Synthesis of (±)-Pregabalin by Utilizing a Three-Step Sequential-Flow System with Heterogeneous Catalysts

24 Apr 2024 | Contributor(s): Ishitani, Haruro, Kanai, Kan, Saito, Yuki, Tsubogo, Tetsu, Kobayashi, Shū

(±)-Pregabalin, a γ-amino acid derivative, has been synthesized by utilizing flow methods. A three-step sequential-flow reaction starting from commercial isovaleraldehyde and methyl malonate proceeded smoothly with heterogeneous catalysts to afford the precursor of pregabalin in yields of 75–100...

Synthesis of a Highly Functionalized Quinazoline Organozinc toward KRAS G12C Inhibitor Divarasib (GDC-6036), Enabled through Continuous Flow Chemistry

25 Jun 2024 | Contributor(s): Kelly, Sean M., Lebl, René, Malig, Thomas C., Bass, Thomas M., Kummli, Dominique, Kaldre, Dainis, Orcel, Ugo, Tröndlin, Lars, Linder, David, Sedelmeier, Joerg, Bachmann, Stephan, Han, Chong, Zhang, Haiming, Gosselin, Francis

The development of a scalable continuous flow process to synthesize a densely functionalized quinazoline organozinc intermediate toward KRAS G12C inhibitor divarasib (GDC-6036) is reported herein. A traditional cryogenic batch metalation process was initially employed, but instability of the...

Synthesis of Celecoxib, Mavacoxib, SC-560, Fluxapyroxad, and Bixafen Enabled by Continuous Flow Reaction Modules

10 May 2024 | Contributor(s): Britton, Joshua, Jamison, Timothy F.

Multi-step continuous flow synthesis enables a parallel approach to obtain agrochemicals and pharmaceuticals containing 3-fluoroalkyl pyrazole cores. In this system, fluorinated amines are transformed into pyrazole cores through a telescoped in situ generation and consumption of diazoalkanes....

Synthesis of Dolutegravir Exploiting Continuous Flow Chemistry

10 May 2024 | Contributor(s): Nqeketo, Sinazo, Watts, Paul

An efficient continuous flow process for the synthesis of dolutegravir, an active pharmaceutical ingredient (API) for HIV treatment, was investigated. The synthetic procedure starts from a readily available benzyl-protected pyran via six chemical transformations using continuous flow reactors....

Synthesis of the Antibiotic Precursor Thiazolyl-7-Aminocephalosporanic Acid in a Microstructured Flow System

25 Jun 2024 | Contributor(s): Wirth, Vanessa, Volkmar, Julia, Bayer, Thomas

The synthesis of thiazolyl-7-aminocephalosporanic acid, a pharmaceutical precursor of the β-lactam antibiotic drug cefodizime, could be successfully realized in a continuous microstructured flow system. This was accomplished by changing the process window from batch, having a reaction temperature...

Synthesis of the Brivaracetam Employing Asymmetric Photocatalysis and Continuous Flow Conditions

25 Jun 2024 | 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...

Synthesis of treprostinil: key Claisen rearrangement and catalytic Pauson–Khand reactions in continuous flow

10 May 2024 | Contributor(s): García-Lacuna, Jorge, Domínguez, Gema, Blanco-Urgoiti, Jaime, Pérez-Castells, Javier

A new synthesis of treprostinil is described using a plug flow reactor in two of the key steps. First, a Claisen rearrangement reaction is described in scaled flow at multigram amounts. Yields and selectivity of this step are sharply improved compared to those from previous syntheses. Second, the...

System for Continuous Wet Granulation based on a High-shear Mixer

09 Jun 2023 | Contributor(s): Chao, Chi, Steffens, Klaus-Juergen

A new system for continuous wet granulation and drying, based on a modified high-shear-mixer is investigated using met-formine, paracetamole and ibuprofene as active ingredients. First experiments reveal the excellent shape and particle size distribution of the granules. Tabletting investigations...

System model development and computer experiments for continuous API manufacturing

09 Jun 2023 | Contributor(s): Lee, BW, Peterson, JJYin, KH, Stockdale, GS, Liu, YC, O'Brien, A

This work details development of a system/process model and usage of Computer Experiments methodology for continuous manufacturing of Active Pharmaceutical Ingredients (API). The process of interest has three interconnected continuous unit operations, with the first two being reactors and the...

System-wide hybrid MPC–PID control of a continuous pharmaceutical tablet manufacturing process via direct compaction

09 Jun 2023 | Contributor(s): Singh, Ravendra, Ierapetritou, Marianthi, Ramachandran, Rohit

The next generation of QbD based pharmaceutical products will be manufactured through continuous processing. This will allow the integration of online/inline monitoring tools, coupled with an efficient advanced model-based feedback control systems, to achieve precise control of process variables,...

Systematic computer-aided method and tool (ICAS-PAT) for design, analysis &/or validation of process monitoring and analysis systems (PAT systems)

09 Jun 2023 | Contributor(s): Singh, Ravendra, Gernaey, Krist, Gani, Rafiqul

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Systematic development of a high dosage formulation to enable direct compression of a poorly flowing API: A case study

09 Jun 2023 | Contributor(s): Schaller, BE, Moroney, KM, Castro-Dominguez, B, Cronin, P, Belen-Girona, J, Ruane, P, Croker, DM, Walker, GM

In this work, the transfer of oral solid dosage forms, currently manufactured via wet granulation, to a continuous direct compression process was considered. Two main challenges were addressed: (1) a poorly flowing API (Canagliflozin) and (2) high drug loading (51 wt%). A scientific approach was...

Systematic Framework for Design and Adaption of Fast, Flexible, Continuous Modular Plants

09 Jun 2023 | Contributor(s): Singh, Ravendra, Gernaey, Krist Gani, Rafiqul, Woodley, John

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Systematic framework for implementation of material traceability into continuous pharmaceutical tablet manufacturing process

09 Jun 2023 | Contributor(s): Billups, Matthew, Singh, Ravendra

Purpose: With the applications of more advanced manufacturing technologies being applied to the pharmaceutical industry, continuous processes are at the forefront of innovation. One area that is highly desired to be systematically investigated is material traceability in continuous manufacturing...

Systematic investigation of the impact of screw elements in continuous wet granulation

10 Sep 2024 | Peer-reviewed journal | Contributor(s): Katharina Kiricenko, Peter Kleinebudde, Robin Meier

Twin-screw wet granulation (TSG) is a continuous manufacturing technique either for granules as final dosage form or as an intermediate before tableting or capsule filling. A comprehensive process understanding is required to implement TSG, considering various parameters influencing granule and...

Systematic substrate adoption methodology (SAM) for future flexible, generic pharmaceutical production processes

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Singh, Ravendra, Godfrey, Andy Gregertsen, Björn Muller, Frans Gernaey, Krist V Gani, Rafiqul, Woodley, John M

The discovery of an effective and safe pharmaceutical product is based on success in clinical trials. Often, several candidate compounds targeting the same disease area are tested in order to identify the most efficacious products. This involves the manufacture of small quantities of compounds...

Tablet coating by injection molding technology - Optimization of coating formulation attributes and coating process parameters

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Desai, Parind M., Puri, Vibha, Brancazio, David, Halkude, Bhakti S., Hartman, Jeremy E., Wahane, Aniket V., Martinez, Alexander R., Jensen, Keith D., Harinath, Eranda, Braatz, Richard D., Chun, Jung-Hoon, Trout, Bernhardt L.

We developed and evaluated a solvent-free injection molding (IM) coating technology that could be suitable for continuous manufacturing via incorporation with IM tableting. Coating formulations (coating polymers and plasticizers) were prepared using hot-melt extrusion and screened via...

Tablet Quality-Prediction Model Using Quality Material Attributes: Toward Flexible Switching Between Batch and Continuous Granulation

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Arai, H, Nagato, TKoide, T, Yonemochi, E, Yamamoto, H, Sugiyama, H

Purpose The purpose of the study was to develop a model to predict the critical quality attribute (CQA) of tablets during continuous and batch manufacturing using only critical material attributes (CMAs). Methods Experiments were performed using ethenzamide as the active pharmaceutical ingredient...

Tableting model assessment of porosity and tensile strength using a continuous wet granulation route

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Wang, Li Ge, Omar, Chalak, Li, Jianfeng, Mitchell, Niall, Bellinghausen, Stefan, Barrasso, Dana, Salman, Agba, Slade, David

This paper presents a comprehensive assessment of the most widely used tablet compaction models in a continuous wet granulation tableting process. The porosity models, tensile strength models and lubricant models are reviewed from the literature and classified based on their formulations i.e....

Tailoring the crystal size distribution of an active pharmaceutical ingredient by continuous antisolvent crystallization in a planar oscillatory flow crystallizer

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Cruz, P, Alvarez, CRocha, F, Ferreira, A

An active pharmaceutical ingredient is currently produced in a traditional batch antisolvent crystallization process. Although well-established, this process lacks flexibility to control the crystal size distribution (CSD). Therefore, a new process was developed to enable the control of the CSD...

Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

09 Jun 2023 | Document

Document highlights the product lifecycle and the various considerations for maintaining consistent quality through both shelf life and entire lifecycle.

Technoeconomic MINLP Optimisation of Liquid-Liquid Extraction (LLE) Cascades for Continuous Pharmaceutical Manufacturing (CPM) of Atropine

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Diab, S, Mytis, NBoudouvis, AG, Gerogiorgis, DL

Continuous pharmaceutical manufacturing (CPM) has the potential to revolutionise the production of active pharmaceutical ingredients (APIs), offering operational and economic benefits over the currently dominant batch methods implemented by industry. Atropine is a nerve agent API, whose...

Technoeconomic optimisation and comparative environmental impact evaluation of continuous crystallisation and antisolvent selection for artemisinin recovery

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Jolliffe, HG, Gerogiorgis, DI

Systematic nonlinear optimisation is a valuable tool towards evaluating the performance of conceptual Continuous Pharmaceutical Manufacturing (CPM) flowsheets. This study considers total cost minimisation of multiple plausible design choices and eight candidate antisolvents for the continuous...

Technoeconomic Optimization of a Conceptual Flowsheet for Continuous Separation of an Analgaesic Active Pharmaceutical Ingredient (API)

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Jolliffe, HG, Gerogiorgis, DI

Continuous Pharmaceutical Manufacturing (CPM) has recently emerged as a promising alternative to current batch production methods, which require significant expenditures in order to ensure product quality and process reliability. Advances in new continuous synthesis routes, demonstrations of full...

Technoeconomic Optimization of Continuous Crystallization for Three Active Pharmaceutical Ingredients: Cyclosporine, Paracetamol, and Aliskiren

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Diab, S, Gerogiorgis, DI

Mixed suspension, mixed product removal (MSMPR) crystallizers are widely implemented for the continuous crystallization of active pharmaceutical ingredients (APIs), allowing enhanced efficiency, flexibility, and product quality compared to currently dominant batch crystallizer designs....