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Pharmaceutics
Special Issues
Drug Formulation and Process Optimization
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Drug Formulation and Process Optimization

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

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 13769

Special Issue Editors

Dr. Kirsten J. M. Schimmel

E-Mail Website
Guest Editor
Leiden University Medical Center - LUMC, P.O. Box 9600, 2300 RC Leiden, The Netherlands
Interests: 3D printing; drug manufacturing; pharmacy preparations
Dr. Paul Le Brun

E-Mail Website
Guest Editor
Leiden University Medical Center - LUMC, P.O. Box 9600, 2300 RC Leiden, The Netherlands
Interests: aseptic manufacturing; inhalation of medication; quality assurance

Special Issue Information

Dear Colleagues,

Drug substances can have fantastic properties; however, good formulation is critical for high-quality care. Different formulations or routes of administration can change the release of the substance from its matrix, thereby altering pharmacokinetic or dynamic properties. Moreover, good application of medication relies on ease of use, and knowledge of dosage forms and formulation is paramount, especially for the development and understanding of biologicals, vaccines and ATMPs. This knowledge also supports process optimisation and guarantees good-quality products.

Changes in the way we treat diseases also have consequences. Personalized therapy asks for fast and flexible dosing and different manufacturing processes. There is constant innovation in treatments, leading to new formulations and dosage forms, which makes this an interesting research area from a patient but also a production perspective. From 3D printing to cellular therapies, the production of medication remains a fascinating area.

Dr. Kirsten J. M. Schimmel
Dr. Paul Le Brun
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/or quality by design
  • process optimisation
  • manufacturing
  • 3D printing
  • cell therapy
  • inhalation therapy
  • (optimising) aseptic processing
  • vaccines
  • ATMP
  • biologicals

Published Papers (7 papers)

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Research

14 pages, 2550 KiB  
Article
Manufacturability of a Tetraethyl Orthosilicate-Based Hydrogel for Use as a Single Application Otitis Externa Therapeutic
by Emma Barrett-Catton, Elizabeth M. Arrigali, Bogdan A. Serban, Kolton C. Sandau and Monica A. Serban
Pharmaceutics 2022, 14(10), 2020; https://doi.org/10.3390/pharmaceutics14102020 - 23 Sep 2022
Viewed by 1282
Abstract
Otitis externa, also known as outer ear infection, is a frequent affliction in both humans and animals. The most prevalent treatment for otitis externa is ear drops, but it is difficult to adhere properly to this treatment, causing poor patient compliance and the [...] Read more.
Otitis externa, also known as outer ear infection, is a frequent affliction in both humans and animals. The most prevalent treatment for otitis externa is ear drops, but it is difficult to adhere properly to this treatment, causing poor patient compliance and the potential for complications. As a result, we have developed a tetraethyl orthosilicate-based hydrogel for use as single application treatment for otitis externa to increase ease of use and improve patient outcomes. Herein, we investigated the manufacturability of the hydrogel, focusing on several key aspects: formulation repeatability and reproducibility, material source and tolerances, release of a variety of model drugs, and impact of application-specific physiological factors, specifically local pH and enzymatic activity on drug release. Overall, our results indicate that these hydrogels are well suited for production and scalability, as they have a robust manufacturing process, have a wide tolerance for pH level, release a variety of model drugs, and are not impacted by outer ear canal-specific physiological factors. Full article
(This article belongs to the Special Issue Drug Formulation and Process Optimization)
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13 pages, 2076 KiB  
Article
Predicting Throughput and Melt Temperature in Pharmaceutical Hot Melt Extrusion
by Tobias Gottschalk, Cihangir Özbay, Tim Feuerbach and Markus Thommes
Pharmaceutics 2022, 14(9), 1757; https://doi.org/10.3390/pharmaceutics14091757 - 23 Aug 2022
Cited by 6 | Viewed by 1546
Abstract
Even though hot melt extrusion (HME) is a commonly applied process in the pharmaceutical area, determination of the optimal process parameters is demanding. The goal of this study was to find a rational approach for predetermining suitable extrusion parameters, with a focus on [...] Read more.
Even though hot melt extrusion (HME) is a commonly applied process in the pharmaceutical area, determination of the optimal process parameters is demanding. The goal of this study was to find a rational approach for predetermining suitable extrusion parameters, with a focus on material temperature and throughput. A two-step optimization procedure, called scale-independent optimization strategy (SIOS), was applied and developed further, including the use of an autogenic extrusion mode. Three different polymers (Plasdone S-630, Soluplus, and Eudragit EPO) were considered, and different optimal process parameters were assessed. The maximum barrel load was dependent on the polymers’ bulk density and the extruder size. The melt temperature was influenced by the screw speed and the rheological behavior of the polymer. The melt viscosity depended mainly on the screw speed and was self-adjusted in the autogenic extrusion. A new approach, called SIOS 2.0, was suggested for calculating the extrusion process parameters (screw speed, melt temperature and throughput) based on the material data and a few extrusion experiments. Full article
(This article belongs to the Special Issue Drug Formulation and Process Optimization)
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26 pages, 5822 KiB  
Article
The Impact of the Oil Phase Selection on Physicochemical Properties, Long-Term Stability, In Vitro Performance and Injectability of Curcumin-Loaded PEGylated Nanoemulsions
by Jelena B. Đoković, Sotiria Demisli, Sanela M. Savić, Bojan D. Marković, Nebojša D. Cekić, Danijela V. Randjelovic, Jelena R. Mitrović, Dominique Jasmin Lunter, Vassiliki Papadimitriou, Aristotelis Xenakis and Snežana D. Savić
Pharmaceutics 2022, 14(8), 1666; https://doi.org/10.3390/pharmaceutics14081666 - 10 Aug 2022
Cited by 4 | Viewed by 2044
Abstract
A nanotechnology-based approach to drug delivery presents one of the biggest trends in biomedical science that can provide increased active concentration, bioavailability, and safety compared to conventional drug-delivery systems. Nanoemulsions stand out amongst other nanocarriers for being biodegradable, biocompatible, and relatively easy to [...] Read more.
A nanotechnology-based approach to drug delivery presents one of the biggest trends in biomedical science that can provide increased active concentration, bioavailability, and safety compared to conventional drug-delivery systems. Nanoemulsions stand out amongst other nanocarriers for being biodegradable, biocompatible, and relatively easy to manufacture. For improved drug-delivery properties, longer circulation for the nanoemulsion droplets should be provided, to allow the active to reach the target site. One of the strategies used for this purpose is PEGylation. The aim of this research was assessing the impact of the oil phase selection, soybean or fish oil mixtures with medium chain triglycerides, on the physicochemical characteristics and injectability of curcumin-loaded PEGylated nanoemulsions. Electron paramagnetic resonance spectroscopy demonstrated the structural impact of the oil phase on the stabilizing layer of nanoemulsions, with a more pronounced stabilizing effect of curcumin observed in the fish oil nanoemulsion compared to the soybean oil one. The design of the experiment study, employed to simultaneously assess the impact of the oil phase, different PEGylated phospholipids and their concentrations, as well as the presence of curcumin, showed that not only the investigated factors alone, but also their interactions, had a significant influence on the critical quality attributes of the PEGylated nanoemulsions. Detailed physicochemical characterization of the NEs found all formulations were appropriate for parenteral administration and remained stable during two years of storage, with the preserved antioxidant activity demonstrated by DPPH and FRAP assays. In vitro release studies showed a more pronounced release of curcumin from the fish oil NEs compared to that from the soybean oil ones. The innovative in vitro injectability assessment, designed to mimic intravenous application, proved that all formulations tested in selected experimental setting could be employed in prospective in vivo studies. Overall, the current study shows the importance of oil phase selection when formulating PEGylated nanoemulsions. Full article
(This article belongs to the Special Issue Drug Formulation and Process Optimization)
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15 pages, 2597 KiB  
Article
Flow Equations for Free-Flowable Particle Fractions of Sorbitol for Direct Compression: An Exploratory Multiple Regression Analysis of Particle and Orifice Size Influence
by Julia Marushka, Hana Hurychová, Zdenka Šklubalová and Jurjen Duintjer Tebbens
Pharmaceutics 2022, 14(8), 1653; https://doi.org/10.3390/pharmaceutics14081653 - 08 Aug 2022
Viewed by 1232
Abstract
Flowability is among the most important properties of powders, especially when fine particle size fractions need to be processed. In this study, our goal was to find a possibly simple but accurate mathematical model for predicting the mass flow rate for different fractions [...] Read more.
Flowability is among the most important properties of powders, especially when fine particle size fractions need to be processed. In this study, our goal was to find a possibly simple but accurate mathematical model for predicting the mass flow rate for different fractions of the pharmaceutical excipient sorbitol for direct compression. Various regression models derived from the Jones–Pilpel equation for the prediction of the mass flow rate were investigated. Using validation with experimental data for various particle and hopper orifice sizes, we focused on the prediction accuracy of the respective models, i.e., on the relative difference between measured and model-predicted values. Classical indicators of regression quality from statistics were addressed as well, but we consider high prediction accuracy to be particularly important for industrial processing in practice. For individual particle size fractions, the best results (an average prediction accuracy of 3.8%) were obtained using simple regression on orifice size. However, for higher accuracy (3.1%) in a unifying model, valid in the broad particle size range 0.100–0.346 mm, a fully quadratic model, incorporating interaction between particle and orifice size, appears to be most appropriate. Full article
(This article belongs to the Special Issue Drug Formulation and Process Optimization)
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13 pages, 2552 KiB  
Article
Preparation of Pickering Emulsions Stabilized by Modified Silica Nanoparticles via the Taguchi Approach
by Fatemeh Heidari, Seid Mahdi Jafari, Aman Mohammad Ziaiifar and Nicolas Anton
Pharmaceutics 2022, 14(8), 1561; https://doi.org/10.3390/pharmaceutics14081561 - 28 Jul 2022
Cited by 4 | Viewed by 1968
Abstract
In this study, oil-in-water Pickering emulsions (PEs) were prepared by modified silica nanoparticles (MSNs) with cetyltrimethylammonium bromide (CTAB) using the Taguchi approach. The surface modification of SiO2 nanoparticles (NPs) was performed in different conditions, temperatures, pH levels, and amounts of CTAB as [...] Read more.
In this study, oil-in-water Pickering emulsions (PEs) were prepared by modified silica nanoparticles (MSNs) with cetyltrimethylammonium bromide (CTAB) using the Taguchi approach. The surface modification of SiO2 nanoparticles (NPs) was performed in different conditions, temperatures, pH levels, and amounts of CTAB as a coating agent, followed by an evaluation of their physicochemical properties. After treatment of the SiO2 NPs, the relationship of the MSNs’ surface properties and their efficiency in stabilizing Pickering emulsions was investigated by considering the zeta potential (ZP) and emulsion physical stability as main responses, respectively. Results disclosed were then supported by additional characterization, such as thermogravimetric analysis (TGA), Fourier transform infrared (FTIR) spectroscopy, contact angle (CA), and scanning electron microscopy. Results demonstrated that temperature has the most important role in the treatment of SiO2 nanoparticles, and allows for the identification of the best experimental conditions, i.e., range of zeta potential of MSNs to produce more efficient NPs, as well as the best stabilization of PEs. Full article
(This article belongs to the Special Issue Drug Formulation and Process Optimization)
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31 pages, 22154 KiB  
Article
Development of a Personalized Tumor Neoantigen Based Vaccine Formulation (FRAME-001) for Use in a Phase II Trial for the Treatment of Advanced Non-Small Cell Lung Cancer
by Linette T. Oosting, Katka Franke, Michael V. Martin, Wigard P. Kloosterman, Jennifer A. Jamieson, Laura A. Glenn, Miranda W. de Jager, Jacoba van Zanten, Derk P. Allersma and Bahez Gareb
Pharmaceutics 2022, 14(7), 1515; https://doi.org/10.3390/pharmaceutics14071515 - 21 Jul 2022
Cited by 6 | Viewed by 2954
Abstract
Stage III–IV non-small cell lung cancer (NSCLC) is a devastating disease characterized by a poor prognosis. NSCLC tumors carry genetic mutations, which can lead to the expression of altered protein sequences. Peptides originating from mutated proteins and bound to MHC molecules on the [...] Read more.
Stage III–IV non-small cell lung cancer (NSCLC) is a devastating disease characterized by a poor prognosis. NSCLC tumors carry genetic mutations, which can lead to the expression of altered protein sequences. Peptides originating from mutated proteins and bound to MHC molecules on the tumor cell surface are referred to as neoantigens, as they are tumor-specific and not expressed in normal cells. Due to their tumor specificity, neoantigens have a strong potential to induce an anti-tumor immune response and have been investigated for development of personalized therapeutic cancer vaccines. The current study describes the development of a clinical grade neoantigen vaccine formulation (FRAME-001) intended as immunotherapy in advanced NSCLC in combination with the immune checkpoint inhibitor pembrolizumab. The detection of aberrant tumor-specific transcripts as well as an algorithm to select immunogenic neoantigen peptides are described. Subsequently, selected neoantigen peptides were synthesized with a high throughput synthesis platform and aseptically formulated under good manufacturing practice (GMP) conditions into four aqueous peptides mixtures that each contained six neoantigen peptides. A validated stability-indicating analytical method was developed in which we considered the personalized nature of the formulation. An extensive stability study performed either at −25 °C or −80 °C showed that the formulation was stable for up to 32 weeks. The formulation was mixed with the vaccine adjuvant Montanide ISA 51 VG, which yielded the final vaccine emulsion. The stability of the vaccine emulsion was demonstrated using microscopic examination, differential light scattering, and the water-drop test. The presented data show that FRAME-001 is a feasible personalized vaccine formulation for the treatment of stage III–IV NSCLC. The presented data may give guidance in the development of novel personalized therapeutic vaccines since this formulation strategy could be used for any cancer indication. Full article
(This article belongs to the Special Issue Drug Formulation and Process Optimization)
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10 pages, 2098 KiB  
Communication
Radiolabeling Method for Lyophilizate for Dry Powder Inhalation Formulations
by Kahori Miyamoto, Tomomi Akita and Chikamasa Yamashita
Pharmaceutics 2022, 14(4), 759; https://doi.org/10.3390/pharmaceutics14040759 - 31 Mar 2022
Cited by 1 | Viewed by 1499
Abstract
Human lung deposition data is non-mandatory for drug approval but very useful for the development of orally inhaled drug products. Lung deposition of inhaled drugs can be quantified by radionuclide imaging, for which one of the first considerations is the method used to [...] Read more.
Human lung deposition data is non-mandatory for drug approval but very useful for the development of orally inhaled drug products. Lung deposition of inhaled drugs can be quantified by radionuclide imaging, for which one of the first considerations is the method used to radiolabel formulations. In this study, we report the development of a radiolabeling method for lyophilizate for dry powder inhalation (LDPI) formulations. TechneCoatTM is one method that can radiolabel drug particles without using solvents. In this method, particles are radiolabeled with a dispersion of 99mTc-labeled nanoparticles called TechnegasTM. Because a LDPI formulation is not comprised of particles but is a lyophilized cake aerosolized by air impact, the TechneCoat method cannot be used for the radiolabeling of LDPI formulations. We therefore modified the TechneCoat apparatus so that LDPI formulations were not aerosolized by the Technegas flow. Radiolabeling using a modified TechneCoat apparatus was validated with model LDPI formulations of interferon alpha (IFN). IFN of 99mTc-unlabeled, IFN of 99mTc-labeled, and 99mTc of 99mTc-labeled LDPI formulations showed similar behavior, and differences from IFN of 99mTc-unlabeled LDPI formulations were within ±15% in aerodynamic particle size distribution measurement. Our radiolabeling method for LDPI formulations may be useful for the quantification of drug deposition in human lungs. Full article
(This article belongs to the Special Issue Drug Formulation and Process Optimization)
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