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 perspective on Quality-by-Control (QbC) in pharmaceutical continuous manufacturing

09 Jun 2023 | Contributor(s): Su, Qinglin, Ganesh, Sudarshan Moreno, Mariana Bommireddy, Yasasvi, Gonzalez, Marcial, Reklaitis, Gintaras V., Nagy, Zoltan K.

The Quality-by-Design (QbD) guidance issued by the US Food and Drug Administration (FDA) has catalyzed the modernization of pharmaceutical manufacturing practices including the adoption of continuous manufacturing. Active process control was highlighted recently as a means to improve the QbD...

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 Shared Vision for Pharmaceutical Development and Manufacturing in the 21st Century: Contributions of the PAT Initiative

28 Mar 2024 | Document | Contributor(s): Ajaz S. Hussain

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

10 May 2024 | Peer-reviewed journal | 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...

Achieving Continuous Manufacturing for Final Dosage Formation: Challenges and How to Meet Them

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Byrn, Stephen, Futran, Maricio, Thomas, Hayden, Jayjock, Eric, Maron, Nicola, Meyer, Robert F., Myerson, Allan S., Thien, Michael P., Trout, Bernhardt L.

We describe the key issues and possibilities for continuous final dosage formation, otherwise known as downstream processing or drug product manufacturing. A distinction is made between heterogeneous processing and homogeneous processing, the latter of which is expected to add more value to...

Adequacy and Verifiability of Pharmaceutical Mixtures and Dose Units by Variographic Analysis (Theory of Sampling) - A Call for a Regulatory Paradigm Shift

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Esbensen, Kim H, Román-Ospino, Andrés D., Sanchez, Adriluz, Romañach, Rodolfo J.

In spite of intense efforts in the last 20 years, the current state of affairs regarding evaluation of adequacy of pharmaceutical mixing is at an impressive standstill, characterized by two draft guidances, one withdrawn, and the other never approved. We here analyze the regulatory, scientific...

Advanced methodologies for cocrystal synthesis

09 Jun 2023 | Peer-reviewed journal | 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 | Peer-reviewed journal | 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 | Peer-reviewed journal | 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...

Analytical Procedure Development

09 Jun 2023 | Document

Guideline provides a foundation for consistent development of analytical methods to maintain precision and accuracy, contirubting to the maintenance of quality products.

Analytical Validation

09 Jun 2023 | Document

Guideline establishes the requirements for validationg analytical methods, ensuring consistency in the routeine measurements of pharmaceutical products and their intermediates.

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

09 Jun 2023 | Peer-reviewed journal | 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 | Peer-reviewed journal | 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 | Chapter Book | 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 | Chapter Book | 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 | Peer-reviewed journal | 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 | Peer-reviewed journal | 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 in the Pharmaceutical Industry: Enhancing Drug Production

23 Jul 2024 | Website | Contributor(s): Timmerman, Siebe

A significant shift towards continuous manufacturing (CM) is currently underway in the pharmaceutical industry. Unlike the more commonly used batch processing, CM operates continuously. This method potentially offers increased efficiency, agility, and flexibility in the manufacturing of drug...

Continuous Manufacturing of Drug Substances and Drug Products

09 Jun 2023 | Document

Guideline gives information and requirements for the production of API in pharmaceutical continuous manufactring processes.

Continuous Manufacturing to Improve Pharmaceutical Quality: Research Examples and Opportunities

20 Nov 2023 | Workshop | Contributor(s): Geng Tian

Continuous manufacturing (CM) of drug substances and drug productsProcess modeling and simulation (M&S) for CM at FDACM research highlightsOpportunities of CM for generic drug productsPharmaceutical Quality Symposium 2023: Quality, Supply Chain & Advanced Manufacturing -...

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,...