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Pharmaceutics
Special Issues
15th Anniversary of Pharmaceutics—Advances in Process and Formulation Modeling
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15th Anniversary of Pharmaceutics—Advances in Process and Formulation Modeling

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: 30 May 2024 | Viewed by 5017

Special Issue Editors

Prof. Dr. Ecevit Bilgili

E-Mail Website
Guest Editor
Otto H. York Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA
Interests: particle engineering; pharmaceutical nanotechnology; drug nanosuspensions and nanocomposites; amorphous solid dispersions; multi-scale process modeling; pharmaceutical unit operations; milling; granulation; spray drying; extrusion
Special Issues, Collections and Topics in MDPI journals
Dr. Sadegh Poozesh

E-Mail Website
Guest Editor
Senior Scientist, Biopharmaceutical Development, AstraZeneca, Gaithersburg, MD 20878, USA
Interests: particle engineering; bio-pharmaceutical development; unit operation modeling; scale-up; fluid-flow and heat transfer; drug product characterization
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The modeling of processes and formulations, being an inherent component of quality by design (QbD), has significantly enhanced product development in the pharmaceutical industry. During process development, engineers routinely consolidate computational fluid dynamics, population balance models, discrete element models and their combination. Modeling helps scientists, formulators and engineers gain fundamental insights and understanding, leading to a streamlined and faster development of pharmaceutical products.

This Special Issue aims to bring academics and industry practitioners to disseminate recent advances in the development, application, training, testing and validation of models. While there is no restriction on the type of models, with possibilities of including mechanistic, phenomenological, stochastic, molecular, statistical or hybrid models, novel studies are expected to discuss how to design, optimize and intensify pharmaceutical processes and formulations. Hence, reports that solely focus on experimental work or computational method development are not of significant interest. In this context, studies on the following topics are especially welcome: new process development areas, such as continuous manufacturing and 3D-additive manufacturing; the simulation, control and scale-up of pharmaceutical processes; development of hybrid, coupled and/or multi-scale models; machine learning and data mining for process formulation development; and models for various in vivo and in vitro performance tests, including dissolution tests, permeability tests and/or PKPD models.

Prof. Dr. Ecevit Bilgili
Dr. Sadegh Poozesh
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

  • formulation and process development
  • process optimization
  • modeling
  • simulations
  • computational fluid dynamics
  • population balance model
  • discrete element model
  • multi-scale models
  • machine learning
  • statistical models

Published Papers (5 papers)

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Research

27 pages, 4839 KiB  
Article
Investigating the Effects of Mixing Dynamics on Twin-Screw Granule Quality Attributes via the Development of a Physics-Based Process Map
by Lalith Kotamarthy, Subhodh Karkala, Ashley Dan, Andrés D. Román-Ospino and Rohit Ramachandran
Pharmaceutics 2024, 16(4), 456; https://doi.org/10.3390/pharmaceutics16040456 - 25 Mar 2024
Viewed by 735
Abstract
Twin-screw granulation (TSG) is an emerging continuous wet granulation technique that has not been widely applied in the industry due to a poor mechanistic understanding of the process. This study focuses on improving this mechanistic understanding by analyzing the effects of the mixing [...] Read more.
Twin-screw granulation (TSG) is an emerging continuous wet granulation technique that has not been widely applied in the industry due to a poor mechanistic understanding of the process. This study focuses on improving this mechanistic understanding by analyzing the effects of the mixing dynamics on the granule quality attributes (PSD, content uniformity, and microstructure). Mixing is an important dynamic process that simultaneously occurs along with the granulation rate mechanisms during the wet granulation process. An improved mechanistic understanding was achieved by identifying and quantifying the physically relevant intermediate parameters that affect the mixing dynamics in TSG, and then their effects on the granule attributes were analyzed by investigating their effects on the granulation rate mechanisms. The fill level, granule liquid saturation, extent of nucleation, and powder wettability were found to be the key physically relevant intermediate parameters that affect the mixing inside the twin-screw granulator. An improved geometrical model for the fill level was developed and validated against existing experimental data. Finally, a process map was developed to depict the effects of mixing on the temporal and spatial evolution of the materials inside the twin-screw granulator. This process map illustrates the mechanism of nucleation and the growth of the granules based on the fundamental material properties of the primary powders (solubility and wettability), liquid binders (viscosity), and mixing dynamics present in the system. Furthermore, it was shown that the process map can be used to predict the granule product quality based on the granule growth mechanism. Full article
(This article belongs to the Special Issue 15th Anniversary of Pharmaceutics—Advances in Process and Formulation Modeling)
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20 pages, 12958 KiB  
Article
Triboelectric Charging Properties of the Functional Groups of Common Pharmaceutical Materials Using Density Functional Theory Calculations
by James R. Middleton, Mojtaba Ghadiri and Andrew J. Scott
Pharmaceutics 2024, 16(3), 433; https://doi.org/10.3390/pharmaceutics16030433 - 21 Mar 2024
Viewed by 610
Abstract
Triboelectrification is a ubiquitous and poorly understood phenomenon in powder processing, particularly for pharmaceutical powders. Charged particles can adhere to vessel walls, causing sheeting; they can also cause agglomeration, threatening the stability of powder formulations, and in extreme cases electrostatic discharges, which present [...] Read more.
Triboelectrification is a ubiquitous and poorly understood phenomenon in powder processing, particularly for pharmaceutical powders. Charged particles can adhere to vessel walls, causing sheeting; they can also cause agglomeration, threatening the stability of powder formulations, and in extreme cases electrostatic discharges, which present a serious fire and explosion hazard. Triboelectrification is highly sensitive to environmental and material conditions, which makes it very difficult to compare experimental results from different publications. In this work, density functional theory (DFT) is used to investigate the charge transfer characteristics of several functional groups of paracetamol in order to better understand the mechanisms of charging at the nanoscale and the influence of the environmental and material properties on charge transfer. This is achieved by studying the structure and electronic properties at the molecule–substrate interface. Using this molecule–substrate approach, the charging contributions of individual functional groups are explored by examining the Hirschfeld charges, the charge density difference between the molecule and substrate, the density of states, and the location of the frontier orbitals (HOMO and LUMO) of a paracetamol molecule. Charge density difference calculations indicate a significant transfer of charge from the molecule to the surface. Observable regions of electron density enrichment and depletion are evident around the electron-donating and -withdrawing groups, respectively. The density of states for the paracetamol molecule evolves as it approaches the surface, and the band gap disappears upon contact with the substrate. Hirshfeld charge analysis reveals asymmetry in the charge redistribution around the molecule, highlighting the varying charging tendencies of different atoms. Full article
(This article belongs to the Special Issue 15th Anniversary of Pharmaceutics—Advances in Process and Formulation Modeling)
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35 pages, 5303 KiB  
Article
Development of a Semi-Mechanistic Modeling Framework for Wet Bead Milling of Pharmaceutical Nanosuspensions
by Donald J. Clancy, Gulenay Guner, Sayantan Chattoraj, Helen Yao, M. Connor Faith, Zahra Salahshoor, Kailey N. Martin and Ecevit Bilgili
Pharmaceutics 2024, 16(3), 394; https://doi.org/10.3390/pharmaceutics16030394 - 13 Mar 2024
Viewed by 1247
Abstract
This study aimed to develop a practical semi-mechanistic modeling framework to predict particle size evolution during wet bead milling of pharmaceutical nanosuspensions over a wide range of process conditions and milling scales. The model incorporates process parameters, formulation parameters, and equipment-specific parameters such [...] Read more.
This study aimed to develop a practical semi-mechanistic modeling framework to predict particle size evolution during wet bead milling of pharmaceutical nanosuspensions over a wide range of process conditions and milling scales. The model incorporates process parameters, formulation parameters, and equipment-specific parameters such as rotor speed, bead type, bead size, bead loading, active pharmaceutical ingredient (API) mass, temperature, API loading, maximum bead volume, blade diameter, distance between blade and wall, and an efficiency parameter. The characteristic particle size quantiles, i.e., x10, x50, and x90, were transformed to obtain a linear relationship with time, while the general functional form of the apparent breakage rate constant of this relationship was derived based on three models with different complexity levels. Model A, the most complex and general model, was derived directly from microhydrodynamics. Model B is a simpler model based on a power-law function of process parameters. Model C is the simplest model, which is the pre-calibrated version of Model B based on data collected from different mills across scales, formulations, and drug products. Being simple and computationally convenient, Model C is expected to reduce the amount of experimentation needed to develop and optimize the wet bead milling process and streamline scale-up and/or scale-out. Full article
(This article belongs to the Special Issue 15th Anniversary of Pharmaceutics—Advances in Process and Formulation Modeling)
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27 pages, 8768 KiB  
Article
A Novel PBM for Nanomilling of Drugs in a Recirculating Wet Stirred Media Mill: Impacts of Batch Size, Flow Rate, and Back-Mixing
by Hamidreza Heidari, Nontawat Muanpaopong, Gulenay Guner, Helen F. Yao, Donald J. Clancy and Ecevit Bilgili
Pharmaceutics 2024, 16(3), 353; https://doi.org/10.3390/pharmaceutics16030353 - 02 Mar 2024
Viewed by 874
Abstract
We examined the evolution of fenofibrate (FNB, drug) particle size distribution (PSD) during the production of nanosuspensions via wet stirred media milling (WSMM) with a cell-based population balance model (PBM). Our objective was to elucidate the potential impacts of batch size, suspension volumetric [...] Read more.
We examined the evolution of fenofibrate (FNB, drug) particle size distribution (PSD) during the production of nanosuspensions via wet stirred media milling (WSMM) with a cell-based population balance model (PBM). Our objective was to elucidate the potential impacts of batch size, suspension volumetric flow rate, and imperfect mixing in a recirculating WSMM. Various specific breakage rate functions were fitted to experimental PSD data at baseline conditions assuming perfect mixing. Then, the best function was used to simulate the PSD evolution at various batch sizes and flow rates to validate the model. A novel function, which is a product of power–law and logistic functions, fitted the evolution the best, signifying the existence of a transition particle size commensurate with a grinding limit. Although larger batches yielded coarser and wider PSDs, the suspensions had identical PSDs when milled for the same effective milling time. The flow rate had an insignificant influence on the PSD. Furthermore, the imperfect mixing in the mill chamber was simulated by considering more than one cell and different back-mixing flow ratios. The effects were weak and restricted to the first few turnovers. These insights contribute to our understanding of recirculating WSMM, providing valuable guidance for process development. Full article
(This article belongs to the Special Issue 15th Anniversary of Pharmaceutics—Advances in Process and Formulation Modeling)
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17 pages, 3147 KiB  
Article
Design Space and Control Strategy for the Manufacturing of Wet Media Milled Drug Nanocrystal Suspensions by Adopting Mechanistic Process Modeling
by André Bitterlich, Andrej Mihorko and Michael Juhnke
Pharmaceutics 2024, 16(3), 328; https://doi.org/10.3390/pharmaceutics16030328 - 26 Feb 2024
Viewed by 869
Abstract
Wet media milling is a fully industrialized technology for the manufacturing of drug nanocrystal suspensions. This work describes the development of an advanced control strategy and an associated design space for a manufacturing process at a commercial scale. Full-scale experiments and mechanistic process [...] Read more.
Wet media milling is a fully industrialized technology for the manufacturing of drug nanocrystal suspensions. This work describes the development of an advanced control strategy and an associated design space for a manufacturing process at a commercial scale. Full-scale experiments and mechanistic process modeling have been used to establish a physically reasonable control strategy of factors relevant to the quality attributes of the nanocrystal suspension. The design space has been developed based on a mature mechanistic process model of the wet media milling procedure. It presents the process–product attribute relationship between a multidimensional range of measured process parameters and a range of the product-quality attribute mean particle sizes. The control strategy allows for simple, robust, and sound scientific process control as well as the operational flexibility of the suspension batch size. This is an industrial case study of control strategy and design-space definition with the crucial contribution of mechanistic process modeling for an intended commercial manufacturing process. Full article
(This article belongs to the Special Issue 15th Anniversary of Pharmaceutics—Advances in Process and Formulation Modeling)
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