Feature Papers in Pharmaceutical Technology

A topical collection in Pharmaceutics (ISSN 1999-4923). This collection belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

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Laboratory for the Conception and Application of Bioactive Molecules, Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France
Interests: microencapsulation; nanoemulsions; biopharmacy; formulation; pharmaceutical engineering
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Topical Collection Information

Dear Colleagues,

Pharmaceutical technology is the discipline of pharmacy that deals with the process of turning a new chemical entity (NCE) or old drug into a medication to be used safely and effectively by patients. It is also called the science of dosage form design. There are many chemicals with pharmacological properties which need special measures to help them to achieve therapeutically relevant amounts at their sites of action by decreasing the side effects and undesirable effects. The pharmaceutical technology itself is directly linked to the formulation of drugs to their delivery and disposition in the body. Pharmaceutical technology deals with the formulation of a pure drug substance into an appropriate dosage form. To do this, appropriate pharmaceutical technologies have to be used, such as crystallization, freeze drying, dried granulation, and holt-melt granulation; physical pharmacy to improve the chemical stability of drugs; novel functionalities of excipients; materials selection and characterization; pharmaceutical process development; new drug delivery devices intended and appropriate for oral, ocular, parenteral, vaginal, rectal, and topical applications; new concepts to administer drugs in colloidal drug delivery systems; and pharmaceutical manufacturing.

Today, most drugs are administered as part of a dosage form. The clinical performance of drugs depends on their form of presentation to the patient. Therefore, the appropriate dosage forms is directly dependent of the processes used to design them. At present, several technologies are able to improve the bioavailability by the process itself. Therefore, these methods are very important and illustrate the importance of factors other than the composition of the dosage forms.

This Topical Collection aims to highlight the latest research activities using pharmaceutical technologies from all stages of the design and the development of a dosage form. We invite researchers to submit original research articles and reviews in this field.

Prof. Dr. Thierry Vandamme
Collection Editor

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Published Papers (18 papers)

2024

Jump to: 2023, 2022, 2021

14 pages, 2158 KiB  
Article
Evaluation of Drug Blood-Brain-Barrier Permeability Using a Microfluidic Chip
by Jung Yoon Yang, Dae-Seop Shin, Moonkyu Jeong, Seong Soon Kim, Ha Neul Jeong, Byung Hoi Lee, Kyu-Seok Hwang, Yuji Son, Hyeon-Cheol Jeong, Chi-Hoon Choi, Kyeong-Ryoon Lee and Myung Ae Bae
Pharmaceutics 2024, 16(5), 574; https://doi.org/10.3390/pharmaceutics16050574 - 23 Apr 2024
Viewed by 643
Abstract
The blood-brain-barrier (BBB) is made up of blood vessels whose permeability enables the passage of some compounds. A predictive model of BBB permeability is important in the early stages of drug development. The predicted BBB permeabilities of drugs have been confirmed using a [...] Read more.
The blood-brain-barrier (BBB) is made up of blood vessels whose permeability enables the passage of some compounds. A predictive model of BBB permeability is important in the early stages of drug development. The predicted BBB permeabilities of drugs have been confirmed using a variety of in vitro methods to reduce the quantities of drug candidates needed in preclinical and clinical trials. Most prior studies have relied on animal or cell-culture models, which do not fully recapitulate the human BBB. The development of microfluidic models of human-derived BBB cells could address this issue. We analyzed a model for predicting BBB permeability using the Emulate BBB-on-a-chip machine. Ten compounds were evaluated, and their permeabilities were estimated. Our study demonstrated that the permeability trends of ten compounds in our microfluidic-based system resembled those observed in previous animal and cell-based experiments. Furthermore, we established a general correlation between the partition coefficient (Kp) and the apparent permeability (Papp). In conclusion, we introduced a new paradigm for predicting BBB permeability using microfluidic-based systems. Full article
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19 pages, 4868 KiB  
Article
Nanoparticles of Thiolated Xanthan Gum for the Oral Delivery of Miconazole Nitrate: In Vitro and In Vivo Evaluation
by Nader I. Namazi, Hamad Alrbyawi, Abdulkareem Ali Alanezi, Afaf F Almuqati, Anwar Shams and Hany S. M. Ali
Pharmaceutics 2024, 16(2), 225; https://doi.org/10.3390/pharmaceutics16020225 - 4 Feb 2024
Viewed by 927
Abstract
The objective of this research was to develop a mucoadhesive delivery system that improves permeation for the administration of poorly absorbed oral medications. Thiolation of xanthan gum (XGM) was carried out by esterification with mercaptobutyric acid. Fourier-transformed infrared spectroscopy was used to confirm [...] Read more.
The objective of this research was to develop a mucoadhesive delivery system that improves permeation for the administration of poorly absorbed oral medications. Thiolation of xanthan gum (XGM) was carried out by esterification with mercaptobutyric acid. Fourier-transformed infrared spectroscopy was used to confirm thiol-derivatization. Using Ellman’s technique, it was revealed that the xanthan-mercaptobutyric acid conjugate had 4.7 mM of thiol groups in 2 mg/mL of polymeric solution. Using mucosa of sheep intestine, the mucoadhesive properties of XGM and thiolated xanthan gum (TXGM) nanoparticles were investigated and we found that TXGM had a longer bioadhesion time than XGM. The disulfide link that forms between mucus and thiolated XGM explains why it has better mucoadhesive properties than XGM. A study on in vitro miconazole (MCZ) release using phosphate buffer (pH 6.8) found that TXGM nanoparticles released MCZ more steadily than MCZ dispersion did. A 1-fold increase in the permeation of MCZ was observed from nanoparticles using albino rat intestine compared to MCZ. Albino rats were used to test the pharmacokinetics of MCZ, and the results showed a 4.5-fold increase in bioavailability. In conclusion, the thiolation of XGM enhances its bioavailability, controlled release of MCZ for a long period of time, and mucoadhesive activity. Full article
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2023

Jump to: 2024, 2022, 2021

29 pages, 7593 KiB  
Article
Do Mixtures of Beads with Different Sizes Improve Wet Stirred Media Milling of Drug Suspensions?
by Gulenay Guner, Mirsad Mehaj, Natasha Seetharaman, Sherif Elashri, Helen F. Yao, Donald J. Clancy and Ecevit Bilgili
Pharmaceutics 2023, 15(9), 2213; https://doi.org/10.3390/pharmaceutics15092213 - 26 Aug 2023
Cited by 1 | Viewed by 1621
Abstract
The impacts of bead sizes and bead mixtures on breakage kinetics, the number of milling cycles applied to prevent overheating, and power consumption during the nanomilling of drug (griseofulvin) suspensions were investigated from both an experimental and theoretical perspective. Narrowly sized zirconia beads [...] Read more.
The impacts of bead sizes and bead mixtures on breakage kinetics, the number of milling cycles applied to prevent overheating, and power consumption during the nanomilling of drug (griseofulvin) suspensions were investigated from both an experimental and theoretical perspective. Narrowly sized zirconia beads with nominal sizes of 100, 200, and 400 µm and their half-and-half binary mixtures were used at 3000 and 4000 rpm with two bead loadings of 0.35 and 0.50. Particle size evolution was measured during the 3 h milling experiments using laser diffraction. An nth-order breakage model was fitted to the experimental median particle size evolution, and various microhydrodynamic parameters were calculated. In general, the beads and their mixtures with smaller median sizes achieved faster breakage. While the microhydrodynamic model explained the impacts of process parameters, it was limited in describing bead mixtures. For additional test runs performed, the kinetics model augmented with a decision tree model using process parameters outperformed that augmented with an elastic-net regression model using the microhydrodynamic parameters. The evaluation of the process merit scores suggests that the use of bead mixtures did not lead to notable process improvement; 100 µm beads generally outperformed bead mixtures and coarser beads in terms of fast breakage, low power consumption and heat generation, and low intermittent milling cycles. Full article
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20 pages, 5422 KiB  
Article
Comparative Evaluation of the Powder and Tableting Properties of Regular and Direct Compression Hypromellose from Different Vendors
by Nihad Mawla, Maen Alshafiee, John Gamble, Mike Tobyn, Lande Liu, Karl Walton, Barbara R. Conway, Peter Timmins and Kofi Asare-Addo
Pharmaceutics 2023, 15(8), 2154; https://doi.org/10.3390/pharmaceutics15082154 - 17 Aug 2023
Cited by 1 | Viewed by 1584
Abstract
Hypromellose, a widely used polymer in the pharmaceutical industry, is available in several grades, depending on the percentage of substitution of the methoxyl and hydroxypropyl groups and molecular weight, and in various functional forms (e.g., suitable for direct compression tableting). These differences can [...] Read more.
Hypromellose, a widely used polymer in the pharmaceutical industry, is available in several grades, depending on the percentage of substitution of the methoxyl and hydroxypropyl groups and molecular weight, and in various functional forms (e.g., suitable for direct compression tableting). These differences can affect their physicomechanical properties, and so this study aims to characterise the particle size and mechanical properties of HPMC K100M polymer grades from four different vendors. Eight polymers (CR and DC grades) were analysed using scanning electron microscopy (SEM) and light microscopy automated image analysis particle characterisation to examine the powder’s particle morphology and particle size distribution. Bulk density, tapped density, and true density of the materials were also analysed. Flow was determined using a shear cell tester. Flat-faced polymer compacts were made at five different compression forces and the mechanical properties of the compacts were evaluated to give an indication of the powder’s capacity to form a tablet with desirable strength under specific pressures. The results indicated that the CR grades of the polymers displayed a smaller particle size and better mechanical properties compared to the DC grade HPMC K100M polymers. The DC grades, however, had better flow properties than their CR counterparts. The results also suggested some similarities and differences between some of the polymers from the different vendors despite the similarity in substitution level, reminding the user that care and consideration should be given when substitution is required. Full article
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13 pages, 3103 KiB  
Article
An Innovative Polymeric Platform for Controlled and Localized Drug Delivery
by Monica Elbjorn, Jacob Provencio, Paige Phillips, Javier Sainz, Noah Harrison, David Di Rocco, Ada Jaramillo, Priya Jain, Alejandro Lozano and R. Lyle Hood
Pharmaceutics 2023, 15(7), 1795; https://doi.org/10.3390/pharmaceutics15071795 - 23 Jun 2023
Cited by 1 | Viewed by 1433
Abstract
Precision medicine aims to optimize pharmacological treatments by considering patients’ genetic, phenotypic, and environmental factors, enabling dosages personalized to the individual. To address challenges associated with oral and injectable administration approaches, implantable drug delivery systems have been developed. These systems overcome issues like [...] Read more.
Precision medicine aims to optimize pharmacological treatments by considering patients’ genetic, phenotypic, and environmental factors, enabling dosages personalized to the individual. To address challenges associated with oral and injectable administration approaches, implantable drug delivery systems have been developed. These systems overcome issues like patient adherence, bioavailability, and first-pass metabolism. Utilizing new combinations of biodegradable polymers, the proposed solution, a Polymeric Controlled Release System (PCRS), allows minimally invasive placement and controlled drug administration over several weeks. This study’s objective was to show that the PCRS exhibits a linear biphasic controlled release profile, which would indicate potential as an effective treatment vehicle for cervical malignancies. An injection mold technique was developed for batch manufacturing of devices, and in vitro experiments demonstrated that the device’s geometry and surface area could be varied to achieve various drug release profiles. This study’s results motivate additional development of the PCRS to treat cervical cancer, as well as other malignancies, such as lung, testicular, and ovarian cancers. Full article
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19 pages, 5538 KiB  
Article
Characterization and Validation of a New 3D Printing Ink for Reducing Therapeutic Gap in Pediatrics through Individualized Medicines
by Eduardo Díaz-Torres, Javier Suárez-González, Cecilia N. Monzón-Rodríguez, Ana Santoveña-Estévez and José B. Fariña
Pharmaceutics 2023, 15(6), 1642; https://doi.org/10.3390/pharmaceutics15061642 - 2 Jun 2023
Cited by 3 | Viewed by 1546
Abstract
3D printing technology can be used to develop individualized medicines in hospitals and pharmacies, allowing a high degree of personalization and the possibility to adjust the dose of the API based on the quantity of material extruded. The main goal of incorporating this [...] Read more.
3D printing technology can be used to develop individualized medicines in hospitals and pharmacies, allowing a high degree of personalization and the possibility to adjust the dose of the API based on the quantity of material extruded. The main goal of incorporating this technology is to have a stock of API-load print cartridges that could be used at different storage times and for different patients. However, it is necessary to study the extrudability, stability, and buildability of these print cartridges during storage time. A paste-like formulation containing hydrochlorothiazide as a model drug was prepared and distributed in five print cartridges, each of which was studied for different storage times (0 h–72 h) and conditions, for repeated use on different days. For each print cartridge, an extrudability analysis was performed, and subsequently, 100 unit forms of 10 mg hydrochlorothiazide were printed. Finally, various dosage units containing different doses were printed, taking into account the optimized printing parameters based on the results of the extrudability analysis carried out previously. An appropriate methodology for the rapid development of appropriate SSE 3DP inks for pediatrics was established and evaluated. The extrudability analysis and several parameters allowed the detection of changes in the mechanical behavior of the printing inks, the pressure interval of the steady flow, and the selection of the volume of ink to be extruded to obtain each of the required doses. The print cartridges were stable for up to 72 h after processing, and orodispersible printlets containing 6 mg to 24 mg of hydrochlorothiazide can be produced using the same print cartridge and during the same printing process with guaranteed content and chemical stability. The proposed workflow for the development of new printing inks containing APIs will allow the optimization of feedstock material and human resources in pharmacy or hospital pharmacy services, thus speeding up their development and reducing costs. Full article
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17 pages, 3064 KiB  
Article
Influence of Physicochemical Properties of Budesonide Micro-Suspensions on Their Expected Lung Delivery Using a Vibrating Mesh Nebulizer
by Katarzyna Dobrowolska, Andrzej Emeryk, Kamil Janeczek, Radosław Krzosa, Michał Pirożyński and Tomasz R. Sosnowski
Pharmaceutics 2023, 15(3), 752; https://doi.org/10.3390/pharmaceutics15030752 - 23 Feb 2023
Cited by 1 | Viewed by 1998
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
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18 pages, 4118 KiB  
Article
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
Cited by 1 | Viewed by 1753
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
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2022

Jump to: 2024, 2023, 2021

19 pages, 5526 KiB  
Article
Predicting the Temperature Evolution during Nanomilling of Drug Suspensions via a Semi-Theoretical Lumped-Parameter Model
by Gulenay Guner, Dogacan Yilmaz, Helen F. Yao, Donald J. Clancy and Ecevit Bilgili
Pharmaceutics 2022, 14(12), 2840; https://doi.org/10.3390/pharmaceutics14122840 - 18 Dec 2022
Cited by 3 | Viewed by 1680
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 Qgen 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
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23 pages, 4934 KiB  
Article
Chemical Attachment of 5-Nitrosalicylaldimine Motif to Silatrane Resulting in an Organic–Inorganic Structure with High Medicinal Significance
by Mirela-Fernanda Zaltariov, Mihaela Turtoi, Dragos Peptanariu, Ana-Maria Macsim, Lilia Clima, Corneliu Cojocaru, Nicoleta Vornicu, Bianca-Iulia Ciubotaru, Alexandra Bargan, Manuela Calin and Maria Cazacu
Pharmaceutics 2022, 14(12), 2838; https://doi.org/10.3390/pharmaceutics14122838 - 18 Dec 2022
Cited by 3 | Viewed by 1700
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 MPRO COVID-19 protease demonstrated their potential in the development of new drugs for combined therapy. Full article
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19 pages, 4710 KiB  
Article
Solid Lipid Microparticles by Spray Congealing of Water/Oil Emulsion: An Effective/Versatile Loading Strategy for a Highly Soluble Drug
by Alessandro Candiani, Andrea Milanesi, Andrea Foglio Bonda, Giada Diana, Elia Bari, Lorena Segale, Maria Luisa Torre and Lorella Giovannelli
Pharmaceutics 2022, 14(12), 2805; https://doi.org/10.3390/pharmaceutics14122805 - 14 Dec 2022
Cited by 1 | Viewed by 1795
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
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16 pages, 5001 KiB  
Article
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 - 3 Oct 2022
Cited by 3 | Viewed by 2315
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
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13 pages, 3000 KiB  
Article
Complexation: An Interesting Pathway for Combining Two APIs at the Solid State
by Fucheng Leng, Oleksii Shemchuk, Koen Robeyns and Tom Leyssens
Pharmaceutics 2022, 14(9), 1960; https://doi.org/10.3390/pharmaceutics14091960 - 16 Sep 2022
Cited by 2 | Viewed by 1480
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
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38 pages, 9775 KiB  
Review
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 - 6 Apr 2022
Cited by 7 | Viewed by 3781
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
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18 pages, 1123 KiB  
Article
Analytical Quality by Design (AQbD) Approach to the Development of In Vitro Release Test for Topical Hydrogel
by Réka Szoleczky, Mária Budai-Szűcs, Erzsébet Csányi, Szilvia Berkó, Péter Tonka-Nagy, Ildikó Csóka and Anita Kovács
Pharmaceutics 2022, 14(4), 707; https://doi.org/10.3390/pharmaceutics14040707 - 26 Mar 2022
Cited by 7 | Viewed by 4406
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
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2021

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16 pages, 2866 KiB  
Article
Modeling of High-Density Compaction of Pharmaceutical Tablets Using Multi-Contact Discrete Element Method
by Kostas Giannis, Carsten Schilde, Jan Henrik Finke and Arno Kwade
Pharmaceutics 2021, 13(12), 2194; https://doi.org/10.3390/pharmaceutics13122194 - 18 Dec 2021
Cited by 12 | Viewed by 4140
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
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19 pages, 5938 KiB  
Article
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 6 | Viewed by 2600
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
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27 pages, 3341 KiB  
Review
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 20 | Viewed by 8972
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
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