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 framework of hybrid model development with identification of plant-model mismatch

09 Jun 2023 | Contributor(s): Chen, Yingjie, Ierapetritou, Marianthi

Abstract Hybrid modeling has attracted increasing attention in order to take advantage of the additional data to improve process understanding. Current practice often adopts mechanistic models to predict process behaviors. These mechanistic models are based on physical understandings and...

A hybrid model for multipoint real time potency observation in continuous direct compression manufacturing operations

09 Jun 2023 | 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...

A hybrid NIR-soft sensor method for real time in-process control during continuous direct compression manufacturing operations

09 Jun 2023 | 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...

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 Systematic Framework for Data Management and Integration in a Continuous Pharmaceutical Manufacturing Processing Line

09 Jun 2023 | Contributor(s): Cao, Huiyi, Mushnoori, Srinivas, Higgins, Barry, Kollipara, Chandrasekhar, Fermier, Adam, Hausner, Douglas, Jha, Shantenu, Singh, Ravendra, Ierapetritou, Marianthi, Ramachandran, Rohit

As the pharmaceutical industry seeks more efficient methods for the production of higher value therapeutics, the associated data analysis, data visualization, and predictive modeling require dependable data origination, management, transfer, and integration. As a result, the management and...

A systematic reactor design approach for the synthesis of active pharmaceutical ingredients

09 Jun 2023 | Contributor(s): Emenike, VN, Schenkendorf, R, Krewer, U

Today's highly competitive pharmaceutical industry is in dire need of an accelerated transition from the drug development phase to the drug production phase. At the heart of this transition are chemical reactors that facilitate the synthesis of active pharmaceutical ingredients (APIs) and whose...

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 very boring 120 h: 15million tablets under a continuous state of control

09 Jun 2023 | Contributor(s): Holman, James, Tantuccio, Anthony, Palmera, Jhon, Doninck, Tom van, Meyer, Robert

The aimof this study is to showthe robustness of a commercial direct compression system running continuously under relevant process conditions for over 120 h. The study will apply a representative commercial control strategy including real time monitoring of process parameters, rejection of OOS...

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 1: CDI-Promoted Amide Bond Formation

09 Jun 2023 | Contributor(s): Içten, Elçin, Maloney, Andrew J., Beaver, Matthew G., Shen, Dongying E., Zhu, Xiaoxiang, Graham, Lauren R., Robinson, Jo A., Huggins, Seth, Allian, Ayman, Hart, Roger, Walker,Shawn D., Rolandi, Pablo, Braatz, Richard D.

This article details process characterization efforts and the development of corresponding process models to inform a process control strategy to produce a carfilzomib drug substance intermediate, morpholine amide 3. Model calibration for relevant unit operations and development of a dynamic...

Active pharmaceutical ingredient (API) production involving continuous processes - A process systems engineering (PSE)-assisted design framework

09 Jun 2023 | Contributor(s): Cervera-Padrell, AE, Skovby, TKiil, S, Gani, R, Gernaey, KV

A systematic framework is proposed for the design of continuous pharmaceutical manufacturing processes. Specifically, the design framework focuses on organic chemistry based, active pharmaceutical ingredient (API) synthetic processes, but could potentially be extended to biocatalytic and...

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...

Advanced Model Predictive Feedforward/Feedback Control of a Tablet Press

09 Jun 2023 | Contributor(s): Haas, Nicholas Townsend, Ierapetritou, Marianthi, Singh, Ravendra

In continuous pharmaceutical manufacturing, real-time precise control of critical quality attributes (CQAs) is necessary for quality by design (QbD)-based manufacturing and real-time release (RTR) with minimum consumption of time, space, and resources. Pharmaceutical tablets can be produced...

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...

Artificial neural network modelling of continuous wet granulation using a twin-screw extruder

09 Jun 2023 | Contributor(s): Shirazian, Saeed, Kuhs, Manuel, Darwish, Shaza, Croker, Denise., Walker, Gavin M

Computational modelling of twin-screw granulation was conducted by using an artificial neural network (ANN) approach. Various ANN configurations were considered with changing hidden layers, nodes and activation functions to determine the optimum model for the prediction of the process. The neural...

Biocatalytic Continuous Manufacturing of Diabetes Drug: Plantwide Process Modeling, Optimization, and Environmental and Economic Analysis

09 Jun 2023 | Contributor(s): Ho, CH, Yi, JR, Wang, XN

This work proposes a comprehensive framework of biocatalytic continuous manufacturing of sitagliptin, the active pharmaceutical ingredient of the leading dipeptidyl peptidase-4 inhibitor antidiabetic drug. Continuous manufacturing has the advantages of quality consistency, reduced waste...

Characterization of material properties

09 Jun 2023 | Contributor(s): Razavi, Sonia, Oka, Sarang, Escotet-Espinoza, M. Sebastian, Wang, Yifan, Li, Tianyi, Futran Mauricio., Muzzio, Fernando

This chapter describes the importance of deepening our understanding of material properties and their effect on process performance. There are many measurement techniques to describe the complex nature of powders, some of which are provided in this chapter. Strong knowledge of multivariate...

Combined feedforward/feedback control of an integrated continuous granulation process

09 Jun 2023 | Contributor(s): Pereira, Glinka Cathy, Muddu, Shashank Venkat Román-Ospino, Andrés David Clancy, Don Igne, Benoit Airiau, Christian Muzzio, Fernando J Ierapetritou, Marianthi Ramachandran, Rohit, Singh, Ravendra

Continuous manufacturing offers shorter processing times and increased product quality assurance, among several other advantages. This makes it an ever-growing interest among pharmaceutical companies. A suitable efficient control system is however desired for continuous pharmaceutical...

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...