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Solid Multicomponent Systems: Continuous Manufacturing Approaches for Improved Drug Product...
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Solid Multicomponent Systems: Continuous Manufacturing Approaches for Improved Drug Product Quality

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (20 October 2021) | Viewed by 38013

Special Issue Editors

Dr. Saeed Shirazian

E-Mail Website
Guest Editor
Department of Chemical Sciences, Bernal Institute, University of Limerick, Limerick, Ireland
Interests: pharmaceutics; process engineering; modelling; separation; nanomaterials
Dr. Rahamatullah Shaikh

E-Mail Website
Guest Editor
Department of Chemical Sciences, Bernal Institute, University of Limerick, Limerick, Ireland
Interests: pharmaceutical cocrystals; continuous manufacturing; formulation; controlled release; analytical chemistry

Special Issue Information

Dear Colleagues,

In recent years, academia and the pharmaceutical industry have been increasingly interested in the manipulation of the solid-state of APIs to improve physicochemical properties. There are various approaches for solid-state pharmaceutical development, such as the formation of salts, amorphous formulations, solvates, cocrystals, liquid crystals, and nano-cocrystals. An important goal of solid-state pharmaceutical development is to mitigate the solubility, stability, and manufacturability of the final drug form.

In the pharmaceutical industry, manufacturing processes have traditionally favored batch processing. However, In recent times, interest in continuous manufacturing has also increased, which provides significant advantages including shorter development times, production of higher-quality products, reduced cost, real-time monitoring, and better process control. Scalable and continuous processes such as continuous crystallizers, high-shear granulation, hot melt extrusion (HME), and spray drying have recently been used for various multicomponent continuous preparation. Despite extensive research in the field of multicomponent systems, the development of end-product formulations has generally been understudied.

There is a need to understand the scientifically challenging questions relevant to this field, including the following:

Is it possible to enhance the capabilities in the context of computational techniques to rationalize multicomponent system experimental results?

How can we gain more insight into underlying mechanisms during solid-state pharmaceutical development to ensure multicomponent systems product quality attributes?

Is it possible to design and optimize processes to manufacture engineered multicomponent systems?

Is it possible to develop efficient production methods on a large scale for solid-state multicomponent systems?

By answering these questions, we can efficiently overcome obstacles facing the design of scalable and continuous processes for multicomponent systems that result in more uniform final products. Therefore, this Special Issue will highlight the current state and future perspectives on developing a multicomponent system drug product from screening to process design. We invite contributions on all aspects of the topic from both industry and academia.

Dr. Saeed Shirazian
Dr. Rahamatullah Shaikh
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • continuous pharmaceutical manufacturing
  • multicomponent systems
  • process analytical technology (PAT)
  • formulation
  • large-scale production
  • process design and optimization
  • computational methods

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Published Papers (7 papers)

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Research

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21 pages, 6779 KiB  
Article
Development and Evaluation of Amorphous Oral Thin Films Using Solvent-Free Processes: Comparison between 3D Printing and Hot-Melt Extrusion Technologies
by Jiaxiang Zhang, Anqi Lu, Rishi Thakkar, Yu Zhang and Mohammed Maniruzzaman
Pharmaceutics 2021, 13(10), 1613; https://doi.org/10.3390/pharmaceutics13101613 - 3 Oct 2021
Cited by 24 | Viewed by 6000
Abstract
Conventional oral dosage forms may not always be optimal especially for those patients suffering from dysphasia or difficulty swallowing. Development of suitable oral thin films (OTFs), therefore, can be an excellent alternative to conventional dosage forms for these patient groups. Hence, the main [...] Read more.
Conventional oral dosage forms may not always be optimal especially for those patients suffering from dysphasia or difficulty swallowing. Development of suitable oral thin films (OTFs), therefore, can be an excellent alternative to conventional dosage forms for these patient groups. Hence, the main objective of the current investigation is to develop oral thin film (OTF) formulations using novel solvent-free approaches, including additive manufacturing (AM), hot-melt extrusion, and melt casting. AM, popularly recognized as 3D printing, has been widely utilized for on-demand and personalized formulation development in the pharmaceutical industry. Additionally, in general active pharmaceutical ingredients (APIs) are dissolved or dispersed in polymeric matrices to form amorphous solid dispersions (ASDs). In this study, acetaminophen (APAP) was selected as the model drug, and Klucel™ hydroxypropyl cellulose (HPC) E5 and Soluplus® were used as carrier matrices to form the OTFs. Amorphous OTFs were successfully manufactured by hot-melt extrusion and 3D printing technologies followed by comprehensive studies on the physico-chemical properties of the drug and developed OTFs. Advanced physico-chemical characterizations revealed the presence of amorphous drug in both HME and 3D printed films whereas some crystalline traces were visible in solvent and melt cast films. Moreover, advanced surface analysis conducted by Raman mapping confirmed a more homogenous distribution of amorphous drugs in 3D printed films compared to those prepared by other methods. A series of mathematical models were also used to describe drug release mechanisms from the developed OTFs. Moreover, the in vitro dissolution studies of the 3D printed films demonstrated an improved drug release performance compared to the melt cast or extruded films. This study suggested that HME combined with 3D printing can potentially improve the physical properties of formulations and produce OTFs with preferred qualities such as faster dissolution rate of drugs. Full article
(This article belongs to the Special Issue Solid Multicomponent Systems: Continuous Manufacturing Approaches for Improved Drug Product Quality)
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11 pages, 3802 KiB  
Article
Urea as a Cocrystal Former—Study of 3 Urea Based Pharmaceutical Cocrystals
by Fucheng Leng, Koen Robeyns and Tom Leyssens
Pharmaceutics 2021, 13(5), 671; https://doi.org/10.3390/pharmaceutics13050671 - 7 May 2021
Cited by 14 | Viewed by 4104
Abstract
Cocrystallization is commonly used for its ability to improve the physical properties of APIs, such as solubility, bioavailability, compressibility, etc. The pharmaceutical industry is particularly interested in those cocrystals comprising a GRAS former in connection with the target API. In this work, we [...] Read more.
Cocrystallization is commonly used for its ability to improve the physical properties of APIs, such as solubility, bioavailability, compressibility, etc. The pharmaceutical industry is particularly interested in those cocrystals comprising a GRAS former in connection with the target API. In this work, we focus on the potential of urea as a cocrystal former, identifying three novel pharmaceutical cocrystal systems with catechin, 3-hydroxyl-2-naphthoic and ellagic acid. Interestingly, the stability of catechin under high humidity or high temperature environment is improved upon cocrystallization with urea. Moreover, the solubility of ellagic acid is improved about 17 times. This work displays the latent possibility of urea in improving the physical property of drug molecules using a cocrystallization approach. Full article
(This article belongs to the Special Issue Solid Multicomponent Systems: Continuous Manufacturing Approaches for Improved Drug Product Quality)
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20 pages, 3591 KiB  
Article
Continuous Manufacture and Scale-Up of Theophylline-Nicotinamide Cocrystals
by Steven A. Ross, Andrew P. Hurt, Milan Antonijevic, Nicolaos Bouropoulos, Adam Ward, Pat Basford, Mark McAllister and Dennis Douroumis
Pharmaceutics 2021, 13(3), 419; https://doi.org/10.3390/pharmaceutics13030419 - 20 Mar 2021
Cited by 11 | Viewed by 3468
Abstract
The aim of the study was the manufacturing and scale-up of theophylline-nicotinamide (THL-NIC) pharmaceutical cocrystals processed by hot-melt extrusion (HME). The barrel temperature profile, feed rate and screw speed were found to be the critical processing parameters with a residence time of approximately [...] Read more.
The aim of the study was the manufacturing and scale-up of theophylline-nicotinamide (THL-NIC) pharmaceutical cocrystals processed by hot-melt extrusion (HME). The barrel temperature profile, feed rate and screw speed were found to be the critical processing parameters with a residence time of approximately 47 s for the scaled-up batches. Physicochemical characterization using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction of bulk and extruded materials revealed the formation of high purity cocrystals (98.6%). The quality of THL-NIC remained unchanged under accelerated stability conditions. Full article
(This article belongs to the Special Issue Solid Multicomponent Systems: Continuous Manufacturing Approaches for Improved Drug Product Quality)
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17 pages, 645 KiB  
Article
Characterization of Simultaneous Evolution of Size and Composition Distributions Using Generalized Aggregation Population Balance Equation
by Mehakpreet Singh, Ashish Kumar, Saeed Shirazian, Vivek Ranade and Gavin Walker
Pharmaceutics 2020, 12(12), 1152; https://doi.org/10.3390/pharmaceutics12121152 - 27 Nov 2020
Cited by 20 | Viewed by 2631
Abstract
The application of multi-dimensional population balance equations (PBEs) for the simulation of granulation processes is recommended due to the multi-component system. Irrespective of the application area, numerical scheme selection for solving multi-dimensional PBEs is driven by the accuracy in (size) number density prediction [...] Read more.
The application of multi-dimensional population balance equations (PBEs) for the simulation of granulation processes is recommended due to the multi-component system. Irrespective of the application area, numerical scheme selection for solving multi-dimensional PBEs is driven by the accuracy in (size) number density prediction alone. However, mixing the components, i.e., the particles (excipients and API) and the binding liquid, plays a crucial role in predicting the granule compositional distribution during the pharmaceutical granulation. A numerical scheme should, therefore, be able to predict this accurately. Here, we compare the cell average technique (CAT) and finite volume scheme (FVS) in terms of their accuracy and applicability in predicting the mixing state. To quantify the degree of mixing in the system, the sum-square χ2 parameter is studied to observe the deviation in the amount binder from its average. It has been illustrated that the accurate prediction of integral moments computed by the FVS leads to an inaccurate prediction of the χ2 parameter for a bicomponent population balance equation. Moreover, the cell average technique (CAT) predicts the moments with moderate accuracy; however, it computes the mixing of components χ2 parameter with higher precision than the finite volume scheme. The numerical testing is performed for some benchmarking kernels corresponding to which the analytical solutions are available in the literature. It will be also shown that both numerical methods equally well predict the average size of the particles formed in the system; however, the finite volume scheme takes less time to compute these results. Full article
(This article belongs to the Special Issue Solid Multicomponent Systems: Continuous Manufacturing Approaches for Improved Drug Product Quality)
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Review

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31 pages, 8239 KiB  
Review
Advances in Twin-Screw Granulation Processing
by Uttom Nandi, Vivek Trivedi, Steven A. Ross and Dennis Douroumis
Pharmaceutics 2021, 13(5), 624; https://doi.org/10.3390/pharmaceutics13050624 - 27 Apr 2021
Cited by 20 | Viewed by 11734
Abstract
Twin-screw granulation (TSG) is a pharmaceutical process that has gained increased interest from the pharmaceutical industry for its potential for the development of oral dosage forms. The technology has evolved rapidly due to the flexibility of the equipment design, the selection of the [...] Read more.
Twin-screw granulation (TSG) is a pharmaceutical process that has gained increased interest from the pharmaceutical industry for its potential for the development of oral dosage forms. The technology has evolved rapidly due to the flexibility of the equipment design, the selection of the process variables and the wide range of processed materials. Most importantly, TSG offers the benefits of both batch and continuous manufacturing for pharmaceutical products, accompanied by excellent process control, high product quality which can be achieved through the implementation of Quality by Design (QbD) approaches and the integration of Process Analytical Tools (PAT). Here, we present basic concepts of the various twin-screw granulation techniques and present in detail their advantages and disadvantages. In addition, we discuss the detail of the instrumentation used for TSG and how the critical processing paraments (CPP) affect the critical quality attributes (CQA) of the produced granules. Finally, we present recent advances in TSG continuous manufacturing including the paradigms of modelling of continuous granulation process, QbD approaches coupled with PAT monitoring for granule optimization and process understanding. Full article
(This article belongs to the Special Issue Solid Multicomponent Systems: Continuous Manufacturing Approaches for Improved Drug Product Quality)
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21 pages, 2536 KiB  
Review
Applications of Supercritical Anti-Solvent Process in Preparation of Solid Multicomponent Systems
by Guijin Liu, Junjian Li and Shiming Deng
Pharmaceutics 2021, 13(4), 475; https://doi.org/10.3390/pharmaceutics13040475 - 1 Apr 2021
Cited by 37 | Viewed by 3189
Abstract
Solid multicomponent systems (SMS) are gaining an increasingly important role in the pharmaceutical industry, to improve the physicochemical properties of active pharmaceutical ingredients (APIs). In recent years, various processes have been employed for SMS manufacturing. Control of the particle solid-state properties, such as [...] Read more.
Solid multicomponent systems (SMS) are gaining an increasingly important role in the pharmaceutical industry, to improve the physicochemical properties of active pharmaceutical ingredients (APIs). In recent years, various processes have been employed for SMS manufacturing. Control of the particle solid-state properties, such as size, morphology, and crystal form is required to optimize the SMS formulation. By utilizing the unique and tunable properties of supercritical fluids, supercritical anti-solvent (SAS) process holds great promise for the manipulation of the solid-state properties of APIs. The SAS techniques have been developed from batch to continuous mode. Their applications in SMS preparation are summarized in this review. Many pharmaceutical co-crystals and solid dispersions have been successfully produced via the SAS process, where the solid-state properties of APIs can be well designed by controlling the operating parameters. The underlying mechanisms on the manipulation of solid-state properties are discussed, with the help of on-line monitoring and computational techniques. With continuous researching, SAS process will give a large contribution to the scalable and continuous manufacturing of desired SMS in the near future. Full article
(This article belongs to the Special Issue Solid Multicomponent Systems: Continuous Manufacturing Approaches for Improved Drug Product Quality)
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25 pages, 3254 KiB  
Review
3DP Printing of Oral Solid Formulations: A Systematic Review
by Chiara R. M. Brambilla, Ogochukwu Lilian Okafor-Muo, Hany Hassanin and Amr ElShaer
Pharmaceutics 2021, 13(3), 358; https://doi.org/10.3390/pharmaceutics13030358 - 9 Mar 2021
Cited by 48 | Viewed by 5516
Abstract
Three-dimensional (3D) printing is a recent technology, which gives the possibility to manufacture personalised dosage forms and it has a broad range of applications. One of the most developed, it is the manufacture of oral solid dosage and the four 3DP techniques which [...] Read more.
Three-dimensional (3D) printing is a recent technology, which gives the possibility to manufacture personalised dosage forms and it has a broad range of applications. One of the most developed, it is the manufacture of oral solid dosage and the four 3DP techniques which have been more used for their manufacture are FDM, inkjet 3DP, SLA and SLS. This systematic review is carried out to statistically analyze the current 3DP techniques employed in manufacturing oral solid formulations and assess the recent trends of this new technology. The work has been organised into four steps, (1) screening of the articles, definition of the inclusion and exclusion criteria and classification of the articles in the two main groups (included/excluded); (2) quantification and characterisation of the included articles; (3) evaluation of the validity of data and data extraction process; (4) data analysis, discussion, and conclusion to define which technique offers the best properties to be applied in the manufacture of oral solid formulations. It has been observed that with SLS 3DP technique, all the characterisation tests required by the BP (drug content, drug dissolution profile, hardness, friability, disintegration time and uniformity of weight) have been performed in the majority of articles, except for the friability test. However, it is not possible to define which of the four 3DP techniques is the most suitable for the manufacture of oral solid formulations, because the selection is affected by different parameters, such as the type of formulation, the physical-mechanical properties to achieve. Moreover, each technique has its specific advantages and disadvantages, such as for FDM the biggest challenge is the degradation of the drug, due to high printing temperature process or for SLA is the toxicity of the carcinogenic risk of the photopolymerising material. Full article
(This article belongs to the Special Issue Solid Multicomponent Systems: Continuous Manufacturing Approaches for Improved Drug Product Quality)
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