Understanding Powder Behavior in Continuous Feeding: Powder Densification and Screw Layering

16 Oct 2024 | Peer-reviewed journal | Contributor(s): Sara Fathollahi, Pauline H. M. Janssen, Bram Bekaert, Dirk Vanderroost, Valerie Vanhoorne, Bastiaan H. J. Dickhoff

Background: Precise continuous feeding of active pharmaceutical ingredients (APIs) and excipients is crucial in a continuous powder-to-tablet manufacturing setup, as any inconsistency can affect the final tablet quality. Method: This study investigated the impact of various materials on the...

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...

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...

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...

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...

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...

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...

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...

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

18 Jul 2024 | 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...

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

25 Jun 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...

Synthesis of the Brivaracetam Employing Asymmetric Photocatalysis and Continuous Flow Conditions

25 Jun 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...

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 2: Enone Synthesis via a Barbier-Type Grignard Process

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Içten, Elçin, Maloney, Andrew J., Beaver, Matthew G., Zhu, Xiaoxiang, Shen, Dongying E., Robinson, Jo Anna, Parsons, Andrew T., Allian, Ayman, Huggins, Seth, Hart, Roger, Rolandi, Pablo, Walker, Shawn D., Braatz, Richard D.

This article details efforts to characterize and develop a process control strategy for the manufacture of enone 2, a carfilzomib drug substance intermediate obtained through a Barbier-type Grignard reaction of morpholine amide 1. This includes the development of a novel mechanistic model for the...

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...

Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 4: Formylation–Cyclization as a Flow–Batch Process Leads to Significant Improvements in Process Mass Intensity (PMI) and CO Generated versus the Batch–

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Otte, Douglas A. L., Basu, Kallol, Jellett, Lisa, Whittington, Michael, Spencer, Glenn, Burris, Matthew, Corcoran, Emily B., Stone, Kevin, Nappi, Jarod, Arvary, Rebecca A., Donoghue, David, Ren, Hong, Maloney, Kevin M., Naber, John R.

Gefapixant citrate (MK-7264) is a P2X3 antagonist for the treatment of chronic cough. The second generation manufacturing route developed for the Step 3A/3B formylation–cyclization reaction to generate the key intermediate diaminopyrimidine (1) (AF-072) required a significant excess of ethyl...

Continuous Selective Hydrogenation of Refametinib Iodo-nitroaniline Key Intermediate DIM-NA over Raney Cobalt Catalyst at kg/day Scale with Online UV–Visible Conversion Control

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Said, Mourad Ben, Baramov, Todor, Herrmann, Tanja, Gottfried, Michael, Hassfeld, Jorma, Roggan, Stefan

The continuous selective hydrogenation of the iodo-nitroaromatic refametinib active pharmaceutical ingredient (API) intermediate (2,3-difluoro-5-methoxy-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (DIM-NA) to the corresponding iodo-aniline...

End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts†

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Snead, David R., Jamison, Timothy F.

A continuous end-to-end synthesis and purification of diphenhydramine hydrochloride featuring atom economy and waste minimization is described. Combining a 1 : 1 molar ratio of the two starting material streams (chlorodiphenylmethane and N,N-dimethylaminoethanol) in the absence of additional...

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

25 Jun 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...

Polymorphs, Particle Size, and a Pandemic: Development of a Scalable Crystallization Process for Molnupiravir, an Antiviral for the Treatment of COVID-19

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Bade, Rachel, Bothe, Jameson R., Sirota, Eric, Brunskill, Andrew P. J., Newman, Justin A., Zhang, Yongqian, Tan, Melissa, Zheng, Michelle, Brito, Gilmar, Poirier, Marc, Fier, Patrick S., Xu, Yingju, Ward, Michael D., Stone, Kevin, Lee, Ivan H., Gmitter, Andrew J., Bernardoni, Frank, Zompa, Michael A., Luo, Hanlin, Patel, Sanjaykumar, Masiuk, Tina, Mora, Jeff, Ni, Tong, Okoh, Grace A., Tarabokija, James, Liu, Jiaying, Lowinger, Michael B., Mahmood, Tariq

Molnupiravir is a small-molecule active pharmaceutical ingredient (API) prodrug of a nucleoside analog that was demonstrated to be efficacious for the treatment of patients with COVID-19. Early in the pandemic, Merck & Co. Inc. partnered with Ridgeback Biotherapeutics to accelerate the...

Improved Continuous Flow Processing: Benzimidazole Ring Formation via Catalytic Hydrogenation of an Aromatic Nitro Compound

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Chen, Jian, Przyuski, Katrin, Roemmele, Renee, Bakale, Roger P.

In the development of a new route to bendamustine hydrochloride, the API in Treanda, the key benzimidazole intermediate 5 was generated via catalytic heterogeneous hydrogenation of an aromatic nitro compound using a batch reactor. Because of safety concerns and a site limitation on hydrogenation...

Comparison of a Batch and Flow Approach for the Lipase-Catalyzed Resolution of a Cyclopropanecarboxylate Ester, A Key Building Block for the Synthesis of Ticagrelor

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Hugentobler, Katharina G., Rasparini, Marcello, Thompson, Lisa A., Jolley, Katherine E., Blacker, A. John, Turner, Nicholas J.

In this study a batch reactor process is compared to a flow chemistry approach for lipase-catalyzed resolution of the cyclopropanecarboxylate ester (±)-3. (1R,2R)-3 is a precursor of the amine (1R,2S)-2 which is a key building block of the API ticagrelor. For both flow and batch operation, the...

Improvement of a pharmaceutical powder mixing process in a tote blender via DEM simulations

04 Jun 2024 | Peer-reviewed journal | Contributor(s): Benedict Benque, Luca Orefice, Thomas Forgber, Matthias Habeler, Beate Schmid, Johan Remmelgas, Johannes Khinast

An industrial-scale pharmaceutical powder blending process was studied via discrete element method (DEM) simulations. A DEM model of two active pharmaceutical ingredient (API) components and a combined excipient component was calibrated by matching the simulated response in a dynamic angle of...

Development and Application of Control Concepts for Twin-Screw Wet Granulation in the ConsiGmaTM-25: Part 2 Granule Size

04 Jun 2024 | Peer-reviewed journal | Contributor(s): Selma Celikovic, Johannes Poms, Johannes Khinast, Martin Horn, Jakob Rehrl

Traditional operation modes, such as running the production processes at constant process settings or within a narrow design space, do not fully exploit the advantages of continuous pharmaceutical manufacturing. Integrating Quality by Control (QbC) algorithms as a standard component of...