

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2025-01-15 DOI: 10.1021/acs.oprd.4c00545

Kai Yin, Youlan He, Hao Wu, Xubin He

引用次数: 0