Development of a high-fidelity digital twin using the discrete element method for a continuous direct compression process. Part 1. Calibration workflow

24 Oct 2024 | Peer-reviewed journal | Contributor(s): Peter Toson, Marko Matić, Theresa Hörmann-Kincses, Michela Beretta, Jakob Rehrl, Johannes Poms, Thomas O’Connor, Abdollah Koolivand, Geng Tian, Scott M. Krull, Johannes G. Khinast, Dalibor Jajcevic, Johan Remmelgas

In this work, a high-fidelity digital twin was developed to support the design and testing of control strategies for drug product manufacturing via direct compression. The high-fidelity digital twin platform was based on typical pharmaceutical equipment, materials, and direct compression...

Continuous Processing. Continuous Evolution

08 Oct 2024 | Magazine | Contributor(s): Douglas Hausner

Continuous processing for small molecule products has been a hot topic for years, but where does the industry stand with it today? We speak with Doug Hausner, Senior Manager, Continuous Manufacturing, Oral Solid Dose, Pharma Services at Thermo Fisher Scientific, to find out.

Continuous Processing. Continuous Evolution

08 Oct 2024 | Magazine | Contributor(s): Douglas Hausner

Continuous processing for small molecule products has been a hot topic for years, but where does the industry stand with it today? We speak with Doug Hausner, Senior Manager, Continuous Manufacturing, Oral Solid Dose, Pharma Services at Thermo Fisher Scientific, to find out.

Continuous micro feeding and mixing of solid dosage forms under vibrational excitation

08 Oct 2024 | Peer-reviewed journal | Contributor(s): Haifeng Lu, Liang Zhang, Hui Du, Xiaolei Guo, Haifeng Liu

Continuous manufacturing has intrigued many researchers in the pharmaceutical industry in the post-COVID-19 world. We experimentally studied the discharge characteristics of pharmaceutical excipients under vibrational excitation. The successful accurate dosing and filling of powders at fill...

Continuous manufacturing: Changing the paradigm in the pharmaceutical manufacturing sector

23 Sep 2024 | Magazine | Contributor(s): Indu Bhushan

The author explains how continuous manufacturing is reshaping pharmaceutical production

Pharmaceutical Continuous Manufacturing: Content Uniformity With PAT And RTR

16 Sep 2024 | Website | Contributor(s): Richard Steiner

In pharmaceutical continuous manufacturing (PCM), technical solutions ensuring critical quality attributes for content uniformity and unit dose exist for online, in-line, and at-line measurements. Process analytical technology (PAT) allows in-line measurement and control of critical process...

Systematic investigation of the impact of screw elements in continuous wet granulation

10 Sep 2024 | Peer-reviewed journal | Contributor(s): Katharina Kiricenko, Peter Kleinebudde, Robin Meier

Twin-screw wet granulation (TSG) is a continuous manufacturing technique either for granules as final dosage form or as an intermediate before tableting or capsule filling. A comprehensive process understanding is required to implement TSG, considering various parameters influencing granule and...

The Use of a Closed Feed Frame for the Development of Near-Infrared Spectroscopic Calibration Model to Determine Drug Concentration

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Movilla-Meza, Nathaly A., Sierra-Vega, Nobel O., Alvarado-Hernández, Bárbara B., Méndez, Rafael, Romañach, Rodolfo J.

Purpose: This study evaluates the use of the closed feed frame as a material sparing approach to develop near-infrared (NIR) spectroscopic calibration models for monitoring blend uniformity. The effect of shear induced by recirculation on NIR spectra was also studied. Methods: Calibration models...

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...

Cleaning of direct compression continuous manufacturing equipment through displacement of API residues by excipients

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Patel, Dhavalkumar S, Méndez, Rafael, Romañach, Rodolfo J

This feasibility study evaluates a cleaning process designed to avoid the use of detergents and reduce operator exposure to the active pharmaceutical ingredient (API). The continuous manufacturing equipment was cleaned using excipients to displace ibuprofen residues from the system. The cleaning...

Process analytics for the new era of continuous RNA manufacturing

23 Jul 2024 | Website | Contributor(s): Botonjic-Sehic, Edita

In this article, Edita Botonjic-Sehic, Head of Process Analytics and Data Science at ReciBioPharm, examines the need for a digitally controlled continuous manufacturing process to correct the shortcomings of the current standard of batch processing. She highlights the critical role in-line...

Blend uniformity monitoring in a continuous manufacturing mixing process for a low-dosage formulation using a stream sampler and near infrared spectroscopy

19 Jul 2024 | 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...

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

25 Jun 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...

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

25 Jun 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

25 Jun 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

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

25 Jun 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

25 Jun 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...

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

25 Jun 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...

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

25 Jun 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...

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

25 Jun 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...

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

25 Jun 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...

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

25 Jun 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...

Development of a Continuous Flow Process for a Matteson Reaction: From Lab Scale to Full-Scale Production of a Pharmaceutical Intermediate

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Stueckler, Clemens, Hermsen, Peter, Ritzen, Bas, Vasiloiu, Maria, Poechlauer, Peter, Steinhofer, Stefan, Pelz, Andreas, Zinganell, Christopher, Felfer, Ulfried, Boyer, Serge, Goldbach, Michel, de Vries, André, Pabst, Thomas, Winkler, Georg, LaVopa, Vito, Hecker, Scott, Schuster, Christian

Within this paper, we present the design, development, and scale-up of a process for a continuous Matteson reaction to produce a key intermediate toward the β-lactamase inhibitor vaborbactam. This includes the successful implementation of the continuous concept at a multiton production scale for...

A Continuous Flow Sulfuryl Chloride-Based Reaction—Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Souza, Juliana M. de, Berton, Mateo, Snead, David R., McQuade, D. Tyler

We demonstrate a continuous two-step sequence in which sulfenyl chloride is formed, trapped by vinyl acetate, and chlorinated further via a Pummerer rearrangement. These reactions produce a key intermediate in our new approach to the oxathiolane core used to prepare the antiretroviral medicines...