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Orodispersible films: Product transfer from lab-scale to continuous manufacturing
23 Jul 2024 | Contributor(s):: Thabet, Yasmin, Breitkreutz, Joerg
Orodispersible films have been described as new beneficial dosage forms for special patient populations. Due to various production settings, different requirements on film formulations are required for non- continuous and continuous manufacturing. In this study, a continuous coating machine was...
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The effect of binder types on the breakage and drying behavior of granules in a semi-continuous fluid bed dryer after twin screw wet granulation
23 Jul 2024 | Contributor(s):: Vandevivere, L., Denduyver, P., Portier, C., Häusler, O., De Beer, T., Vervaet, C., Vanhoorne, V.
Current study investigated the effect of different binder types on the granule drying process and the granule breakage behavior in a semi-continuous fluid bed dryer integrated in the C25 ConsiGma-system. The studied binders (i.e. hydroxypropyl pea starch, hydroxypropyl methylcellulose E15,...
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Delta-mannitol to enable continuous twin-screw granulation of a highly dosed, poorly compactable formulation
23 Jul 2024 | Contributor(s):: Vanhoorne, V., Almey, R., De Beer, T., Vervaet, C.
In current study, it was investigated if the moisture-mediated polymorphic transition from δ- to β-mannitol during twin screw granulation (TSG) also took place in high drug loaded formulations and if the specific granule morphology associated with the polymorphic transition could enable tableting...
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Twin Screw Melt Granulation: Alternative Approach for Improving Solubility and Permeability of a Non-steroidal Anti-inflammatory Drug Ibuprofen
23 Jul 2024 | Contributor(s):: Nyavanandi, Dinesh, Narala, Sagar, Mandati, Preethi, Alzahrani, Abdullah, Kolimi, Praveen, Almotairy, Ahmed, Repka, Michael A.
The current research is focused on investigating the suitability of the twin screw melt granulation (TSMG) approach for improving the solubility of a non-steroidal anti-inflammatory (NSAIDs) drug (ibuprofen), by developing granules using lipid surfactants. The solubility of the drug within the...
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Application of Transition-Metal Catalysis, Biocatalysis, and Flow Chemistry as State-of-the-Art Technologies in the Synthesis of LCZ696
23 Jul 2024 | 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...
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One-Step Synthesis of 2-Fluoroadenine Using Hydrogen Fluoride Pyridine in a Continuous Flow Operation
23 Jul 2024 | 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...
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Process Intensification via End-to-End Continuous Manufacturing of Atorvastatin Calcium Using an Integrated, Modular Reaction-Crystallization-Spherical Agglomeration-Filtration-Drying Process
23 Jul 2024 | Contributor(s):: Parvaresh, Rojan, Nagy, Zoltan K.
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...
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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
25 Jun 2024 | 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...
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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.
25 Jun 2024 | 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...
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Telescoped Hybrid Batch–Flow Synthesis of 2-Butylbenzofuran
25 Jun 2024 | 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...
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Modular Synthesis of Benzoylpyridines Exploiting a Reductive Arylation Strategy
25 Jun 2024 | 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...
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Development of a Horizontal Dynamically Mixed Flow Reactor for Laboratory Scale-Up of Photochemical Wohl–Ziegler Bromination
25 Jun 2024 | 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...
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A Tandem Ring Closure and Nitrobenzene Reduction with Sulfide Provides an Improved Route to an Important Intermediate for the Anti-Tuberculosis Drug Candidate Sutezolid
25 Jun 2024 | 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...
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Continuous-Flow Synthesis of the Nucleobase Unit of Remdesivir
25 Jun 2024 | 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...
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Continuous Platinum-Mediated Hydrogenation of Refametinib Iodo-nitroaniline Key Intermediate DIM-NA: The Combined Challenges of Selectivity and Catalyst Deactivation
25 Jun 2024 | 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...
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Process parameter and kinetic study for the azidation of a zidovudine intermediate with sodium azide in microreactors
25 Jun 2024 | 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...
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Establishment and Development of Organolithium-Mediated Continuous Flow Process for Intermediate of Canagliflozin
25 Jun 2024 | 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...
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Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 4─Applications of Process Analytical Technology in Heterogeneous Biocatalytic Hydroxylation
25 Jun 2024 | 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...
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Development of a Manufacturing Process toward the Convergent Synthesis of the COVID-19 Antiviral Ensitrelvir
25 Jun 2024 | 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...
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Application of Transition-Metal Catalysis, Biocatalysis, and Flow Chemistry as State-of-the-Art Technologies in the Synthesis of LCZ696
25 Jun 2024 | 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...
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Development and Scale-up of a Flow Chemistry Lithiation–Borylation Route to a Key Boronic Acid Starting Material
25 Jun 2024 | 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...
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Synthesis of the Antibiotic Precursor Thiazolyl-7-Aminocephalosporanic Acid in a Microstructured Flow System
25 Jun 2024 | 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...
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Optimization of aqueous two-phase systems for the production of 6-aminopenicillanic acid in integrated microfluidic reactors-separators
25 Jun 2024 | 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...
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Safe and highly efficient adaptation of potentially explosive azide chemistry involved in the synthesis of Tamiflu using continuous-flow technology
25 Jun 2024 | 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...
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Continuous Flow Conditions for High Temperature Formation of a Benzodioxan Pharmaceutical Intermediate: Rapid Scaleup for Early Phase Material Delivery
25 Jun 2024 | 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...