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100% visual inspection of tablets produced with continuous direct compression and coating
09 Jun 2023 | Contributor(s): Barimani, Shirin, Sibanc, Rok, Tomazevic, Dejan, Meier, Robin, Kleinebudde, Peter
Visual appearance of tablets is an important property for patients. Since the visual appearance is most strongly influenced by the applied coating, this necessitates a high level of process control and homogeneity in the coating process. In recent years, a number of tablet coaters have been...
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3D Printed Reactors for Synthesis of Active Pharmaceutical Ingredients in Continuous Flow
09 Jun 2023 | Contributor(s): Maier, MC, Valotta, AHiebler, K, Soritz, S, Gavric, K, Grabner, B, Gruber-Woelfler, H
Advances in flow chemistry to produce active pharmaceutical ingredients (APIs) require performing reactions in tailor-made equipment as complexity of the planned setups increases. To react quickly and with low costs to these demanding reactions, additive manufacturing, also known as 3D printing,...
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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...
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7-Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Ziegler, RE, Desai, BKJee, JA, Gupton, BF, Roper, TD, Jamison, TF
Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapy for the treatment of HIV, has been synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chemistry batch route for Cabotegravir, DTG was produced in 4.5h in sequential...
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A brief review on Process Analytical Technology (PAT)
09 Jun 2023 | Peer-reviewed journal | 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...
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A Co-Processed API Approach for a Shear Sensitive Compound Affording Improved Chemical Stability and Streamlined Drug Product Processing
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Schenck, L, Neri, CJia, XJ, Schafer, W, Axnanda, S, Canfield, N, Li, F, Shah, V
The physical properties of active pharmaceutical ingredients (API) are critical to both drug substance (DS) isolation and drying operations, as well as streamlined drug product (DP) processing and the quality of final dosage units. High aspect ratio, low bulk density, API 'needles' in particular...
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A Combined Feed-Forward/Feed-Back Control System for a QbD-Based Continuous Tablet Manufacturing Process
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Singh, Ravendra, Muzzio, Fernando J, Ierapetritou, Marianthi, Ramachandran, Rohit
Continuous pharmaceutical manufacturing together with PAT (Process Analytical Technology) provides a suitable platform for automatic control of the end product quality as desired by QbD (quality by design)-based efficient manufacturing. The precise control of the quality of the pharmaceutical...
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A comprehensive overview of extended release oral dosage forms manufactured through hot melt extrusion and its combination with 3D printing
09 Jun 2023 | Peer-reviewed journal | 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...
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A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries
09 Jun 2023 | Peer-reviewed journal | 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...
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A Concise Flow Synthesis of Efavirenz
10 May 2024 | Peer-reviewed journal | Contributor(s): Correia, Camille A., Gilmore, Kerry, McQuade, D. Tyler, Seeberger, Peter H.
Efavirenz is an essential medicine for the treatment of HIV, which is still inaccessible to millions of people worldwide. A novel, semi-continuous process provides rac-Efavirenz with an overall yield of 45 %. This streamlined proof-of-principle synthesis relies on the efficient copper-catalyzed...
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A Continuous Flow Process for the Synthesis of Hymexazol
10 May 2024 | Peer-reviewed journal | Contributor(s): Ma, Xin-peng, Chen, Jin-sha, Du, Xiao-hua
Hymexazol is an efficient and low-toxicity soil fungicide. In this work, a fully continuous flow process for the synthesis of hymexazol has been developed. This process begins with combining ethyl acetoacetate and hydroxylamine hydrochloride to form a hydroxamic acid intermediate. The reaction...
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A Continuous Flow Sulfuryl Chloride-Based Reaction—Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine
25 Jun 2024 | Peer-reviewed journal | 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...
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A Continuous Flow Sulfuryl Chloride-Based Reaction—Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine
23 Jul 2024 | Peer-reviewed journal | 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...
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A continuous manufacturing concept for a pharmaceutical oral suspension
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Bostijn, N, Van, Renterghem, JDhondt, W, Vervaet, C, De;Beer, T
The aim of this study was to investigate the applicability of an innovative continuous manufacturing system for semi-solid and liquid pharmaceutical formulations. A commercially available pharmaceutical oral suspension was selected as model formulation. Premixes of the raw materials were dosed...
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A Continuous Process for Manufacturing Apremilast. Part I: Process Development and Intensification by Utilizing Flow Chemistry Principles
24 Apr 2024 | Peer-reviewed journal | Contributor(s): Hsieh, Hsiao-Wu, Griffin, Daniel J., Ananthoji, Padmini, Avci, Nadide Hazal, Brown, Derek B., Ericson, Ari, Fostinis, James D., Irfan, Muhammad, Langille, Neil, Lovette, Michael A., Murray, James I., Spada, Simone, Thiel, Oliver R., Aiello, Frankie, Daou, Joseph, Goudas-Salomon, Nicole, Pan, Ende, Sarkar, Nandini, Wimalasinghe, Rasangi, Wu, Zufan Steven, Zeng, Alicia, Beaver, Matthew G., Cohen, Carolyn M.
Herein, we report the development of an integrated continuous manufacturing (CM) process for the penultimate step in the synthesis of apremilast, the drug substance (DS) of the commercial product Otezla. This development effort was motivated by the desire to create an alternative manufacturing...
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A Continuous Process for Manufacturing Apremilast. Part II: Process Characterization to Establish a Parametric Control Strategy
03 Apr 2024 | Peer-reviewed journal | Contributor(s): Griffin, Daniel J., Avci, Nadide Hazal, Sarkar, Nandini, Fostinis, James D., Klitzing, Nicholas, Murray, James I., Wimalasinghe, Rasangi, Spada, Simone, Zeng, Alicia, Beaver, Matthew G., Hsieh, Hsiao-Wu
This is Part II of a series on the development and characterization of an integrated continuous manufacturing (CM) process developed for the penultimate step in the synthesis of the drug substance Apremilast (Otezla). Part I gives the development history and highlights the achieved process...
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A flow-based synthesis of telmisartan
10 May 2024 | Peer-reviewed journal | Contributor(s): Martin, Alex D., Siamaki, Ali R., Belecki, Katherine, Gupton, B. Frank
A highly efficient continuous synthesis has been developed for telmisartan, the active ingredient in the antihypertensive drug, Micardis. This synthetic route employs a convergent strategy that requires no intermediate purifications or solvent exchanges. The key step in the reaction scheme is a...
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A Focused and Flexible Analytical Strategy is Key to Unlocking the Benefits of Continuous Manufacturing
11 Apr 2024 | Website | Contributor(s): Bikash Chatterjee
Continuous manufacturing processes promise shorter manufacturing cycle times without the need for intermediate storage, sampling testing and release of intermediate process steps, and shorter product release times through the intelligent application of in-line and at-line testing strategies....
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A Framework for Representative Sampling for NIR Analysis – Theory of Sampling (TOS)
09 Jun 2023 | Chapter Book | Contributor(s): Esbensen, Kim H, Ciurczak, Emil W., Igne, Benoît, Workman, Jr.,Jerome, Burns, Donald A., Romañach, Rodolfo J.
This chapter deals with all critical steps before near-infrared spectroscopy (NIR) analysis, irrespective of whether the total sampling error contribution is large, intermediate, or small – all cases can be treated identically, including the widespread sensor-based solutions from the...
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A hybrid model for multipoint real time potency observation in continuous direct compression manufacturing operations
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Gallo-Molina, Juan Pablo, Cogoni, Giuseppe, Peeters, Elisabeth, Rao Ambati, Seshagiri, Nopens, Ingmar
The ongoing transition from batch to continuous manufacturing offers both challenges and opportunities in the field of oral solid dosage form production. In turn, Process Analytical Technology (PAT) offers a path towards the successful deployment of continuous tablet manufacturing in rotary...
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A Hybrid MPC-PID Control System Design for the Continuous Purification and Processing of Active Pharmaceutical Ingredients
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Sen, M, Singh, R, Ramachandran, R
In this work, a hybrid MPC (model predictive control)-PID (proportional-integral-derivative) control system has been designed for the continuous purification and processing framework of active pharmaceutical ingredients (APIs). The specific unit operations associated with the purification and...
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A hybrid NIR-soft sensor method for real time in-process control during continuous direct compression manufacturing operations
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Cogoni, Giuseppe, Husain, Anas, Alam, Md Anik, Liu, Yang Angela, Kamyar, Reza
Near Infrared (NIR) spectroscopy is commonly utilized for continuous manufacturing as Process Analytical Technology (PAT) tool. This paper focus on a continuous direct compression manufacturing process, in which an NIR PAT probe is integrated into the tablet press feed frame and into the tablet...
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A large-scale experimental comparison of batch and continuous technologies in pharmaceutical tablet manufacturing using ethenzamide
09 Jun 2023 | Peer-reviewed journal | 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...
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A modeling and control framework for extraction processes
05 Sep 2024 | Peer-reviewed journal | Contributor(s): Peter Neugebauer, Jakob Rehrl, Peter Poechlauer, Dirk Kirschneck, Martin Horn, Martin Steinberger, Stephan Sacher, Joscha Boehm, Daniel Moser
Many continuously operated pharmaceutical process routes have been presented recently. Most of these cover the synthesis of the active pharmaceutical ingredient (API) or solid dosage processing. However, the API purification is also gaining attraction. One widespread and waste-intensive unit...
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A modeling and control framework for extraction processes
05 Sep 2024 | Peer-reviewed journal | Contributor(s): Peter Neugebauer, Jakob Rehrl, Peter Poechlauer, Dirk Kirschneck, Martin Horn, Martin Steinberger, Stephan Sacher, Joscha Boehm, Daniel Moser
Many continuously operated pharmaceutical process routes have been presented recently. Most of these cover the synthesis of the active pharmaceutical ingredient (API) or solid dosage processing. However, the API purification is also gaining attraction. One widespread and waste-intensive unit...