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Have you had challenges with CM adhesion/cohesion? Experts are discussing this topic in the Oral Solid Dosage Group,, broken out into the following key areas: conveying, feeding, transfer hoppers, and transition pipes. Learn from their experience by reading the full conversation here: https://cmkc.usp.org/groups/oralsoliddose/forum/default-section/discussions/111
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  1. Blend uniformity monitoring in a continuous manufacturing mixing process for a low-dosage formulation using a stream sampler and near infrared spectroscopy

    Peer-reviewed journal | Contributor(s): Rodolfo Romanach, Raúl S. Rangel-Gil, Juan M. Nasrala-Álvarez, Rafael Méndez

    Continuous manufacturing has the potential to offer several benefits for the production of oral solid dosage forms, including reduced costs, low-scale equipment, and the application of process analytical technology (PAT) for real-time process control. This study focuses on the implementation of...

  2. Inverse Method-Based Kinetic Modelling and Process Optimization of Reverse-Phase Chromatography for Molnupiravir Synthesis

    Peer-reviewed journal | Contributor(s): Fernando Muzzio, George Tsilomelekis, Ravendra Singh, Athanasios Kritikos

    Our research addresses the shift towards continuous manufacturing in the pharmaceutical industry, focusing on optimizing chromatographic separation for the synthesis of molnupiravir. Using an inverse method with six different inlet concentrations for a single objective function, we...

  3. Advanced Manufacturing: An answer to supply chain woes?

    Magazine | Contributor(s): Atul Dubey

    Advanced Manufacturing technologies (AMTs) in the pharmaceutical industry have increasingly gained attention in the last decade. Amongst the AMTs, continuous manufacturing (CM) has had the most prominent impact so far. International efforts to define manufacturing approaches, terms, regulatory...

  4. Control oriented modeling of twin-screw granulation in the ConsiGmaTM-25 production plant

    Peer-reviewed journal | Contributor(s): Johannes Khinast, Martin Horn, Jakob Rehrl, Selma Celikovic, Johannes Poms

    ConsiGmaTM-25 is a continuous production plant integrating a twin-screw granulation, fluid bed drying, granule conditioning, and a tableting unit. The particle size distribution (PSD), active pharmaceutical ingredient (API) content, and liquid content of wet granules after twin-screw...

  5. Implementation of a fully integrated continuous manufacturing line for direct compression and coating at a commercial pharmaceutical facility – Part 1: Operational considerations and control strategy

    Peer-reviewed journal | Contributor(s): Conway, Stephen L., Rosas, Juan G., Overton, Paul, Tugby, Neil, Cryan, Phillip, Witulski, Frank, Hurley, Samantha, Wareham, Laura, Tantuccio, Anthony, Ramasamy, Manoharan, Lalloo, Anita, Gibbs, Mason, Meyer, Robert F.

    We implement a fully integrated continuous manufacturing (CM) line for direct compression and coating of a pharmaceutical oral solid dosage form in a commercial production facility. In this first paper of a two-part series, we describe process design and operational choices made to introduce CM...

  6. Implementation of a fully integrated CM direct compression and coating process at a commercial pharmaceutical facility - Part 2: PAT and RTD results for normal operational conditions batches.

    Peer-reviewed journal | Contributor(s): Rosas, JG, Brush, P, Thompson, B, Miller, C, Overton, P, Tugby, N, Stoliarskaia, D, Hurley, S, Ramasamy, M, Conway, SL

    This is the second of two articles detailing the continuous manufacturing (CM) development and implementation activities for an marketed product which have been realized in novel, qualified equipment, using validated control strategy elements to enable manufacture of batches under current good...

  7. Telescoped Hybrid Batch–Flow Synthesis of 2-Butylbenzofuran

    Peer-reviewed journal | Contributor(s): Dedè, Fabiana, Ciancimino, Cristina, Danelli, Piero, Piccolo, Oreste, Vigo, Daniele

    The present work describes the development of an improved synthesis of the pharmaceutically relevant building block 2-butylbenzofuran (BBF). The telescoped hybrid batch–flow process is composed of three steps and affords the final product in high yield and purity. The key cyclization step is...

  8. Modular Synthesis of Benzoylpyridines Exploiting a Reductive Arylation Strategy

    Peer-reviewed journal | Contributor(s): Alfano, Antonella Ilenia, Smyth, Megan, Wharry, Scott, Moody, Thomas S., Baumann, Marcus

    Herein we disclose a telescoped flow strategy to access electronically differentiated bisaryl ketones as potentially new and tunable photosensitizers containing both electron-rich benzene systems and electron-deficient pyridyl moieties. Our approach merges a light-driven (365 nm) and...

  9. Development of a Horizontal Dynamically Mixed Flow Reactor for Laboratory Scale-Up of Photochemical Wohl–Ziegler Bromination

    Peer-reviewed journal | Contributor(s): Pratley, Cassie, Shaalan, Youssef, Boulton, Lee, Jamieson, Craig, Murphy, John A., Edwards, Lee J.

    Flow reactors with enhanced mixing are of interest to the pharmaceutical industry for a range of photochemical applications. Taylor–Couette (vortex, dynamically mixed) reactors have been reported to have intensified mixing and have been used with heterogeneous systems. Our photochemical workflow...

  10. A Tandem Ring Closure and Nitrobenzene Reduction with Sulfide Provides an Improved Route to an Important Intermediate for the Anti-Tuberculosis Drug Candidate Sutezolid

    Peer-reviewed journal | Contributor(s): Kalmode, Hanuman P., Ravikumar, Ongolu, Paymode, Dinesh J., Bachert, John, Burns, Justina M., Stringham, Rodger W., Aleshire, Sarah L., Nelson, Ryan C.

    Sutezolid is an in-development thiomorpholine derivative of the FDA-approved tuberculosis (TB) treatment linezolid. Current synthetic routes for preparing sutezolid start with thiomorpholine as a key structural building block; unfortunately, this material was identified as a major cost driver for...

  11. Continuous-Flow Synthesis of the Nucleobase Unit of Remdesivir

    Peer-reviewed journal | Contributor(s): Guo, Yongxing, Liu, Minjie, Jiang, Meifen, Tao, Yuan, Cheng, Dang, Chen, Fen-Er

    In this work, the nucleobase unit of the antiviral drug remdesivir, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine, was synthesized through five-step continuous flow. By adapting batch synthetic chemistry, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine was successfully produced through sequential flow...

  12. Continuous Platinum-Mediated Hydrogenation of Refametinib Iodo-nitroaniline Key Intermediate DIM-NA: The Combined Challenges of Selectivity and Catalyst Deactivation

    Peer-reviewed journal | Contributor(s): Baramov, Todor, Hassfeld, Jorma, Gottfried, Michael, Bauer, Hermann, Herrmann, Tanja, Ben Said, Mourad, Roggan, Stefan

    The chemoselective, continuous, multistep reduction of iodo-nitroaromatics in a fixed-bed hydrogenation reactor has been investigated. This transformation poses challenges upon both the catalyst and process conditions if high yields are to be achieved. First, the stability and selectivity of four...

  13. Process parameter and kinetic study for the azidation of a zidovudine intermediate with sodium azide in microreactors

    Peer-reviewed journal | Contributor(s): Jiang, Rongkun, Xue, Xiao, Zhao, Fang, Zhu, Weiping, Shang, Minjing, Su, Yuanhai, Xu, Yufang, Qian, Xuhong

    Zidovudine, i.e., AZT, is an indispensable anti-AIDS drug for highly active antiretroviral therapy. The azidation step is of the most vital importance in the synthetic route of zidovudine. Herein we report the use of microreactors in combination with the simplified azidation system instead of...

  14. Establishment and Development of Organolithium-Mediated Continuous Flow Process for Intermediate of Canagliflozin

    Peer-reviewed journal | Contributor(s): Yano, Gemba, Hyakumura, Mai, Nakano, Kimihiro, Yasukouchi, Hiroaki, Kawachi, Hideo, Funabashi, Makoto, Ohishi, Takahiro, Ogawa, Yu, Nishiyama, Akira

    Organolithium species are among the most reactive and useful reagents in organic synthesis, performing a diverse array of valuable chemical transformations, including C–C bond formation in complex compounds. Organolithium-mediated reactions, however, typically require cryogenic conditions to...

  15. Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 4─Applications of Process Analytical Technology in Heterogeneous Biocatalytic Hydroxylation

    Peer-reviewed journal | Contributor(s): Qin, Yangzhong, Mattern, Keith A., Zhang, Victoria, Abe, Kotoe, Kim, Jungchul, Zheng, Michelle, Gangam, Rekha, Kalinin, Alexei, Kolev, Joshua N., Axnanda, Stephanus, Dance, Zachary E. X., Ayesa, Umme, Ji, Yining, Grosser, Shane T., Appiah-Amponsah, Emmanuel, McMullen, Jonathan P.

    Belzutifan has been approved recently by the U.S. Food and Drug Administration (FDA) for treating patients with certain types of Von Hippel-Lindau (VHL) disease-associated tumors. Although a commercial synthetic process has been established to make belzutifan, a further optimized process with...

  16. Development of a Manufacturing Process toward the Convergent Synthesis of the COVID-19 Antiviral Ensitrelvir

    Peer-reviewed journal | Contributor(s): Kawajiri, Takahiro, Kijima, Akihito, Iimuro, Atsuhiro, Ohashi, Eisaku, Yamakawa, Katsuya, Agura, Kazushi, Masuda, Kengo, Kouki, Kensuke, Kasamatsu, Koji, Yanagisawa, Shuichi, Nakashima, Sho, Shibahara, Setsuya, Toyota, Takashi, Higuchi, Takafumi, Suto, Takahiro, Oohara, Tadashi, Maki, Toshikatsu, Sahara, Naoto, Fukui, Nobuaki, Wakamori, Hisayuki, Ikemoto, Hidaka, Murakami, Hiroaki, Ando, Hiroyasu, Hosoya, Masahiro, Sato, Mizuki, Suzuki, Yusuke, Nakagawa, Yuta, Unoh, Yuto, Hirano, Yoichi, Nagasawa, Yoshitomo, Goda, Satoshi, Ohara, Takafumi, Tsuritani, Takayuki

    We describe the development of the practical manufacturing of Ensitrelvir, which was discovered as a SARS-CoV-2 antiviral candidate. Scalable synthetic methods of indazole, 1,2,4-triazole and 1,3,5-triazinone structures were established, and convergent couplings of these fragments enabled the...

  17. Application of Transition-Metal Catalysis, Biocatalysis, and Flow Chemistry as State-of-the-Art Technologies in the Synthesis of LCZ696

    Peer-reviewed journal | Contributor(s): Gu, Xingxian, Zhao, Jibin, Chen, Like, Li, Yunzhong, Yu, Bo, Tian, Xiangguang, Min, Zhongcheng, Xu, Su, Gu, Huijuan, Sun, Junjie, Lu, Xiaoquan, Chang, Meng, Wang, Xufan, Zhao, Liqun, Ye, Shengqing, Yang, Hongwei, Tian, Yingtao, Gao, Feng, Gai, Yu, Jia, Guanghua, Wu, Jingjing, Wang, Yan, Zhang, Jianghua, Zhang, Xuesong, Liu, Weichun, Gu, Xin, Luo, Xi, Dong, Hai, Wang, Huaimin, Schenkel, Berthold, Venturoni, Francesco, Filipponi, Paolo, Guelat, Bertrand, Allmendinger, Thomas, Wietfeld, Bernhard, Hoehn, Pascale, Kovacic, Nikola, Hermann, Luca, Schlama, Thierry, Ruch, Thomas, Derrien, Nadine, Piechon, Philippe, Kleinbeck, Florian

    LCZ696 is a novel treatment for patients suffering from heart failure that combines the two active pharmaceutical ingredients sacubitril and valsartan in a single chemical compound. While valsartan is an established drug substance, a new manufacturing process suitable for large-scale commercial...

  18. Development and Scale-up of a Flow Chemistry Lithiation–Borylation Route to a Key Boronic Acid Starting Material

    Peer-reviewed journal | Contributor(s): Usutani, Hirotsugu, Nihei, Takashi, Papageorgiou, Charles D., Cork, David G.

    A flow chemistry process for the synthesis of a key boronic acid starting material was developed utilizing flow flash chemistry that allowed formation and subsequent productive reaction of an unstable organolithium intermediate. Rapid scale-up from Discovery Chemistry and process optimization to...

  19. Continuous Flow Chemistry of Metal Mediated Carboxylation and α-Arylation Reactions

    Chapter Book | Contributor(s): Venkatraman, Sripathy, Tweedie, Scott, McLaws, Mark, Lathbury, David

    Utility of continuous flow chemistry in a carboxylation reaction and palladium-mediated α-arylation reaction is described. A two-step carboxylation reaction of an aryl group involving an anion formation, followed by quench with gaseous carbon dioxide was developed on small scale using HDPE tubes...

  20. Synthesis of the Antibiotic Precursor Thiazolyl-7-Aminocephalosporanic Acid in a Microstructured Flow System

    Peer-reviewed journal | Contributor(s): Wirth, Vanessa, Volkmar, Julia, Bayer, Thomas

    The synthesis of thiazolyl-7-aminocephalosporanic acid, a pharmaceutical precursor of the β-lactam antibiotic drug cefodizime, could be successfully realized in a continuous microstructured flow system. This was accomplished by changing the process window from batch, having a reaction temperature...

  21. Optimization of aqueous two-phase systems for the production of 6-aminopenicillanic acid in integrated microfluidic reactors-separators

    Peer-reviewed journal | Contributor(s): Vobecká, Lucie, Romanov, Alexandr, Slouka, Zdeněk, Hasal, Pavel, Přibyl, Michal

    Aqueous two-phase systems (ATPSs) were screened for the production of 6-aminopenicillanic acid (6-APA) catalyzed by penicillin acylase, followed by the extractive separation of 6-APA from the reaction mixture. The key point of this study was to find an ATPS exhibiting a large difference in the...

  22. Safe and highly efficient adaptation of potentially explosive azide chemistry involved in the synthesis of Tamiflu using continuous-flow technology

    Peer-reviewed journal | Contributor(s): Sagandira, Cloudius R., Watts, Paul

    Tamiflu is one of the most effective anti-influenza drugs, which is currently manufactured by Hoffmann-La Roche from shikimic acid. Owing to its importance, more than 60 synthetic routes have been developed to date, however, most of the synthetic routes utilise the potentially hazardous azide...

  23. Continuous Flow Conditions for High Temperature Formation of a Benzodioxan Pharmaceutical Intermediate: Rapid Scaleup for Early Phase Material Delivery

    Peer-reviewed journal | Contributor(s): Li, Pengbin, Yang, Shaohui, Zhu, Ruiheng, Sun, Baoquan, Li, Zhongbo, Huang, Ping, Buser, Jonas Y., Minguez, Jose Miguel, Ryan, Sarah J.

    We have developed a continuous flow method to enable rapid scaleup of an enantioenriched benzodioxan intermediate. We propose that the reaction proceeds through an intramolecular SNAr cyclization. Interestingly, traditional SNAr conditions resulted in impurity formation. When the starting...

  24. Organophotocatalytic N-Demethylation of Oxycodone Using Molecular Oxygen

    Peer-reviewed journal | Contributor(s): Chen, Yuesu, Glotz, GabrielCantillo, David, Kappe, C. Oliver

    N-Demethylation of oxycodone is one of the key steps in the synthesis of important opioid antagonists like naloxone or analgesics like nalbuphine. The reaction is typically carried out using stoichiometric amounts of toxic and corrosive reagents. Herein, we present a green and scalable...

  25. One-Step Synthesis of 2-Fluoroadenine Using Hydrogen Fluoride Pyridine in a Continuous Flow Operation

    Peer-reviewed journal | Contributor(s): Salehi Marzijarani, Nastaran, Snead, David R., McMullen, Jonathan P., Lévesque, François, Weisel, Mark, Varsolona, Richard J., Lam, Yu-hong, Liu, Zhijian, Naber, John R.

    We report the development of a one-pot synthesis of 2-fluoroadenine from an inexpensive 2,6-diaminopurine starting material using diazonium chemistry in a continuous fashion. Given the sensitivity of this transformation to temperature, we conducted critical experiments to study the exothermicity...