No More Than Three: Technoeconomic Mixed Integer Nonlinear Programming Optimization of Mixed Suspension, Mixed Product Removal Crystallizer Cascades for Melitracen, an Antidepressant API

09 Jun 2023 | Contributor(s): Diab, S, Gerogiorgis, DI

Mixed Suspension, Mixed Product Removal (MSMPR) crystallizers have been considered in numerous cases as a continuous mode of operation in the production of Active Pharmaceutical Ingredients (APIs). The steady-state continuous MSMPR crystallization of melitracen via cooling has been recently...

Non-destructive detection of disintegrant levels in compressed oral solid dosage forms

23 Jul 2024 | Contributor(s): Sultan, Tipu, Rozin, Enamul Hasan, Dave, Vivek S., Cetinkaya, Cetin

Quality issues related to compressed oral solid dosage (OSD) forms, such as tablets, arise during the design, development, and production stages, despite established processes and robust production tools. One of the primary quality concerns is the disintegration properties and drug release...

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...

Nondestructive measurements of the compact strength and the particle-size distribution after milling of roller compacted powders by near-infrared spectroscopy

09 Jun 2023 | Contributor(s): Gupta, A, Peck, GE, Miller, RW, Morris, KR

Compact strength and the particle-size distribution of milled roller compacted compacts were correlated to the slope of the best-fit line through near-infrared spectra for samples prepared under different roll speeds and feed rates. The above correlations were found to hold for compacts prepared...

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 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 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 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...

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-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...

On-line monitoring of blend uniformity in continuous drug product manufacturing process -The impact of powder flow rate and the choice of spectrometer: Dispersive vs. FT

09 Jun 2023 | Contributor(s): Shi, Zhenqi, McGhehey, Kathryn C, Leavesley, Ian M., Manley, Leo F.

One of the commonly acknowledged issues in continuous manufacturing of drug products is how to provide a representative sampling on flowing powder to assure its blend uniformity. An investigation was conducted to improve understanding on the impact of powder flow rate under different continuous...

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...

One-Step Continuous Flow Synthesis of Antifungal WHO Essential Medicine Flucytosine Using Fluorine

10 May 2024 | Contributor(s): Harsanyi, Antal, Conte, Annelyse, Pichon, Laurent, Rabion, Alain, Grenier, Sandrine, Sandford, Graham

In Africa around 625 000 mortalities per annum (20% of HIV/AIDS related deaths) are due to the affects of the Cryptococcal meningitis (CM) fungal infection. Recently, the World Health Organisation (WHO) and the Infectious Disease Society of America (IDSA) recommended that the first line treatment...

One-Step Synthesis of 2-Fluoroadenine Using Hydrogen Fluoride Pyridine in a Continuous Flow Operation

25 Jun 2024 | Contributor(s): Salehi Marzijarani, Nastaran, Snead, David R., McMullen, Jonathan P., Lévesque, François, Weisel, Mark, Varsolona, Richard J., Lam, Yu-hong, Liu, Zhijian, Naber, John R.

We report the development of a one-pot synthesis of 2-fluoroadenine from an inexpensive 2,6-diaminopurine starting material using diazonium chemistry in a continuous fashion. Given the sensitivity of this transformation to temperature, we conducted critical experiments to study the exothermicity...

One-Step Synthesis of 2-Fluoroadenine Using Hydrogen Fluoride Pyridine in a Continuous Flow Operation

23 Jul 2024 | Contributor(s): Salehi Marzijarani, Nastaran, Snead, David R., McMullen, Jonathan P., Lévesque, François, Weisel, Mark, Varsolona, Richard J., Lam, Yu-hong, Liu, Zhijian, Naber, John R.

We report the development of a one-pot synthesis of 2-fluoroadenine from an inexpensive 2,6-diaminopurine starting material using diazonium chemistry in a continuous fashion. Given the sensitivity of this transformation to temperature, we conducted critical experiments to study the exothermicity...

Operation Strategy Development for Grignard Reaction in a Continuous Stirred Tank Reactor

25 Jun 2024 | Contributor(s): Wong, Sze-Wing, Changi, Shujauddin M., Shields, Richard, Bell, Willis, McGarvey, Bernard, Johnson, Martin D., Sun, Wei-Ming, Braden, Tim M., Kopach, Michael E., Spencer, Richard D., Flanagan, Gordon, Murray, Michael

This paper presents a case study in establishing the operation space of a Grignard reaction in a continuous stirred tank reactor (CSTR). The operation space is the multivariate space with the boundary defined by the proven acceptable range of every CSTR process parameter such as flow rates and...

Opportunities for Process Control and Quality Assurance Using Online NIR Analysis to a Continuous Wet Granulation Tableting Line

09 Jun 2023 | Contributor(s): Palmer J., O’Malley C.J., Wade M.J., Martin E.B., Page T., Montague G.A.

This paper investigates the application of online near-infrared measurements as a means to measure blend uniformity in a continuous tableting line. Underlying all the monitoring and control methods is the ability to measure key tablet properties online at a rate suitable for control purposes. The...

Optimal Dynamic Continuous Manufacturing of Pharmaceuticals with Recycle

09 Jun 2023 | Contributor(s): Patrascu, Michael, Barton, Paul I.

Continuous manufacturing of pharmaceuticals is challenged by short campaigns due to the low volume of some products. This calls for optimization of the entire dynamic campaign to achieve the highest overall yields and productivity and to minimize waste. In this paper, we investigate how recycles...

Optimization and Scale-Up of the Continuous Flow Acetylation and Nitration of 4-Fluoro-2-methoxyaniline to Prepare a Key Building Block of Osimertinib

25 Jun 2024 | Contributor(s): Köckinger, Manuel, Wyler, Benjamin, Aellig, Christof, Roberge, Dominique M., Hone, Christopher A., Kappe, C. Oliver

The development of a scalable telescoped continuous flow procedure for the acetylation and nitration of 4-fluoro-2-methoxyaniline is described. A subsequent batch deprotection then affords 4-fluoro-2-methoxy-5-nitroaniline, a key building block in the synthesis of osimertinib, a third-generation...