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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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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 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 design aid for crystal growth engineering
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Li, Jinjin, Tilbury, Carl J. Kim, Seung Ha, Doherty, Michael F.
With the highly competitive development of chemical and pharmaceutical industries, mastering crystal growth is becoming increasingly necessary. Modern industrial manufacturers place high importance on the ability to grow crystals with a specific habit using tailored operating conditions. A...
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A Digital Twin for Process Optimisation in Pharmaceutical Manufacturing
09 Jun 2023 | Chapter Book | Contributor(s): Gerogiorgis, Dimitrios I., Castro-Rodriguez, Daniel
Organic synthesis is a critical step in producing any Active Pharmaceutical Ingredient (API): it encompasses a series of organic (mostly catalytic) reactions and separations, whose purpose is to arrive at a solution of a target molecule, which must then undergo crystallisation for purification,...
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A fast moving horizon estimation algorithm based on nonlinear programming sensitivity
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Zavala, Victor M, Laird, Carl D, Biegler, Lorenz T
Moving horizon estimation (MHE) is an efficient optimization-based strategy for state estimation. Despite the attractiveness of this method, its application in industrial settings has been rather limited. This has been mainly due to the difficulty to solve, in real-time, the associated dynamic...
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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 flowsheet model for the development of a continuous process for pharmaceutical tablets: An industrial perspective
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Garcia-Munoz, Salvador, Butterbaugh, Adam Leavesley, Ian Manley, Leo Francis, Slade, David, Bermingham, Sean
A dynamic model of a continuous direct compression process for pharmaceutical tablets is presented. The objective is to assess the impact of the variability from the feeder system on the concentration of drug in the powder in the feed frame of a tablet press. The model is based on principles of...
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A framework for model reliability and estimability analysis of crystallization processes with multi-impurity multi-dimensional population balance models
09 Jun 2023 | Peer-reviewed journal | Contributor(s): Fysikopoulos, D, Benyahia, B Borsos, A Nagy, Z K, Rielly, C D
The development of reliable mathematical models for crystallization processes may be very challenging due the complexity of the underlying phenomena, the inherent Population Balance Models (PBMs) and the large number of parameters that need to be identified from experimental data. Due to the poor...
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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 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...