Tracking raw material flow through a continuous direct compression line. Part II of II: Predicting dynamic changes in quality attributes of tablets due to disturbances in raw material properties using an independent residence time distribution model

09 Jun 2023 | Contributor(s): Peterwitz, M, Buchgeister, SMeier, R, Schembecker, G

Continuous manufacturing of pharmaceuticals promises many advantages regarding economics and quality. However, tracing deviating material in such processes is much more challenging than in batch processes due to axial back-mixing. The literature has proven the traceability of disturbances in the...

Transfer from High-Shear Batch to Continuous Twin Screw Wet Granulation: A Case Study in Understanding the Relationship Between Process Parameters and Product Quality Attributes

09 Jun 2023 | Contributor(s): Beer, Paul, Wilson, David, Huang, Zhenyu, De Matas, Marcel

A twin screw to high-shear batch granulation technology switch was evaluated for a pharmaceutical development project. Differences in granule (particle size distribution and porosity) and tablet (dissolution) quality attributes were analysed for both continuous and batch technologies. Liquid to...

Tuning Morphology in Active Pharmaceutical Ingredients: Controlling the Crystal Habit of Lovastatin through Solvent Choice and Non-Size-Matched Polymer Additives

09 Jun 2023 | Contributor(s): Hatcher, LE, Li, WPayne, P, Benyahia, B, Rielly, CD, Wilson, CC

Additive crystallization routes to control the crystal habit of the active pharmaceutical ingredient (API) lovastatin are presented, at small scale up to 25 mL. Lovastatin is an archetypical example of an API that forms needle-like crystals via solution-based recrystallization, causing issues for...

Twin Screw Continuous Wet Granulation

09 Jun 2023 | Contributor(s): Shah, Ankita V., Serajuddin, Abu T. M.

Granulation has become an integral part of the formulation of tablets. Wet granulation and roller compaction, which were developed over 50 years ago in the 1950s and 1960s, are still the most commonly used granulation methods in the pharmaceutical industry. However, these are batch processes and...

Twin screw granulation - review of current progress

09 Jun 2023 | Contributor(s): Thompson, M. R.

Twin screw granulation (TSG) is a new process of interest to the pharmaceutical community that can continuously wet granulate powders, doing so at lower liquid concentrations and with better product consistency than found by a high shear batch mixer. A considerable body of Research Article has...

Twin screw granulation as a simple and efficient tool for continuous wet granulation

09 Jun 2023 | Contributor(s): Keleb, EI, Vermeire, A, Vervaet, C, Remon, JP

The modification of a twin screw extruder for continuous wet granulation was investigated. Modification of the extruder setup as well as the screw design allowed the continuous wet granulation of alpha-lactose monohydrate without the need of a wet sieving step. The robustness of twin screw...

Twin Screw Granulation: Effects of Properties of Primary Powders

09 Jun 2023 | Contributor(s): Lute, Sushma, V, Dhenge, Ranjit M., Salman, Agba D.

Lactose and mannitol are some of the most commonly used powders in the pharmaceutical industry. The limited Research Article published so far highlights the effects of process and formulation parameters on the properties of the granules and the tablets produced using these two types of powders...

Twin Screw Melt Granulation: Alternative Approach for Improving Solubility and Permeability of a Non-steroidal Anti-inflammatory Drug Ibuprofen

23 Jul 2024 | Contributor(s): Nyavanandi, Dinesh, Narala, Sagar, Mandati, Preethi, Alzahrani, Abdullah, Kolimi, Praveen, Almotairy, Ahmed, Repka, Michael A.

The current research is focused on investigating the suitability of the twin screw melt granulation (TSMG) approach for improving the solubility of a non-steroidal anti-inflammatory (NSAIDs) drug (ibuprofen), by developing granules using lipid surfactants. The solubility of the drug within the...

Twin-screw granulation and high-shear granulation: The influence of mannitol grade on granule and tablet properties

09 Jun 2023 | Contributor(s): Megarry, Andrew, Taylor, Agnes, Gholami, Aida, Wikstrom, Hakan, Tajarobi, Pirjo

Granule structure has a key influence on tablet critical quality attributes. The ability to control this structure through excipient choice is an important part of formulation development. Mannitol is a popular diluent and the choice of input grade has been shown to impact granule properties....

Twin-screw melt granulation: Current progress and challenges

09 Jun 2023 | Contributor(s): Kittikunakorn, Nada, Liu, Tongzhou, Zhang, Feng

Twin-screw melt granulation (TSMG) is a new alternative method for granulation that offers several advantages over wet and dry granulation methods. TSMG has rapidly gained interest over recent years in the pharmaceutical industry. Since it is an inherently continuous process with controlled...

Two-Stage Crystallizer Design for High Loading of Poorly Water-Soluble Pharmaceuticals in Porous Silica Matrices

09 Jun 2023 | Contributor(s): Dwyer, L, Kulkarni, SRuelas, L, Myerson, A

While porous silica supports have been previously studied as carriers for nanocrystalline forms of poorly water-soluble active pharmaceutical ingredients (APIs), increasing the loading of API in these matrices is of great importance if these carriers are to be used in drug formulations. A...

Understanding API Static Drying with Hot Gas Flow: Design and Test of a Drying Rig Prototype and Drying Modeling Development

09 Jun 2023 | Contributor(s): Ottoboni, S, Coleman, SJSteven, C, Siddique, M, Fraissinet, M, Joannes, M, Laux, A, Barton, A, Firth, P, Price, CJ, Mulheran, PA

Developing a continuous isolation process to produce a pure, dry, free-flowing active pharmaceutical ingredient (API) is the final barrier to the implementation of continuous end-to-end pharmaceutical manufacturing. Recent work has led to the development of continuous filtration and washing...

Understanding pharmaceutical quality by design

09 Jun 2023 | Contributor(s): Yu, Lawrence X, Amidon, Gregory Khan, Mansoor A Hoag, Stephen W, Polli, James, Raju, G K, Woodcock, Janet

This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product; (2) product design and...

Understanding Powder Behavior in Continuous Feeding: Powder Densification and Screw Layering

16 Oct 2024 | Peer-reviewed journal | Contributor(s): Sara Fathollahi, Pauline H. M. Janssen, Bram Bekaert, Dirk Vanderroost, Valerie Vanhoorne, Bastiaan H. J. Dickhoff

Background: Precise continuous feeding of active pharmaceutical ingredients (APIs) and excipients is crucial in a continuous powder-to-tablet manufacturing setup, as any inconsistency can affect the final tablet quality. Method: This study investigated the impact of various materials on the...

Use of a continuous twin screw granulation and drying system during formulation development and process optimization

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Vercruysse, J., Peeters, E., Fonteyne, M., Cappuyns, P., Delaet, U., Van Assche, I., De Beer, T., Remon, J. P., Vervaet, C.

Since small scale is key for successful introduction of continuous techniques in the pharmaceutical industry to allow its use during formulation development and process optimization, it is essential to determine whether the product quality is similar when small quantities of materials are...

Use of a “Catalytic” Cosolvent, N,N-Dimethyl Octanamide, Allows the Flow Synthesis of Imatinib with no Solvent Switch

10 May 2024 | Peer-reviewed journal | Contributor(s): Yang, Jeffrey C., Niu, Dawen, Karsten, Bram P., Lima, Fabio, Buchwald, Stephen L.

A general, efficient method for C−N cross-coupling has been developed using N,N-dimethyloctanamide as a catalytic cosolvent for biphasic continuous-flow applications. The described method was used to generate a variety of biarylamines and was integrated into a two-step sequence which converted...

Use of High-Throughput Tools for Telescoped Continuous Flow Synthesis of an Alkynylnaphthyridine Anticancer Agent, HSN608

10 May 2024 | Peer-reviewed journal | Contributor(s): Biyani, Shruti A., Qi, Qingqing, Wu, Jingze, Moriuchi, Yuta, Larocque, Elizabeth A., Sintim, Herman O., Thompson, David H.

Developing continuous syntheses of lead compounds to support in vivo studies and preclinical evaluation remains an underdeveloped area. We report a telescoped continuous flow synthesis of an alkynylnaphthyridine lead compound for the treatment of FLT3 mutations in acute myeloid leukemia....

Use of Lithium Diisopropylamide in Flow: Operability and Safety Challenges Encountered on a Multigram Scale

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Alonso, Marta, Garcia, Maria Cruz, McKay, Christopher, Thorp, Lee R., Webb, Michael, Edwards, Lee J.

A workflow for the development of organometallic processes in flow was applied to synthesize 1-(5-bromopyridin-2-yl)-2-methylpropan-2-ol, a pharmaceutical intermediate. Key factors and corresponding practical assessments required for the scale-up when transferring from batch to flow are...

Use of near-infrared spectroscopy to quantify drug content on a continuous blending process: Influence of mass flow and rotation speed variations

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Martínez, Lizbeth, Peinado, Antonio, Liesum, Lorenz, Betz, Gabriele

The aim of this study was to develop a quantitative Near-Infrared (NIR) method which monitors the homogeneity of a pharmaceutical formulation coming out of a continuous blender. For this purpose, a NIR diode array spectrometer with fast data acquisition was selected. Additionally, the dynamic...

Use of Terahertz-Raman Spectroscopy to Determine Solubility of the Crystalline Active Pharmaceutical Ingredient in Polymeric Matrices during Hot Melt Extrusion

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Bordos, E, Islam, MTFlorence, AJ, Halbert, GW, Robertson, J

Polymer-based amorphous solid dispersions (ASDs) comprise one of the most promising formulation strategies devised to improve the oral bioavailability of poorly water-soluble drugs. Exploitation of such systems in marketed products has been limited because of poor understanding of physical...

Use of the channel fill level in defining a design space for twin screw wet granulation

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Gorringe, L. J., Kee, G. S., Saleh, M. F., Fa, N. H., Elkes, R. G.

Twin screw wet granulation is a key process in the continuous manufacture of oral solid dosage forms. Previous Research Article has qualitatively suggested that the channel fill level influences the granules produced. In this paper a quantitative measure of the total volumetric fraction of the...

Using a material property library to find surrogate materials for pharmaceutical process development

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Escotet-Espinoza, MS, Moghtadernejad, SScicolone, J, Wang, YF, Pereira, G, Schafer, E, Vigh, T, Klingeleers, D, Ierapetritou, M, Muzzio, FJ

Material properties are known to have a significant impact on pharmaceutical manufacturing performance, particularly for solid product processes. Evaluating the performance of a specific material, for example an active pharmaceutical ingredient or excipient, is critical during development stages...

Using Flow To Outpace Fast Proton Transfer in an Organometallic Reaction for the Manufacture of Verubecestat (MK-8931)

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Thaisrivongs, David A., Naber, John R., McMullen, Jonathan P.

We report that an organolithium addition to a chiral ketimine, which because of competitive proton transfer proceeds with only modest yield in batch, can be significantly improved in flow. The transformation was discovered to be highly mixing-sensitive but remarkably temperature-independent in...

Using online mass spectrometry to predict the end point during drying of pharmaceutical products

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Dodda, Aditya G., Saranteas, Kostas, Henson, Michael A.

Drying of active pharmaceutical ingredients (APIs) is an energy-intensive process that is often a manufacturing bottleneck due to the relatively long processing times. A key objective is the ability to determine the drying end point, the time at which all solvent has been evaporated from the...