3D printing and continuous flow chemistry technology to advance pharmaceutical manufacturing in developing countries

09 Jun 2023 | Contributor(s): Sagandira, CR, Siyawamwaya, M, Watts, P

The realization of a downward spiralling of diseases in developing countries requires them to become self-sufficient in pharmaceutical products. One of the ways to meet this need is by boosting the local production of active pharmaceutical ingredients and embracing enabling technologies. Both 3D...

A brief review on Process Analytical Technology (PAT)

09 Jun 2023 | Contributor(s): Mali, Akash, Jagtap, Monali, Karekar, P., Maruska, A

Process analytical technology (PAT) has been defined as a mechanism to design, analyze and control pharmaceutical manufacturing processes through measurement of critical process parameters which affect critical quality attributes. PAT checks the quality of raw material attributes both physically...

A comprehensive overview of extended release oral dosage forms manufactured through hot melt extrusion and its combination with 3D printing

09 Jun 2023 | Contributor(s): Nashed, Nour, Lam, Matthew, Nokhodchi, Ali

Oral dosage formulations are considered to be the most convenient pharmaceutical dosage forms for almost all ages because of their simplicity and non-invasive administration compared to other dosage forms. To improve therapeutic efficacy and avoid frequent daily doses, extending drug release...

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

09 Jun 2023 | Contributor(s): Gambacorta, G, Sharley, JS, Baxendale, IR

Due to their intrinsic physical properties, which includes being able to perform as volatile liquids at room and biological temperatures, fragrance ingredients/intermediates make ideal candidates for continuous-flow manufacturing. This review highlights the potential crossover between a...

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

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 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 Continuous Process for Buchwald–Hartwig Amination at Micro-, Lab-, and Mesoscale Using a Novel Reactor Concept

25 Jun 2024 | Contributor(s): Falß, Sebastian, Tomaiuolo, Giovanna, Perazzo, Antonio, Hodgson, Paul, Yaseneva, Polina, Zakrzewski, Jacek, Guido, Stefano, Lapkin, Alexei, Woodward, Robert, Meadows, Rebecca E.

A continuous Buchwald–Hartwig reaction using the bulky N-heterocyclic carbene (NHC) precatalyst [Pd(IPr*)(cin)Cl] 4 has been developed for the synthesis of a key pharmaceutical intermediate 2. Using microreactor technology, the reaction could be optimized under dilute conditions with low material...

A Continuous Process for Buchwald–Hartwig Amination at Micro-, Lab-, and Mesoscale Using a Novel Reactor Concept

23 Jul 2024 | Contributor(s): Falß, Sebastian, Tomaiuolo, Giovanna, Perazzo, Antonio, Hodgson, Paul, Yaseneva, Polina, Zakrzewski, Jacek, Guido, Stefano, Lapkin, Alexei, Woodward, Robert, Meadows, Rebecca E.

A continuous Buchwald–Hartwig reaction using the bulky N-heterocyclic carbene (NHC) precatalyst [Pd(IPr*)(cin)Cl] 4 has been developed for the synthesis of a key pharmaceutical intermediate 2. Using microreactor technology, the reaction could be optimized under dilute conditions with low material...

A Flow Process Built upon a Batch Foundation—Preparation of a Key Amino Alcohol Intermediate via Multistage Continuous Synthesis

25 Jun 2024 | Contributor(s): Lim, John Jin, Arrington, Kenneth, Dunn, Anna L., Leitch, David C., Andrews, Ian, Curtis, Neil R., Hughes, Mark J., Tray, Daniel R., Wade, Charles E., Whiting, Matthew P., Goss, Charles, Liu, Yangmu Chloe, Roesch, Brian M.

This paper describes recent efforts to apply flow technology in the preparation of the key amino alcohol intermediate 3b so as to address manufacturability issues present in the batch process of a PRMT5 inhibitor. The continuous process, one of the first reported pharmaceutical processes to use...

A Flow Process Built upon a Batch Foundation—Preparation of a Key Amino Alcohol Intermediate via Multistage Continuous Synthesis

23 Jul 2024 | Contributor(s): Lim, John Jin, Arrington, Kenneth, Dunn, Anna L., Leitch, David C., Andrews, Ian, Curtis, Neil R., Hughes, Mark J., Tray, Daniel R., Wade, Charles E., Whiting, Matthew P., Goss, Charles, Liu, Yangmu Chloe, Roesch, Brian M.

This paper describes recent efforts to apply flow technology in the preparation of the key amino alcohol intermediate 3b so as to address manufacturability issues present in the batch process of a PRMT5 inhibitor. The continuous process, one of the first reported pharmaceutical processes to use...

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 Continuous Flow Chemistry in the Pharmaceutical Industry

09 Jun 2023 | Contributor(s): Baumann, M, Moody, TSSmyth, M, Wharry, S

Continuous flow manufacture is an innovative technology platform, which is gaining momentum within the pharmaceutical industry. The key advantages of continuous flow include faster and safer reactions, which can be more environmentally friendly, smaller footprint, better quality product, and...

A review of emerging technologies enabling improved solid oral dosage form manufacturing and processing

09 Jun 2023 | Contributor(s): Sohail Arshad, Muhammad, Zafar, Saman, Yousef, Bushra, Alyassin, Yasmine, Ali, Radeyah, AlAsiri, Ali, Chang, Ming-Wei, Ahmad, Zeeshan, Ali Elkordy, Amal, Faheem, Ahmed, Pitt, Kendal

Tablets are the most widely utilized solid oral dosage forms because of the advantages of self-administration, stability, ease of handling, transportation, and good patient compliance. Over time, extensive advances have been made in tableting technology. This review aims to provide an insight...

A review of PAT strategies in secondary solid oral dosage manufacturing of small molecules

09 Jun 2023 | Contributor(s): Laske, Stephan, Paudel, Amrit, Scheibelhofer, Otto, Sacher, Stephan, Hoermann, Theresa, Khinast, Johannes, Kelly, Adrian, Rantannen, Jukka, Korhonen, Ossi, Stauffer, Fanny, De Leersnyder, Fien, De Beer, Thomas, Mantanus, Jerome, Chavez, Pierre-Francois, Thoorens, Benjamin, Ghiotti, Patrizia, Schubert, Martin, Tajarobi, Pirjo, Haeffler, Gunnar, Lakio, Satu, Fransson, Magnus, Sparen, Anders, Abrahmsen-Alami, Susanna, Folestad, Staffan, Funke, Adrian, Backx, Ivo, Kavsek, Barbara, Kjell, Francois, Michaelis, Marc, Page, Trevor, Palmer, John, Schaepman, Alexander, Sekulic, Sonja, Hammond, Steve, Braun, Birgit, Colegrove, Brenda

Pharmaceutical solid oral dosage product manufacturing is a well-established, yet revolutionizing area. To this end, process analytical technology (PAT) involves interdisciplinary and multivariate (chemical, physical, microbiological and mathematical) methods for material (e.g. materials,...

A Review of Process Analytical Technology (PAT) in the U.S. Pharmaceutical Industry

09 Jun 2023 | Contributor(s): Munson, James, Stanfield, C. Freeman, Gujral, Bir

Process Analytical Technologies (PAT) are used to provide timely analysis of critical quality parameters with the end goal of improving final product quality as well as reducing manufacturing costs, thereby significantly benefiting the Pharmaceutical Industry. PAT involves mostly on-line or...

A review of twin screw wet granulation mechanisms in relation to granule attributes

09 Jun 2023 | Contributor(s): Zhang, Yi, Liu, Tongzhou, Kashani-Rahimi, Shahab, Zhang, Feng

Due to the trend of continuous pharmaceutical manufacturing, twin screw wet granulation (TSWG), a continuous process, has gained increased Research Article interest as a potential substitution of traditional batch granulation processes. Despite the complex nature of TSWG, its mechanisms have been...

A review on the taste masking of bitter APIs: hot-melt extrusion (HME) evaluation

09 Jun 2023 | Contributor(s): Maniruzzaman, M, Boateng, JSChowdhry, BZ, Snowden, MJ, Douroumis, D

The majority of active pharmaceutical ingredients (APIs) found in oral dosage forms have a bitter taste. Masking the unpleasant taste of bitter, APIs is a major challenge in the development of such oral dosage forms. Taste assessment is an important quality-control parameter for evaluating...

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 Tandem Ring Closure and Nitrobenzene Reduction with Sulfide Provides an Improved Route to an Important Intermediate for the Anti-Tuberculosis Drug Candidate Sutezolid

25 Jun 2024 | Contributor(s): Kalmode, Hanuman P., Ravikumar, Ongolu, Paymode, Dinesh J., Bachert, John, Burns, Justina M., Stringham, Rodger W., Aleshire, Sarah L., Nelson, Ryan C.

Sutezolid is an in-development thiomorpholine derivative of the FDA-approved tuberculosis (TB) treatment linezolid. Current synthetic routes for preparing sutezolid start with thiomorpholine as a key structural building block; unfortunately, this material was identified as a major cost driver for...

A Tandem Ring Closure and Nitrobenzene Reduction with Sulfide Provides an Improved Route to an Important Intermediate for the Anti-Tuberculosis Drug Candidate Sutezolid

23 Jul 2024 | Contributor(s): Kalmode, Hanuman P., Ravikumar, Ongolu, Paymode, Dinesh J., Bachert, John, Burns, Justina M., Stringham, Rodger W., Aleshire, Sarah L., Nelson, Ryan C.

Sutezolid is an in-development thiomorpholine derivative of the FDA-approved tuberculosis (TB) treatment linezolid. Current synthetic routes for preparing sutezolid start with thiomorpholine as a key structural building block; unfortunately, this material was identified as a major cost driver for...

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...

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 2: Enone Synthesis via a Barbier-Type Grignard Process

25 Jun 2024 | Contributor(s): Içten, Elçin, Maloney, Andrew J., Beaver, Matthew G., Zhu, Xiaoxiang, Shen, Dongying E., Robinson, Jo Anna, Parsons, Andrew T., Allian, Ayman, Huggins, Seth, Hart, Roger, Rolandi, Pablo, Walker, Shawn D., Braatz, Richard D.

This article details efforts to characterize and develop a process control strategy for the manufacture of enone 2, a carfilzomib drug substance intermediate obtained through a Barbier-type Grignard reaction of morpholine amide 1. This includes the development of a novel mechanistic model for the...

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 2: Enone Synthesis via a Barbier-Type Grignard Process

23 Jul 2024 | Contributor(s): Içten, Elçin, Maloney, Andrew J., Beaver, Matthew G., Zhu, Xiaoxiang, Shen, Dongying E., Robinson, Jo Anna, Parsons, Andrew T., Allian, Ayman, Huggins, Seth, Hart, Roger, Rolandi, Pablo, Walker, Shawn D., Braatz, Richard D.

This article details efforts to characterize and develop a process control strategy for the manufacture of enone 2, a carfilzomib drug substance intermediate obtained through a Barbier-type Grignard reaction of morpholine amide 1. This includes the development of a novel mechanistic model for the...