A modeling and control framework for extraction processes

05 Sep 2024 | Peer-reviewed journal | Contributor(s): Peter Neugebauer, Jakob Rehrl, Peter Poechlauer, Dirk Kirschneck, Martin Horn, Martin Steinberger, Stephan Sacher, Joscha Boehm, Daniel Moser

Many continuously operated pharmaceutical process routes have been presented recently. Most of these cover the synthesis of the active pharmaceutical ingredient (API) or solid dosage processing. However, the API purification is also gaining attraction. One widespread and waste-intensive unit...

Critical review on the role of excipient properties in pharmaceutical powder-to-tablet continuous manufacturing

13 Aug 2024 | Peer-reviewed journal | Contributor(s): Sara Fathollahi, Pauline H. M. Janssen, Bastiaan H. J. Dickhoff, Henderik W. Frijlink

The pharmaceutical industry is gradually changing batch-wise manufacturing processes to continuous manufacturing processes, due to the advantages it has to offer. The final product quality and process efficiency of continuous manufacturing processes is among others impacted by the properties of...

Matrix-assisted cocrystallization (MAC) simultaneous production and formulation of pharmaceutical cocrystals by hot-melt extrusion

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Boksa, Kevin, Otte, Andrew, Pinal, Rodolfo

A novel method for the simultaneous production and formulation of pharmaceutical cocrystals, matrix-assisted cocrystallization (MAC), is presented. Hot-melt extrusion (HME) is used to create cocrystals by coprocessing the drug and coformer in the presence of a matrix material. Carbamazepine...

Orodispersible films: Product transfer from lab-scale to continuous manufacturing

23 Jul 2024 | Peer-reviewed journal | 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...

Formulation development of a continuously manufactured orodispersible film containing warfarin sodium for individualized dosing

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Niese, Svenja, Quodbach, Julian

Continuously manufactured orodispersible films (ODFs) offer a promising approach for individualized therapy with an easy to administer solid dosage form. The aim of this study was to develop a long ODF containing warfarin sodium to enable safe and more flexible dosing. Formulation development was...

Managing active pharmaceutical ingredient raw material variability during twin-screw blend feeding

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Stauffer, F., Vanhoorne, V., Pilcer, G., Chavez, Pierre-François, Schubert, M. A., Vervaet, C., De Beer, T.

Continuous powder feeding is a critical step in continuous manufacturing of solid dosage forms, as this unit operation should ensure the mass flow consistency at the desired powder feed rate to guarantee the process throughput and final product consistency. In this study, twin-screw feeding of a...

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

23 Jul 2024 | 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...

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.

23 Jul 2024 | 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...

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

23 Jul 2024 | 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...

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

23 Jul 2024 | 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...

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

23 Jul 2024 | 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...

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

23 Jul 2024 | 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...

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

23 Jul 2024 | 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...

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

23 Jul 2024 | 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...

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

23 Jul 2024 | 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...

Flash Chemistry Approach to Organometallic C-Glycosylation for the Synthesis of Remdesivir

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Keutz, Timo von, Williams, Jason D., Kappe, C. Oliver

In a rapidly changing environment, such as the current COVID-19 pandemic, continuous flow reactors bear the potential to increase the production of urgently needed active pharmaceutical ingredients (APIs) on demand. In the synthesis of remdesivir, the organometallic C-glycosylation step was...

Use of Lithium Diisopropylamide in Flow: Operability and Safety Challenges Encountered on a Multigram Scale

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Alonso, Marta, Garcia, Maria Cruz, McKay, Christopher, Thorp, Lee R., Webb, Michael, Edwards, Lee J.

A workflow for the development of organometallic processes in flow was applied to synthesize 1-(5-bromopyridin-2-yl)-2-methylpropan-2-ol, a pharmaceutical intermediate. Key factors and corresponding practical assessments required for the scale-up when transferring from batch to flow are...

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

23 Jul 2024 | 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...

Synthesis of the Brivaracetam Employing Asymmetric Photocatalysis and Continuous Flow Conditions

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Franco, Marcelo S., Silva, Rodrigo C., Rosa, Gabriel H. S., Flores, Lara M., Oliveira, Kleber T. de, Assis, Francisco F. de

An original total synthesis of the antiepileptic drug brivaracetam (BRV) is reported. The key step in the synthesis consists of an enantioselective photochemical Giese addition, promoted by visible-light and the chiral bifunctional photocatalyst Δ-RhS. Continuous flow conditions were employed to...

Axial Chirality in the Sotorasib Drug Substance, Part 2: Leveraging a High-Temperature Thermal Racemization to Recycle the Classical Resolution Waste Stream

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Beaver, Matthew G., Brown, Derek B., Campbell, Kiersten, Fang, Yuan-Qing, Ford, David D., Mardirossian, Narbe, Nagy, Kevin D., Rötheli, Andreas R., Sheeran, Jillian W., Telmesani, Reem, Parsons, Andrew T.

The development and kilogram-scale demonstration of a high-temperature continuous-flow racemization process to recycle the off-enantiomer of an atropisomeric sotorasib intermediate is described. Part 1 of this two-part series details the design and execution of a classical resolution to generate...

Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Induced Benzylic Bromination

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Bottecchia, Cecilia, Lévesque, François, McMullen, Jonathan P., Ji, Yining, Reibarkh, Mikhail, Peng, Feng, Tan, Lushi, Spencer, Glenn, Nappi, Jarod, Lehnherr, Dan, Narsimhan, Karthik, Wismer, Michael K., Chen, Like, Lin, Yipeng, Dalby, Stephen M.

We report the development and scale-up of a continuous flow photochemical benzylic bromination en route to belzutifan (MK-6482), a small molecule for the treatment of renal cell carcinoma associated with Von Hippel–Lindau syndrome. Compared with the clinical supply route, the photochemical...

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 3: Manganese-Catalyzed Asymmetric Epoxidation, Crystallization, and Filtration

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Maloney, Andrew J., Içten, Elçin, Capellades, Gerard, Beaver, Matthew G., Zhu, Xiaoxiang, Graham, Lauren R., Brown, Derek B., Griffin, Daniel J., Sangodkar, Rahul, Allian, Ayman, Huggins, Seth, Hart, Roger, Rolandi, Pablo, Walker, Shawn D., Braatz, Richard D.

This article describes the process characterization and development of models to inform a process control strategy to prepare (R,R)-epoxy ketone 2, an intermediate in the manufacture of carfilzomib. Model calibration for relevant unit operations and the development of a dynamic integrated...

Development and Scale-Up of a Continuous Manufacturing Process for a Hydrazine Condensation Reaction

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Zhu, Ruiheng, Reddy, Ramesh, Ding, Man, Xu, Ming, Deng, Chaoyi, Tadayon, Sam, Li, Hui, Depew, Kristopher, Lane, Benjamin

The development of a continuous manufacturing process for a hydrazine condensation reaction at high temperature is reported. This continuous process represents a safer approach to manufacture 3-phenyl-1H-pyrazol-5-amine at scale and exhibits better impurity control compared to a traditional batch...

Development and Scale-Up of a Continuous Manufacturing Process for a Hydrazine Condensation Reaction

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Zhu, Ruiheng, Reddy, Ramesh, Ding, Man, Xu, Ming, Deng, Chaoyi, Tadayon, Sam, Li, Hui, Depew, Kristopher, Lane, Benjamin

The development of a continuous manufacturing process for a hydrazine condensation reaction at high temperature is reported. This continuous process represents a safer approach to manufacture 3-phenyl-1H-pyrazol-5-amine at scale and exhibits better impurity control compared to a traditional batch...

Development and Scale-Up of a Continuous Reaction for Production of an Active Pharmaceutical Ingredient Intermediate

23 Jul 2024 | Peer-reviewed journal | Contributor(s): McMullen, Jonathan P., Marton, Christopher H., Sherry, Benjamin D., Spencer, Glenn, Kukura, Joseph, Eyke, Natalie S.

Examples of continuous flow reactions in the laboratory setting are becoming commonplace in pharmaceutical drug substance research. Developing these processes for robust commercialization and identifying the scale-up parameters remains a challenge. An aldol reaction in the formation of an active...