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Keywords = BCS II APIs

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16 pages, 3233 KB  
Article
Study of the Influence of Pharmaceutical Excipients on the Solubility and Permeability of BCS Class II Drugs
by Vivien Bárdos, Rita Szolláth, Petra Tőzsér, Arash Mirzahosseini, Bálint Sinkó, Réka Angi and Krisztina Takács-Novák
Sci. Pharm. 2025, 93(2), 19; https://doi.org/10.3390/scipharm93020019 - 11 Apr 2025
Cited by 1 | Viewed by 3424
Abstract
Most novel active pharmaceutical ingredients have low water solubility; therefore, solubility-enhancing methods are applied. The aim of the present investigation is to study the impact of nine commonly used pharmaceutical excipients (fillers, surfactants, cyclodextrins, polymers) on solubility, permeability and their relationship. This is [...] Read more.
Most novel active pharmaceutical ingredients have low water solubility; therefore, solubility-enhancing methods are applied. The aim of the present investigation is to study the impact of nine commonly used pharmaceutical excipients (fillers, surfactants, cyclodextrins, polymers) on solubility, permeability and their relationship. This is crucial for ensuring optimal bioavailability. Carbamazepine, naproxen and pimobendan were chosen as model compounds due to their different acid–base properties. Equilibrium solubility was measured by the traditional shake flask method. Effective permeability was determined by the PAMPA model. Measurements of ionizable compounds were carried out at three pH values. The pH-dependent change in the investigated parameters is maintained even in the presence of excipients. Fillers resulted in a slight or no effect, while the impact of other excipients showed a significant concentration dependence. The impact of excipients was influenced by the structure and ionization state of the molecules. The dominance of the ionized form moderates the impact of excipients. The changes in solubility were more pronounced than in the case of permeability. By examining the effect of the ionization state and interactions with excipients, this work supports the development of formulations that enhance solubility with minimal impacts on permeability. Additionally, it can serve as good basis for preformulation studies and design optimization. Full article
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23 pages, 6549 KB  
Article
Co-Amorphization, Dissolution, and Stability of Quench-Cooled Drug–Drug Coamorphous Supersaturating Delivery Systems with RT-Unstable Amorphous Components
by Yan-Fei Zhang, Qian Yao, Xiao-Ying Lin, Ying-Hui Ma, Hui-Feng Zhang, Huan Yu, Shang-Qiang Mu, Chuang Zhang, Hao Geng, Cheng-Yi Hao, Li-Li Zuo, Di Wu, Yue Li, Li-Li Jin and Nian-Qiu Shi
Pharmaceutics 2024, 16(12), 1488; https://doi.org/10.3390/pharmaceutics16121488 - 21 Nov 2024
Cited by 3 | Viewed by 1325
Abstract
Background: Supersaturating drug delivery systems (SDDSs) have gained significant attention as a promising strategy to enhance the solubility and bioabsorption of Biopharmaceutics Classification System (BCS) II drugs. To overcome challenges associated with polymer-based amorphous SDDS (aSDDS), coamorphous (CAM) systems have emerged as [...] Read more.
Background: Supersaturating drug delivery systems (SDDSs) have gained significant attention as a promising strategy to enhance the solubility and bioabsorption of Biopharmaceutics Classification System (BCS) II drugs. To overcome challenges associated with polymer-based amorphous SDDS (aSDDS), coamorphous (CAM) systems have emerged as a viable alternative. Among them, “drug-drug” CAM (ddCAM) systems show considerable potential for combination drug therapy. However, many drugs in their pure amorphous forms are unstable at room temperature (RT), complicating their formation and long-term stability profiles. Consequently, limited knowledge exists regarding the behavior of ddCAMs containing RT-unstable components formed via quench cooling. Methods: In this study, we used naproxen (NAP), a RT-unstable amorphous drug, in combination with felodipine (FEL) or nitrendipine (NTP), two RT-stable amorphous drugs, to create “FEL-NAP” and “NTP-NAP” ddCAM pairs via quench cooling. Our work used a series of methods to perform a detailed analysis on the co-amorphization, dissolution, solubility, and stability profiles of ddCAMs containing RT-unstable drugs, contributing to advancements in co-amorphization techniques for generating SDDS. Results: This study revealed that the co-amorphization and stability profiles of ddCAMs containing RT-unstable components produced via a quench-cooling method were closely related to drug-drug pairing types and ratios. Both quench-cooling and incorporation into coamorphous systems improved the dissolution, solubility, and physical stability of individual APIs. Conclusions: Our findings provide deeper insight into the co-amorphization, dissolution, and stability characteristics of specific drug-drug coamorphous systems FEL-NAP and NTP-NAP, offering valuable guidance for developing new ddCAM coamorphous formulations containing some RT-unstable drugs. Full article
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15 pages, 4901 KB  
Article
Evaluation of a Three-Fluid Nozzle Spraying Process for Facilitating Spray Drying of Hydrophilic Polymers for the Creation of Amorphous Solid Dispersions
by Lena Karin Mueller, Laura Halstenberg, Nicole Di Gallo and Thomas Kipping
Pharmaceutics 2023, 15(11), 2542; https://doi.org/10.3390/pharmaceutics15112542 - 27 Oct 2023
Cited by 5 | Viewed by 3189
Abstract
Amorphous solid dispersions (ASDs) enable formulations to improve the solubility of poorly soluble active pharmaceutical ingredients (APIs). The amorphous state is reached through the disruption of the crystalline lattice of an API resulting in an increased apparent solubility with faster disintegration. Nevertheless, this [...] Read more.
Amorphous solid dispersions (ASDs) enable formulations to improve the solubility of poorly soluble active pharmaceutical ingredients (APIs). The amorphous state is reached through the disruption of the crystalline lattice of an API resulting in an increased apparent solubility with faster disintegration. Nevertheless, this form is characterized by a high-energy state which is prone to re-crystallization. To ensure a stable ASD, excipients, e.g., polymers that form a matrix in which an API is dispersed, are used. The applicable polymer range is usually linked to their solubility in the respective solvent, therefore limiting the use of hydrophilic polymers. In this work, we show the applicability of the hydrophilic polymer, polyvinyl alcohol (PVA), in spray-dried solid dispersions. Using a three-fluid nozzle approach, this polymer can be used to generate ASDs with a targeted dissolution profile that is characterized by a prominent spring and desired parachute effect showing both supersaturation and crystallization inhibition. For this purpose, the polymer was tested in formulations containing the weakly basic drug, ketoconazole, and the acidic drug, indomethacin, both classified as Biopharmaceutics Classification System (BSC) class II drugs, as well as the weakly basic drug ritonavir classified as BCS IV. Furthermore, ritonavir was used to show the enhanced drug-loading capacity of PVA derived from the advantageous viscosity profile that makes the polymer an interesting candidate for spray drying applications. Full article
(This article belongs to the Special Issue Solid Dispersions for Bioavailability Enhancement)
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22 pages, 5052 KB  
Article
Hot Melt Extruded Posaconazole-Based Amorphous Solid Dispersions—The Effect of Different Types of Polymers
by Daniel Kramarczyk, Justyna Knapik-Kowalczuk, Mateusz Kurek, Witold Jamróz, Renata Jachowicz and Marian Paluch
Pharmaceutics 2023, 15(3), 799; https://doi.org/10.3390/pharmaceutics15030799 - 28 Feb 2023
Cited by 19 | Viewed by 5211
Abstract
Four model polymers, representing (i) amorphous homopolymers (Kollidon K30, K30), (ii) amorphous heteropolymers (Kollidon VA64, KVA), (iii) semi-crystalline homopolymers (Parteck MXP, PXP), and (iv) semi-crystalline heteropolymers (Kollicoat IR, KIR), were examined for their effectiveness in creating posaconazole-based amorphous solid dispersions (ASDs). Posaconazole (POS) [...] Read more.
Four model polymers, representing (i) amorphous homopolymers (Kollidon K30, K30), (ii) amorphous heteropolymers (Kollidon VA64, KVA), (iii) semi-crystalline homopolymers (Parteck MXP, PXP), and (iv) semi-crystalline heteropolymers (Kollicoat IR, KIR), were examined for their effectiveness in creating posaconazole-based amorphous solid dispersions (ASDs). Posaconazole (POS) is a triazole antifungal drug that has activity against Candida and Aspergillus species, belonging to class II of the biopharmaceutics classification system (BCS). This means that this active pharmaceutical ingredient (API) is characterized by solubility-limited bioavailability. Thus, one of the aims of its formulation as an ASD was to improve its aqueous solubility. Investigations were performed into how polymers affected the following characteristics: melting point depression of the API, miscibility and homogeneity with POS, improvement of the amorphous API’s physical stability, melt viscosity (and associated with it, drug loading), extrudability, API content in the extrudate, long term physical stability of the amorphous POS in the binary drug–polymer system (in the form of the extrudate), solubility, and dissolution rate of hot melt extrusion (HME) systems. The obtained results led us to conclude that the physical stability of the POS-based system increases with the increasing amorphousness of the employed excipient. Copolymers, compared to homopolymers, display greater homogeneity of the investigated composition. However, the enhancement in aqueous solubility was significantly higher after utilizing the homopolymeric, compared to the copolymeric, excipients. Considering all of the investigated parameters, the most effective additive in the formation of a POS-based ASD is an amorphous homopolymer—K30. Full article
(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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24 pages, 5601 KB  
Article
Tailored Supersaturable Immediate Release Behaviors of Hypotensive Supersaturating Drug-Delivery Systems Combined with Hot-Melt Extrusion Technique and Self-Micellizing Polymer
by Huan Yu, Yinghui Ma, Yanfei Zhang, Huifeng Zhang, Lili Zuo, Chengyi Hao, Weilun Yu, Xiaoying Lin, Yong Zhang, Xianrong Qi and Nianqiu Shi
Polymers 2022, 14(22), 4800; https://doi.org/10.3390/polym14224800 - 8 Nov 2022
Cited by 4 | Viewed by 2444
Abstract
The short-term immediate release of supersaturated drug-delivery systems (SDDSs) presents an interesting process that can be tailored to multi-stage release events including initial release after dosing and dissolution, evolved release over longer dissolution periods for biological absorption, and terminal release following the end [...] Read more.
The short-term immediate release of supersaturated drug-delivery systems (SDDSs) presents an interesting process that can be tailored to multi-stage release events including initial release after dosing and dissolution, evolved release over longer dissolution periods for biological absorption, and terminal release following the end of immediate release. However, although comprehensive analysis of these critical release behaviors is often ignored yet essential for understanding the supersaturable immediate-release events for supersaturable solid formations when employing new techniques or polymers matched to a particular API. Hot-melt extrusion (HME) has become a popular continuous thermodynamic disordering technique for amorphization. The self-micellizing polymer Soluplus® is reported to be a potential amorphous and amphiphilic graft copolymer frequently used in many nano/micro supersaturable formulations. Our current work aims to develop hypotensive supersaturating solid dispersion systems (faSDDSHME) containing the BCS II drug, felodipine, when coordinately employing the HME technique and self-micellizing Soluplus®, and to characterize their amorphization as well as immediate release. Other discontinuous techniques were used to prepare control groups (faSDDSSE and faSDDSQC). Tailored initial/evolved/terminal three-stage supersaturable immediate-release behaviors were identified and possible mechanisms controlling the release were explored. HME produced the highest initial release in related faSDDSHME. During the evolved-release period, highly extended “spring-parachute” process was found in HME-induced amorphization owing to its superior supersaturation duration. Due to the enhanced crystallization inhibition effect, faSDDSHME displayed the strongest terminal release as measured by solubility. For release mechanisms associated with HME, molecular interaction is not the likely dominant mechanism responsible for the improved properties induced by faSDDSHME. For release mechanisms involved with the polymer Soluplus® itself, they were found to inhibit drug recrystallization, spontaneously solubilize the drug and lead to improved molecular interactions in all SDDS systems, which were the factors responsible for the improved release. These mechanisms play an important role for the generation of an extended multi-stage immediate release produced via HME or self-micellizing polymer. This study provides a deeper understanding on amorphization and superior multi-stage supersaturable immediate-release behaviors for a particular hypotensive supersaturated delivery system combined with an HME-based continuous manufacturing technique and self-micellizing polymer strategy. Full article
(This article belongs to the Special Issue Advanced Properties in Amorphous Polymers)
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20 pages, 4822 KB  
Article
Integrating Elastic Tensor and PC-SAFT Modeling with Systems-Based Pharma 4.0 Simulation, to Predict Process Operations and Product Specifications of Ternary Nanocrystalline Suspensions
by Andreas Ouranidis, Christina Davidopoulou and Kyriakos Kachrimanis
Pharmaceutics 2021, 13(11), 1771; https://doi.org/10.3390/pharmaceutics13111771 - 22 Oct 2021
Cited by 4 | Viewed by 2980
Abstract
Comminution of BCS II APIs below the 1 μm threshold followed by solidification of the obtained nanosuspensions improves their dissolution properties. The breakage process reveals new crystal faces, thus creating altered crystal habits of improved wettability, facilitated by the adsorption of stabilizing polymers. [...] Read more.
Comminution of BCS II APIs below the 1 μm threshold followed by solidification of the obtained nanosuspensions improves their dissolution properties. The breakage process reveals new crystal faces, thus creating altered crystal habits of improved wettability, facilitated by the adsorption of stabilizing polymers. However, process-induced transformations remain unpredictable, mirroring the current limitations of our atomistic level of understanding. Moreover, conventional equations of estimating dissolution, such as Noyes–Whitney and Nernst–Brunner, are not suitable to quantify the solubility enhancement due to the nanoparticle formation; hence, neither the complex stabilizer contribution nor the adsorption influence on the interfacial tension occurring between the water and APIs is accounted for. For such ternary mixtures, no numeric method exists to correlate the mechanical properties with the interfacial energy, capable of informing the key process parameters and the thermodynamic stability assessment of nanosuspensions. In this work, an elastic tensor analysis was performed to quantify the API stability during process implementation. Moreover, a novel thermodynamic model, described by the stabilizer-coated nanoparticle Gibbs energy anisotropic minimization, was structured to predict the material’s system solubility quantified by the application of PC-SAFT modeling. Comprehensively merging elastic tensor and PC-SAFT analysis into the systems-based Pharma 4.0 algorithm provided a validated, multi-level, built-in method capable of predicting the critical material quality attributes and corresponding key process parameters. Full article
(This article belongs to the Special Issue Nanosuspensions for the Improvement of Drug Bioavailability)
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26 pages, 2765 KB  
Article
Slow Magnetic Relaxation in {[CoCxAPy)] 2.15 H2O}n MOF Built from Ladder-Structured 2D Layers with Dimeric SMM Rungs
by Ana Arauzo, Elena Bartolomé, Javier Luzón, Pablo J. Alonso, Angelica Vlad, Maria Cazacu, Mirela F. Zaltariov, Sergiu Shova, Juan Bartolomé and Constantin Turta
Molecules 2021, 26(18), 5626; https://doi.org/10.3390/molecules26185626 - 16 Sep 2021
Cited by 5 | Viewed by 2941
Abstract
We present the magnetic properties of the metal-organic framework {[CoCxAPy]·2.15 H2O}n (Cx = bis(carboxypropyl)tetramethyldisiloxane; APy = 4,4`-azopyridine) (1) that builds up from the stacking of 2D coordination polymers. The 2D-coordination polymer in the bc plane is formed by [...] Read more.
We present the magnetic properties of the metal-organic framework {[CoCxAPy]·2.15 H2O}n (Cx = bis(carboxypropyl)tetramethyldisiloxane; APy = 4,4`-azopyridine) (1) that builds up from the stacking of 2D coordination polymers. The 2D-coordination polymer in the bc plane is formed by the adjacent bonding of [CoCxAPy] 1D two-leg ladders with Co dimer rungs, running parallel to the c-axis. The crystal packing of 2D layers shows the presence of infinite channels running along the c crystallographic axis, which accommodate the disordered solvate molecules. The Co(II) is six-coordinated in a distorted octahedral geometry, where the equatorial plane is occupied by four carboxylate oxygen atoms. Two nitrogen atoms from APy ligands are coordinated in apical positions. The single-ion magnetic anisotropy has been determined by low temperature EPR and magnetization measurements on an isostructural compound {[Zn0.8Co0.2CxAPy]·1.5 CH3OH}n (2). The results show that the Co(II) ion has orthorhombic anisotropy with the hard-axis direction in the C2V main axis, lying the easy axis in the distorted octahedron equatorial plane, as predicted by the ab initio calculations of the g-tensor. Magnetic and heat capacity properties at very low temperatures are rationalized within a S* = 1/2 magnetic dimer model with anisotropic antiferromagnetic interaction. The magnetic dimer exhibits slow relaxation of the magnetization (SMM) below 6 K in applied field, with a tlf ≈ 2 s direct process at low frequencies, and an Orbach process at higher frequencies with U/kB = 6.7 ± 0.5 K. This compound represents a singular SMM MOF built-up of Co-dimers with an anisotropic exchange interaction. Full article
(This article belongs to the Special Issue 2D Magnetic Molecular Materials)
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20 pages, 4895 KB  
Article
Different BCS Class II Drug-Gelucire Solid Dispersions Prepared by Spray Congealing: Evaluation of Solid State Properties and In Vitro Performances
by Serena Bertoni, Beatrice Albertini and Nadia Passerini
Pharmaceutics 2020, 12(6), 548; https://doi.org/10.3390/pharmaceutics12060548 - 12 Jun 2020
Cited by 25 | Viewed by 5882
Abstract
Delivery of poorly water soluble active pharmaceutical ingredients (APIs) by semi-crystalline solid dispersions prepared by spray congealing in form of microparticles (MPs) is an emerging method to increase their oral bioavailability. In this study, solid dispersions based on hydrophilic Gelucires® (Gelucire® [...] Read more.
Delivery of poorly water soluble active pharmaceutical ingredients (APIs) by semi-crystalline solid dispersions prepared by spray congealing in form of microparticles (MPs) is an emerging method to increase their oral bioavailability. In this study, solid dispersions based on hydrophilic Gelucires® (Gelucire® 50/13 and Gelucire® 48/16 in different ratio) of three BCS class II model compounds (carbamazepine, CBZ, tolbutamide, TBM, and cinnarizine, CIN) having different physicochemical properties (logP, pKa, Tm) were produced by spray congealing process. The obtained MPs were investigated in terms of morphology, particles size, drug content, solid state properties, drug-carrier interactions, solubility, and dissolution performances. The solid-state characterization showed that the properties of the incorporated drug had a profound influence on the structure of the obtained solid dispersion: CBZ recrystallized in a different polymorphic form, TBM crystallinity was significantly reduced as a result of specific interactions with the carrier, while smaller crystals were observed in case of CIN. The in vitro tests suggested that the drug solubility was mainly influenced by carrier composition, while the drug dissolution behavior was affected by the API solid state in the MPs after the spray congealing process. Among the tested APIs, TBM-Gelucire dispersions showed the highest enhancement in drug dissolution as a result of the reduced drug crystallinity. Full article
(This article belongs to the Special Issue Emerging Micro- and Nanofabrication Technologies for Drug Delivery)
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