Recent Advances in Amorphous Drug

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

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 27326

Special Issue Editors


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Guest Editor
Centro de Química Estrutural, Institute of Molecular Sciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
Interests: amorphous; polymorphism; dielectric techniques; calorimetry; polymers

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LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal
Interests: glassy state; molecular mobility; dielectric relaxation spectroscopy; calorimetry

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Guest Editor
Centro de Química Estrutural, Institute of Molecular Sciences, Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
Interests: thermal behavior and molecular mobility studies on amorphous API´s and polymers

Special Issue Information

Dear Colleagues,

The research on amorphous forms of drugs has been intensified in recent years. One of the main reasons for the increasing interest is the favorable changes that these highly energetic and disordered forms can induce in substance properties used as ingredients in either food, cosmetics, nutraceuticals or pharmaceutics. The dissolution rate, a critical subject for poorly water soluble molecules, can be, for instance, potentially improved. Additionally, developments in this form of matter will contribute to a better understanding of the glass transition origin which remains a challenge in the aims of condensed matter physics.

An in-depth physicochemical characterization is required either if the amorphous state is taken as the starting form for formulation constituents, or if it is a consequence of, for instance, incorporation in a nanostructured carrier. Then, a multidisciplinary approach will help to define the appropriate conditions to obtain and stabilize drugs in this thermodynamically unstable form, allowing for establishing the optimal conditions to be safely handled during preparation, storage and administration.

This Special Issue is dedicated to the latest cutting-edge research in amorphous pharmaceuticals including bulk materials, multicomponent mixtures and drug delivery systems. Contributions of original research manuscripts exploring their preparation, characterization and bioavailability/therapeutic evaluation are welcome in the present Special Issue.

Dr. María Teresa Viciosa
Dr. Madalena Dionísio
Dr. Hermínio P. Diogo
Guest Editors

Manuscript Submission Information

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Keywords

  • amorphous
  • glass transition
  • pharmaceutics
  • supercooled liquid
  • molecular mobility
  • disorder
  • coamorphous
  • nanoconfinement
  • metastable forms
  • amorphous solid dispersions

Published Papers (15 papers)

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Research

21 pages, 5928 KiB  
Article
Inhalable Combination Powder Formulations for Treating Latent and Multidrug-Resistant Tuberculosis: Formulation and In Vitro Characterization
by Basanth Babu Eedara, Claire Fan, Shubhra Sinha, Prakash Khadka and Shyamal C. Das
Pharmaceutics 2023, 15(9), 2354; https://doi.org/10.3390/pharmaceutics15092354 - 20 Sep 2023
Viewed by 1206
Abstract
Tuberculosis (TB) is an infectious disease resulting in millions of deaths annually worldwide. TB treatment is challenging due to a huge number of global latent infections and due to multidrug-resistant forms of TB. Inhaled administration of anti-TB drugs using dry powder inhalers has [...] Read more.
Tuberculosis (TB) is an infectious disease resulting in millions of deaths annually worldwide. TB treatment is challenging due to a huge number of global latent infections and due to multidrug-resistant forms of TB. Inhaled administration of anti-TB drugs using dry powder inhalers has various advantages over oral administration due to its direct drug delivery and minimization of systemic side effects. Pretomanid (PA-824, PA) is a relatively new drug with potent activity against both active and latent forms of Mycobacterium tuberculosis (Mtb). It is also known for its synergistic effects in combination with pyrazinamide (PYR) and moxifloxacin (MOX). Fixed-dose combination powder formulations of either PYR and PA or PYR and MOX were prepared for inhaled delivery to the deep lung regions where the Mtb habitats were located. Powder formulations were prepared by spray drying using L-leucine as the aerosolization enhancer and were characterized by their particle size, morphology and solid-state properties. In vitro aerosolization behaviour was studied using a Next Generation Impactor, and stability was assessed after storage at room temperature and 30% relative humidity for three months. Spray drying with L-leucine resulted in spherical dimpled particles, 1.9 and 2.4 µm in size for PYR-PA and PYR-MOX combinations, respectively. The powder formulations had an emitted dose of >83% and a fine particle fraction of >65%. PA and MOX showed better stability in the combination powders compared to PYR. Combination powder formulations with high aerosolization efficiency for direct delivery to the lungs were developed in this study for use in the treatment of latent and multidrug-resistant TB infections. Full article
(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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15 pages, 1707 KiB  
Article
EHO-85, Novel Amorphous Antioxidant Hydrogel, Containing Olea europaea Leaf Extract—Rheological Properties, and Superiority over a Standard Hydrogel in Accelerating Early Wound Healing: A Randomized Controlled Trial
by José Verdú-Soriano, Marisol de Cristino-Espinar, Silvia Luna-Morales, Caridad Dios-Guerra, Antonio Casado-Díaz, José Manuel Quesada-Gómez, Gabriel Dorado, Miriam Berenguer-Pérez, Susana Vílchez, Jordi Esquena, Leocadio Rodríguez-Mañas and José Luis Lázaro-Martínez
Pharmaceutics 2023, 15(7), 1925; https://doi.org/10.3390/pharmaceutics15071925 - 11 Jul 2023
Cited by 3 | Viewed by 1270
Abstract
Many advanced wound healing dressings exist, but there is little high-quality evidence to support them. To determine the performance of a novel amorphous hydrogel (EHO-85) in relation to its application, we compared its rheological properties with those of other standard hydrogels (SH), and [...] Read more.
Many advanced wound healing dressings exist, but there is little high-quality evidence to support them. To determine the performance of a novel amorphous hydrogel (EHO-85) in relation to its application, we compared its rheological properties with those of other standard hydrogels (SH), and we assessed the induction of acceleration of the early stages of wound healing as a secondary objective of a prospective, multicenter, randomized, observer-blinded, controlled trial. The patients were recruited if they had pressure, venous, or diabetic foot ulcers and were treated with EHO-85 (n = 103) or VariHesive® (SH) (n = 92), and their response was assessed by intention-to-treat as wound area reduction (WAR (%)) and healing rate (HR mm2/day) in the second and fourth weeks of treatment. Results: EHO-85 had the highest shear thinning and G′/G″ ratio, the lowest viscous modulus, G″, and relatively low cohesive energy; EHO-85 had a significantly superior effect over SH in WAR and HR, accelerating wound healing in the second and fourth weeks of application (p: 0.002). This superiority is likely based on its optimal moisturizing capacity and excellent pH-lowering and antioxidant properties. In addition, the distinct shear thinning of EHO-85 facilitates spreading by gentle hand pressure, making it easier to apply to wounds. These rheological properties contribute to its improved performance. Full article
(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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27 pages, 4465 KiB  
Article
Understanding Fenofibrate Release from Bare and Modified Mesoporous Silica Nanoparticles
by Giorgia Figari, José L. M. Gonçalves, Hermínio P. Diogo, Madalena Dionísio, José Paulo Farinha and María Teresa Viciosa
Pharmaceutics 2023, 15(6), 1624; https://doi.org/10.3390/pharmaceutics15061624 - 30 May 2023
Cited by 2 | Viewed by 1141
Abstract
To investigate the impact of the surface functionalization of mesoporous silica nanoparticle (MSN) carriers in the physical state, molecular mobility and the release of Fenofibrate (FNB) MSNs with ordered cylindrical pores were prepared. The surface of the MSNs was modified with either (3-aminopropyl) [...] Read more.
To investigate the impact of the surface functionalization of mesoporous silica nanoparticle (MSN) carriers in the physical state, molecular mobility and the release of Fenofibrate (FNB) MSNs with ordered cylindrical pores were prepared. The surface of the MSNs was modified with either (3-aminopropyl) triethoxysilane (APTES) or trimethoxy(phenyl)silane (TMPS), and the density of the grafted functional groups was quantified via 1H-NMR. The incorporation in the ~3 nm pores of the MSNs promoted FNB amorphization, as evidenced via FTIR, DSC and dielectric analysis, showing no tendency to undergo recrystallization in opposition to the neat drug. Moreover, the onset of the glass transition was slightly shifted to lower temperatures when the drug was loaded in unmodified MSNs, and MSNs modified with APTES composite, while it increased in the case of TMPS-modified MSNs. Dielectric studies have confirmed these changes and allowed researchers to disclose the broad glass transition in multiple relaxations associated with different FNB populations. Moreover, DRS showed relaxation processes in dehydrated composites associated with surface-anchored FNB molecules whose mobility showed a correlation with the observed drug release profiles. Full article
(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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17 pages, 3770 KiB  
Article
Kinetics of Water-Induced Amorphous Phase Separation in Amorphous Solid Dispersions via Raman Mapping
by Adrian Krummnow, Andreas Danzer, Kristin Voges, Samuel O. Kyeremateng, Matthias Degenhardt and Gabriele Sadowski
Pharmaceutics 2023, 15(5), 1395; https://doi.org/10.3390/pharmaceutics15051395 - 02 May 2023
Cited by 1 | Viewed by 1903
Abstract
The poor bioavailability of an active pharmaceutical ingredient (API) can be enhanced by dissolving it in a polymeric matrix. This formulation strategy is commonly known as amorphous solid dispersion (ASD). API crystallization and/or amorphous phase separation can be detrimental to the bioavailability. Our [...] Read more.
The poor bioavailability of an active pharmaceutical ingredient (API) can be enhanced by dissolving it in a polymeric matrix. This formulation strategy is commonly known as amorphous solid dispersion (ASD). API crystallization and/or amorphous phase separation can be detrimental to the bioavailability. Our previous work (Pharmaceutics 2022, 14(9), 1904) provided analysis of the thermodynamics underpinning the collapse of ritonavir (RIT) release from RIT/poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) ASDs due to water-induced amorphous phase separation. This work aimed for the first time to quantify the kinetics of water-induced amorphous phase separation in ASDs and the compositions of the two evolving amorphous phases. Investigations were performed via confocal Raman spectroscopy, and spectra were evaluated using so-called Indirect Hard Modeling. The kinetics of amorphous phase separation were quantified for 20 wt% and 25 wt% drug load (DL) RIT/PVPVA ASDs at 25 °C and 94% relative humidity (RH). The in situ measured compositions of the evolving phases showed excellent agreement with the ternary phase diagram of the RIT/PVPVA/water system predicted by PC-SAFT in our previous study (Pharmaceutics 2022, 14(9), 1904). Full article
(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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16 pages, 3498 KiB  
Article
Veering to a Continuous Platform of Fused Deposition Modeling Based 3D Printing for Pharmaceutical Dosage Forms: Understanding the Effect of Layer Orientation on Formulation Performance
by Vineet R. Kulkarni, Jaidev Chakka, Faez Alkadi and Mohammed Maniruzzaman
Pharmaceutics 2023, 15(5), 1324; https://doi.org/10.3390/pharmaceutics15051324 - 23 Apr 2023
Viewed by 1621
Abstract
Three-dimensional (3D) printing of pharmaceuticals has been centered around the idea of personalized patient-based ‘on-demand’ medication. Fused deposition modeling (FDM)-based 3D printing processes provide the capability to create complex geometrical dosage forms. However, the current FDM-based processes are associated with printing lag time [...] Read more.
Three-dimensional (3D) printing of pharmaceuticals has been centered around the idea of personalized patient-based ‘on-demand’ medication. Fused deposition modeling (FDM)-based 3D printing processes provide the capability to create complex geometrical dosage forms. However, the current FDM-based processes are associated with printing lag time and manual interventions. The current study tried to resolve this issue by utilizing the dynamic z-axis to continuously print drug-loaded printlets. Fenofibrate (FNB) was formulated with hydroxypropyl methylcellulose (HPMC AS LG) into an amorphous solid dispersion using the hot-melt extrusion (HME) process. Thermal and solid-state analyses were used to confirm the amorphous state of the drug in both polymeric filaments and printlets. Printlets with a 25, 50, and 75% infill density were printed using the two printing systems, i.e., continuous, and conventional batch FDM printing methods. Differences between the two methods were observed in the breaking force required to break the printlets, and these differences reduced as the infill density went up. The effect on in vitro release was significant at lower infill densities but reduced at higher infill densities. The results obtained from this study can be used to understand the formulation and process control strategies when switching from conventional FDM to the continuous printing of 3D-printed dosage forms. Full article
(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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28 pages, 7333 KiB  
Article
Evidence of Strong Guest–Host Interactions in Simvastatin Loaded in Mesoporous Silica MCM-41
by Teresa Cordeiro, Inês Matos, Florence Danède, João C. Sotomayor, Isabel M. Fonseca, Marta C. Corvo, Madalena Dionísio, María Teresa Viciosa, Frédéric Affouard and Natália T. Correia
Pharmaceutics 2023, 15(5), 1320; https://doi.org/10.3390/pharmaceutics15051320 - 22 Apr 2023
Cited by 1 | Viewed by 1703
Abstract
A rational design of drug delivery systems requires in-depth knowledge not only of the drug itself, in terms of physical state and molecular mobility, but also of how it is distributed among a carrier and its interactions with the host matrix. In this [...] Read more.
A rational design of drug delivery systems requires in-depth knowledge not only of the drug itself, in terms of physical state and molecular mobility, but also of how it is distributed among a carrier and its interactions with the host matrix. In this context, this work reports the behavior of simvastatin (SIM) loaded in mesoporous silica MCM-41 matrix (average pore diameter ~3.5 nm) accessed by a set of experimental techniques, evidencing that it exists in an amorphous state (X-ray diffraction, ssNMR, ATR-FTIR, and DSC). The most significant fraction of SIM molecules corresponds to a high thermal resistant population, as shown by thermogravimetry, and which interacts strongly with the MCM silanol groups, as revealed by ATR-FTIR analysis. These findings are supported by Molecular Dynamics (MD) simulations predicting that SIM molecules anchor to the inner pore wall through multiple hydrogen bonds. This anchored molecular fraction lacks a calorimetric and dielectric signature corresponding to a dynamically rigid population. Furthermore, differential scanning calorimetry showed a weak glass transition that is shifted to lower temperatures compared to bulk amorphous SIM. This accelerated molecular population is coherent with an in-pore fraction of molecules distinct from bulklike SIM, as highlighted by MD simulations. MCM-41 loading proved to be a suitable strategy for a long-term stabilization (at least three years) of simvastatin in the amorphous form, whose unanchored population releases at a much higher rate compared to the crystalline drug dissolution. Oppositely, the surface-attached molecules are kept entrapped inside pores even after long-term release assays. Full article
(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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22 pages, 5052 KiB  
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 6 | Viewed by 2600
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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20 pages, 8370 KiB  
Article
Nanoseeded Desupersaturation and Dissolution Tests for Elucidating Supersaturation Maintenance in Amorphous Solid Dispersions
by Gulenay Guner, Ayesha Amjad, Matthew Berrios, Manisha Kannan and Ecevit Bilgili
Pharmaceutics 2023, 15(2), 450; https://doi.org/10.3390/pharmaceutics15020450 - 30 Jan 2023
Cited by 5 | Viewed by 2030
Abstract
The impact of residual drug crystals that are formed during the production and storage of amorphous solid dispersions (ASDs) has been studied using micron-sized seed crystals in solvent-shift (desupersaturation) and dissolution tests. This study examines the impacts of the seed size loading on [...] Read more.
The impact of residual drug crystals that are formed during the production and storage of amorphous solid dispersions (ASDs) has been studied using micron-sized seed crystals in solvent-shift (desupersaturation) and dissolution tests. This study examines the impacts of the seed size loading on the solution-mediated precipitation from griseofulvin ASDs. Nanoparticle crystals (nanoseeds) were used as a more realistic surrogate for residual crystals compared with conventional micron-sized seeds. ASDs of griseofulvin with Soluplus (Sol), Kollidon VA64 (VA64), and hydroxypropyl methyl cellulose (HPMC) were prepared by spray-drying. Nanoseeds produced by wet media milling were used in the dissolution and desupersaturation experiments. DLS, SEM, XRPD, and DSC were used for characterization. The results from the solvent-shift tests suggest that the drug nanoseeds led to a faster and higher extent of desupersaturation than the as-received micron-sized crystals and that the higher seed loading facilitated desupersaturation. Sol was the only effective nucleation inhibitor; the overall precipitation inhibition capability was ranked: Sol > HPMC > VA64. In the dissolution tests, only the Sol-based ASDs generated significant supersaturation, which decreased upon an increase in the nanoseed loading. This study has demonstrated the importance of using drug nanocrystals in lieu of conventional coarse crystals in desupersaturation and dissolution tests in ASD development. Full article
(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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20 pages, 2815 KiB  
Article
Improving the Bioactivity of Norfloxacin with Tablets Made from Paper
by Ayat Abdelkader, Laura Nallbati and Cornelia M. Keck
Pharmaceutics 2023, 15(2), 375; https://doi.org/10.3390/pharmaceutics15020375 - 21 Jan 2023
Cited by 2 | Viewed by 1781
Abstract
(1) Background: Many drugs possess poor bioavailability, and many strategies are available to overcome this issue. In this study, smartFilm technology, i.e., a porous cellulose matrix (paper), in which the active compound can be loaded onto in an amorphous state was utilised for [...] Read more.
(1) Background: Many drugs possess poor bioavailability, and many strategies are available to overcome this issue. In this study, smartFilm technology, i.e., a porous cellulose matrix (paper), in which the active compound can be loaded onto in an amorphous state was utilised for oral administration to improve the solubility and bioactivity of a poorly soluble BSC class IV antibiotic. (2) Methods: Norfloxacin was used as the model drug and loaded into commercially available paper. The resulting norfloxacin-loaded smartFilms were transformed into smartFilm granules via wet granulation and the resulting norfloxacin-loaded smartFilm granules were transformed into norfloxacin-loaded tablets made from paper, i.e., smartFilm tablets. The crystalline state of norfloxacin was investigated, as well as the pharmaceutical properties of the granules and the tablets. The bioactivity of the smartFilm tablets was assessed in vitro and ex vivo to determine the antibacterial activity of norfloxacin. The results were compared to a physical mixture tablet that contained non-loaded paper granules and equal amounts of norfloxacin as a crystalline powder. (3) Results: Norfloxacin-loaded smartFilm granules and norfloxacin-loaded smartFilm tablets contained norfloxacin in an amorphous state, which resulted in an improved and faster release of norfloxacin when compared to the physical mixture tablet. The bioactivity was up to three times higher when compared to the physical mixture tablet. The ex vivo model was demonstrated to be a useful tool that allows for a fast and cost-effective discrimination between “good” and “bad” formulations. It provides realistic physiological conditions and can therefore yield meaningful, additional biopharmaceutical information that cannot be assessed in classical in vitro experiments. (4) Conclusions: smartFilm tablets are a promising, universal, industrially feasible and cost-effective formulation strategy for improved solubility and enhanced bioactivity of poorly soluble drugs. Full article
(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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13 pages, 8464 KiB  
Article
Mechanism for Stabilizing an Amorphous Drug Using Amino Acids within Co-Amorphous Blends
by Yannick Guinet, Laurent Paccou and Alain Hédoux
Pharmaceutics 2023, 15(2), 337; https://doi.org/10.3390/pharmaceutics15020337 - 19 Jan 2023
Cited by 3 | Viewed by 1418
Abstract
Designing co-amorphous formulations is now recognized as a relevant strategy for improving the bioavailability of low-molecular-weight drugs. In order to determine the most suitable low-molecular-weight excipients for stabilizing the drug in the amorphous state, screening methods were developed mostly using amino acids as [...] Read more.
Designing co-amorphous formulations is now recognized as a relevant strategy for improving the bioavailability of low-molecular-weight drugs. In order to determine the most suitable low-molecular-weight excipients for stabilizing the drug in the amorphous state, screening methods were developed mostly using amino acids as co-formers. The present study focused on the analysis of the thermal stability of co-amorphous blends prepared by cryo-milling indomethacin with several amino acids in order to understand the stabilization mechanism of the drug in the amorphous state. Combining low- and mid-frequency Raman investigations has provided information on the relation between the physical properties of the blends and those of the H-bond network of the amorphous drug. This study revealed the surprising capabilities of L-arginine to stiffen the H-bond network in amorphous indomethacin and to drastically improve the stability of its amorphous state. As a consequence, this study suggests that amino acids can be considered as stiffeners of the H-bond network of indomethacin, thereby improving the stability of the amorphous state. Full article
(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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19 pages, 3722 KiB  
Article
Eutectic Mixture Formation and Relaxation Dynamics of Coamorphous Mixtures of Two Benzodiazepine Drugs
by Sofia Valenti, Claudio Cazorla, Michela Romanini, Josep Lluís Tamarit and Roberto Macovez
Pharmaceutics 2023, 15(1), 196; https://doi.org/10.3390/pharmaceutics15010196 - 05 Jan 2023
Cited by 1 | Viewed by 1690
Abstract
The formation of coamorphous mixtures of pharmaceuticals is an interesting strategy to improve the solubility and bioavailability of drugs, while at the same time enhancing the kinetic stability of the resulting binary glass and allowing the simultaneous administration of two active principles. In [...] Read more.
The formation of coamorphous mixtures of pharmaceuticals is an interesting strategy to improve the solubility and bioavailability of drugs, while at the same time enhancing the kinetic stability of the resulting binary glass and allowing the simultaneous administration of two active principles. In this contribution, we describe kinetically stable amorphous binary mixtures of two commercial active pharmaceutical ingredients, diazepam and nordazepam, of which the latter, besides being administered as a drug on its own, is also the main active metabolite of the other in the human body. We report the eutectic equilibrium-phase diagram of the binary mixture, which is found to be characterized by an experimental eutectic composition of 0.18 molar fraction of nordazepam, with a eutectic melting point of Te = 395.4 ± 1.2 K. The two compounds are barely miscible in the crystalline phase. The mechanically obtained mixtures were melted and supercooled to study the glass-transition and molecular-relaxation dynamics of amorphous mixtures at the corresponding concentration. The glass-transition temperature was always higher than room temperature and varied linearly with composition. The Te was lower than the onset of thermal decomposition of either compound (pure nordazepam decomposes upon melting and pure diazepam well above its melting point), thus implying that the eutectic liquid and glass can be obtained without any degradation of the drugs. The eutectic glass was kinetically stable against crystallization for at least a few months. The relaxation processes of the amorphous mixtures were studied by dielectric spectroscopy, which provided evidence for a single structural (α) relaxation, a single Johari–Goldstein (β) relaxation, and a ring-inversion conformational relaxation of the diazepinic ring, occurring on the same timescale in both drugs. We further characterized both the binary mixtures and pure compounds by FTIR spectroscopy and first-principles density functional theory (DFT) simulations to analyze intermolecular interactions. The DFT calculations confirm the presence of strong attractive forces within the heteromolecular dimer, leading to large dimer interaction energies of the order of −0.1 eV. Full article
(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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15 pages, 3374 KiB  
Article
Inhibition of Liquid–Liquid Phase Separation for Breaking the Solubility Barrier of Amorphous Solid Dispersions to Improve Oral Absorption of Naftopidil
by Masafumi Fukiage, Kyosuke Suzuki, Maki Matsuda, Yohei Nishida, Michinori Oikawa, Takuya Fujita and Kohsaku Kawakami
Pharmaceutics 2022, 14(12), 2664; https://doi.org/10.3390/pharmaceutics14122664 - 30 Nov 2022
Cited by 4 | Viewed by 1382
Abstract
Amorphous solid dispersion (ASD) is one of the most promising technologies for improving the oral absorption of poorly soluble compounds. In this study, naftopidil (NFT) ASDs were prepared using vinylpyrrolidone-vinyl acetate copolymer (PVPVA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and poly(methacrylic acid-co-methyl methacrylate) L100-55 [...] Read more.
Amorphous solid dispersion (ASD) is one of the most promising technologies for improving the oral absorption of poorly soluble compounds. In this study, naftopidil (NFT) ASDs were prepared using vinylpyrrolidone-vinyl acetate copolymer (PVPVA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and poly(methacrylic acid-co-methyl methacrylate) L100-55 (Eudragit) to improve the dissolution and oral absorption behaviors of NFT. During the dissolution process of ASD, liquid–liquid phase separation (LLPS) may occur when certain requirements are met for providing a maximum quasi-stable concentration achievable by amorphization. The occurrence of LLPS was confirmed in the presence of PVPVA and HPMCAS; however, Eudragit inhibited LLPS owing to its molecular interaction with NFT. Although the dissolution behavior of the Eudragit ASD was found to be markedly poorer than that of other ASDs, it offered the best oral absorption in rats. The findings of the current study highlight the possibility for improving the oral absorption of poorly soluble drugs by this ASD, which should be eliminated from candidate formulations based on the conventional in vitro tests. Full article
(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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11 pages, 2358 KiB  
Article
Amorphicity and Aerosolization of Soluplus-Based Inhalable Spray Dried Powders
by Bishal Raj Adhikari and Shyamal C. Das
Pharmaceutics 2022, 14(12), 2618; https://doi.org/10.3390/pharmaceutics14122618 - 27 Nov 2022
Cited by 1 | Viewed by 1587
Abstract
Soluplus is a polymer that has been explored to prepare nanocomposites for pulmonary drug delivery and is non-toxic. However, its aerosolization attributes when spray-dried have not been investigated. Hence, this work aimed to investigate the aerosol performance of soluplus-based spray-dried powders. In addition, [...] Read more.
Soluplus is a polymer that has been explored to prepare nanocomposites for pulmonary drug delivery and is non-toxic. However, its aerosolization attributes when spray-dried have not been investigated. Hence, this work aimed to investigate the aerosol performance of soluplus-based spray-dried powders. In addition, the potential use of leucine to improve the aerosolization of such particles was also investigated by including leucine at 10 or 20% w/w. 4% w/w salbutamol was used as a model drug in all the formulations primarily to aid quantification during aerosolization evaluation and for assessing the interaction between the drug and soluplus using infrared spectroscopy with the multivariate analysis approach of principal component analysis (PCA). Three formulations (4% salbutamol/96% soluplus, 4% salbutamol/86% soluplus/10% leucine, 4% salbutamol/76% soluplus/20% leucine) were prepared. The formulations were characterized in terms of solid-state, water content, particle size/morphology, and aerosolization. Similarly, two additional formulations (14% salbutamol/86% soluplus and 24% salbutamol/76% soluplus) were prepared to assess potential non-covalent interactions between salbutamol and soluplus. The formulations with only salbutamol and soluplus were amorphous, as evident from X-ray diffraction. Leucine was crystalline in the formulations. All the spray-dried formulations were irregular spheres with surface corrugation. The 96% soluplus powder showed an emitted fraction (EF) and fine particles fraction (FPF) of 91.9 and 49.8%, respectively. The inclusion of leucine at 10% did not increase the EF; however, an increase in FPF (69.7%) was achieved with 20% leucine. PCA of the infrared spectra suggested potential non-covalent interactions between salbutamol and soluplus. It hinted at the potential involvement of ketone groups of the excipient. This study concludes that soluplus-based spray-dried powder with or without leucine can potentially be utilized for pulmonary drug delivery. In addition, PCA can effectively be utilized in assessing interactions and overcoming limitations associated with visual assessment of the spectra of such formulations. Full article
(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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14 pages, 2552 KiB  
Article
Oral Delivery of Niclosamide as an Amorphous Solid Dispersion That Generates Amorphous Nanoparticles during Dissolution
by Miguel O. Jara, Zachary N. Warnken, Sawittree Sahakijpijarn, Rishi Thakkar, Vineet R. Kulkarni, Dale J. Christensen, John J. Koleng and Robert O. Williams III.
Pharmaceutics 2022, 14(12), 2568; https://doi.org/10.3390/pharmaceutics14122568 - 23 Nov 2022
Cited by 6 | Viewed by 2852
Abstract
Niclosamide is an FDA-approved anthelmintic that is being studied in clinical trials as a chemotherapeutic and broad-spectrum antiviral. Additionally, several other applications are currently in the preclinical stage. Unfortunately, niclosamide is a poorly water soluble molecule, with reduced oral bioavailability, which hinders its [...] Read more.
Niclosamide is an FDA-approved anthelmintic that is being studied in clinical trials as a chemotherapeutic and broad-spectrum antiviral. Additionally, several other applications are currently in the preclinical stage. Unfortunately, niclosamide is a poorly water soluble molecule, with reduced oral bioavailability, which hinders its use for new indications. Moreover, niclosamide is a poor glass former; in other words, the molecule has a high tendency to recrystallize, and it is virtually impossible to generate a stable amorphous solid employing the neat molecule. Previously, our group reported the development of an amorphous solid dispersion (ASD) of niclosamide (niclosamide ASD) that generates nanoparticles during its dissolution, not only increasing niclosamide’s apparent solubility from 6.6 ± 0.4 to 481.7 ± 22.2 µg/mL in fasted state simulated intestinal fluid (FaSSIF) but also its oral bioavailability 2.6-fold in Sprague–Dawley rats after being administered as a suspension. Nevertheless, niclosamide ASD undergoes recrystallization in acidic media, and an enteric oral dosage form is needed for its translation into the clinic. In this work, we further characterized the nanoparticles that generated during the dissolution of the niclosamide ASD. Cryogenic transmission electron microscopy (Cryo-TEM) and wide-angle X-ray scattering (WAXS) revealed that the nanoparticles were amorphous and had a particle size of ~150 nm. The oral dosage forms of niclosamide ASD were formulated using commercial enteric capsules (Capsuline® and EudracapTM) and as enteric-coated tablets. The enteric dosage forms were tested using pH-shift dissolution and acid-uptake tests, using the USP type II dissolution apparatus and the disintegration apparatus, respectively. The capsules exhibited a higher percentage of weight gain, and visual rupture of the Capsuline capsules was observed. Eudracap capsules protected the formulation from the acidic media, but polymer gelling and the formation of a nondispersible plug were noted during dissolution testing. In contrast, enteric-coated tablets protected the formulation from acid ingress and maintained the performance of niclosamide ASD granules during dissolution in FaSSIF media. These enteric-coated tablets were administered to beagle dogs at a niclosamide dose of 75 mg/kg, resulting in plasma concentrations of niclosamide higher than those reported in the literature using solubilized niclosamide at a higher dose (i.e., 100 mg/kg). In summary, an enteric oral dosage form of niclosamide ASD was formulated without hindering the generation of nanoparticles while maintaining the increase in the niclosamide’s apparent solubility. The enteric-coated tablets successfully increased the niclosamide plasma levels in dogs when compared to a niclosamide solution prepared using organic solvents. Full article
(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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20 pages, 24662 KiB  
Article
Evaluation of Different Thermoanalytical Methods for the Analysis of the Stability of Naproxen-Loaded Amorphous Solid Dispersions
by Edina Szabó, Anna Haraszti, Petra Záhonyi, Dániel Vadas, István Csontos, Zsombor Kristóf Nagy, Guy Van den Mooter and György Marosi
Pharmaceutics 2022, 14(11), 2508; https://doi.org/10.3390/pharmaceutics14112508 - 18 Nov 2022
Cited by 1 | Viewed by 1629
Abstract
The aim of this research was to investigate three thermoanalytical techniques from the glass transition temperature (Tg) determination point of view. In addition, the examination of the correlation between the measured Tg values and the stability of the amorphous solid [...] Read more.
The aim of this research was to investigate three thermoanalytical techniques from the glass transition temperature (Tg) determination point of view. In addition, the examination of the correlation between the measured Tg values and the stability of the amorphous solid dispersions (ASDs) was also an important part of the work. The results showed that a similar tendency of the Tg can be observed in the case of the applied methods. However, Tg values measured by thermally stimulated depolarization currents showed higher deviation from the theoretical calculations than the values measured by modulated differential scanning calorimetry, referring better to the drug-polymer interactions. Indeed, the investigations after the stress stability tests revealed that micro-thermal analysis can indicate the most sensitive changes in the Tg values, better indicating the instability of the samples. In addition to confirming that the active pharmaceutical ingredient content is a crucial factor in the stability of ASDs containing naproxen and poly(vinylpyrrolidone-co-vinyl acetate), it is worthwhile applying orthogonal techniques to better understand the behavior of ASDs. The development of stable ASDs can be facilitated via mapping the molecular mobilities with suitable thermoanalytical methods. Full article
(This article belongs to the Special Issue Recent Advances in Amorphous Drug)
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