Supervised Extended Iterative Optimization Technology for Estimation of Powder Compositions in Pharmaceutical Applications: Method and Lifecycle Management

09 Jun 2023 | Contributor(s): Muñoz, Salvador García, Torres, Eduardo Hernández

Further enhancements to the extended iterative optimization technology (EIOT) method are presented. These are meant to include the effects of nonchemical interferences of known origin in the EIOT parameters and to manage the lifecycle of the method in a pharmaceutical manufacturing application. A...

Supervisory Control System for Monitoring a Pharmaceutical Hot Melt Extrusion Process

09 Jun 2023 | Contributor(s): Markl, Daniel, Wahl, Patrick R, Menezes, José C, Koller, Daniel M, Kavsek, Barbara, Francois, Kjell, Roblegg, Evaa, Khinast, Johannes G.

Continuous pharmaceutical manufacturing processes are of increased industrial interest and require uni- and multivariate Process Analytical Technology (PAT) data from different unit operations to be aligned and explored within the Quality by Design (QbD) context. Real-time pharmaceutical process...

Surrogate-based Optimization for Pharmaceutical Manufacturing Processes

09 Jun 2023 | Contributor(s): Wang, Zilong, Escotet-Espinoza, M Sebastian Singh, Ravendra, Ierapetritou, Marianthi

The development of pharmaceutical manufacturing processes has been facilitated by recent advances in the process simulation area. However, since the simulations are usually complex and the analytical expressions of the model can be unknown, it is difficult to directly apply traditional...

Surrogate-Based Optimization of Expensive Flowsheet Modeling for Continuous Pharmaceutical Manufacturing

09 Jun 2023 | Contributor(s): Boukouvala, Fani, Ierapetritou, Marianthi G.

Simulation-based optimization is a Research Article area that is currently attracting a lot of attention in many industrial applications, where expensive simulators are used to approximate, design, and optimize real systems. Pharmaceuticals are typical examples of high-cost products which involve...

Switching from batch to continuous granulation: A case study of metoprolol succinate ER tablets

09 Jun 2023 | Contributor(s): Kotamarthy, Lalith, Feng, Xin, Alayoubi, Alaadin, Bolla, Pradeep Kumar, Ramachandran, Rohit, Ashraf, Muhammad, O'Connor, Thomas, Zidan, Ahmed

Continuous manufacturing (CM) has been used to produce several immediate release drug products. No extended-release (ER) product manufactured employing CM technology has been approved yet. This study investigated the critical aspects of switching from the batch mode of high shear granulation to...

System for Continuous Wet Granulation based on a High-shear Mixer

09 Jun 2023 | Contributor(s): Chao, Chi, Steffens, Klaus-Juergen

A new system for continuous wet granulation and drying, based on a modified high-shear-mixer is investigated using met-formine, paracetamole and ibuprofene as active ingredients. First experiments reveal the excellent shape and particle size distribution of the granules. Tabletting investigations...

System model development and computer experiments for continuous API manufacturing

09 Jun 2023 | Contributor(s): Lee, BW, Peterson, JJYin, KH, Stockdale, GS, Liu, YC, O'Brien, A

This work details development of a system/process model and usage of Computer Experiments methodology for continuous manufacturing of Active Pharmaceutical Ingredients (API). The process of interest has three interconnected continuous unit operations, with the first two being reactors and the...

Systematic computer-aided method and tool (ICAS-PAT) for design, analysis &/or validation of process monitoring and analysis systems (PAT systems)

09 Jun 2023 | Contributor(s): Singh, Ravendra, Gernaey, Krist, Gani, Rafiqul

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Small-Volume Continuous Manufacturing of Merestinib. Part 1. Process Development and Demonstration

09 Jun 2023 | Contributor(s): Cole, KP, Reizman, BJHess, M, Groh, JM, Laurila, ME, Cope, RF, Campbell, BM, Forst, MB, Burt, JL, Maloney, TD, Johnson, MD, Mitchell, D, Polster, CS, Mitra, AW, Boukerche, M, Conder, EW, Braden, TM, Miller, RD, Heller, MR, Phillips, JL, Howell, JR

Development of a small volume continuous process that used a combination of batch and flow unit operations to manufacture the small molecule oncolytic candidate merestinib is described. Continuous processing was enabled following the identification and development of suitable chemical...

Small-Volume Continuous Manufacturing of Merestinib. Part 2.Technology Transfer and cGMP Manufacturing

09 Jun 2023 | Contributor(s): Reizman, Brandon J., Hess, Molly, Burt, Justin L., Maloney, Todd D., Johnson, Martin D., Laurila, Michael E., Cope, Richard F., Luciani, Carla V., Buser, Jonas Y., Campbell, Bradley M., Forst, Mindy B., Mitchell, David, Braden, Timothy M., Lippelt, Christopher K., Boukerche, Moussa, Starkey, Derek R., Miller, Richard D., Chen, Jing, Sun, Baoquan, Kwok, Martin, Zhang, Xin, Tadayon, Sam, Huang, Ping

Technology transfer of a small volume continuous (SVC) process and Current Good Manufacturing Practices (cGMP) manufacturing of merestinib are described. A hybrid batch-SVC campaign was completed at a contract manufacturing organization under cGMP. The decision process by which unit operations...

Solid Dosage Form Analysis by near Infrared Spectroscopy: Comparison of Reflectance and Transmittance Measurements Including the Determination of Effective Sample Mass

09 Jun 2023 | Contributor(s): Iyer, M., Morris, H. R., Drennen, J. K.

Investigations into the near infrared analysis of intact tablets allow comparison of the reflectance and transmittance methodologies. The studies involved estimation of the effective sample mass and the effect of sample inhomogeneities. An empirical method for determining effective sample mass...

Solid forms of pharmaceuticals: Polymorphs, salts and cocrystals

09 Jun 2023 | Contributor(s): Sarma, B, Chen, JHsi, HY, Myerson, AS

Control and selection of the properties of active pharmaceutical ingredients is a crucial part of the drug development process. One major part of this process is the selection of an appropriate solid form. This review will discuss three major types of crystalline solids, polymorphs, salts and...

Solid-liquid axial dispersion performance of a mesoscale continuous oscillatory flow crystalliser with smooth periodic constrictions using a non-invasive dual backlit imaging technique

09 Jun 2023 | Contributor(s): Onyemelukwe, II, Nagy, ZK, Rielly, CD

A dual backlit imaging technique has been developed for liquid and solid phase residence time distribution (RTD) measurements in a mesoscale (millilitre) continuous oscillatory flow crystalliser with smooth periodic constrictions (herein known as the SPC mesoscale crystalliser). The pixel-based...

Solvothermal Crystallization Kinetics and Control of Crystal Size Distribution of MOF-808 in a Continuous Flow Reactor

09 Jun 2023 | Contributor(s): Bagi, Sujay D., Myerson, Allan S. Román-Leshkov, Yuriy, Román-Leshkov, Yuriy

A fundamental understanding of the crystallization pathways for metal-organic frameworks (MOFs) allows for exploring the untapped combinatorial space of the organic and inorganic building units, creating possibilities to synthesize highly crystalline frameworks with desired physicochemical...

Spectroscopic characterization of tablet properties in a continuous powder blending and tableting process

09 Jun 2023 | Contributor(s): Nagy, Brigitta, Farkas, Attila, Magyar, Krisztina, Démuth, Balázs, Marosi, György

By the advent of continuous pharmaceutical manufacturing, fast and accurate characterization of product quality has become of a major interest. Although it also promotes the real-time release testing approach, so far mainly content uniformity studies were performed by near-infrared (NIR)...

Spherical Crystallization of Glycine from Monodisperse Microfluidic Emulsions

09 Jun 2023 | Contributor(s): Toldy, AI, Badruddoza, AZMZheng, L, Hatton, TA, Gunawan, R, Rajagopaan, R, Khan, SA

Emulsion-based crystallization to produce spherical crystalline agglomerates (SAs) is an attractive route to control crystal size during downstream processing of active pharmaceutical ingredients (APIs). However, conventional methods of emulsification in stirred vessels pose several problems that...

Spray granulation for drug formulation

09 Jun 2023 | Contributor(s): Loh, Zhi Hui, Er, Dawn Z. L., Chan, Lai Wah, Liew, Celine V., Heng, Paul W. S.

Introduction: Granulation is a key unit process in the production of pharmaceutical solid dosage forms and involves the agglomeration of fine particles with the aid of a binding agent. Fluidized bed granulation, a classic example of spray granulation, is a technique of particle agglomeration...

Stability and repeatability of a continuous twin screw granulation and drying system

09 Jun 2023 | Contributor(s): Vercruysse, J., Delaet, U., Van Assche, I., Cappuyns, P., Arata, F., Caporicci, G., De Beer, T., Remon, J. P., Vervaet, C.

The aim of this study was to investigate the process transfer of a commercially available product from the current batch fluid bed granulation and drying production method to an innovative continuously operating from powder to tablet production line using twin screw granulation as an intermediate...

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...

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...

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...