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...

Simplified end-to-end continuous manufacturing by feeding API suspensions in twin-screw wet granulation

09 Jun 2023 | Contributor(s): Schmidt, A, de, Waard, HMoll, KP, Kleinebudde, P, Krumme, M

This study focussed on investigating the coupling of continuous manufacturing of drug substance and continuous manufacture of drug product. An important step in such an integrated end-to-end continuous manufacturing was envisioned by dosing the API as suspension into a twin-screw wet granulation...

Simplified formulations with high drug loads for continuous twin-screw granulation

09 Jun 2023 | Contributor(s): Meier, R., Thommes, M., Rasenack, N., Krumme, M., Moll, K. -P., Kleinebudde, P.

As different batches of the same excipients will be intermixed during continuous processes, the traceability of batches is complicated. Simplified formulations may help to reduce problems related to batch intermixing and traceability. Twin-screw granulation with subsequent tableting was used to...

Simulated moving bed chromatography for the separation of enantiomers

09 Jun 2023 | Contributor(s): Rajendran, A, Paredes, G, Mazzotti, M

Simulated moving bed (SMB) chromatography, a continuous multi-column chromatographic process, has become one of the preferred techniques for the separation of the enantiomers of a chiral compound. Several active pharmaceutical ingredients, including blockbuster drugs, are manufactured using the...

Simulation-Based Design of an Efficient Control System for the Continuous Purification and Processing of Active Pharmaceutical Ingredients

09 Jun 2023 | Contributor(s): Sen, M, Singh, R, Ramachandran, R

In this study, an efficient system-wide controlsystem has been designed for the integrated continuous purification and processing of the active pharmaceutical ingredient (API). The control strategy is based on the regulatory PID controller which is most widely used in the manufacturing industry...

Simultaneous micronization and surface modification for improvement of flow and dissolution of drug particles

09 Jun 2023 | Contributor(s): Han, Xi, Ghoroi, Chinmay, To, Daniel, Chen, Yuhua, Dave, Rajesh

Simultaneous micronization and surface modification of drug particles is considered in order to mitigate disadvantages of micronization, e.g., agglomeration, poor flowability, marginal increase in surface area and low bulk density. Particles of ibuprofen (102 mu m), a model drug, pre-blended with...

Single-crystal Drying: Development of a Continuous Drying Prototype to Optimize Particle Flow and Residence Time Distribution

09 Jun 2023 | Contributor(s): Zettl, M, Aigner, IHauser, C, Mannschott, T, van, der, Wel, P, Schrottner, H, Khinast, J, Krumme, M

Purpose In the pharmaceutical industry, there has been a growing interest in continuous manufacturing in recent years. Many efforts have been made to implement new process equipment for various production steps. One step which is not yet covered well is the continuous drying of the active...

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...

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 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....

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...

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...

Residence time distribution of a continuously-operated capsule filling machine: Development of a measurement technique and comparison of three volume-reducing inserts

09 Jun 2023 | Contributor(s): Kruisz, Julia, Faulhammer, Eva, Rehrl, Jakob, Scheibelhofer, Otto, Witschnigg, Andreas, Khinast, Johannes G.

This paper presents the measurement and analysis of the residence time distribution (RTD) of a tamping-pin capsule filling machine. The tamping speed and the amount of material inside the powder bowl proved to have a significant effect on the RTD. Various inserts into the powder bowl that reduce...

Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms

09 Jun 2023 | Contributor(s): Wahlich, John

Continuous manufacturing (CM) is defined as a process in which the input material(s) are continuously fed into and transformed, and the processed output materials are continuously removed from the system. CM can be considered as matching the FDA’s so-called ‘Desired State’ of pharmaceutical...

Rheological characterization of microcrystalline cellulose and silicified microcrystalline cellulose wet masses using a mixer torque rheometer

09 Jun 2023 | Contributor(s): Luukkonen, P, Schaefer, T, Hellen, L, Juppo, AM, Yliruusi, J

The rheological properties of silicified microcrystalline cellulose (Prosolv 50) were compared with those of standard grades of microcrystalline cellulose (Emcocel 50 and Avicel PH 101). Cellulose samples were analyzed using nitrogen adsorption together with particle size, flowability, density...

Risk Considerations on Developing a Continuous Crystallization System for Carbamazepine

09 Jun 2023 | Contributor(s): Yang, Xiaochuan, Acevedo, David, Mohammad, Adil, Pavurala, Naresh, Wu, Huiquan, Brayton, Alex L., Shaw, Ryan A., Goldman, Mark J., He, Fan, Li, Shuaili, Fisher, Robert J., O'Connor, Thomas F., Cruz, Celia N.

Continuous manufacturing (CM) is an emerging technology in the pharmaceutical manufacturing sector, and the understanding of the impact on product quality is currently evolving. As the final purification and isolation step, crystallization has a significant impact on the final physicochemical...

Robust nonlinear model predictive control of batch processes

09 Jun 2023 | Contributor(s): Nagy, Zoltan K., Braatz, Richard D.

NMPC explicitly addresses constraints and nonlinearities during the feedback control of batch processes. This NMPC algorithm also explicitly takes parameter uncertainty into account in the state estimation and state feedback controller designs. An extended Kalman filter estimates the process...

Robust State Estimation of Feeding-Blending Systems in Continuous Pharmaceutical Manufacturing

09 Jun 2023 | Contributor(s): Liu, Jianfeng, Su, Qinglin, Moreno, Mariana, Laird, Carl, Nagy, Zoltan, Reklaitis, Gintaras

State estimation is a fundamental part of monitoring, control, and real-time optimization in continuous pharmaceutical manufacturing. For nonlinear dynamic systems with hard constraints, moving horizon estimation (MHE) can estimate the current state by solving a well-defined optimization problem...

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...

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...