-
Development of a Continuous Schotten–Baumann Route to an Acyl Sulfonamide
Contributor(s):: White, Timothy D., Berglund, K. Derek, Groh, Jennifer McClary, Johnson, Martin D., Yates, Matthew H.
The development and scale-up of a synthetic route to tasisulam sodium (5-bromo-thiophene-2-sulfonic acid 2,4-dichlorobenzoylamide sodium salt, hereafter referred to as tasisulam) utilizing continuous Schotten–Baumann reaction conditions is disclosed. A new synthetic route for the cytotoxic API...
-
Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical
Contributor(s):: Heider, Patrick L., Born, Stephen C., Basak, Soubir, Benyahia, Brahim, Lakerveld, Richard, Zhang, Haitao, Hogan, Rachael, - Buchbinder, Louis, Wolfe, Aaron, Mascia, Salvatore, Evans, James M. B., Jamison, Timothy F., Jensen, Klavs F.
The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active...
-
Selective preparation of elusive and alternative single component polymorphic solid forms through multi-component crystallisation routes
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...
-
Simulation-Based Design of an Efficient Control System for the Continuous Purification and Processing of Active Pharmaceutical Ingredients
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...
-
Selective crystallization of the metastable α-form of L-glutamic acid using concentration feedback control
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...
-
Recent Developments in the Crystallization Process: Toward the Pharmaceutical Industry
Contributor(s):: Gao, Zhenguo, Gong, Junbo, Rohani, Sohrab, Wang, Jingkang
Crystallization is one of the oldest separation and purification unit operations, and has recently contributed to significant improvements in producing higher-value products with specific properties and in building efficient manufacturing processes. In this paper, we review recent developments in...
-
Real-time feasible model-based crystal size and shape control of crystallization processes
Contributor(s):: Szilagyi, Botond, Nagy, Zoltan K.
The simultaneous control of crystal size and shape is particularly important in fine chemical and pharmaceutical crystallization. These two quantities influence the dissolution rate and bioavailability of final drug products, and also contribute to the manufacturability and efficiency of...
-
Process dynamics and control of API manufacturing and purification processes
Contributor(s):: Sen, Maitraye, Singh, Ravendra, Ramachandran, Rohit
The pharmaceutical industries have started transitioning toward continuous mode of manufacturing recently. Due to many advantages of the continuous manufacturing over the traditional alternatives, the industries are putting huge effort to efficiently adapt the continuous processing mode. However,...
-
Process Analytical Technology for Crystallization of Active Pharmaceutical Ingredients
Contributor(s):: Malwade, CR, Qu, HY
Background: Pharmaceutical industry is witnessing increased pressure to introduce innovative and efficient processes for manufacturing Active Pharmaceutical Ingredients (APIs) in order to be competitive as well as to meet the stringent product quality requirements set by regulatory authorities....
-
Population Balance Modeling to Predict Particle Size Distribution upon Scale-Up of a Combined Antisolvent and Cooling Crystallization of an Active Pharmaceutical Ingredient
Contributor(s):: Rosenbaum, Tamar, Tan, Li Dummeldinger, Michael Mitchell, Niall, Engstrom, Joshua
Herein, a population balance model (PBM) for a combined cooling and antisolvent crystallization process for an active pharmaceutical ingredient (API) has been developed and utilized to predict the product particle size distribution (PSD) for two sets of four ∼35 kg scale plant batches, with...
-
Pharmaceutical Crystallization
Contributor(s):: Chen, J, Sarma, BEvans, JMB, Myerson, AS
Crystallization is crucial in the pharmaceutical industry as a separation process for intermediates and as the final step in the manufacture of active pharmaceutical ingredients (APIs). In this perspective article to celebrate 10 years of Crystal Growth & Design, we focus on three areas related...
-
Particle Engineering of an Active Pharmaceutical Ingredient for Improved Micromeritic Properties
Contributor(s):: Sowa, M, Klapwijk, AROstendorf, M, Beckmann, W
A range of particle-engineering techniques were applied to modify unfavorable bulk solid properties of an active pharmaceutical ingredient (API), with the solid-state form of the compound remaining constant. The compound under investigation has been crystallized as needle-like particles, which...
-
Optimization in seeded cooling crystallization: A parameter estimation and dynamic optimization study
Contributor(s):: Nowee, S. Mostafa, Abbas, Ali, Romagnoli, Jose A.
In this solution crystallization study, a population balance model that predicts the crystal size distribution (CSD) is used for targeting, by optimization, the product mean size and the coefficient of variation of the final CSD. The model is robust over a wide range of conditions and predicts...
-
Nucleation kinetics of paracetamolethanol solutions from induction time experiments using Lasentec FBRM®
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 Studies of Active Pharmaceutical Ingredients in an Air-Segmented Microfluidic Drop-Based Crystallizer
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...
-
Multi-Impurity Adsorption Model for Modeling Crystal Purity and Shape Evolution during Crystallization Processes in Impure Media
Contributor(s):: Borsos, Akos, Majumder, Aniruddha, Nagy, Zoltan K.
The impurity effect on the crystal properties, such as particle size and shape distribution, is significant, having significant impact on the downstream processes as well as on the product effectiveness. Currently very few studies exist that provide a quantitative model to describe crystal purity...
-
Multi-scale flowsheet simulation of an integrated continuous purification-downstream pharmaceutical manufacturing process
Contributor(s):: Sen, M, Chaudhury, ASingh, R, John, J, Ramachandran, R
Properties of active pharmaceutical ingredients influence the critical quality attributes (CQAs) of final solid dosage forms (e. g. tablets). In the last decade, continuous manufacturing has been shown to be a promising alternative to batch processing in the pharmaceutical industry. Therefore, a...
-
Model-based evaluation of direct nucleation control approaches for the continuous cooling crystallization of paracetamol in a mixed suspension mixed product removal system
Contributor(s):: Acevedo, David, Yang, Yang Warnke, Daniel J., Nagy, Zoltan K. ;
Direct nucleation control (DNC) is a model-free feedback control approach based on the measurement of particle number in the crystallization process. The experimental implementation has demonstrated that this approach is efficient to produce large and uniform crystals in batch crystallization, or...
-
Microfluidic droplet liquid reactors for active pharmaceutical ingredient crystallization by diffusion controlled solvent extraction
Contributor(s):: Tona, RM, McDonald, TAOAkhavein, N, Larkin, JD, Lai, D
A novel method for crystallization utilizing solvent/antisolvent extraction in microfluidic droplet liquid reactors has been developed for rapid and low-cost screening of crystal polymorphism (i. e. molecular crystallographic arrangement or internal structure) and habit (i.e. crystallographic...
-
Model Based Estimation of 2D Crystallization Kinetics From Concentration and CLD Measurements
Contributor(s):: Szilagyi, Botond, Borsos, Akos Simone, Elena Nagy, Zoltan K., Espuña, Antonio, Graells, Moisès, Puigjaner, Luis
Due to the fact that crystal size and shape influence relevant macroscopic properties of solid particles, the understanding and control of these quantities have increasing importance in particulate science. Crystallization, the primary crystal formation and purification process, is usually...
-
Investigation of Wet Milling and Indirect Ultrasound as Means for Controlling Nucleation in the Continuous Crystallization of an Active Pharmaceutical Ingredient
Contributor(s):: Yang, YH, Ahmed, BMitchell, C, Quon, JL, Siddique, H, Houson, I, Florence, AJ, Papageorgiou, CD
This study compares the use of wet milling and indirect ultrasound for promoting nucleation and controlling the particle size during the continuous crystallization of a hard-to-nucleate active pharmaceutical ingredient (API). Both an immersion and an external wet mill installed on a recirculation...
-
Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions
Contributor(s):: Cole, Kevin, Groh, Jennifer McClary, Johnson, Martin D., Burcham, Christopher L., Campbell, Bradley M., Diseroad, William D., Heller, Michael R., Howell, John R., Kallman, Neil J., Koenig, Thomas M., May, Scott A., Miller, Richard D., Mitchell, David, Myers, David P., Myers, Steven S., Phillips, Joseph L., Polster, Christopher S., White, Timothy D., Cashman, Jim, Hurley, Declan, Moylan, Robert, Sheehan, Paul, Spencer, Richard D., Desmond, Kenneth, Desmond, Paul., Gowran, Olivia
Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process...
-
Integrated design and control for robust performance: Application to an MSMPR crystallizer
Contributor(s):: Grosch, R., Mönnigmann, M., Marquardt, W.
The interplay of different types of performance constraints in an integrated design and control problem is studied by means of a case study. This integrated problem is based on a recent method for robust process design [M. Mönnigmann, W. Marquardt, Normal vectors on manifolds of critical points...
-
Integrated Purification and Formulation of an Active Pharmaceutical Ingredient via Agitated Bed Crystallization and Fluidized Bed Processing
Contributor(s):: Stocker, MW, Harding, MJTodaro, V, Healy, AM, Ferguson, S
Integrated API and drug product processing enable molecules with high clinical efficacy but poor physicochemical characteristics to be commercialized by direct co-processing with excipients to produce advanced multicomponent intermediates. Furthermore, developing isolation-free frameworks would...
-
From form to function: Crystallization of active pharmaceutical ingredients
Contributor(s):: Variankaval, Narayan, Cote, Aaron S., Doherty, Michael F.
In this perspective, we describe the state-of-the-art in API crystal product and process design, highlight barriers that currently prevent the production of better, cheaper crystalline products, and give our best estimate of where the field is going and should go during the next decade.