Continuous Crystallization Processes in Pharmaceutical Manufacturing: A Review

09 Jun 2023 | Contributor(s): Orehek, J, Teslic, D, Likozar, B

This scientific paper presents an overview of continuous solution crystallization in the pharmaceutical industry. Since the specific knowledge spectrum of precipitation is very broad, topics covering the following were analyzed and assessed in detail: a comparison between batch and continuous...

Continuous Crystallization with Impurity Complexation and Nanofiltration Recycle

09 Jun 2023 | Contributor(s): Vartak, S, Myerson, AS

For crystal-impurity systems with similar structures and molecular weights, the impurity has a strong tendency to incorporate into the crystal lattice, making it difficult to obtain high purity with a single crystallization or even multiple crystallizations. In such cases, complexation of the...

Continuous direct compression as manufacturing platform for sustained release tablets

09 Jun 2023 | Contributor(s): Vanhoorne, V, Holman, J., Cunningham, C., Kumar, A., Vercruysse, J., De Beer, T., Remon, J. P, Vervaet, C

This study presents a framework for process and product development on a continuous direct compression manufacturing platform. A challenging sustained release formulation with high content of a poorly flowing low density drug was selected. Two HPMC grades were evaluated as matrix former: standard...

Continuous direct compression: Development of an empirical predictive model and challenges regarding PAT implementation

09 Jun 2023 | Contributor(s): Bekaert, B., Van Snick, B., Pandelaere, K., Dhondt, J., Di Pretoro, G., De Beer, T., Vervaet, C., Vanhoorne, V.

In this study, an empirical predictive model was developed based on the quantitative relationships between blend properties, critical quality attributes (CQA) and critical process parameters (CPP) related to blending and tableting. The blend uniformity and API concentration in the tablets were...

Continuous direct tablet compression: effects of impeller rotation rate, total feed rate and drug content on the tablet properties and drug release

09 Jun 2023 | Contributor(s): Jarvinen, Maiju A., Paaso, Janne, Paavola, Marko, Leiviska, Kauko, Juuti, Mikko, Muzzio, Fernando, Jarvinen, Kristiina

Context: Continuous processing is becoming popular in the pharmaceutical industry for its cost and quality advantages. Objective: This study evaluated the mechanical properties, uniformity of dosage units and drug release from the tablets prepared by continuous direct compression process....

Continuous downstream processing of milled electrospun fibers to tablets monitored by near-infrared and Raman spectroscopy

09 Jun 2023 | Contributor(s): Szabo, E, Zahonyi, PGyurkes, M, Nagy, B, Galata, DL, Madarasz, L, Hirsch, E, Farkas, A, Andersen, SK, Vigh, T, Verreck, G, Csontos, I, Marosi, G, Nagy, ZK

Electrospinning is a technology for manufacture of nano- and micro-sized fibers, which can enhance the dissolution properties of poorly water-soluble drugs. Tableting of electrospun fibers have been demonstrated in several studies, however, continuous manufacturing of tablets have not been...

Continuous end-to-end production of solid drug dosage forms: Coupling flow synthesis and formulation by electrospinning

09 Jun 2023 | Contributor(s): Balogh, Attila, Domokos, András, Farkas, Balázs, Farkas, Attila, Rapi, Zsolt, Kiss, Domokos, Nyiri, Zoltán, Eke, Zsuzsanna, Szarka, Györgyi, Örkényi, Róbert, Mátravölgyi, Béla, Faigl, Ferenc

Based on the concept of continuous manufacturing an end-to-end benchtop device was developed unprecedented for the production of solid drug dosage forms by connecting flow synthesis and formulation via electrospinning (ES). Together with the optimized two-step continuous-flow synthesis of...

Continuous flow asymmetric synthesis of chiral active pharmaceutical ingredients and their advanced intermediates

09 Jun 2023 | Contributor(s): Otvos, SB, Kappe, CO

Catalytic enantioselective transformations provide well-established and direct access to stereogenic synthons that are broadly distributed among active pharmaceutical ingredients (APIs). These reactions have been demonstrated to benefit considerably from the merits of continuous processing and...

Comparison of a continuous ring layer wet granulation process with batch high shear and fluidized bed granulation processes

09 Jun 2023 | Contributor(s): Jarvinen, MA, Paavola, M, Poutiainen, S, Itkonen, P, Pasanen, V, Uljas, K, Leiviska, K, Juuti, M, Ketolainen, J, Jarvinen, K

The traditional batch wet granulation processes encounter several challenges, such as problems in the scale-up step, batch-to-batch variability together with the multivariate and difficult to control nature of the process. A continuous wet granulation technique could be a possible solution for...

Complexation-Assisted Continuous Crystallization of Isomeric Systems with Nanofiltration Recycle

09 Jun 2023 | Contributor(s): Vartak, S, Myerson, AS

In API-impurity systems consisting of structural isomers, the impurity has a strong affinity to incorporate into the host crystal owing to their identical molecular weight and similar structure. Conventional successive recrystallization turns out to be an unattractive purification strategy in...

Composite Hydrogels Laden with Crystalline Active Pharmaceutical Ingredients of Controlled Size and Loading

09 Jun 2023 | Contributor(s): Eral, HB, O'Mahony, MShaw, R, Trout, BL, Myerson, AS, Doyle, PS

Efficient control of crystallization and crystal properties still represents a bottleneck in the manufacturing of crystalline materials ranging from pigments to semiconductor particles. In the case of pharmaceutical drug manufacture, current methods for controlling critical crystal properties...

Comprehensive modelling of pharmaceutical solvation energy in different solvents

09 Jun 2023 | Contributor(s): Panwar, A, Shirazian, SSingh, M, Walker, GM

Crystallization is an important processing step in production of active pharmaceutical ingredients (API). This process is used to recover/separate the synthesized APIs for further processing to final solid dosage oral formulations. Control and understanding of crystallization are of great...

Computer Aided Design of Solvent Blends for Hybrid Cooling and Antisolvent Crystallization of Active Pharmaceutical Ingredients

09 Jun 2023 | Contributor(s): Watson, OL, Jonuzaj, SMcGinty, J, Sefcik, J, Galindo, A, Jackson, G, Adjiman, CS

Choosing a solvent and an antisolvent for a new crystallization process is challenging due to the sheer number of possible solvent mixtures and the impact of solvent composition and crystallization temperature on process performance. To facilitate this choice, we present a general computer aided...

Concentration monitoring with near infrared chemical imaging in a tableting press

09 Jun 2023 | Contributor(s): Dalvi, Himmat, Fauteux-Lefebvre, Clémence, Guay, Jean-Maxime, Abatzoglou, Nicolas, Gosselin, Ryan

Monitoring powder potency and homogeneity is important in achieving real-time release testing in a continuous tablet manufacturing operation. If quality related issues are encountered, monitoring powder potency inside a feed frame offers a last opportunity to intervene in the process before...

Conceptual framework for model-based analysis of residence time distribution in twin-screw granulation

09 Jun 2023 | Contributor(s): Kumar, Ashish, Vercruysse, Jurgen, Vanhoorne, Valerie, Toiviainen, Maunu, Panouillot, Pierre-Emmanuel, Juuti, Mikko, Vervaet, Chris, Remon, Jean Paul, Gernaey, Krist V., De Beer, Thomas, Nopens, Ingmar

Twin-screw granulation is a promising continuous alternative for traditional batchwise wet granulation processes. The twin-screw granulator (TSG) screws consist of transport and kneading element modules. Therefore, the granulation to a large extent is governed by the residence time distribution...

Concurrent Antisolvent Electrospraying: A Novel Continuous Crystallization Technique

09 Jun 2023 | Contributor(s): Perge, L, Grols, JSegura, DF, Al-Ani, A, Wilkinson, M, Castro-Dominguez, B

Pharmaceutical co-crystals (CCs) are multicomponent materials that enable the development of novel therapeutic products by enhancing the properties of active pharmaceutical ingredients, such as solubility, permeability and bioavailability. Currently, CCs are a commercial reality; theless, their...

Construction of ultrathin PTMSP/Porous nanoadditives membranes for highly efficient organic solvent nanofiltration (OSN)

09 Jun 2023 | Contributor(s): Liu, Q, Smith, SJDKonstas, K, Ng, D, Zhang, KS, Hill, MR, Xie, ZL

Organic solvent nanofiltration (OSN), also known as solvent resistant nanofiltration (SRNF), has enormous potential for industrial applications. Among the emerging high-performance membrane materials, some have proven challenging to fabricate ultrathin selective layers and at a scale large enough...

Continuous and Scalable Process for the Production of Hollow Crystals of a Poorly Water-Soluble Active Pharmaceutical Ingredient for Dissolution Enhancement and Inhaled Delivery

09 Jun 2023 | Contributor(s): Sheng, F, Chow, PSDong, YC, Heng, D, Lee, SH, Tan, RBH

This study reports a new technique for the manufacture of micron-sized, hollow crystals of a poorly water-soluble pharmaceutical compound, spironolactone, by a continuous and scalable antisolvent precipitation platform called a static mixer. Additives (polyvinylpyrrolidone (PVP) and Tween 80)...

Continuous blending monitored and feedback controlled by machine vision-based PAT tool

09 Jun 2023 | Contributor(s): Lászlo Galata, Dorián, Mészaros, Lilla, Ficzere Máté, Vass, Panna, Nagy, Brigitta, Szabó, Edina, Domokos, András, Farkas, Attila, Csontos, István, Marosi, György, Nagy, Zsombor Kristóf

In a continuous powder blending process machine vision is utilized as a Process Analytical Technology (PAT) tool. While near-infrared (NIR) and Raman spectroscopy are reliable methods in this field, measurements become challenging when concentrations below 2 w/w% are quantified. However, an...

Characterizing drug product continuous manufacturing residence time distributions of major/minor excipient step changes using near infrared spectroscopy and process parameters

09 Jun 2023 | Contributor(s): Shi, Zhenqi, Manley, Leo

The material residence time distribution in a continuous manufacturing process can be utilized to develop, design and justify the process control strategy. This paper successfully demonstrates using both major and minor formulation component step changes to determine the system response using...

Closed-loop feedback control of a continuous pharmaceutical tablet manufacturing process via wet granulation

09 Jun 2023 | Contributor(s): Singh, Ravendra, Barrasso, Dana Chaudhury, Anwesha Sen, Maitraye Ierapetritou, Marianthi Ramachandran, Rohit

The wet granulation route of tablet manufacturing in a pharmaceutical manufacturing process is very common due to its numerous processing advantages such as enhanced powder flow and decreased segregation. However, this route is still operated in batch mode with little (if any) usage of an...

Co-crystals of diflunisal and isomeric pyridinecarboxamides - a thermodynamics and crystal engineering contribution

09 Jun 2023 | Contributor(s): Evora, AOL, Castro, RAEMaria, TMR, Silva, MR, ter, Horst, JH, Canotilho, J, Eusebio, MES

Diflunisal is an anti-inflammatory, non-steroidal drug, class II of the Biopharmaceutical Classification System, which has recently been the subject of renewed interest due to its potential for use in the oral therapy of familial amyloid polyneuropathy. In this study, a thermodynamics based...

Combination of PAT and mechanistic modeling tools in a fully continuous powder to granule line: Rapid and deep process understanding

09 Jun 2023 | Contributor(s): Domokos, András, Pusztai, Éva, Madarász, Lajos, Nagy, Brigitta, Gyürkés, Martin, Farkas, Attila (24372641300), Fülöp, Gergő, Casian, Tibor, Szilágyi, Botond., Nagy, Zsombor Kristóf

Comprehensive understanding of an integrated continuous pharmaceutical technology was achieved in this study by a combining design of experiments and mechanistic modeling-based simulations. The powder to granule line consisted of twin-screw wet granulation, vibrational fluid-bed drying and...

Combined feedforward/feedback control of an integrated continuous granulation process

09 Jun 2023 | Contributor(s): Pereira, Glinka Cathy, Muddu, Shashank Venkat Román-Ospino, Andrés David Clancy, Don Igne, Benoit Airiau, Christian Muzzio, Fernando J Ierapetritou, Marianthi Ramachandran, Rohit, Singh, Ravendra

Continuous manufacturing offers shorter processing times and increased product quality assurance, among several other advantages. This makes it an ever-growing interest among pharmaceutical companies. A suitable efficient control system is however desired for continuous pharmaceutical...

Compaction properties of melt coated coarse drug particles

09 Jun 2023 | Contributor(s): Gren, T, Nystrom, C

Xylitol and stearic acid were applied onto the surfaces of coarse particles of paracetamol and acetylsalicylic acid by continuous multipurpose melt technology. The effect of melt coating on radial and axial tensile strength was studied and compared to that of dry mixing of paracetamol and...