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...

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 | 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 | 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 | 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 | 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 | 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 | 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 | 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...

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

09 Jun 2023 | 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...

Supervisory Control System for Monitoring a Pharmaceutical Hot Melt Extrusion Process

09 Jun 2023 | Contributor(s): Markl, Daniel, Wahl, Patrick R, Menezes, José C, Koller, Daniel M, Kavsek, Barbara, Francois, Kjell, Roblegg, Evaa, Khinast, Johannes G.

Continuous pharmaceutical manufacturing processes are of increased industrial interest and require uni- and multivariate Process Analytical Technology (PAT) data from different unit operations to be aligned and explored within the Quality by Design (QbD) context. Real-time pharmaceutical process...

Selective preparation of elusive and alternative single component polymorphic solid forms through multi-component crystallisation routes

09 Jun 2023 | Contributor(s): Thomas, LH, Wales, C, Wilson, CC

A transferable, simple, method for producing previously elusive and novel polymorphic forms of important active pharmaceutical ingredients (APIs; paracetamol (acetaminophen), piroxicam and piracetam) is demonstrated. Nitrogen heterocyclic co-molecules are employed to influence the self-assembly...

Simulation-Based Design of an Efficient Control System for the Continuous Purification and Processing of Active Pharmaceutical Ingredients

09 Jun 2023 | Contributor(s): Sen, M, Singh, R, Ramachandran, R

In this study, an efficient system-wide controlsystem has been designed for the integrated continuous purification and processing of the active pharmaceutical ingredient (API). The control strategy is based on the regulatory PID controller which is most widely used in the manufacturing industry...

Selective crystallization of the metastable α-form of L-glutamic acid using concentration feedback control

09 Jun 2023 | Contributor(s): Kee, Nicholas C.S., Tan, Reginald B.H. Braatz, Richard D., Braatz, Richard D.

A systematic methodology is presented for the selective crystallization of the metastable form of a monotropic dimorph, L-glutamic acid, for batch cooling crystallization. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy coupled with chemometrics was used to...

Robustness of a continuous direct compression line against disturbances in feeding

09 Jun 2023 | Contributor(s): Karttunen A.-P., Poms J., Sacher S., Sparén A., Ruiz Samblás C., Fransson M., Martin De Juan L., Remmelgas J., Wikström H., Hsiao W.-K., Folestad S., Korhonen O.

The aim of the current study was to characterize the robustness of an integrated continuous direct compression (CDC) line against disturbances from feeding, i.e. impulses of API and short step disturbances. These disturbances mimicked typical variations that can be encountered during long-term...

Recent Developments in the Crystallization Process: Toward the Pharmaceutical Industry

09 Jun 2023 | Contributor(s): Gao, Zhenguo, Gong, Junbo, Rohani, Sohrab, Wang, Jingkang

Crystallization is one of the oldest separation and purification unit operations, and has recently contributed to significant improvements in producing higher-value products with specific properties and in building efficient manufacturing processes. In this paper, we review recent developments in...

Real-time monitoring of drug concentration in a continuous powder mixing process using NIR spectroscopy

09 Jun 2023 | Contributor(s): Vanarase, Aditya, Alcalà, Manel, Jerez-Rozo, Jackeline, Muzzio, Fernando, Romañach, Rodolfo

A non-destructive NIR spectroscopic method was used to acquire on-line spectra of a continuous mixing process, and evaluate the performance of this novel system. Partial least squares (PLS) calibration models were developed and used for real-time determination of active ingredient concentration...

Real-time process monitoring in a semi-continuous fluid-bed dryer - microwave resonance technology versus near-infrared spectroscopy

09 Jun 2023 | Contributor(s): Peters, Johanna, Teske, Andreas, Taute, Wolfgang, Döscher, Claas, Höft, Michael, Knöchel, Reinhard, Breitkreutz, Jörg

The trend towards continuous manufacturing in the pharmaceutical industry is associated with an increasing demand for advanced control strategies. It is a mandatory requirement to obtain reliable real-time information on critical quality attributes (CQA) during every process step as the decision...

Real-Time Quantification of Low-Dose Cohesive Formulations within a Sampling Interface for Flowing Powders

09 Jun 2023 | Contributor(s): Sierra-Vega, Nobel. O., Romañach, Rodolfo J., Mendez, Rafael

This study investigates the performance of a sampling interface for monitoring cohesive, flowing powder formulations with Hausner's Ratio and Carr's Index higher than 1.5 and 35%, respectively. The sampler device was operated in combination with near-infrared (NIR) spectroscopy to quantify...

Real-time monitoring of particle size distribution in a continuous granulation and drying process by near infrared spectroscopy

09 Jun 2023 | Contributor(s): Pauli, V, Roggo, YKleinebudde, P, Krumme, M

In continuous granulation, it can be important to control granules particle size distribution (PSD), as it may affect final product quality. Near infrared spectroscopy (NIRS) is already a routine analytical procedure within pharmaceutical continuous manufacturing for the in-line analysis of...

Real-time feasible model-based crystal size and shape control of crystallization processes

09 Jun 2023 | Contributor(s): Szilagyi, Botond, Nagy, Zoltan K.

The simultaneous control of crystal size and shape is particularly important in fine chemical and pharmaceutical crystallization. These two quantities influence the dissolution rate and bioavailability of final drug products, and also contribute to the manufacturability and efficiency of...

Quality-by-Design III: Application of Near-Infrared Spectroscopy to Monitor Roller Compaction In-process and Product Quality Attributes of Immediate Release Tablets

09 Jun 2023 | Contributor(s): Kona, Ravikanth, Fahmy, Raafat M., Claycamp, Gregg, Polli, James E., Martinez, Marilyn, Hoag, Stephen W.

The objective of this study is to use near-infrared spectroscopy (NIRS) coupled with multivariate chemometric models to monitor granule and tablet quality attributes in the formulation development and manufacturing of ciprofloxacin hydrochloride (CIP) immediate release tablets. Critical roller...

Process dynamics and control of API manufacturing and purification processes

09 Jun 2023 | Contributor(s): Sen, Maitraye, Singh, Ravendra, Ramachandran, Rohit

The pharmaceutical industries have started transitioning toward continuous mode of manufacturing recently. Due to many advantages of the continuous manufacturing over the traditional alternatives, the industries are putting huge effort to efficiently adapt the continuous processing mode. However,...

Process Analytical Technology for Crystallization of Active Pharmaceutical Ingredients

09 Jun 2023 | Contributor(s): Malwade, CR, Qu, HY

Background: Pharmaceutical industry is witnessing increased pressure to introduce innovative and efficient processes for manufacturing Active Pharmaceutical Ingredients (APIs) in order to be competitive as well as to meet the stringent product quality requirements set by regulatory authorities....