A Continuous Flow Sulfuryl Chloride-Based Reaction—Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine

25 Jun 2024 | Contributor(s): Souza, Juliana M. de, Berton, Mateo, Snead, David R., McQuade, D. Tyler

We demonstrate a continuous two-step sequence in which sulfenyl chloride is formed, trapped by vinyl acetate, and chlorinated further via a Pummerer rearrangement. These reactions produce a key intermediate in our new approach to the oxathiolane core used to prepare the antiretroviral medicines...

A Continuous Flow Sulfuryl Chloride-Based Reaction—Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine

23 Jul 2024 | Contributor(s): Souza, Juliana M. de, Berton, Mateo, Snead, David R., McQuade, D. Tyler

We demonstrate a continuous two-step sequence in which sulfenyl chloride is formed, trapped by vinyl acetate, and chlorinated further via a Pummerer rearrangement. These reactions produce a key intermediate in our new approach to the oxathiolane core used to prepare the antiretroviral medicines...

A large-scale experimental comparison of batch and continuous technologies in pharmaceutical tablet manufacturing using ethenzamide

09 Jun 2023 | Contributor(s): Matsunami, Kensaku, Nagato, Takuya, Hasegawa, Koji, Sugiyama, Hirokazu

This paper compares batch and continuous technologies in terms of product quality and process performance in pharmaceutical tablet manufacturing using ethenzamide as the active pharmaceutical ingredient. Batch and continuous processes using wet granulation were investigated by performing...

A Scalable Two-Step Continuous Flow Synthesis of Nabumetone and Related 4-Aryl-2-butanones

24 Apr 2024 | Contributor(s): Viviano, Monica, Glasnov, Toma N., Reichart, Benedik, Tekautz, Guenter, Kappe, C. Oliver

Three different continuous flow strategies for the generation of important 4-aryl-2-butanone derivatives including the anti-inflammatory drug nabumetone [4-(6-methoxy-2-naphthalenyl)-2-butanone] and the aroma compounds raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] and its methyl ether...

A Three-Minute Synthesis and Purification of Ibuprofen: Pushing the Limits of Continuous-Flow Processing

10 May 2024 | Contributor(s): Snead, David R., Jamison, Timothy F.

In a total residence time of three minutes, ibuprofen was assembled from its elementary building blocks with an average yield of above 90 % for each step. A scale-up of this five-stage process (3 bond-forming steps, one work-up, and one in-line liquid–liquid separation) provided ibuprofen at a...

Advanced methodologies for cocrystal synthesis

09 Jun 2023 | Contributor(s): Douroumis, D, Ross, SA, Nokhodchi, A

Pharmaceutical cocrystals are multicomponent systems composed of two or more molecules and held together by H-bonding. Currently, cocrystals provide exciting opportunities in the pharmaceutical industry for the development and manufacturing of new medicines by improving poor physical properties...

Advancing Flow Chemistry Portability: A Simplified Approach to Scaling Up Flow Chemistry

25 Jun 2024 | Contributor(s): Lévesque, François, Rogus, Nicholas J., Spencer, Glenn, Grigorov, Plamen, McMullen, Jonathan P., Thaisrivongs, David A., Davies, Ian W., Naber, John R.

We report mixing characterization of five lab-scale and eight production-scale static mixers using a modified fourth Bourne reaction. An efficient inline method relying on UV–vis spectroscopy was developed to streamline analysis of the product distribution. As a result of these studies, we have...

Advancing Flow Chemistry Portability: A Simplified Approach to Scaling Up Flow Chemistry

23 Jul 2024 | Contributor(s): Lévesque, François, Rogus, Nicholas J., Spencer, Glenn, Grigorov, Plamen, McMullen, Jonathan P., Thaisrivongs, David A., Davies, Ian W., Naber, John R.

We report mixing characterization of five lab-scale and eight production-scale static mixers using a modified fourth Bourne reaction. An efficient inline method relying on UV–vis spectroscopy was developed to streamline analysis of the product distribution. As a result of these studies, we have...

API Continuous Cooling and Antisolvent Crystallization for Kinetic Impurity Rejection in cGMP Manufacturing

09 Jun 2023 | Contributor(s): Johnson, MD, Burcham, CLMay, SA, Calvin, JR, Groh, JM, Myers, SS, Webster, LP, Roberts, JC, Reddy, VR, Luciani, CV, Corrigan, AP, Spencer, RD, Moylan, R, Boyse, R, Murphy, JD, Stout, JR

Crystallization of 204 kg of final active pharmaceutical ingredient was accomplished continuously using a cascade of mixed suspension mixed product removal crystallizers in cGMP manufacturing. This article describes the journey taken to transform a set of technical to final batch crystallizations...

Continuous downstream processing of milled electrospun fibers to tablets monitored by near-infrared and Raman spectroscopy

09 Jun 2023 | Contributor(s): Szabo, E, Zahonyi, PGyurkes, M, Nagy, B, Galata, DL, Madarasz, L, Hirsch, E, Farkas, A, Andersen, SK, Vigh, T, Verreck, G, Csontos, I, Marosi, G, Nagy, ZK

Electrospinning is a technology for manufacture of nano- and micro-sized fibers, which can enhance the dissolution properties of poorly water-soluble drugs. Tableting of electrospun fibers have been demonstrated in several studies, however, continuous manufacturing of tablets have not been...

Continuous Flow Chemistry of Metal Mediated Carboxylation and α-Arylation Reactions

25 Jun 2024 | Contributor(s): Venkatraman, Sripathy, Tweedie, Scott, McLaws, Mark, Lathbury, David

Utility of continuous flow chemistry in a carboxylation reaction and palladium-mediated α-arylation reaction is described. A two-step carboxylation reaction of an aryl group involving an anion formation, followed by quench with gaseous carbon dioxide was developed on small scale using HDPE tubes...

Continuous Flow Chemistry of Metal Mediated Carboxylation and α-Arylation Reactions

23 Jul 2024 | Contributor(s): Venkatraman, Sripathy, Tweedie, Scott, McLaws, Mark, Lathbury, David

Utility of continuous flow chemistry in a carboxylation reaction and palladium-mediated α-arylation reaction is described. A two-step carboxylation reaction of an aryl group involving an anion formation, followed by quench with gaseous carbon dioxide was developed on small scale using HDPE tubes...

Continuous Flow Conditions for High Temperature Formation of a Benzodioxan Pharmaceutical Intermediate: Rapid Scaleup for Early Phase Material Delivery

25 Jun 2024 | Contributor(s): Li, Pengbin, Yang, Shaohui, Zhu, Ruiheng, Sun, Baoquan, Li, Zhongbo, Huang, Ping, Buser, Jonas Y., Minguez, Jose Miguel, Ryan, Sarah J.

We have developed a continuous flow method to enable rapid scaleup of an enantioenriched benzodioxan intermediate. We propose that the reaction proceeds through an intramolecular SNAr cyclization. Interestingly, traditional SNAr conditions resulted in impurity formation. When the starting...

Continuous Flow Conditions for High Temperature Formation of a Benzodioxan Pharmaceutical Intermediate: Rapid Scaleup for Early Phase Material Delivery

23 Jul 2024 | Contributor(s): Li, Pengbin, Yang, Shaohui, Zhu, Ruiheng, Sun, Baoquan, Li, Zhongbo, Huang, Ping, Buser, Jonas Y., Minguez, Jose Miguel, Ryan, Sarah J.

We have developed a continuous flow method to enable rapid scaleup of an enantioenriched benzodioxan intermediate. We propose that the reaction proceeds through an intramolecular SNAr cyclization. Interestingly, traditional SNAr conditions resulted in impurity formation. When the starting...

Continuous flow production in the final step of vortioxetine synthesis. Piperazine ring formation on a flow platform with a focus on productivity and scalability

10 May 2024 | Peer-reviewed journal | Contributor(s): Boros, Zoltán, Nagy-Győr, László, Kátai-Fadgyas, Katalin, Kőhegyi, Imre, Ling, István, Nagy, Tamás, Iványi, Zoltán, Oláh, Márk, Ruzsics, György, Temesi, Ottó, Volk, Balázs

In this study, the piperazine formation step of vortioxetine synthesis was investigated under continuous flow conditions. The batch variant of this step could be carried out at laboratory scale at 130–135 °C with a long reaction time (27 h) followed by a laborious optimization...

Continuous manufacturing via hot-melt extrusion and scale up: regulatory matters

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Mohammed Maniruzzaman, Ali Nokhodchi

Over recent decades, HME techniques have appeared as an innovative manufacturing platform for various pharmaceutical applications. HME has been successfully applied to develop multiple drug delivery systems for various applications (e.g., solubility enhancement, sustained release, taste masking,...

Continuous-Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Gutmann, B, Cantillo, D, Kappe, CO

In the past few years, continuous-flow reactors with channel dimensions in the micro- or millimeter region have found widespread application in organic synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of...

Development and Manufacturing GMP Scale-Up of a Continuous Ir Catalyzed Homogeneous Reductive Amination Reaction

23 Jul 2024 | Peer-reviewed journal | Contributor(s): May, Scott A., Johnson, Martin D. Buser, Jonas Y. Campbell, Alison N. Frank, Scott A., Haeberle, Brian D., Hoffman, Philip C., Lambertus, Gordon R., McFarland, Adam D., Moher, Eric D., White, Timothy D., Hurley, D. Declan, Corrigan, Aoife P., Gowran, Olivia, Kerrigan, Niall G., Kissane, Marie G., Lynch, Regina R., Sheehan, Paul, Spencer, Richard D., Pulley, Shon R., Stout, James R.

The design, development, and scale-up of a continuous iridium-catalyzed homogeneous high pressure reductive amination reaction to produce 6, the penultimate intermediate in Lilly’s CETP inhibitor evacetrapib, is described. The scope of this report involves initial batch chemistry screening at...

Development and Manufacturing GMP Scale-Up of a Continuous IrCatalyzed Homogeneous Reductive Amination Reaction

25 Jun 2024 | Peer-reviewed journal | Contributor(s): May, Scott A., Johnson, Martin D., Buser, Jonas Y., Campbell, Alison N., Frank, Scott A., Haeberle, Brian D., Hoffman, Philip C., Lambertus, Gordon R., McFarland, Adam D., Moher, Eric D., White, Timothy D., Hurley, D. Declan, Corrigan, Aoife P., Gowran, Olivia, Kerrigan, Niall G., Kissane, Marie G., Lynch, Regina R., Sheehan, Paul, Spencer, Richard D., Pulley, Shon R., Stout, James R.

The design, development, and scale-up of a continuous iridium-catalyzed homogeneous high pressure reductive amination reaction to produce 6, the penultimate intermediate in Lilly’s CETP inhibitor evacetrapib, is described. The scope of this report involves initial batch chemistry screening at...

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...

Development and Scale-Up of a Continuous Manufacturing Process for a Hydrazine Condensation Reaction

23 Jul 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...

Development and Scale-Up of a Continuous Reaction for Production of an Active Pharmaceutical Ingredient Intermediate

25 Jun 2024 | Peer-reviewed journal | Contributor(s): McMullen, Jonathan P., Marton, Christopher H., Sherry, Benjamin D., Spencer, Glenn, Kukura, Joseph, Eyke, Natalie S.

Examples of continuous flow reactions in the laboratory setting are becoming commonplace in pharmaceutical drug substance research. Developing these processes for robust commercialization and identifying the scale-up parameters remains a challenge. An aldol reaction in the formation of an active...

Development and Scale-Up of a Continuous Reaction for Production of an Active Pharmaceutical Ingredient Intermediate

23 Jul 2024 | Peer-reviewed journal | Contributor(s): McMullen, Jonathan P., Marton, Christopher H., Sherry, Benjamin D., Spencer, Glenn, Kukura, Joseph, Eyke, Natalie S.

Examples of continuous flow reactions in the laboratory setting are becoming commonplace in pharmaceutical drug substance research. Developing these processes for robust commercialization and identifying the scale-up parameters remains a challenge. An aldol reaction in the formation of an active...

Development and Scale-up of a Flow Chemistry Lithiation–Borylation Route to a Key Boronic Acid Starting Material

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Usutani, Hirotsugu, Nihei, Takashi, Papageorgiou, Charles D., Cork, David G.

A flow chemistry process for the synthesis of a key boronic acid starting material was developed utilizing flow flash chemistry that allowed formation and subsequent productive reaction of an unstable organolithium intermediate. Rapid scale-up from Discovery Chemistry and process optimization to...

Development and Scale-up of a Flow Chemistry Lithiation–Borylation Route to a Key Boronic Acid Starting Material

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Usutani, Hirotsugu, Nihei, Takashi, Papageorgiou, Charles D., Cork, David G.

A flow chemistry process for the synthesis of a key boronic acid starting material was developed utilizing flow flash chemistry that allowed formation and subsequent productive reaction of an unstable organolithium intermediate. Rapid scale-up from Discovery Chemistry and process optimization to...