Novel Impinging Jet and Continuous Crystallizer Design for Rapid Reactive Crystallization of Pharmaceuticals

09 Jun 2023 | Contributor(s): Liu, WJ, Ma, CY, Wang, XZ

Reactive crystallization is an important operation in the pharmaceutical industry for the production of the active pharmaceutical ingredients (APIs), but has not been as widely studied as cooling or anti-solvent crystallization. Reactive crystallization has many unique features that make them...

Nucleation kinetics of paracetamolethanol solutions from induction time experiments using Lasentec FBRM®

09 Jun 2023 | Contributor(s): Mitchell, Niall A., Ó'Ciardhá, Clifford T., Frawley, Patrick J.

A study of the nucleation kinetics for cooling crystallisation of paracetamolethanol solutions in a batch reactor is described in this paper. Induction time experiments were conducted in order to estimate the nucleation kinetics of the system. Measured induction times can be affected by numerous...

ON-OFF Feedback Control of Plug-Flow Crystallization: A Case of Quality-by-Control in Continuous Manufacturing

09 Jun 2023 | Contributor(s): Koswara, Andy, Nagy, Zoltan K.

Plug-flow crystallization (PFC) is a promising candidate to realizing the paradigm shift from batch-to-continuous pharmaceutical manufacturing. While PFC has been recently touted as the ideal continuous crystallizer due to its compact design, proper mixing, and flexible cooling and antisolvent...

On-Demand Continuous Manufacturing of Ciprofloxacin in Portable Plug-and-Play Factories: Development of a Highly Efficient Synthesis for Ciprofloxacin

09 Jun 2023 | Contributor(s): Armstrong, Cameron, Miyai, Yuma, Formosa, Anna, Thomas Dale, Chen, Esther, Hart, Travis, Schultz, Victor, Desai, Bimbisar, Cai, Angela, Almasy, Alexandra, Jensen, Klavs, Roper, Thomas

The experimental approach taken and challenges overcome in developing a high-purity production (>100 g) scale process for the telescoped synthesis of the antibiotic ciprofloxacin is outlined. The process was first optimized for each step sequentially with regard to purity and yield, with...

Novel Impinging Jet and Continuous Crystallizer Design for Rapid Reactive Crystallization of Pharmaceuticals

09 Jun 2023 | Contributor(s): Liu, WJ, Ma, CY, Wang, XZ

Reactive crystallization is an important operation in the pharmaceutical industry for the production of the active pharmaceutical ingredients (APIs), but has not been as widely studied as cooling or anti-solvent crystallization. Reactive crystallization has many unique features that make them...

Novel innovation systems for a cellular approach to continuous process chemistry from discovery to market

09 Jun 2023 | Contributor(s): Schwalbe, T, Autze, VHohmann, M, Stirner, W

Continuous processing of liquid/liquid synthesis and microreaction technology are shown to reduce the cost of process development and manufacturing of active pharmaceutical ingredients and other functional molecules on a commercial scale. Combinatorial synthesis systems for continuous chemistry...

Novel Technique for Filtration Avoidance in Continuous Crystallization

09 Jun 2023 | Contributor(s): Yazdanpanah, N, Ferguson, STMyerson, AS, Trout, BL

Fouling and clogging of lines in both continuous crystallization and flow chemistry still present a challenge in designing continuous processes. This paper presents a proof of concept for a novel unit operation designed for purification and to eliminate the need for slurry handling in API...

Nucleation kinetics of paracetamolethanol solutions from induction time experiments using Lasentec FBRM®

09 Jun 2023 | Contributor(s): Mitchell, Niall A., Ó'Ciardhá, Clifford T., Frawley, Patrick J.

A study of the nucleation kinetics for cooling crystallisation of paracetamolethanol solutions in a batch reactor is described in this paper. Induction time experiments were conducted in order to estimate the nucleation kinetics of the system. Measured induction times can be affected by numerous...

Nucleation kinetics of polymorphs: Induction period and interfacial energy measurements

09 Jun 2023 | Contributor(s): Teychené, S., Biscans, B.

Nucleation kinetics of eflucimibe polymorphs have been investigated in ethanol and n-heptane mixture. The two eflucimibe polymorphs, A and B, crystallize concomitantly for a wide range of operating conditions. The effects of supersaturation on the nucleation rates of the two existing polymorphs...

Nucleation Studies of Active Pharmaceutical Ingredients in an Air-Segmented Microfluidic Drop-Based Crystallizer

09 Jun 2023 | Contributor(s): Lu, Jennifer, Litster, James D., Nagy, Zoltan K.

In this work, an innovative experimental platform to study the nucleation behavior of an active pharmaceutical ingredient (API) using a gas-segmented flow produced by a microfluidic T-junction device with fine perfluoroalkoxy alkane (PFA) tubing is presented. In the experiments, a continuous...

On Identification of Critical Material Attributes for Compression Behaviour of Pharmaceutical Diluent Powders

09 Jun 2023 | Contributor(s): Zhang, JY, Wu, CYPan, X, Wu, CB

As one of the commonly-used solid dosage forms, pharmaceutical tablets have been widely used to deliver active drugs into the human body, satisfying patient's therapeutic requirements. To manufacture tablets of good quality, diluent powders are generally used in formulation development to...

ON-OFF Feedback Control of Plug-Flow Crystallization: A Case of Quality-by-Control in Continuous Manufacturing

09 Jun 2023 | Contributor(s): Koswara, Andy, Nagy, Zoltan K.

Plug-flow crystallization (PFC) is a promising candidate to realizing the paradigm shift from batch-to-continuous pharmaceutical manufacturing. While PFC has been recently touted as the ideal continuous crystallizer due to its compact design, proper mixing, and flexible cooling and antisolvent...

On-Demand Continuous Manufacturing of Ciprofloxacin in Portable Plug-and-Play Factories: Development of a Highly Efficient Synthesis for Ciprofloxacin

09 Jun 2023 | Contributor(s): Armstrong, Cameron, Miyai, Yuma, Formosa, Anna, Thomas Dale, Chen, Esther, Hart, Travis, Schultz, Victor, Desai, Bimbisar, Cai, Angela, Almasy, Alexandra, Jensen, Klavs, Roper, Thomas

The experimental approach taken and challenges overcome in developing a high-purity production (>100 g) scale process for the telescoped synthesis of the antibiotic ciprofloxacin is outlined. The process was first optimized for each step sequentially with regard to purity and yield, with...

On-Demand Continuous Manufacturing of Ciprofloxacin in Portable Plug-and-Play Factories: Implementation and in Situ Control of Downstream Production

09 Jun 2023 | Contributor(s): Capellades, Gerard, Neurohr, Clemence Briggs, Naomi Rapp, Kersten, Hammersmith, Gregory, Brancazio, David, Derksen, Bridget, Myerson, Allan S.

Traditional pharmaceutical manufacturing operates around a supply chain that is subject to complex logistics and is vulnerable to spikes in demand and interruptions. In this context, continuous pharmaceutical manufacturing in portable, refrigerator-sized factories is a promising solution with...

On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system

09 Jun 2023 | Contributor(s): Adamo, A, Beingessner, RLBehnam, M, Chen, J, Jamison, TF, Jensen, KF, Monbaliu, JCM, Myerson, AS, Revalor, EM, Snead, DR, Stelzer, T, Weeranoppanant, N, Wong, SY, Zhang, P

Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis...

Nucleation and Growth Kinetics for Combined Cooling and Antisolvent Crystallization in a Mixed-Suspension, Mixed-Product Removal System: Estimating Solvent Dependency

09 Jun 2023 | Contributor(s): Schall, JM, Mandur, JSBraatz, RD, Myerson, AS

Combined cooling and antisolvent crystallization is a critical unit operation in pharmaceutical manufacturing, especially for heat-sensitive or poorly soluble active pharmaceutical ingredients. The model-based design of these systems relies on the accuracy of the underlying growth and nucleation...

Nucleation kinetics of paracetamolethanol solutions from metastable zone widths

09 Jun 2023 | Contributor(s): Mitchell, Niall A., Frawley, Patrick J.

A study of the nucleation kinetics for a cooling crystallisation of paracetamolethanol solutions in a batch reactor is described in this paper. Metastable zone width (MSZW) experiments were conducted in order to estimate the nucleation kinetics of the system. Measured MSZWs can be affected by...

Near infrared spectroscopic calibration models for real time monitoring of powder density

09 Jun 2023 | Contributor(s): Román-Ospino, Andrés, Singh, Ravendra, Ierapetritoua, Marianthi, Ramachandrana, Rohit, Mendez, Rafael, Ortega-Zuñiga, Carlos, Muzzio, Fernando, Romañach, Rodolfo

Near infrared spectroscopic (NIRS) calibration models for real time prediction of powder density (tap, bulk and consolidated) were developed for a pharmaceutical formulation. Powder density is a critical property in the manufacturing of solid oral dosages, related to critical quality attributes...

Near Infrared Method Development for a Continuous Manufacturing Blending Process

09 Jun 2023 | Contributor(s): Colon, Yleana, Florian, Miguel, Acevedo, David, Mendez, Rafael, Romañach, Rodolfo

Purpose This study describes the validation of a near infrared spectroscopic method for monitoring a continuous manufacturing system. The achievement of this goal requires determining the near infrared (NIR) method’s accuracy, precision, obtaining an estimate of the sample volume analyzed, and...

Near infrared spectroscopic calibration models for real time monitoring of powder density

09 Jun 2023 | Contributor(s): Román-Ospino, Andrés, Singh, Ravendra, Ierapetritoua, Marianthi, Ramachandrana, Rohit, Mendez, Rafael, Ortega-Zuñiga, Carlos, Muzzio, Fernando, Romañach, Rodolfo

Near infrared spectroscopic (NIRS) calibration models for real time prediction of powder density (tap, bulk and consolidated) were developed for a pharmaceutical formulation. Powder density is a critical property in the manufacturing of solid oral dosages, related to critical quality attributes...

Near-Infrared Spectroscopy as Process Analytical Technology in Continuous Solid Dosage Form Manufacturing

09 Jun 2023 | Contributor(s): Peeters, M., De Beer, T., Narang, Ajit S., Dubey, Atul., Kumar, A

In this chapter titled “Near-infrared Spectroscopy as Process Analytical Technology in Continuous Solid Dosage Form Manufacturing” the fundamentals of near-infrared spectroscopy (NIRS) and the mainstream and emerging NIRS analyzer technologies for process analytical technology (PAT) applications...

Near-infrared Spectroscopy for the In-line Characterization of Powder Voiding Part I: Development of the Methodology

09 Jun 2023 | Contributor(s): Ropero, Jorge, Beach, Lauren, Alcala, Manel, Rentas, Raizza, Dave, Rajesh N., Romanach, Rodolfo J.

In-line near-infrared spectroscopy (NIR) spectra were acquired and analyzed to assess the relationship between physical and chemical properties of voiding powders and their spectral changes. NIR spectra were obtained for powders voiding from a conical glass funnel while the powder flow was...

Near-Infrared Spectroscopy for the In-Line Characterization of Powder Voiding Part II: Quantification of Enhanced Flow Properties of Surface Modified Active Pharmaceutical Ingredients

09 Jun 2023 | Contributor(s): Beach, Lauren, Ropero, Jorge, Mujumdar, Ajit, Alcala, Manel, Romanach, Rodolfo J., Dave, Rajesh N.

In this work, dry-particle coating was used to modify the surface properties of active pharmaceutical ingredients (APIs) having extremely poor flow properties. Near-infrared (NIR) spectroscopy was utilized as a novel approach to characterize the improved flow behavior of APIs and their blends....

Non-invasive, continuous, quantitative detection of powder level and mass holdup in a metal feed tube

09 Jun 2023 | Contributor(s): Louge, Michel Y, Mandur, Jasdeep, Blincoe, William, Tantuccio, Anthony, Meyer, Robert F

We describe a quantitative, non-invasive capacitance detector providing a rapid signal that varies continuously with powder level and/or mass holdup in the metal feed tube of a tablet press. We outline the principle of its processing electronics, provide an algorithm for the accurate...

Near Infrared Method Development for a Continuous Manufacturing Blending Process

09 Jun 2023 | Contributor(s): Colon, Yleana, Florian, Miguel, Acevedo, David, Mendez, Rafael, Romañach, Rodolfo

Purpose This study describes the validation of a near infrared spectroscopic method for monitoring a continuous manufacturing system. The achievement of this goal requires determining the near infrared (NIR) method’s accuracy, precision, obtaining an estimate of the sample volume analyzed, and...