Concurrent Antisolvent Electrospraying: A Novel Continuous Crystallization Technique

09 Jun 2023 | Contributor(s): Perge, L, Grols, JSegura, DF, Al-Ani, A, Wilkinson, M, Castro-Dominguez, B

Pharmaceutical co-crystals (CCs) are multicomponent materials that enable the development of novel therapeutic products by enhancing the properties of active pharmaceutical ingredients, such as solubility, permeability and bioavailability. Currently, CCs are a commercial reality; theless, their...

Construction of ultrathin PTMSP/Porous nanoadditives membranes for highly efficient organic solvent nanofiltration (OSN)

09 Jun 2023 | Contributor(s): Liu, Q, Smith, SJDKonstas, K, Ng, D, Zhang, KS, Hill, MR, Xie, ZL

Organic solvent nanofiltration (OSN), also known as solvent resistant nanofiltration (SRNF), has enormous potential for industrial applications. Among the emerging high-performance membrane materials, some have proven challenging to fabricate ultrathin selective layers and at a scale large enough...

Continuous and Scalable Process for the Production of Hollow Crystals of a Poorly Water-Soluble Active Pharmaceutical Ingredient for Dissolution Enhancement and Inhaled Delivery

09 Jun 2023 | Contributor(s): Sheng, F, Chow, PSDong, YC, Heng, D, Lee, SH, Tan, RBH

This study reports a new technique for the manufacture of micron-sized, hollow crystals of a poorly water-soluble pharmaceutical compound, spironolactone, by a continuous and scalable antisolvent precipitation platform called a static mixer. Additives (polyvinylpyrrolidone (PVP) and Tween 80)...

Continuous blending monitored and feedback controlled by machine vision-based PAT tool

09 Jun 2023 | Contributor(s): Lászlo Galata, Dorián, Mészaros, Lilla, Ficzere Máté, Vass, Panna, Nagy, Brigitta, Szabó, Edina, Domokos, András, Farkas, Attila, Csontos, István, Marosi, György, Nagy, Zsombor Kristóf

In a continuous powder blending process machine vision is utilized as a Process Analytical Technology (PAT) tool. While near-infrared (NIR) and Raman spectroscopy are reliable methods in this field, measurements become challenging when concentrations below 2 w/w% are quantified. However, an...

Continuous Crystallization of Aliskiren Hemifumarate

09 Jun 2023 | Contributor(s): Quon, JL, Zhang, HAlvarez, A, Evans, J, Myerson, AS, Trout, BL

Active ingredients in most pharmaceutical products are complex organic molecules that require crystallization as a purification and isolation step that results in a pure product at a high process yield. Knowledge of the operating conditions required to obtain crystals with the desired crystal...

Continuous Crystallization of Paracetamol (Acetaminophen) Form II: Selective Access to a Metastable Solid Form

09 Jun 2023 | Contributor(s): Agnew, LR, McGlone, TWheatcroft, HP, Robertson, A, Parsons, AR, Wilson, CC

The first continuous crystallization of a metastable polymorphic form of an active pharmaceutical ingredient is reported. Paracetamol form II, which displays enhanced solubility and compressibility in comparison to the stable form I, has been successfully crystallized in two continuous platforms:...

Continuous crystallization of pharmaceuticals using a continuous oscillatory baffled crystallizer

09 Jun 2023 | Contributor(s): Lawton, Simon, Steele, Gerry Shering, Phil Zhao, Lihua, Laird, Ian, Ni,, Xiong Wei

In this paper, we report an investigation into the continuous crystallization of a model active pharmaceutical ingredient (API) using a continuous oscillatory baffled crystallizer (COBC). The results show that continuous crystallization offers significant advantages in terms of process, operation...

Continuous Crystallization Processes in Pharmaceutical Manufacturing: A Review

09 Jun 2023 | Contributor(s): Orehek, J, Teslic, D, Likozar, B

This scientific paper presents an overview of continuous solution crystallization in the pharmaceutical industry. Since the specific knowledge spectrum of precipitation is very broad, topics covering the following were analyzed and assessed in detail: a comparison between batch and continuous...

Continuous Crystallization with Impurity Complexation and Nanofiltration Recycle

09 Jun 2023 | Contributor(s): Vartak, S, Myerson, AS

For crystal-impurity systems with similar structures and molecular weights, the impurity has a strong tendency to incorporate into the crystal lattice, making it difficult to obtain high purity with a single crystallization or even multiple crystallizations. In such cases, complexation of the...

Continuous direct compression as manufacturing platform for sustained release tablets

09 Jun 2023 | Contributor(s): Vanhoorne, V, Holman, J., Cunningham, C., Kumar, A., Vercruysse, J., De Beer, T., Remon, J. P, Vervaet, C

This study presents a framework for process and product development on a continuous direct compression manufacturing platform. A challenging sustained release formulation with high content of a poorly flowing low density drug was selected. Two HPMC grades were evaluated as matrix former: standard...

Continuous direct compression: Development of an empirical predictive model and challenges regarding PAT implementation

09 Jun 2023 | Contributor(s): Bekaert, B., Van Snick, B., Pandelaere, K., Dhondt, J., Di Pretoro, G., De Beer, T., Vervaet, C., Vanhoorne, V.

In this study, an empirical predictive model was developed based on the quantitative relationships between blend properties, critical quality attributes (CQA) and critical process parameters (CPP) related to blending and tableting. The blend uniformity and API concentration in the tablets were...

Continuous direct tablet compression: effects of impeller rotation rate, total feed rate and drug content on the tablet properties and drug release

09 Jun 2023 | Contributor(s): Jarvinen, Maiju A., Paaso, Janne, Paavola, Marko, Leiviska, Kauko, Juuti, Mikko, Muzzio, Fernando, Jarvinen, Kristiina

Context: Continuous processing is becoming popular in the pharmaceutical industry for its cost and quality advantages. Objective: This study evaluated the mechanical properties, uniformity of dosage units and drug release from the tablets prepared by continuous direct compression process....

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 end-to-end production of solid drug dosage forms: Coupling flow synthesis and formulation by electrospinning

09 Jun 2023 | Contributor(s): Balogh, Attila, Domokos, András, Farkas, Balázs, Farkas, Attila, Rapi, Zsolt, Kiss, Domokos, Nyiri, Zoltán, Eke, Zsuzsanna, Szarka, Györgyi, Örkényi, Róbert, Mátravölgyi, Béla, Faigl, Ferenc

Based on the concept of continuous manufacturing an end-to-end benchtop device was developed unprecedented for the production of solid drug dosage forms by connecting flow synthesis and formulation via electrospinning (ES). Together with the optimized two-step continuous-flow synthesis of...

Continuous flow asymmetric synthesis of chiral active pharmaceutical ingredients and their advanced intermediates

09 Jun 2023 | Contributor(s): Otvos, SB, Kappe, CO

Catalytic enantioselective transformations provide well-established and direct access to stereogenic synthons that are broadly distributed among active pharmaceutical ingredients (APIs). These reactions have been demonstrated to benefit considerably from the merits of continuous processing and...

Continuous Flow C-Glycosylation via Metal-Halogen Exchange: Process Understanding and Improvements toward Efficient Manufacturing of Remdesivir

09 Jun 2023 | Contributor(s): von;Keutz, T, Williams, JD, Kappe, CO

As remdesivir is the first approved treatment for COVID-19 (SARS-CoV-2), its production is likely to be of vital importance in the near future. Continuous flow processing has been demonstrated as a key technology in the manufacturing of highvolume active pharmaceutical ingredients and is...

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 Conditions for High Temperature Formation of a Benzodioxan Pharmaceutical Intermediate: Rapid Scaleup for Early Phase Material Delivery

25 Jun 2024 | Contributor(s): Li, Pengbin, Yang, Shaohui, Zhu, Ruiheng, Sun, Baoquan, Li, Zhongbo, Huang, Ping, Buser, Jonas Y., Minguez, Jose Miguel, Ryan, Sarah J.

We have developed a continuous flow method to enable rapid scaleup of an enantioenriched benzodioxan intermediate. We propose that the reaction proceeds through an intramolecular SNAr cyclization. Interestingly, traditional SNAr conditions resulted in impurity formation. When the starting...

Continuous Flow Intensification for the Synthesis of High-Purity Warfarin

10 May 2024 | Contributor(s): Silva-Brenes, Diana V., Reyes-Vargas, Stephanie K., Duconge, Jorge, Vlaar, Cornelis, Stelzer, Torsten, Monbaliu, Jean-Christophe M.

While racemic warfarin was initially commercialized as a rodenticide, it has become the most prescribed anticoagulant drug for prevention of blood clots and is part of the World Health Organization’s list of essential medicines. The synthesis of warfarin appears straightforward, consisting of a...

Continuous flow production in the final step of vortioxetine synthesis. Piperazine ring formation on a flow platform with a focus on productivity and scalability

10 May 2024 | Peer-reviewed journal | Contributor(s): Boros, Zoltán, Nagy-Győr, László, Kátai-Fadgyas, Katalin, Kőhegyi, Imre, Ling, István, Nagy, Tamás, Iványi, Zoltán, Oláh, Márk, Ruzsics, György, Temesi, Ottó, Volk, Balázs

In this study, the piperazine formation step of vortioxetine synthesis was investigated under continuous flow conditions. The batch variant of this step could be carried out at laboratory scale at 130–135 °C with a long reaction time (27 h) followed by a laborious optimization...

Continuous Flow Synthesis of 16-Dehydropregnenolone Acetate, a Key Synthon for Natural Steroids and Drugs

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Mancino, Valentina, Cerra, Bruno, Piccinno, Alessandro, Gioiello, Antimo

A telescoped multistep process to provide the continuous delivery of 16-dehydropregnenolone acetate (16-DPA) from diosgenin is described. The method was evaluated through batch screenings that helped to identify critical bottlenecks and flowability, and the best conditions were optimized in flow...

Continuous flow synthesis of the URAT1 inhibitor lesinurad

10 May 2024 | Peer-reviewed journal | Contributor(s): Damião, Mariana C. F. C. B., Marçon, Henrique M., Pastre, Julio Cezar

Herein, the urate anion exchange transporter 1 (URAT1) inhibitor lesinurad is synthesized from commercially available building blocks by a five-step linear continuous flow sequence. Our previously developed continuous flow platform was successfully applied to generate the 3-thio-1,2,4-triazole...

Continuous flow technology vs. the batch-by-batch approach to produce pharmaceutical compounds

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Cole, KP, Johnson, MD

Introduction: For the manufacture of small molecule drugs, many pharmaceutical innovator companies have recently invested in continuous processing, which can offer significant technical and economic advantages over traditional batch methodology. This Expert Review will describe the reasons for...

Continuous Flow Total Synthesis of Rufinamide

10 May 2024 | Peer-reviewed journal | Contributor(s): Zhang, Ping, Russell, M. Grace, Jamison, Timothy F.

Small molecules bearing 1,2,3-triazole functionalities are important intermediates and pharmaceuticals. Common methods to access the triazole moiety generally require the generation and isolation of organic azide intermediates. Continuous flow synthesis provides the opportunity to synthesize and...

Continuous flow upgrading of glycerol toward oxiranes and active pharmaceutical ingredients thereof

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Morodo, R, Gerardy, RPetit, G, Monbaliu, JCM

A robust continuous flow procedure for the transformation of bio-based glycerol into high value-added oxiranes (epichlorohydrin and glycidol) is presented. The flow procedure features a central hydrochlorination/dechlorination sequence and provides economically and environmentally favorable...