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

23 Jul 2024 | 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...

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

23 Jul 2024 | 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...

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

23 Jul 2024 | 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 | 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...

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

09 Jul 2024 | 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...

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

25 Jun 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...

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...

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

25 Jun 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, High-Pressure, Asymmetric Hydrogenation Reaction, Workup, and Isolation

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Johnson, Martin D., May, Scott A., Calvin, Joel R., Remacle, Jacob, Stout, James R., Diseroad, William D., Zaborenko, Nikolay, Haeberle, Brian D., Sun, Wei-Ming, Miller, Michael T., Brennan, John

A fully continuous process including an asymmetric hydrogenation reaction operating at 70 bar hydrogen, aqueous extraction, and crystallization was designed, developed, and demonstrated at pilot scale. This paper highlights safety, quality, and throughput advantages of the continuous reaction and...

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...

Development of a Continuous Schotten–Baumann Route to an Acyl Sulfonamide

24 Apr 2024 | Peer-reviewed journal | Contributor(s): White, Timothy D., Berglund, K. Derek, Groh, Jennifer McClary, Johnson, Martin D., Yates, Matthew H.

The development and scale-up of a synthetic route to tasisulam sodium (5-bromo-thiophene-2-sulfonic acid 2,4-dichlorobenzoylamide sodium salt, hereafter referred to as tasisulam) utilizing continuous Schotten–Baumann reaction conditions is disclosed. A new synthetic route for the cytotoxic API...

Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Heider, Patrick L., Born, Stephen C., Basak, Soubir, Benyahia, Brahim, Lakerveld, Richard, Zhang, Haitao, Hogan, Rachael, - Buchbinder, Louis, Wolfe, Aaron, Mascia, Salvatore, Evans, James M. B., Jamison, Timothy F., Jensen, Klavs F.

The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active...

Automated and continuous synthesis of drug substances

24 Apr 2024 | Peer-reviewed journal | Contributor(s): Sacher, Stephan, Castillo, Ismael, Rehrl, Jakob, Sagmeister, Peter, Lebl, René, Kruisz, Julia, Celikovic, Selma, Sipek, Martin, Williams, Jason D., Kirschneck, Dirk, Kappe, C. Oliver, Horn, Martin

A continuous synthesis line was developed integrating different common reaction steps namely nitration, substitution and hydrogenation. Mesalazine as model drug substance was produced from 2-chlorobenzoic acid in continuous flow mode. A multi-instrument PAT strategy was implemented to equip the...

Videometric mass flow control: A new method for real-time measurement and feedback control of powder micro-feeding based on image analysis

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Madarasz, L, Kote, AGyurkes, M, Farkas, A, Hambalko, B, Pataki, H, Fulop, G, Marosi, G, Lengyel, L, Casian, T, Csorba, K, Nagy, ZK

The present paper reports the first monitoring and control of ultra-low dose powder feeding using a camera image-based mass flow measurement system. Caffeine was fed via a single-screw microfeeder as a model active pharmaceutical ingredient (API). The mass, mass flow and sizes of the particles...

Videometric mass flow control: A new method for real-time measurement and feedback control of powder micro-feeding based on image analysis

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Madarasz, L, Kote, AGyurkes, M, Farkas, A, Hambalko, B, Pataki, H, Fulop, G, Marosi, G, Lengyel, L, Casian, T, Csorba, K, Nagy, ZK

The present paper reports the first monitoring and control of ultra-low dose powder feeding using a camera image-based mass flow measurement system. Caffeine was fed via a single-screw microfeeder as a model active pharmaceutical ingredient (API). The mass, mass flow and sizes of the particles...

Using a material property library to find surrogate materials for pharmaceutical process development

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Escotet-Espinoza, MS, Moghtadernejad, SScicolone, J, Wang, YF, Pereira, G, Schafer, E, Vigh, T, Klingeleers, D, Ierapetritou, M, Muzzio, FJ

Material properties are known to have a significant impact on pharmaceutical manufacturing performance, particularly for solid product processes. Evaluating the performance of a specific material, for example an active pharmaceutical ingredient or excipient, is critical during development stages...

Using residence time distribution in pharmaceutical solid dose manufacturing–A critical review

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Bhalode, Pooja, Tian, Huayu Gupta, Shashwat Razavi, Sonia M Roman-Ospino, Andres Talebian, Shahrzad Singh, Ravendra Scicolone, James V Muzzio, Fernando J, Ierapetritou, Marianthi

While continuous manufacturing (CM) of pharmaceutical solid-based drug products has been shown to be advantageous for improving the product quality and process efficiency in alignment with FDA’s support of the quality-by-design paradigm (Lee, 2015; Ierapetritou et al., 2016; Plumb, 2005; Schaber,...

Using Residence Time Distributions (RTDs) to Address the Traceability of Raw Materials in Continuous Pharmaceutical Manufacturing

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Engisch, William, Muzzio, Fernando

Continuous processing in pharmaceutical manufacturing is a relatively new approach that has generated significant attention. While it has been used for decades in other industries, showing significant advantages, the pharmaceutical industry has been slow in its adoption of continuous processing,...

Using residence time distribution in pharmaceutical solid dose manufacturing–A critical review

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Bhalode, Pooja, Tian, Huayu Gupta, Shashwat Razavi, Sonia M Roman-Ospino, Andres Talebian, Shahrzad Singh, Ravendra Scicolone, James V Muzzio, Fernando J, Ierapetritou, Marianthi

While continuous manufacturing (CM) of pharmaceutical solid-based drug products has been shown to be advantageous for improving the product quality and process efficiency in alignment with FDA’s support of the quality-by-design paradigm (Lee, 2015; Ierapetritou et al., 2016; Plumb, 2005; Schaber,...

Twin-screw melt granulation: Current progress and challenges

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Kittikunakorn, Nada, Liu, Tongzhou, Zhang, Feng

Twin-screw melt granulation (TSMG) is a new alternative method for granulation that offers several advantages over wet and dry granulation methods. TSMG has rapidly gained interest over recent years in the pharmaceutical industry. Since it is an inherently continuous process with controlled...

Twin screw granulation - review of current progress

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Thompson, M. R.

Twin screw granulation (TSG) is a new process of interest to the pharmaceutical community that can continuously wet granulate powders, doing so at lower liquid concentrations and with better product consistency than found by a high shear batch mixer. A considerable body of Research Article has...

Towards 4th industrial revolution efficient and sustainable continuous flow manufacturing of active pharmaceutical ingredients

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Sagandira, CR, Nqeketo, SMhlana, K, Sonti, T, Gaqa, S, Watts, P

Continuous flow chemistry has opened a new paradigm in both the laboratory and pharmaceutical industry. This review details the recently reported literature on continuous multistep telescoped synthesis of active pharmaceutical ingredients (APIs), inline flow downstream processing, in-process...

Towards a Greener Pharmacy by More Eco Design

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Baron, M

This review proposes an overview of the main trends explored by the pharmaceutical industry in order to develop a greener and smarter pharmacy minimizing any negative impact to the environment, and using more sustainable processes and drugs. If many drugs have their origin in nature, many active...

The Use of Near-Infrared and Microwave Resonance Sensing to Monitor a Continuous Roller Compaction Process

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Austin, John, Gupta, Anshu, Mcdonnell, Ryan, Reklaitis, Gintaras V., Harris, Michael T

Roller compaction is commonly used in the pharmaceutical and nutraceutical industries to increase and narrow the size distribution of a particulate material, making it easier to process. Both the moisture content of the material and the density of the roller compacted ribbon affect the uniformity...