2023

Jump to: 2022, 2021

Open AccessArticle

Influence of Physicochemical Properties of Budesonide Micro-Suspensions on Their Expected Lung Delivery Using a Vibrating Mesh Nebulizer

by

Katarzyna Dobrowolska

,

,

,

,

and

Pharmaceutics 2023, 15(3), 752; https://doi.org/10.3390/pharmaceutics15030752 - 23 Feb 2023

Viewed by 402

Abstract

The efficiency of lung drug delivery of nebulized drugs is governed by aerosol quality, which depends both on the aerosolization process itself but also on the properties of aerosol precursors. This paper determines physicochemical properties of four analogous micro-suspensions of a micronized steroid [...] Read more.

The efficiency of lung drug delivery of nebulized drugs is governed by aerosol quality, which depends both on the aerosolization process itself but also on the properties of aerosol precursors. This paper determines physicochemical properties of four analogous micro-suspensions of a micronized steroid (budesonide, BUD) and seeks relationships between these properties and the quality of the aerosol emitted from a vibrating mesh nebulizer (VMN). Despite the same BUD content in all tested pharmaceutical products, their physicochemical characteristics (liquid surface tension, viscosity, electric conductivity, BUD crystal size, suspension stability, etc.) are not identical. The differences have a weak influence on droplet size distribution in the mists emitted from the VMN and on theoretical (calculated) regional aerosol deposition in the respiratory system but, simultaneously, there is an influence on the amount of BUD converted by the nebulizer to aerosol available for inhalation. It is demonstrated that the maximum inhaled BUD dose is below 80–90% of the label dose, depending on the nebulized formulation. It shows that nebulization of BUD suspensions in VMN is sensitive to minor dissimilarities among analogous (generic) pharmaceutics. The potential clinical relevance of these findings is discussed. Full article

► Show Figures

Graphical abstract

Open AccessArticle

Influence of the Volatility of Solvent on the Reproducibility of Droplet Formation in Pharmaceutical Inkjet Printing

by

Robert Mau

and

Hermann Seitz

Pharmaceutics 2023, 15(2), 367; https://doi.org/10.3390/pharmaceutics15020367 - 21 Jan 2023

Viewed by 721

Abstract

Drop-on-demand (DOD) inkjet printing enables exact dispensing and positioning of single droplets in the picoliter range. In this study, we investigate the long-term reproducibility of droplet formation of piezoelectric inkjet printed drug solutions using solvents with different volatilities. We found inkjet printability of [...] Read more.

Drop-on-demand (DOD) inkjet printing enables exact dispensing and positioning of single droplets in the picoliter range. In this study, we investigate the long-term reproducibility of droplet formation of piezoelectric inkjet printed drug solutions using solvents with different volatilities. We found inkjet printability of EtOH/ASA drug solutions is limited, as there is a rapid forming of drug deposits on the nozzle of the printhead because of fast solvent evaporation. Droplet formation of c = 100 g/L EtOH/ASA solution was affected after only a few seconds by little drug deposits, whereas for c = 10 g/L EtOH/ASA solution, a negative affection was observed only after t = 15 min, while prominent drug deposits form at the printhead tip. Due to the creeping effect, the crystallizing structures of ASA spread around the nozzle but do not clog it necessarily. When there is a negative affection, the droplet trajectory is affected the most, while the droplet volume and droplet velocity are influenced less. In contrast, no formation of drug deposits could be observed for highly concentrated, low volatile DMSO-based drug solution of c = 100 g/L even after a dispensing time of t = 30 min. Therefore, low volatile solvents are preferable to highly volatile solvents to ensure a reproducible droplet formation in long-term inkjet printing of highly concentrated drug solutions. Highly volatile solvents require relatively low drug concentrations and frequent printhead cleaning. The findings of this study are especially relevant when high droplet positioning precision is desired, e.g., drug loading of microreservoirs or drug-coating of microneedle devices. Full article

► Show Figures

Graphical abstract

2022

Jump to: 2023, 2021

Open AccessArticle

Predicting the Temperature Evolution during Nanomilling of Drug Suspensions via a Semi-Theoretical Lumped-Parameter Model

by

,

,

,

and

Pharmaceutics 2022, 14(12), 2840; https://doi.org/10.3390/pharmaceutics14122840 - 18 Dec 2022

Viewed by 751

Abstract

Although temperature can significantly affect the stability and degradation of drug nanosuspensions, temperature evolution during the production of drug nanoparticles via wet stirred media milling, also known as nanomilling, has not been studied extensively. This study aims to establish both descriptive and predictive [...] Read more.

Although temperature can significantly affect the stability and degradation of drug nanosuspensions, temperature evolution during the production of drug nanoparticles via wet stirred media milling, also known as nanomilling, has not been studied extensively. This study aims to establish both descriptive and predictive capabilities of a semi-theoretical lumped parameter model (LPM) for temperature evolution. In the experiments, the mill was operated at various stirrer speeds, bead loadings, and bead sizes, while the temperature evolution at the mill outlet was recorded. The LPM was formulated and fitted to the experimental temperature profiles in the training runs, and its parameters, i.e., the apparent heat generation rate Q_gen and the apparent overall heat transfer coefficient times surface area UA, were estimated. For the test runs, these parameters were predicted as a function of the process parameters via a power law (PL) model and machine learning (ML) model. The LPM augmented with the PL and ML models was used to predict the temperature evolution in the test runs. The LPM predictions were also compared with those of an enthalpy balance model (EBM) developed recently. The LPM had a fitting capability with a root-mean-squared error (RMSE) lower than 0.9 °C, and a prediction capability, when augmented with the PL and ML models, with an RMSE lower than 4.1 and 2.1 °C, respectively. Overall, the LPM augmented with the PL model had both good descriptive and predictive capability, whereas the one with the ML model had a comparable predictive capability. Despite being simple, with two parameters and obviating the need for sophisticated numerical techniques for its solution, the semi-theoretical LPM generally predicts the temperature evolution similarly or slightly better than the EBM. Hence, this study has provided a validated, simple model for pharmaceutical engineers to simulate the temperature evolution during the nanomilling process, which will help to set proper process controls for thermally labile drugs. Full article

► Show Figures

Graphical abstract

Open AccessArticle

Chemical Attachment of 5-Nitrosalicylaldimine Motif to Silatrane Resulting in an Organic–Inorganic Structure with High Medicinal Significance

by

Mirela-Fernanda Zaltariov

,

,

,

,

,

,

,

Bianca-Iulia Ciubotaru

,

Alexandra Bargan

,

Manuela Calin

and

Maria Cazacu

Pharmaceutics 2022, 14(12), 2838; https://doi.org/10.3390/pharmaceutics14122838 - 18 Dec 2022

Viewed by 647

Abstract

Two chemical motifs of interest for medicinal chemistry, silatrane as 1-(3-aminopropyl) silatrane (SIL M), and nitro group attached in position 5 to salicylaldehyde, are coupled in a new structure, 1-(3-{[(2-hydroxy-5-nitrophenyl)methylidene]amino}propyl)silatrane (SIL-BS), through an azomethine moiety, also known as a versatile pharmacophore. The high [...] Read more.

Two chemical motifs of interest for medicinal chemistry, silatrane as 1-(3-aminopropyl) silatrane (SIL M), and nitro group attached in position 5 to salicylaldehyde, are coupled in a new structure, 1-(3-{[(2-hydroxy-5-nitrophenyl)methylidene]amino}propyl)silatrane (SIL-BS), through an azomethine moiety, also known as a versatile pharmacophore. The high purity isolated compound was structurally characterized by an elemental, spectral, and single crystal X-ray diffraction analysis. Given the structural premises for being a biologically active compound, different specific techniques and protocols have been used to evaluate their in vitro hydrolytic stability in simulated physiological conditions, the cytotoxicity on two cancer cell lines (HepG2 and MCF7), and protein binding ability—with a major role in drug ADME (Absorption, Distribution, Metabolism and Excretion), in parallel with those of the SIL M. While the latter had a good biocompatibility, the nitro-silatrane derivative, SIL-BS, exhibited a higher cytotoxic activity on HepG2 and MCF7 cell lines, performance assigned, among others, to the known capacity of the nitro group to promote a specific cytotoxicity by a “activation by reduction” mechanism. Both compounds exhibited increased bio- and muco-adhesiveness, which can favor an optimized therapeutic effect by increased drug permeation and residence time in tumor location. Additional benefits of these compounds have been demonstrated by their antimicrobial activity on several fungi and bacteria species. Molecular docking computations on Human Serum Albumin (HSA) and M^PRO COVID-19 protease demonstrated their potential in the development of new drugs for combined therapy. Full article

► Show Figures

Graphical abstract

Open AccessArticle

Solid Lipid Microparticles by Spray Congealing of Water/Oil Emulsion: An Effective/Versatile Loading Strategy for a Highly Soluble Drug

by

,

,

,

,

,

,

and

Pharmaceutics 2022, 14(12), 2805; https://doi.org/10.3390/pharmaceutics14122805 - 14 Dec 2022

Viewed by 794

Abstract

Spray congealing technique was exploited to produce solid lipid microparticles (SLMp) loaded with a highly water-soluble drug (metoclopramide hydrochloride) dissolved in the aqueous phase of a water in oil (W/O) emulsion. The use of an emulsion as starting material for a spray congealing [...] Read more.

Spray congealing technique was exploited to produce solid lipid microparticles (SLMp) loaded with a highly water-soluble drug (metoclopramide hydrochloride) dissolved in the aqueous phase of a water in oil (W/O) emulsion. The use of an emulsion as starting material for a spray congealing treatment is not so frequent. Moreover, for this application, a W/O emulsion with a drug dissolved in water is a totally novel path. A ternary diagram was built to optimize the emulsion composition, a factorial design was used to identify the factors affecting the properties of the microparticles and a Design of Experiment strategy was applied to define the impact of process conditions and formulation variables on the SLMp properties. SLMp were characterized by particle size distribution, morphology, residual moisture, drug content, release behavior, FT-IR analysis and XRPD. The obtained microparticles presented a spherical shape, particle size distribution between 54–98 µm depending on atomizing pressure used during the production step and 2–5% residual moisture 4 days after the preparation. XRPD analysis revealed that lipid polymorphic transition alfa-beta occurs depending on the presence of water. In vitro drug release tests highlighted that all the formulations had a reduced release rate compared to the drug alone. These results suggest that spray congealing of a W/O emulsion could be proposed as a good strategy to obtain SLMp with a high loading of a hydrophilic drug and able to control its release rate. Full article

► Show Figures

Figure 1

Open AccessArticle

Pharma 4.0-Artificially Intelligent Digital Twins for Solidified Nanosuspensions

by

Christina Davidopoulou

and

Andreas Ouranidis

Pharmaceutics 2022, 14(10), 2113; https://doi.org/10.3390/pharmaceutics14102113 - 03 Oct 2022

Viewed by 1069

Abstract

Digital twins capacitate the industry 4.0 paradigm by predicting and optimizing the performance of physical assets of interest, mirroring a realistic in-silico representation of their functional behaviour. Although advanced digital twins set forth disrupting opportunities by delineating the in-service product and the related [...] Read more.

Digital twins capacitate the industry 4.0 paradigm by predicting and optimizing the performance of physical assets of interest, mirroring a realistic in-silico representation of their functional behaviour. Although advanced digital twins set forth disrupting opportunities by delineating the in-service product and the related process dynamic performance, they have yet to be adopted by the pharma sector. The latter, currently struggles more than ever before to improve solubility of BCS II i.e., hard-to-dissolve active pharmaceutical ingredients by micronization and subsequent stabilization. Herein we construct and functionally validate the first artificially intelligent digital twin thread, capable of describing the course of manufacturing of such solidified nanosuspensions given a defined lifecycle starting point and predict and optimize the relevant process outcomes. To this end, we referenced experimental data as the sampling source, which we then augmented via pattern recognition utilizing neural network propagations. The zeta-dynamic potential metrics of the nanosuspensions were correlated to the interfacial Gibbs energy, while the density and heat capacity of the material system was calculated via the Saft-γ-Mie statistical fluid theory. The curated data was then fused to physical and empirical laws to choose the appropriate theory and numeric description, respectively, before being polished by tuning the critical parameters to achieve the best fit with reality. Full article

► Show Figures

Graphical abstract

Open AccessArticle

Complexation: An Interesting Pathway for Combining Two APIs at the Solid State

by

,

,

and

Pharmaceutics 2022, 14(9), 1960; https://doi.org/10.3390/pharmaceutics14091960 - 16 Sep 2022

Viewed by 788

Abstract

Combining different drugs into a single crystal form is one of the current challenges in crystal engineering, with the number of reported multi-drug solid forms remaining limited. This paper builds upon an efficient approach to combining Active Pharmaceutical Ingredients (APIs) containing carboxylic groups [...] Read more.

Combining different drugs into a single crystal form is one of the current challenges in crystal engineering, with the number of reported multi-drug solid forms remaining limited. This paper builds upon an efficient approach to combining Active Pharmaceutical Ingredients (APIs) containing carboxylic groups in their structure with APIs containing pyridine moieties. By transforming the former into their zinc salts, they can be successfully combined with the pyridine-containing APIs. This work highlights the successfulness of this approach, as well as the improvement in the physical properties of the obtained solid forms. Full article

► Show Figures

Figure 1

Open AccessReview

Significance of Polymers with “Allyl” Functionality in Biomedicine: An Emerging Class of Functional Polymers

by

Mijanur Rahman

,

Aliaa Ali

,

Erica Sjöholm

,

Sebastian Soindinsalo

,

Carl-Eric Wilén

,

Kuldeep Kumar Bansal

and

Jessica M. Rosenholm

Pharmaceutics 2022, 14(4), 798; https://doi.org/10.3390/pharmaceutics14040798 - 06 Apr 2022

Cited by 3 | Viewed by 1959

Abstract

In recent years, polymer-based advanced drug delivery and tissue engineering have grown and expanded steadily. At present, most of the polymeric research has focused on improving existing polymers or developing new biomaterials with tunable properties. Polymers with free functional groups offer the diverse [...] Read more.

In recent years, polymer-based advanced drug delivery and tissue engineering have grown and expanded steadily. At present, most of the polymeric research has focused on improving existing polymers or developing new biomaterials with tunable properties. Polymers with free functional groups offer the diverse characteristics needed for optimal tissue regeneration and controlled drug delivery. Allyl-terminated polymers, characterized by the presence of a double bond, are a unique class of polymers. These polymers allow the insertion of a broad diversity of architectures and functionalities via different chemical reactions. In this review article, we shed light on various synthesis methodologies utilized for generating allyl-terminated polymers, macromonomers, and polymer precursors, as well as their post-synthesis modifications. In addition, the biomedical applications of these polymers reported in the literature, such as targeted and controlled drug delivery, improvement i aqueous solubility and stability of drugs, tissue engineering, and antimicrobial coatings, are summarized. Full article

► Show Figures

Figure 1

Open AccessArticle

Analytical Quality by Design (AQbD) Approach to the Development of In Vitro Release Test for Topical Hydrogel

by

,

,

,

,

,

and

Pharmaceutics 2022, 14(4), 707; https://doi.org/10.3390/pharmaceutics14040707 - 26 Mar 2022

Cited by 1 | Viewed by 1490

Abstract

The aim of our study was to adapt the analytical quality by design (AQbD) approach to design an effective in vitro release test method using USP apparatus IV with a semi-solid adapter (SSA) for diclofenac sodium hydrogel. The analytical target profile (ATP) of [...] Read more.

The aim of our study was to adapt the analytical quality by design (AQbD) approach to design an effective in vitro release test method using USP apparatus IV with a semi-solid adapter (SSA) for diclofenac sodium hydrogel. The analytical target profile (ATP) of the in vitro release test and ultra-high-performance liquid chromatography were defined; the critical method attributes (CMAs) (min. 70% of the drug should be released during the test, six time points should be obtained in the linear portion of the drug release profile, and the relative standard deviation of the released drug should not be over 10%) were selected. An initial risk assessment was carried out, in which the CMAs (ionic strength, the pH of the media, membrane type, the rate of flow, the volume of the SSA (sample amount), the individual flow rate of cells, drug concentration %, and the composition of the product) were identified. With the results, it was possible to determine the high-risk parameters of the in vitro drug release studies performed with the USP apparatus IV with SSA, which were the pH of the medium and the sample weight of the product. Focusing on these parameters, we developed a test protocol for our hydrogel system. Full article

► Show Figures

Figure 1

2021

Jump to: 2023, 2022

Open AccessArticle

Modeling of High-Density Compaction of Pharmaceutical Tablets Using Multi-Contact Discrete Element Method

by

,

,

and

Pharmaceutics 2021, 13(12), 2194; https://doi.org/10.3390/pharmaceutics13122194 - 18 Dec 2021

Cited by 5 | Viewed by 2853

Abstract

The purpose of this work is to simulate the powder compaction of pharmaceutical materials at the microscopic scale in order to better understand the interplay of mechanical forces between particles, and to predict their compression profiles by controlling the microstructure. For this task, [...] Read more.

The purpose of this work is to simulate the powder compaction of pharmaceutical materials at the microscopic scale in order to better understand the interplay of mechanical forces between particles, and to predict their compression profiles by controlling the microstructure. For this task, the new framework of multi-contact discrete element method (MC-DEM) was applied. In contrast to the conventional discrete element method (DEM), MC-DEM interactions between multiple contacts on the same particle are now explicitly taken into account. A new adhesive elastic-plastic multi-contact model invoking neighboring contact interaction was introduced and implemented. The uniaxial compaction of two microcrystalline cellulose grades (Avicel^® PH 200 (FMC BioPolymer, Philadelphia, PA, USA) and Pharmacel^® 102 (DFE Pharma, Nörten-Hardenberg, Germany) subjected to high confining conditions was studied. The objectives of these simulations were: (1) to investigate the micromechanical behavior; (2) to predict the macroscopic behavior; and (3) to develop a methodology for the calibration of the model parameters needed for the MC-DEM simulations. A two-stage calibration strategy was followed: first, the model parameters were directly measured at the micro-scale (particle level) and second, a meso-scale calibration was established between MC-DEM parameters and compression profiles of the pharmaceutical powders. The new MC-DEM framework could capture the main compressibility characteristics of pharmaceutical materials and could successfully provide predictions on compression profiles at high relative densities. Full article

► Show Figures

Figure 1

Open AccessArticle

Compartmentalized Polymeric Nanoparticles Deliver Vancomycin in a pH-Responsive Manner

by

Merve Seray Ural

,

Mario Menéndez-Miranda

,

Giuseppina Salzano

,

Jérémie Mathurin

,

Ece Neslihan Aybeke

,

Ariane Deniset-Besseau

,

Alexandre Dazzi

,

Marianna Porcino

,

Charlotte Martineau-Corcos

and

Ruxandra Gref

Pharmaceutics 2021, 13(12), 1992; https://doi.org/10.3390/pharmaceutics13121992 - 24 Nov 2021

Cited by 3 | Viewed by 1542

Abstract

Vancomycin (VCM) is a last resort antibiotic in the treatment of severe Gram-positive infections. However, its administration is limited by several drawbacks such as: strong pH-dependent charge, tendency to aggregate, low bioavailability, and poor cellular uptake. These drawbacks were circumvented by engineering pH-responsive [...] Read more.

Vancomycin (VCM) is a last resort antibiotic in the treatment of severe Gram-positive infections. However, its administration is limited by several drawbacks such as: strong pH-dependent charge, tendency to aggregate, low bioavailability, and poor cellular uptake. These drawbacks were circumvented by engineering pH-responsive nanoparticles (NPs) capable to incorporate high VCM payload and deliver it specifically at slightly acidic pH corresponding to infection sites. Taking advantage of peculiar physicochemical properties of VCM, here we show how to incorporate VCM efficiently in biodegradable NPs made of poly(lactic-co-glycolic acid) and polylactic acid (co)polymers. The NPs were prepared by a simple and reproducible method, establishing strong electrostatic interactions between VCM and the (co)polymers’ end groups. VCM payloads reached up to 25 wt%. The drug loading mechanism was investigated by solid state nuclear magnetic resonance spectroscopy. The engineered NPs were characterized by a set of advanced physicochemical methods, which allowed examining their morphology, internal structures, and chemical composition on an individual NP basis. The compartmentalized structure of NPs was evidenced by cryogenic transmission electronic microscopy, whereas the chemical composition of the NPs’ top layers and core was obtained by electron microscopies associated with energy-dispersive X-ray spectroscopy. Noteworthy, atomic force microscopy coupled to infrared spectroscopy allowed mapping the drug location and gave semiquantitative information about the loadings of individual NPs. In addition, the NPs were stable upon storage and did not release the incorporated drug at neutral pH. Interestingly, a slight acidification of the medium induced a rapid VCM release. The compartmentalized NPs could find potential applications for controlled VCM release at an infected site with local acidic pH. Full article

► Show Figures

Figure 1

Open AccessReview

Blend Segregation in Tablets Manufacturing and Its Effect on Drug Content Uniformity—A Review

by

Emilia Jakubowska

and

Natalia Ciepluch

Pharmaceutics 2021, 13(11), 1909; https://doi.org/10.3390/pharmaceutics13111909 - 11 Nov 2021

Cited by 8 | Viewed by 3568

Abstract

Content uniformity (CU) of the active pharmaceutical ingredient is a critical quality attribute of tablets as a dosage form, ensuring reproducible drug potency. Failure to meet the accepted uniformity in the final product may be caused either by suboptimal mixing and insufficient initial [...] Read more.

Content uniformity (CU) of the active pharmaceutical ingredient is a critical quality attribute of tablets as a dosage form, ensuring reproducible drug potency. Failure to meet the accepted uniformity in the final product may be caused either by suboptimal mixing and insufficient initial blend homogeneity, or may result from further particle segregation during storage, transfer or the compression process itself. This review presents the most relevant powder segregation mechanisms in tablet manufacturing and summarizes the currently available, up-to-date research on segregation and uniformity loss at the various stages of production process—the blend transfer from the bulk container to the tablet press, filling and discharge from the feeding hopper, as well as die filling. Formulation and processing factors affecting the occurrence of segregation and tablets’ CU are reviewed and recommendations for minimizing the risk of content uniformity failure in tablets are considered herein, including the perspective of continuous manufacturing. Full article

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Topical Collection "Feature Papers in Pharmaceutical Technology"

Share This Topical Collection

Editor

Topical Collection Information

Published Papers (12 papers)

2023

Jump to: 2022, 2021

2022

Jump to: 2023, 2021

2021

Jump to: 2023, 2022

Further Information

Guidelines

MDPI Initiatives

Follow MDPI