Organic Process Research & Development最新文献

{"title":"A Continuous Hydrogenation Reactor Based on a Powdered Catalyst Enmeshed in an Expanded Poly(tetrafluoroethylene) Matrix","authors":"Sean Breen, Purnima Barua, Yuan-Qing Fang, David D. Ford, Ali Hasan, Manish Joshi, Sara Mason, Kevin D. Nagy, Sifat bin Quadery, Grace Russell, Vladimiros Nikolakis, John D. Holcombe, Andrea Adamo, Lorenzo Milani","doi":"10.1021/acs.oprd.4c00303","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00303","url":null,"abstract":"Fixed bed catalytic reactors are commonly used for hydrogenation in the commodity chemical industry, but adoption in the pharmaceutical industry has been limited by the lack of available catalyst pellets in sizes suitable both for process research and development at scales of 1–50 g substrate per experiment and also for to manufacturing at the metric ton scale. Herein, we describe an approach for continuous flow hydrogenation using catalytic cartridges of powdered catalysts (palladium on carbon in this example) enmeshed in an expanded poly(tetrafluoroethylene) (ePTFE) matrix. Using a modular design, the catalytic layers and supplemental components can be arranged to suit specific reaction conditions, desired results, and throughput. The reactor was demonstrated with three classes of hydrogenation reactions: nitro reduction, debenzylation, and alkene reduction. All substrates could achieve high or full conversion after optimization. The study also includes longevity experiments to understand the long-term reliability of the reactor as well as preliminary results for scaling up to a larger membrane size. The results make this technology promising for scale-up opportunities by using the same modular design.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"5 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142975664","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}

{"title":"Achieving New Scales: The First Successful Pilot Plant Spherical Crystallization","authors":"Stephanie C. Kosnik, Zeno Leuter, Kevin Schwickert","doi":"10.1021/acs.oprd.4c00350","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00350","url":null,"abstract":"Spherical crystallization is a widely used technique for the preparation of spherically shaped agglomerates of crystalline material, which results in free-flowing powders with improved micromeritic properties. In this study, we applied this technique to the reactive crystallization of 3-iodo-7-methyl-1<i>H</i>-indazole, a critical early intermediate for one of our Active Pharmaceutical Ingredients at Boehringer Ingelheim. We utilized a traditional spherical agglomeration approach to identify a bridging liquid that could be easily implemented into the current crystallization process. Our experiments showed that the amount and rate of antisolvent addition were important for the crystallization; however, the stir rate and the amount of bridging liquid were the most critical factors. We successfully scaled up this process to a 300 L pilot plant reactor, keeping a constant power per unit mass during scale-up. The results showed that the spherical crystallizations for both 300 L batches were highly successful with almost identical particle sizes.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"47 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968524","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}

{"title":"Predicting Shock Sensitivity from Differential Scanning Calorimetry Data and Molecular Structure: Beyond the Yoshida Correlation","authors":"Eric L. Margelefsky, Benjamin C. Dobson, Tao Chen, Nelson Lee Afanador","doi":"10.1021/acs.oprd.4c00439","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00439","url":null,"abstract":"The Yoshida correlation is widely used in the pharmaceutical and fine chemical industry to predict explosivity and shock sensitivity of chemical substances based on the initiation temperature and enthalpy of differential scanning calorimetry (DSC) exotherms. We investigate the origins and accuracy of this correlation (and commonly used modifications thereof) by applying it to a large data set of 383 compounds, which are relevant to the pharmaceutical industry, and demonstrate that the initiation temperature and enthalpy variables are not good predictors for shock sensitivity. By incorporating structural information (for the 292 compounds where it was available), we used machine learning to inform and guide a logistic regression technique to develop a shock sensitivity model which has a higher overall accuracy (63%) and a higher accuracy for shock-sensitive compounds (97%) compared to the original Yoshida correlation (52% overall accuracy, 82% accuracy for shock-sensitive compounds). This logistic regression model includes both the original Yoshida variables (DSC initiation temperature and enthalpy) and also incorporates the oxygen balance (OB₁₀₀) and the number of energetic nitrogen groups in the molecule.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"4 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968525","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}

{"title":"Continuous Flow Telescopic Synthesis of 3-Methoxy Propiophenone by the Grignard Reaction","authors":"Pranali Wankhede, Amol A. Kulkarni","doi":"10.1021/acs.oprd.4c00447","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00447","url":null,"abstract":"The synthesis of 3-methoxypropiophenone <b>1</b>, a crucial intermediate in the production of the analgesic tapentadol hydrochloride, was investigated using a multistep continuous flow process. The approach is based on the Grignard reaction. A series of continuously stirred tank reactors (CSTRs) were employed: the first reactors facilitated the continuous generation of Grignard reagents <b>3</b>, which then reacted with propionitrile in the next CSTR to yield <b>1</b>. This was followed by quenching, neutralization, and phase separation, conducted under varying temperatures and residence times. When compared to a 50% yield from an optimized batch synthesis protocol, a continuous flow synthesis helped achieve an 84% yield of the desired product in a much shorter reaction time. A kinetic model was developed to predict the Grignard reagent formation and product yield, revealing that the mass transfer effect is insignificant at a higher stirring rate. The approach is highly scalable for the synthesis of pharmaceutical intermediates.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"45 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940603","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}

{"title":"Therapeutic Peptides Control Strategy: Perspective on Current Industry Practices","authors":"Brian W. Pack, Jeremy Manheim, Osama Chahrour, Brandon Wood, Limin Zhang, Ulf Vogel, Gracie Sheng","doi":"10.1021/acs.oprd.4c00386","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00386","url":null,"abstract":"There is currently a lack of harmonization from health agencies on the control strategies that should be implemented for the manufacture of synthetic peptide active pharmaceutical ingredients throughout clinical development and commercialization. In this Perspective, we use the term “peptide” to refer to an α-amino acid polymer with a specific defined sequence without regard to the total number of amino acids that it contains. In the U.S., the FDA currently defines “proteins” that are subject to biological product licensure as follows: “A protein is any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size. When two or more amino acid chains in an amino acid polymer are associated with each other in a manner that occurs in nature, the size of the amino acid polymer for purposes of this paragraph (h)(6) will be based on the total number of amino acids in those chains, and will not be limited to the number of amino acids in a contiguous sequence” [21 CFR 600.3(h)(6)]. In contrast, other regulatory authorities apply requirements based on the method of manufacture, resulting in regulatory risks of disparate requirements depending on the jurisdiction. To provide visibility into current industry practices on the control strategies applied to synthetic peptides, a benchmark survey of member companies of the IQ Consortium was conducted. This work provides a comprehensive analysis of the survey results. The compiled responses from 10 companies reveal that while most follow similar control strategies for identification, purity, and assay testing, none of the survey questions received a unanimous response. Interestingly, the number and type of analytical techniques utilized for each test differed when comparing the phase of development, the number of amino acids in the peptide, and whether it was for the drug substance or drug product. Additionally, the limits set for impurity reporting, identification, and qualification thresholds throughout development varied widely. The knowledge acquired from the survey in combination with previously published literature and individual company experiences enables the IQ Consortium to put forth appropriate recommendations to achieve harmonization of control strategies for synthetic peptides with regard to assay, identity, impurity reporting and identification thresholds, bioassay, and comparability assessments.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"14 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940605","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}

{"title":"Coupled-Batch Preferential Crystallization of Imeglimin Propionate on a 200 g Scale","authors":"Leela Christian-Tabak, Koji Machida, Hideo Kawachi, Hiroaki Tanaka, Kazuki Hashimoto","doi":"10.1021/acs.oprd.4c00291","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00291","url":null,"abstract":"The application of coupled-batch preferential crystallization (CB-PC) for the propionate salt of the active pharmaceutical ingredient imeglimin is demonstrated herein. Process conditions were chosen based on metastable zone width measurements, and an apparatus with 500 mL-sized crystallization vessels was constructed. A series of CB-PC experiments on an increasing scale were run, and observations on scaling up were made throughout, including the effect of the seeding method, productivity over time, and physical limits of the apparatus. The series culminated in two successive runs each on a 200 g scale, in which the mother liquor from the first run was recycled to the second.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"7 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935909","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}

{"title":"Scalable Flow Electrosynthesis of Iminophosphoranes","authors":"Dan Lehnherr, Longrui Chen, François Lévesque, Christopher Nietupski, Mark Weisel, Velabo Mdluli, Keith Mattern, Brittany M. Armstrong, Tao Chen, Ryan D. Cohen","doi":"10.1021/acs.oprd.4c00372","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00372","url":null,"abstract":"A scalable electrochemical process to synthesize iminophosphorane ligands is reported. The application of these iminophosphoranes was recently reported in Ni-catalyzed cross-electrophile and C–N cross-couplings. The use of parallel plate flow electrochemical reactors enables the synthesis of these iminophosphorane ligands on a multigram scale, with selected examples reported on up to 0.6 kg scale. Direct crystallization from the end of reaction mixture for selected ligands provides facile isolation processes. This article also details improvements in our electrochemical capabilities across scales, including addressing material compatibility issues, increasing accessible range of flow rates, and integration of process analytical technology tools.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"2 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935911","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}

{"title":"Characterization of Amorphous Ibrutinib Thermal Stability","authors":"Dan Trunov, Jan Ižovský, Josef Beranek, Ondřej Dammer, Miroslav Šoóš","doi":"10.1021/acs.oprd.4c00299","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00299","url":null,"abstract":"The choice of method for drug amorphization depends on various factors, including the physicochemical properties of the active pharmaceutical ingredients, the desired formulation, and scalability requirements. It is often important to consider a combination of methods or the use of excipients to further enhance the stability and performance of the amorphous drug. This study presents a comparison of techniques including melt quench, hot melt extrusion, solvent evaporation, ball milling, and lyophilization used for the preparation of amorphous ibrutinib. The amorphous material was thoroughly investigated using numerous techniques to examine changes in the physicochemical properties, stability, and degradation pathways of the drug product. During the examination, the temperature was discovered to be a key parameter for controlling the solubility and permeability of ibrutinib, which is influenced by the presence of the degradation product. We found that this degradation product could potentially polymerize and increase the molecular weight. The quantity, polymerization rate, and structure of the impurity can be regulated by the temperature variation during the amorphization processes. Additionally, the molecular weight of the degradation product was determined using Zimm plot analysis, which appeared for the first time in the literature for molecules of this category.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"98 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935910","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}

{"title":"Review of the Synthesis of Timolol Maleate and Brimonidine Tartrate Drug Substances Used for the Treatment of Open-Angle Glaucoma","authors":"Rajarathnam E. Reddy, Casey J. Maguire, Riley H. Hastings, Timothy L’Hommedieu, Michael C. Dennis, Haiyan L. Grady, Srinivas Peddapatla, Michael A. Haley, II","doi":"10.1021/acs.oprd.4c00280","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00280","url":null,"abstract":"Open-angle glaucoma (OAG) is a chronic and degenerative disorder that causes optic nerve damage and potential blindness. The objective of this review is to provide a brief overview on OAG, with emphasis on the importance of β-blockers and α₂-agonists for eye care. Timolol maleate (<b>1</b>) and brimonidine tartrate (<b>2</b>) are an important β-blocker and α₂-agonist, respectively. Both are used in several medications for the treatment of open-angle glaucoma. A literature review of various synthetic approaches for timolol maleate (<b>1</b>), and brimonidine tartrate (<b>2</b>) drug substances is presented. In addition, the reported timolol maleate (<b>1</b>) and brimonidine tartrate (<b>2</b>) synthetic routes were assessed for strengths and weaknesses from a process chemistry perspective. A summary is provided based on drug substance quality, process, safety, and environmental considerations.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"13 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924796","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}

{"title":"Accelerating the Development of Sustainable Catalytic Processes through Data Science","authors":"Jason M. Stevens, Jacob M. Ganley, Matthew J. Goldfogel, Ariel Furman, Steven R. Wisniewski","doi":"10.1021/acs.oprd.4c00434","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00434","url":null,"abstract":"Herein, we describe the optimization of reaction conditions for a nickel-catalyzed borylation using a combination of machine learning, high-throughput experimentation, and Bayesian optimization. A machine learning model, trained on a data set from Bristol Myers Squibb, was employed to predict the yields of 144 potential reaction conditions across three potential substrates for the target borylation reaction. These predictions guided a high-throughput experimentation study, which identified promising conditions for further development. The most promising condition underwent four rounds of Bayesian optimization, resulting in reaction conditions optimized for both chemical yield (&gt;99%) and cost efficiency. The entire hit-identification and optimization process was completed in just 120 experiments over the course of 1 week by a single scientist. These optimized conditions were successfully validated on a 40 g scale to achieve 83.5% isolated yield.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911596","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}