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...

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...

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...

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 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...

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....

Population Balance Modeling to Predict Particle Size Distribution upon Scale-Up of a Combined Antisolvent and Cooling Crystallization of an Active Pharmaceutical Ingredient

09 Jun 2023 | Contributor(s): Rosenbaum, Tamar, Tan, Li Dummeldinger, Michael Mitchell, Niall, Engstrom, Joshua

Herein, a population balance model (PBM) for a combined cooling and antisolvent crystallization process for an active pharmaceutical ingredient (API) has been developed and utilized to predict the product particle size distribution (PSD) for two sets of four ∼35 kg scale plant batches, with...

Pharmaceutical Crystallization

09 Jun 2023 | Contributor(s): Chen, J, Sarma, BEvans, JMB, Myerson, AS

Crystallization is crucial in the pharmaceutical industry as a separation process for intermediates and as the final step in the manufacture of active pharmaceutical ingredients (APIs). In this perspective article to celebrate 10 years of Crystal Growth & Design, we focus on three areas related...

Particle Engineering of an Active Pharmaceutical Ingredient for Improved Micromeritic Properties

09 Jun 2023 | Contributor(s): Sowa, M, Klapwijk, AROstendorf, M, Beckmann, W

A range of particle-engineering techniques were applied to modify unfavorable bulk solid properties of an active pharmaceutical ingredient (API), with the solid-state form of the compound remaining constant. The compound under investigation has been crystallized as needle-like particles, which...

Optimization in seeded cooling crystallization: A parameter estimation and dynamic optimization study

09 Jun 2023 | Contributor(s): Nowee, S. Mostafa, Abbas, Ali, Romagnoli, Jose A.

In this solution crystallization study, a population balance model that predicts the crystal size distribution (CSD) is used for targeting, by optimization, the product mean size and the coefficient of variation of the final CSD. The model is robust over a wide range of conditions and predicts...

Nucleation kinetics of paracetamolethanol solutions from induction time experiments using Lasentec FBRM®

09 Jun 2023 | Contributor(s): Mitchell, Niall A., Ó'Ciardhá, Clifford T., Frawley, Patrick J.

A study of the nucleation kinetics for cooling crystallisation of paracetamolethanol solutions in a batch reactor is described in this paper. Induction time experiments were conducted in order to estimate the nucleation kinetics of the system. Measured induction times can be affected by numerous...

Nucleation Studies of Active Pharmaceutical Ingredients in an Air-Segmented Microfluidic Drop-Based Crystallizer

09 Jun 2023 | Contributor(s): Lu, Jennifer, Litster, James D., Nagy, Zoltan K.

In this work, an innovative experimental platform to study the nucleation behavior of an active pharmaceutical ingredient (API) using a gas-segmented flow produced by a microfluidic T-junction device with fine perfluoroalkoxy alkane (PFA) tubing is presented. In the experiments, a continuous...

Multi-Impurity Adsorption Model for Modeling Crystal Purity and Shape Evolution during Crystallization Processes in Impure Media

09 Jun 2023 | Contributor(s): Borsos, Akos, Majumder, Aniruddha, Nagy, Zoltan K.

The impurity effect on the crystal properties, such as particle size and shape distribution, is significant, having significant impact on the downstream processes as well as on the product effectiveness. Currently very few studies exist that provide a quantitative model to describe crystal purity...

Multi-scale flowsheet simulation of an integrated continuous purification-downstream pharmaceutical manufacturing process

09 Jun 2023 | Contributor(s): Sen, M, Chaudhury, ASingh, R, John, J, Ramachandran, R

Properties of active pharmaceutical ingredients influence the critical quality attributes (CQAs) of final solid dosage forms (e. g. tablets). In the last decade, continuous manufacturing has been shown to be a promising alternative to batch processing in the pharmaceutical industry. Therefore, a...

Model-based evaluation of direct nucleation control approaches for the continuous cooling crystallization of paracetamol in a mixed suspension mixed product removal system

09 Jun 2023 | Contributor(s): Acevedo, David, Yang, Yang Warnke, Daniel J., Nagy, Zoltan K. ;

Direct nucleation control (DNC) is a model-free feedback control approach based on the measurement of particle number in the crystallization process. The experimental implementation has demonstrated that this approach is efficient to produce large and uniform crystals in batch crystallization, or...

Microfluidic droplet liquid reactors for active pharmaceutical ingredient crystallization by diffusion controlled solvent extraction

09 Jun 2023 | Contributor(s): Tona, RM, McDonald, TAOAkhavein, N, Larkin, JD, Lai, D

A novel method for crystallization utilizing solvent/antisolvent extraction in microfluidic droplet liquid reactors has been developed for rapid and low-cost screening of crystal polymorphism (i. e. molecular crystallographic arrangement or internal structure) and habit (i.e. crystallographic...