Optimization and sustainability assessment of a continuous flow Ru-catalyzed ester hydrogenation for an important precursor of a β2-adrenergic receptor agonist†

25 Jun 2024 | Contributor(s): Prieschl, Michael, García-Lacuna, Jorge, Munday, Rachel, Leslie, Kevin, O'Kearney-McMullan, Anne, Hone, Christopher A., Kappe, C. Oliver

The development of a ruthenium-catalyzed continuous flow ester hydrogenation using hydrogen (H2) gas is reported. The reaction was utilized for the reduction of an important precursor in the synthesis of abediterol, a β2-adrenoceptor agonist that has undergone phase IIa clinical trials for the...

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...

Optimization of a semi-batch tablet coating process for a continuous manufacturing line by design of experiments

09 Jun 2023 | Contributor(s): Barimani, Shirin, Šibanc, Rok, Kleinebudde, Peter

Optimization of aqueous two-phase systems for the production of 6-aminopenicillanic acid in integrated microfluidic reactors-separators

25 Jun 2024 | Contributor(s): Vobecká, Lucie, Romanov, Alexandr, Slouka, Zdeněk, Hasal, Pavel, Přibyl, Michal

Aqueous two-phase systems (ATPSs) were screened for the production of 6-aminopenicillanic acid (6-APA) catalyzed by penicillin acylase, followed by the extractive separation of 6-APA from the reaction mixture. The key point of this study was to find an ATPS exhibiting a large difference in the...

Optimization of critical quality attributes in continuous twin-screw wet granulation via design space validated with pilot scale experimental data

09 Jun 2023 | Contributor(s): Liu, Huolong, Galbraith, S. C., Ricart, Brendon, Stanton, Courtney, Smith-Goettler, Brandye, Verdi, Luke, O'Connor, Thomas, Lee, Sau, Yoon, Seongkyu

In this study, the influence of key process variables (screw speed, throughput and liquid to solid (L/S) ratio) of a continuous twin screw wet granulation (TSWG) was investigated using a central composite face-centered (CCF) experimental design method. Regression models were developed to predict...

Optimization of Critical Quality Attributes in Tablet Film Coating and Design Space Determination Using Pilot-Scale Experimental Data

23 Jul 2024 | Contributor(s): Liu, Huolong, Meyer, Robert, Flamm, Matthew, Wareham, Laura, Metzger, Matthew, Tantuccio, Anthony, Yoon, Seongkyu

In this study, the novel high-speed tablet film coating process in the continuous manufacturing was investigated. The influence of key process variables (inlet air flow rate, inlet air temperature, and suspension spray rate) were investigated using a Box-Behnken experimental design method....

Optimization of residence time distribution in RCDG and an assessment of its applicability in continuous manufacturing

09 Jun 2023 | Contributor(s): Wilms, Annika, Kleinebudde, Peter

Knowledge of residence time is a critical aspect in developing control and material diversion strategies for continuous manufacturing processes in pharmaceutical manufacturing. Dry granulation is a promising continuous granulation technique as it is fast and economical. In this study, a...

Optimized continuous pharmaceutical manufacturing via model-predictive control

09 Jun 2023 | Contributor(s): Rehrl, Jakob, Kruisz, Julia, Sacher, Stephan, Khinast, Johannes, Horn, Martin

This paper demonstrates the application of model-predictive control to a feeding blending unit used in continuous pharmaceutical manufacturing. The goal of this contribution is, on the one hand, to highlight the advantages of the proposed concept compared to conventional PI-controllers, and, on...

Organophotocatalytic N-Demethylation of Oxycodone Using Molecular Oxygen

25 Jun 2024 | Contributor(s): Chen, Yuesu, Glotz, GabrielCantillo, David, Kappe, C. Oliver

N-Demethylation of oxycodone is one of the key steps in the synthesis of important opioid antagonists like naloxone or analgesics like nalbuphine. The reaction is typically carried out using stoichiometric amounts of toxic and corrosive reagents. Herein, we present a green and scalable...

Orodispersible films: Product transfer from lab-scale to continuous manufacturing

23 Jul 2024 | 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...

Orthogonal Redundant Monitoring of a New Continuous Fluid-Bed Dryer for Pharmaceutical Processing by Means of Mass and Energy Balance Calculations and Spectroscopic Techniques

09 Jun 2023 | Contributor(s): Pauli, Victoria, Elbaz, Frantz, Kleinebudde, Peter, Krumme, Markus

In line with the ongoing shift from batch to continuous pharmaceutical production of solid oral dosage forms, a novel continuous fluid-bed dryer was developed. The forced feed nature of the Glatt GPCG2 CM fluid-bed dryer allows continuous, first-in-first-out drying of wet granulate materials...

Oscillatory Flow Reactors (OFRs) for Continuous Manufacturing and Crystallization

09 Jun 2023 | Contributor(s): McGlone, Thomas, Briggs, Naomi E. B., Clark, Catriona A., Brown, Cameron J., Sefcik, Jan, Florence, Alastair J.

Continuous crystallization is an attractive approach for the delivery of consistent particles with specified critical quality attributes (CQAs), which are attracting increased interest for the manufacture of high value materials, including fine chemicals and pharmaceuticals. Oscillatory flow...

Parametric Study of Residence Time Distributions and Granulation Kinetics as a Basis for Process Modeling of Twin-Screw Wet Granulation

09 Jun 2023 | Contributor(s): Plath, Timo, Korte, Carolin, Sivanesapillai, Rakulan, Weinhart, Thomas

Twin-screw wet granulation is a crucial unit operation in shifting from pharmaceutical batch to continuous processes, but granulation kinetics as well as residence times are yet poorly understood. Experimental findings are highly dependent on screw configuration as well as formulation, and thus...

Parametric, Optimization-Based Study on the Feasibility of a Multisegment Antisolvent Crystallizer for in Situ Fines Removal and Matching of Target Size Distribution

09 Jun 2023 | Contributor(s): Ridder, Bradley J., Majumder, Aniruddha, Nagy, Zoltan K.

We have computationally investigated the use of the multisegment, multiaddition, plug-flow crystallizer (MSMA-PFC) for use in producing pharmaceutical crystals. A population balance framework was used to model the crystallization process. The dissolution of crystals can be modeled when solubility...

Part 3: Enhanced Approaches to the Development of the Control Strategy and its Implementation in the Manufacturing Process Description

09 Jun 2023 | Contributor(s): Popkin, ME, Omer, BASeibert, KD, Luciani, CV, Srivastava, S, Hobson, L, Lepore, JV

A series of case histories from IQ consortium member companies will be presented to exemplify how the application of the ICH Q11 vision for enhanced Quality by Design (QbD) development of the active pharmaceutical ingredient (API) can lead to differentiated outcomes for elements such as the API...

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...

Particle Shape Manipulation and Optimization in Cooling Crystallization Involving Multiple Crystal Morphological Forms

09 Jun 2023 | Contributor(s): Wang, Xue, Ma, CY, Wan, Jian

A population balance model for predicting the dynamic evolution of crystal shape distribution is further developed to simulate crystallization processes in which multiple crystal morphological forms co-exist and transitions between them can take place. The new model is applied to derive the...

PAT for pharmaceutical manufacturing process involving solid dosages forms

09 Jun 2023 | Contributor(s): Román-Ospino, Andrés D, Cárdenas, Vanessa Ortega-Zuñiga, Carlos, Singh, Ravendra

This chapter summarizes important considerations to develop multivariate methods for pharmaceuticals process monitoring and quality control in solid dosages forms based on spectroscopic techniques. The stages described in each section aimed to explain relevant knowledge of the calibration...

PAT implementation for advanced process control in solid dosage manufacturing - A practical guide

09 Jun 2023 | Contributor(s): Sacher, Stephan, Poms, Johannes, Rehrl, Jakob, Khinast, Johannes G.

The implementation of continuous pharmaceutical manufacturing requires advanced control strategies rather than traditional end product testing or an operation within a small range of controlled parameters. A high level of automation based on process models and hierarchical control concepts is...

PAT Implementation on a Mobile Continuous Pharmaceutical Manufacturing System: Real-Time Process Monitoring with In-Line FTIR and Raman Spectroscopy

09 Jun 2023 | Contributor(s): Miyai, Yuma, Formosa, Anna, Armstrong, Cameron, Marquardt, Brian, Rogers, Luke, Roper, Thomas

The strategies and experimental methods for implementation of process analytical technology (PAT) on the mobile pharmaceutical manufacturing system, Pharmacy on Demand (PoD), are discussed. With multiple processes to be monitored on the PoD end-to-end continuous manufacturing process, PAT and its...

PAT-based design of agrochemical co-crystallization processes: A case-study for the selective crystallization of 1:1 and 3:2 co-crystals of p-toluenesulfonamideitriphenylphosphine oxide

09 Jun 2023 | Contributor(s): Powell, KA, Croker, DMRielly, CD, Nagy, ZK

In this study, the selective crystallization and characterization of the stoichiometric forms of the p-to-luenesulfonamide/triphenylphosphine oxide (p-TSA-TPPO) co-crystal system in acetonitrile (MeCN) is demonstrated using batch and semi-batch crystallizers. In the batch study, both 1:1 and 3:2...

Periodic steady-state flow crystallization of a pharmaceutical drug using MSMPR operation

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Powell, Keddon A., Saleemi, Ali N, Rielly, Chris D., Nagy, Zoltan K

In this paper, a novel concept of periodic mixed suspension mixed product removal (PMSMPR) crystallization process is demonstrated. An integrated array of process analytical technologies (PATs), based on attenuated total reflectance ultra violet/visible spectroscopy, focused beam reflectance...

Perspectives on the continuous manufacturing of powder‐based pharmaceutical processes

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Marianthi Ierapetritou, Fernando Muzzio, Gintaras Reklaitis

The Pharmaceutical industry is a global business sector with $1 trillion annual sales focused on performance based products designed to address the healthcare needs of the world's population. In the last decade, the industry has been experiencing a number of important changes in its business...