Robustness of a continuous direct compression line against disturbances in feeding

09 Jun 2023 | Contributor(s): Karttunen A.-P., Poms J., Sacher S., Sparén A., Ruiz Samblás C., Fransson M., Martin De Juan L., Remmelgas J., Wikström H., Hsiao W.-K., Folestad S., Korhonen O.

The aim of the current study was to characterize the robustness of an integrated continuous direct compression (CDC) line against disturbances from feeding, i.e. impulses of API and short step disturbances. These disturbances mimicked typical variations that can be encountered during long-term...

Roller compaction: Infrared thermography as a PAT for monitoring powder flow from feeding to compaction zone

09 Jun 2023 | Contributor(s): Yu, Mingzhe, Omar, Chalak, Weidemann, Marcus, Schmidt, Alexander, Litster, James D., Salman, Agba D.

Roller compaction is a continuous dry granulation process, in which powder is compressed by two counter-rotating rollers. During this process, the powder feeding to the compaction zone has a significant effect on product quality. This work investigates the flow of powder from the feeding zone to...

Rolling phenomenon in twin screw granulation with controlled-release excipients

09 Jun 2023 | Contributor(s): Thompson, M. R., O'Donnell, K. P.

The developed knowledge regarding use of twin screw granulators for continuous wet granulation has been primarily limited to immediate release formulations in the literature. The present study highlights an issue previously unreported for wet granulation with twin screw extruders when using...

Route Optimization and Synthesis of Taxadienone

25 Jun 2024 | Contributor(s): Krasutsky, Sergiy G., Jacobo, Sheila H., Tweedie, Scott R., Krishnamoorthy, Ravi, Filatov, Alexander S.

Early process development toward the scalable production of taxadienone on a decagram scale is described. A continuous flow reactor was employed to safely run a potentially hazardous cyclopropane ring opening. The route featured two copper-mediated additions, a Diels–Alder reaction and a...

RTD modeling of a continuous dry granulation process for process control and materials diversion

09 Jun 2023 | Contributor(s): Kruisz, Julia, Rehrl, Jakob, Sacher, Stephan, Aigner, Isabella, Horn, Martin, Khinast, Johannes G., Krumme, Markus

Disturbance propagation during continuous manufacturing processes can be predicted by evaluating the residence time distribution (RTD) of the specific unit operations. In this work, a dry granulation process was modelled and four scenarios of feeding events were simulated. We performed...

RTD-based material tracking in a fully-continuous dry granulation tableting line

09 Jun 2023 | Contributor(s): Martinetz, M. C., Karttunen, A-P, Sacher, S., Wahl, P., Ketolainen, J., Khinast, J. G., Korhonen, O

Continuous manufacturing (CM) offers quality and cost-effectiveness benefits over currently dominating batch processing. One challenge that needs to be addressed when implementing CM is traceability of materials through the process, which is needed for the batch/lot definition and control...

Safe and highly efficient adaptation of potentially explosive azide chemistry involved in the synthesis of Tamiflu using continuous-flow technology

25 Jun 2024 | Contributor(s): Sagandira, Cloudius R., Watts, Paul

Tamiflu is one of the most effective anti-influenza drugs, which is currently manufactured by Hoffmann-La Roche from shikimic acid. Owing to its importance, more than 60 synthetic routes have been developed to date, however, most of the synthetic routes utilise the potentially hazardous azide...

Sample Mass Estimate for the Use of Near-Infrared and Raman Spectroscopy to Monitor Content Uniformity in a Tablet Press Feed Frame of a Drug Product Continuous Manufacturing Process

09 Jun 2023 | Contributor(s): Hetrick, Evan, Castillo, Ismael, Rehrla, Jakob, Sagmeistera, Peter, Lebl, René, Kruisza, Julia, Celikovic, Selma, Sipek, Martin, Williams, Myers, David P

Recently, feed frame-based process analytical technology measurements used to assure product quality during continuous manufacturing processes have received significant attention. These measurements are able to accurately determine uniformity of the powder blend before compression, and in these...

Sampling and Analysis in Flow: The Keys to Smarter, More Controllable, and sustainable Fine-Chemical Manufacturing

09 Jun 2023 | Contributor(s): Morin, Mathieu, Zhang, Wenyao, Mallik, Debasis, Organ, Michael G

Process analytical technology (PAT) is a system designed to help chemists better understand and control manufacturing processes. PAT systems operate through the combination of analytical devices, reactor control elements, and mathematical models to ensure the quality of the final product through...

Sampling optimization for blend monitoring of a low dose formulation in a tablet press feed frame using spatially resolved near-infrared spectroscopy

09 Jun 2023 | Contributor(s): Román-Ospino, Andrés, Baranwal, Yukteshwar, Li, Jingzhe, Vargas, Jenny, Igne, Benoît, Bate, Simon, Brouckaert, Davinia, Chauchard, Fabien, Hausner, Douglas, Ramachandran, Rohit, Singh, Ravendra, Muzzio, Fernando

In-line measurements of low dose blends in the feed frame of a tablet press were performed for API concentration levels as low as 0.10% w/w. The proposed methodology utilizes the advanced sampling capabilities of a Spatially Resolved Near-Infrared (SR-NIR) probe to develop Partial Least-Squares...

Scalable and Sustainable Synthesis of Calcium Dobesilate via Integrated Five-Step Continuous-Flow Chemistry

24 Apr 2024 | Contributor(s): Liu, Minjie, Wan, Li, Gao, Liang, Cheng, Dang, Jiang, Meifen, Chen, Fen-Er

Calcium dobesilate is a widely prescribed veno-tonic drug in over 60 countries for treating chronic venous disease, diabetic retinopathy, and hemorrhoidal attack symptoms. Although two batchwise manufacturing routes to this treatment have been developed, the drawbacks, such as poor...

Scalable continuous flow hydrogenations using Pd/Al2O3-coated rectangular cross-section 3D-printed static mixers

25 Jun 2024 | Contributor(s): Lebl, René, Zhu, Yutong, Ng, Derrick, Hornung, Christian H., Cantillo, David, Kappe, C. Oliver

A novel type of catalytic static mixers with rectangular cross-section coated with Pd/Al2O3 has been developed. The catalytic mixers, produced by additive manufacturing and coated with the metal catalyst, have shown excellent catalytic performance for continuous flow hydrogenation of...

Scalable Continuous Flow Process for the Synthesis of Eflornithine Using Fluoroform as Difluoromethyl Source

09 Jun 2023 | Contributor(s): Kockinger, M, Hone, CAGutrnann, B, Hanselmann, P, Bersier, M, Torvisco, A, Kappe, CO

The development of a scalable telescoped continuous flow procedure for difluoromethylation of a protected amino acid with fluoroform (CHF3, R-23) gas and subsequent high temperature deprotection to provide eflornithine, an important Active Pharmaceutical Ingredient (API), is described....

Scale-Up of a Continuous Manufacturing Process of Edaravone

10 May 2024 | Contributor(s): Zhou, Shuhao, Hong, Qingxia, Mei, Wenliu, He, Yan, Wu, Chengjun, Sun, Tiemin

Edaravone belongs to a class of brain-protective agents, which can scavenge free radicals. To reduce impurities and improve the yield, a continuous flow production process of edaravone was developed. The synthesis is continuously carried out in two steps. The throughput can reach 11.328 kg/day...

Scaling continuous API synthesis from milligram to kilogram: extending the enabling benefits of micro to the plant

09 Jun 2023 | Contributor(s): Berton, M, de, Souza, JMAbdiaj, I, McQuade, DT, Snead, DR

The signature benefits of continuous flow are largely a result of a reactor's micro-sized features. However, as the technology gains industrial traction in the synthesis of active pharmaceutical ingredients (API), the reactors must be scaled to larger size to meet production demands. Often, the...

Scaling-up Electroorganic Synthesis Using a Spinning Electrode Electrochemical Reactor in Batch and Flow Mode

25 Jun 2024 | Contributor(s): Petrović, Nikola, Malviya, Bhanwar K., Kappe, C. Oliver, Cantillo, David

Technology for the rapid scale-up of synthetic organic electrochemistry from milligrams to multigrams or multi-100 g quantities is highly desirable. Traditional parallel plate flow electrolysis cells can produce large quantities of material, but transfer from batch to this flow technology...

Seeded droplet microfluidic system for small molecule crystallization

09 Jun 2023 | Contributor(s): Garg, N, Tona, RMartin, P, Martin-Soladana, PM, Ward, G, Douillet, N, Lai, D

A microfluidic approach to seeded crystallization has been demonstrated using abacavir hemisulfate, a nucleoside analog reverse transcriptase inhibitor, in droplet reactors to control polymorphism and produce particles with a low particle size distribution. Two techniques are introduced: (1) the...

Selective crystallization of the metastable α-form of L-glutamic acid using concentration feedback control

09 Jun 2023 | Contributor(s): Kee, Nicholas C.S., Tan, Reginald B.H. Braatz, Richard D., Braatz, Richard D.

A systematic methodology is presented for the selective crystallization of the metastable form of a monotropic dimorph, L-glutamic acid, for batch cooling crystallization. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy coupled with chemometrics was used to...

Selective preparation of elusive and alternative single component polymorphic solid forms through multi-component crystallisation routes

09 Jun 2023 | Contributor(s): Thomas, LH, Wales, C, Wilson, CC

A transferable, simple, method for producing previously elusive and novel polymorphic forms of important active pharmaceutical ingredients (APIs; paracetamol (acetaminophen), piroxicam and piracetam) is demonstrated. Nitrogen heterocyclic co-molecules are employed to influence the self-assembly...

Semi-continuous multi-step synthesis of lamivudine

10 May 2024 | Contributor(s): Mandala, Devender, Chadaa, Sravanthi, Watts, Paul

We report the first continuous flow synthesis of lamivudine, an antiretroviral drug used in the treatment of HIV/AIDS and hepatitis B. The key intermediate (5-acetoxy oxathiolane) was prepared by an integrated two step continuous flow process from L-menthyl glyoxalate hydrate in a single solvent,...

Semicontinuous Process for GMP Manufacture of a Carbapenem Intermediate via Carbene Insertion Using an Immobilized Rhodium Catalyst

25 Jun 2024 | Contributor(s): Gage, James R., Chen, Furong, Dong, Changming, Gonzalez, Miguel A., Jiang, Yong, Luo, Yong, McLaws, Mark D., Tao, Jian

A two-stage flow process for cGMP manufacture of a commercially important carbapenem intermediate was developed. Stage 1 featured an intramolecular N–H insertion reaction catalyzed by an immobilized rhodium catalyst. In stage 2, phosphorylation of the resulting keto ester intermediate afforded...

Separate mechanisms of ion oligomerization tune the physicochemical properties of n-butylammonium acetate: cation-base clusters vs. anion-acid dimers

09 Jun 2023 | Contributor(s): Berton, P, Kelley, SPWang, H, Myerson, AS, Rogers, RD

We investigated the ability of the ions comprising protic ionic liquids to strongly interact with their neutral acid and base forms through the characterization of n-butylammonium acetate ([C4NH3][OAc]) in the presence of excess n-butylamine (C4NH2) or excess acetic acid (HOAc). The conjugate and...

Separation and Purification in the Continuous Synthesis of Fine Chemicals and Pharmaceuticals

09 Jun 2023 | Contributor(s): O'Mahony, M, Ferguson, SStelzer, T, Myerson, A

The use to both chemists and chemical engineers working in flow synthesis, this chapter provides a summary of separation and purification operations that can be applied to flow synthesis reaction streams. Both single and biphasic separations for the liquid phase are detailed. Separation and...

Separation of Chemical Reaction Intermediates by Metal-Organic Frameworks

09 Jun 2023 | Contributor(s): Centrone, A, Santiso, EE, Hatton, TA

HPLC columns custom-packed with metal-organic framework (MOF) materials are used for the separation of four small intermediates and byproducts found in the commercial synthesis of an important active pharmaceutical ingredient in methanol. In particular, two closely related amines can be separated...

Seven-Step Continuous Flow Synthesis of Linezolid Without Intermediate Purification

24 Apr 2024 | Contributor(s): Russel, M. Grace, Jamison, Timothy F.

Herein, the blockbuster antibacterial drug linezolid is synthesized from simple starting blocks by a convergent continuous flow sequence involving seven (7) chemical transformations. This is the highest total number of distinct reaction steps ever performed in continuous flow without conducting...