Kinetic identification and experimental validation of continuous plug flow crystallisation

09 Jun 2023 | Contributor(s): Zhao, Yan, Kamaraju, Vamsi Krishna Hou, Guangyang Power, Graham, Donnellan, Philip, Glennon, Brian

This paper investigates the suitability of a number of potential crystallisation models to best describe the experimentally observed behaviour of the antisolvent crystallisation of benzoic acid from aqueous ethanol solution using water as an antisolvent, in a continuous plug flow crystalliser....

Laboratory of the future: a modular flow platform with multiple integrated PAT tools for multistep reactions

09 Jun 2023 | Contributor(s): Sagmeister, Peter, Hone, Christopher, Williams, Jason D, Kappe, Oliver

Currently, the monitoring of multistep continuous flow processes by multiple analytical sources is still seen as a resource intensive and specialized activity. In this article, the coupling of a modular microreactor platform with real-time monitoring by inline IR and NMR, in addition to online...

Landscape and opportunities for active pharmaceutical ingredient manufacturing in developing African economies

09 Jun 2023 | Contributor(s): Riley, DL, Strydom, IChikwamba, R, Panayides, JL

Africa is one of the world's fastest growing economies, with South Africa having the fifth highest worldwide pharmaceutical expenditure per capita. In recent years, several companies have considered regional pharmaceutical production but have failed to make the investment, in stark contrast to...

Laser triangulation as a fast and reliable method for determining ribbon solid fraction; focus on accuracy, precision, and measurement time

09 Jun 2023 | Contributor(s): Lillotte, Tim D, Bebernik, Paul, Keck, Johanna, Bommer, Moritz, Schroeder, Daniela, Wagner, Karl G.

Roller compaction and dry granulation represent well-established unit operations in the pharmaceutical industry. The ribbon solid fraction is classified as a critical quality attribute, that directly impacts final product quality and performance. The development and evaluation of novel methods...

Latent Variables-Based Process Modeling of a Continuous Hydrogenation Reaction in API Synthesis of Small Molecules

09 Jun 2023 | Contributor(s): Shi, Zhenqi, Zaborenko, Nikolay, Reed, David

Continuous manufacturing can be benefited by the use of the Quality by Design (QbD) strategy for robust process development and by the use of Process Analytical Technology (PAT) for real-time process monitoring and control. A successful implementation of QbD and PAT for continuous processes...

Life cycle analysis of solvent reduction in pharmaceutical synthesis using continuous adsorption for palladium removal

09 Jun 2023 | Contributor(s): Slater, CS, Savelski, MJ, Ruiz-Felix, MN

The life cycle emissions associated with the reduction of wastes from an adsorption process to remove palladium complexes in drug manufacture have been evaluated. The study assessed a green improvement to a process step in an active pharmaceutical ingredient synthesis where palladium catalyst is...

Light Diffraction Measurement of Particle Size

09 Jun 2023

Standard explain phenomena associated with light interaction with powder.

Linking granulation performance with residence time and granulation liquid distributions in twin-screw granulation: An experimental investigation

09 Jun 2023 | Contributor(s): Kumar, Ashish, Alakarjula, Maija, Vanhoorne, Valerie, Toiviainen, Maunu, De Leersnyder, Fien, Vercruysse, Jurgen, Juuti, Mikko, Ketolainen, Jarkko, Vervaet, Chris, Remon, Jean Paul, Gernaey, Krist V., De Beer, Thomas, Nopens, Ingmar

Twin-screw granulation is a promising wet granulation technique for the continuous manufacturing of pharmaceutical solid dosage forms. A twin screw granulator displays a short residence time. Thus, the solid-liquid mixing must be achieved quickly by appropriate arrangement of transport and...

Liquid API feeding in pharmaceutical HME: Novel options in solid dosage manufacturing

18 Jan 2024 | Peer-reviewed journal | Contributor(s): Simone Eder, Aygün Doğan, Johannes Khinast, Stephan Sacher, Martin Spoerk, Lisa Kuchler

Hot melt extrusion (HME) is a common unit operation. It is broadly applicable in the pharmaceutical industry and can be implemented in a continuous manufacturing line. However, the conventional way of active pharmaceutical ingredient (API) feeding with a pre-blend consisting of a powdered API...

Loss-in-Weight Feeding Trials Case Study: Pharmaceutical Formulation

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Engisch, WE, Muzzio, FJ

This article presents a case study of a continuous feeding strategy for five pharmaceutical components (active pharmaceutical ingredient (API), Prosolv HD90, crospovidone, magnesium stearate, and colloidal silicon dioxide), for the purpose of developing a direct compression continuous...

Loss-in-weight feeding, powder flow and electrostatic evaluation for direct compression hydroxypropyl methylcellulose (HPMC) to support continuous manufacturing

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Allenspach, Carl, Timmins, Peter, Lumay, Geoffroy, Holman, James, Minko, Tamara

Minimizing variability in the feeding process is important for continuous manufacturing since materials are fed individually and can impact the final product. This study demonstrates the importance of measuring powder properties and highlights the need to characterize the feeding performance both...

Low Energy Nanoemulsions as Templates for the Formulation of Hydrophobic Drugs

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Badruddoza, AM, Gupta, AMyerson, AS, Trout, BL, Doyle, PS

Most small molecule active pharmaceutical ingredients (APIs) are hydrophobic which poses formulation challenges due to their poor water solubility. Current approaches are energy intensive and involve presenting the API in a nanoparticle form that is then combined with other additives into a...

Lubricant based determination of design space for continuously manufactured high dose paracetamol tablets

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Taipale-Kovalainen, Krista, Karttunen, Anssi-Pekka, Ketolainen, Jarkko, Korhonen, Ossi

The objective of this study was to devise robust and stable continuous manufacturing process settings, by exploring the design space after an investigation of the lubrication-based parameters influencing the continuous direct compression tableting of high dose paracetamol tablets. Experimental...

Lubricant Sensitivity of Direct Compression Grades of Lactose in Continuous and Batch Tableting Process

16 Nov 2023 | Peer-reviewed journal | Contributor(s): Gerald A. Hebbink, Pauline H. M. Janssen, Jurjen H. Kok, Lorenzo Menarini, Federica Giatti, Caterina Funaro, Salvatore Fabrizio Consoli, Bastiaan H. J. Dickhoff

Modern pharmaceutical manufacturing based on Quality by Design and digitalisation is revolutionising the pharmaceutical industry. Continuous processes are promoted as they increase efficiency and improve quality control. Compared to batch blending, continuous blending is easier to scale and...

Lubrication empirical model to predict tensile strength of directly compressed powder blends

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Nassar, Joelle, Williams, Ben, Davies, Conrad, Lief, Kevin, Elkes, Richard

A new approach is proposed to support prediction of tablet tensile strength as a function of both solid fraction (and/or compression pressure) and extent of lubrication by using empirical data to parameterise the model. This is a pre-requisite for simulation of the compaction unit operation where...

Machine learning framework for extracting micro-viscoelastic and micro-structural properties of compressed oral solid dosage forms

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Sultan, Tipu, Rozin, Enamul Hasan, Paul, Shubhajit, Tseng, Yin-Chao, Cetinkaya, Cetin

A compressed pharmaceutical oral solid dosage (OSD) form is a strongly micro-viscoelastic material composite arranged as a network of agglomerated particles due to its constituent powders and their bonding and fractural mechanical properties. An OSD product's Critical Quality Attributes, such as...

Machine learning modeling for ultrasonic quality attribute assessment of pharmaceutical tablets for continuous manufacturing and real-time release testing

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Sultan, Tipu, Rozin, Enamul Hasan, Paul, Shubhajit, Tseng, Yin-Chao, Dave, Vivek S., Cetinkaya, Cetin

In in-process quality monitoring for Continuous Manufacturing (CM) and Critical Quality Attributes (CQA) assessment for Real-time Release (RTR) testing, ultrasonic characterization is a critical technology for its direct, non-invasive, rapid, and cost-effective nature. In quality evaluation with...

Managing active pharmaceutical ingredient raw material variability during twin-screw blend feeding

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Stauffer, F., Vanhoorne, V., Pilcer, G., Chavez, Pierre-François, Schubert, M. A., Vervaet, C., De Beer, T.

Continuous powder feeding is a critical step in continuous manufacturing of solid dosage forms, as this unit operation should ensure the mass flow consistency at the desired powder feed rate to guarantee the process throughput and final product consistency. In this study, twin-screw feeding of a...

Managing API raw material variability during continuous twin-screw wet granulation

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Stauffer, F, Vanhoorne, VPiker, G, Chavez, PF, Vervaet, C, De;Beer, T

Very few studies have investigated the impact of raw material variability upon the granule critical quality attributes (CQAs) produced via twin-screw wet granulation (i.e., granule size distribution, density, flowability). In this study, the impact of the raw material variability of an active...

Managing API raw material variability in a continuous manufacturing line - Prediction of process robustness

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Stauffer, F, Vanhoorne, VPilcer, G, Chavez, PF, Vervaet, C, De;Beer, T

Many studies on continuous twin-screw granulation only focus on the granulator without linking this process step to the upstream and downstream unit operations. Product critical quality attributes (CQAs) are however not only determined by the granulation step. In this study, the possibility to...

Manipulation of ionic liquid anion-solute-antisolvent interactions for the purification of acetaminophen

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Weber, CC, Kunov-Kruse, AJRogers, RD, Myerson, AS

Hydrogen bond donating cosolvents have been shown to significantly reduce the solubility of acetaminophen (AAP) in ionic liquids containing the acetate anion. Reduced solubility arises from competition for solvation by the acetate anion and can be used for the design of advanced separation...

Manufacturing of Solid Drug

09 Jun 2023 | Chapter Book | Contributor(s): Ierapetritou, Marianthi, Escotet-Espinoza, M Sebastian, Singh, Ravendra

This chapter focuses on the application and development of unit operation and process models of the major routes of continuous solid dose manufacturing. Process models developed in the chapter are very important tools for the design of control system. The chapter also focuses on the current...

Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Induced Benzylic Bromination

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Bottecchia, Cecilia, Lévesque, François, McMullen, Jonathan P., Ji, Yining, Reibarkh, Mikhail, Peng, Feng, Tan, Lushi, Spencer, Glenn, Nappi, Jarod, Lehnherr, Dan, Narsimhan, Karthik, Wismer, Michael K., Chen, Like, Lin, Yipeng, Dalby, Stephen M.

We report the development and scale-up of a continuous flow photochemical benzylic bromination en route to belzutifan (MK-6482), a small molecule for the treatment of renal cell carcinoma associated with Von Hippel–Lindau syndrome. Compared with the clinical supply route, the photochemical...

Manufacturing Process Development for Belzutifan, Part 4: Nitrogen Flow Criticality for Transfer Hydrogenation Control

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Marzijarani, Nastaran Salehi, Fine, Adam J., Dalby, Stephen M., Gangam, Rekha, Poudyal, Samiksha, Behre, Taylor, Ekkati, Anil R., Armstrong, Brittany M., Shultz, C. Scott, Dance, Zachary E. X., Stone, Kevin

A scalable and efficient synthesis of hydroxyindanone 3, a key intermediate for belzutifan (MK-6482), is described. Mechanistic studies revealed the sensitivity of the reduction reaction toward the CO2 byproduct. Special effort was required to design a scale-insensitive process for the removal of...

Mapping key process parameters to the performance of a continuous dry powder blender in a continuous direct compression system

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Palmer, J, Reynolds, GK, Tahir, F, Yadav, IK, Meehan, E, Holman, J, Bajwa, G

This work aims to expand the typical raw material attributes that can successfully be processed on a continuous direct compression line with a particular focus on the continuous dry powder blender. Three grades of Acetaminophen were investigated as model active pharmaceutical ingredients and...