A comprehensive analysis and optimization of continuous twin-screw granulation processes via sequential experimentation strategy

09 Jun 2023 | Contributor(s): Meng, Wei, Rao, Kallakuri Suparna, Snee, Ronald D., Ramachandran, Rohit., Muzzio, Fernando J

Nowadays twin-screw granulation has been emerging as an attractive continuous wet granulation technique. This study was geared towards better process design and understanding with emphasis on bridging the knowledge gap between input and output variables by employing sequential experimentation...

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 MPC-PID Control System Design for the Continuous Purification and Processing of Active Pharmaceutical Ingredients

09 Jun 2023 | 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...

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 New Software Framework for Implementing Crystal Growth Models to Materials of Any Crystallographic Complexity

09 Jun 2023 | Contributor(s): Zhao, Yongsheng, Tilbury, Carl J. Landis, Steven Sun, Yuanyuan, Li, Jinjin, Zhu, Peng, Doherty, Michael F.

To continue the realization of new therapeutics, a more diverse range of solid forms is being considered. Synthetic modalities are broadening beyond simple organic molecules to more complicated structures, including organic salts, cocrystals, and solvates. As in all crystalline applications,...

A Novel Integrated Workflow for Isolation Solvent Selection Using Prediction and Modeling

09 Jun 2023 | Contributor(s): Ottoboni, S, Wareham, BVassileiou, A, Robertson, M, Brown, CJ, Johnston, B, Price, CJ

A predictive tool was developed to aid process design and to rationally select optimal solvents for isolation of active pharmaceutical ingredients. The objective was to minimize the experimental work required to design a purification process by (i) starting from a rationally selected...

A novel robust digital design of a network of industrial continuous cooling crystallizers of dextrose monohydrate: From laboratory experiments to industrial application

09 Jun 2023 | Contributor(s): Nagy, Zoltan K., Szilagyi, Botond Pal, Kanjakha, Tabar, Iman Beheshti ;

This paper presents the first-ever industrial application of the digital design of a complex, large-scale industrial continuous crystallization network. The aim of the work is to optimize a large-scale continuous crystallization network used for the purification of dextrose monohydrate, by...

A Process for the Formation of Nanocrystals of Active Pharmaceutical Ingredients with Poor Aqueous Solubility in a Nanoporous Substrate

09 Jun 2023 | Contributor(s): O'Mahony, M, Leung, AKFerguson, S, Trout, BL, Myerson, AS

A potential process for the formation of nanocrystals of the poorly soluble drug, ibuprofen, within a nanoporous material is demonstrated. Nanocrystalline ibuprofen (IBP) is prepared at <= 106 nm by adding a solution containing IBP to particles of controlled pore glass (CPG) within a column so...

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 Stochastic Population Balance Equation Model for Nucleation and Growth of Crystals with Multiple Polymorphs

09 Jun 2023 | Contributor(s): Maggioni, Giovanni, Mazzotti, Marco

Understanding polymorph crystallization is important due to the different properties, such as bioavailability or crystal shape, exhibited by the different crystal forms. In this work, we present a model, based on population balance equations, describing the unseeded crystallization by cooling of...

A Structured Approach To Cope with Impurities during Industrial Crystallization Development

09 Jun 2023 | Contributor(s): Urwin, SJ, Levilain, GMarziano, I, Merritt, JM, Houson, I, Ter;Horst, JH

The perfect separation with optimal productivity, yield, and purity is very difficult to achieve. Despite its high selectivity, in crystallization unwanted impurities routinely contaminate a crystallization product. Awareness of the mechanism by which the impurity incorporates is key to...

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...

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 3: Manganese-Catalyzed Asymmetric Epoxidation, Crystallization, and Filtration

25 Jun 2024 | Contributor(s): Maloney, Andrew J., Içten, Elçin, Capellades, Gerard, Beaver, Matthew G., Zhu, Xiaoxiang, Graham, Lauren R., Brown, Derek B., Griffin, Daniel J., Sangodkar, Rahul, Allian, Ayman, Huggins, Seth, Hart, Roger, Rolandi, Pablo, Walker, Shawn D., Braatz, Richard D.

This article describes the process characterization and development of models to inform a process control strategy to prepare (R,R)-epoxy ketone 2, an intermediate in the manufacture of carfilzomib. Model calibration for relevant unit operations and the development of a dynamic integrated...

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 3: Manganese-Catalyzed Asymmetric Epoxidation, Crystallization, and Filtration

23 Jul 2024 | Contributor(s): Maloney, Andrew J., Içten, Elçin, Capellades, Gerard, Beaver, Matthew G., Zhu, Xiaoxiang, Graham, Lauren R., Brown, Derek B., Griffin, Daniel J., Sangodkar, Rahul, Allian, Ayman, Huggins, Seth, Hart, Roger, Rolandi, Pablo, Walker, Shawn D., Braatz, Richard D.

This article describes the process characterization and development of models to inform a process control strategy to prepare (R,R)-epoxy ketone 2, an intermediate in the manufacture of carfilzomib. Model calibration for relevant unit operations and the development of a dynamic integrated...

Achieving Continuous Manufacturing: Technologies and Approaches for Synthesis, Workup, and Isolation of Drug Substance May 20-21, 2014 Continuous Manufacturing Symposium

09 Jun 2023 | Contributor(s): Baxendale, IR, Braatz, RDHodnett, BK, Jensen, KF, Johnson, MD, Sharratt, P, Sherlock, JP, Florence, AJ

This whitepaper highlights current challenges and opportunities associated with continuous synthesis, workup, and crystallization of active pharmaceutical ingredients (drug substances). We describe the technologies and requirements at each stage and emphasize the different considerations for...

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...