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15 pages, 2294 KiB

Open AccessArticle

Amorphous Form of Carvedilol Phosphate—The Case of Divergent Properties

by Szymon Sip, Natalia Rosiak, Andrzej Miklaszewski, Patrycja Talarska, Ewa Dudziec and Judyta Cielecka-Piontek

Molecules 2021, 26(17), 5318; https://doi.org/10.3390/molecules26175318 - 1 Sep 2021

Cited by 6 | Viewed by 2755

Abstract

The amorphous form of carvedilol phosphate (CVD) was obtained as a result of grinding. The identity of the obtained amorphous form was confirmed by powder X-ray diffraction (PXRD), different scanning calorimetry (DSC), and FT-IR spectroscopy. The process was optimized in order to obtain [...] Read more.

The amorphous form of carvedilol phosphate (CVD) was obtained as a result of grinding. The identity of the obtained amorphous form was confirmed by powder X-ray diffraction (PXRD), different scanning calorimetry (DSC), and FT-IR spectroscopy. The process was optimized in order to obtain the appropriate efficiency and time. The crystalline form of CVD was used as the reference standard. Solid dispersions of crystalline and amorphous CVD forms with hydrophilic polymers (hydroxypropyl-β-cyclodextrin, Pluronic^® F-127, and Soluplus^®) were obtained. Their solubility at pH 1.2 and 6.8 was carried out, as well as their permeation through a model system of biological membranes suitable for the gastrointestinal tract (PAMPA-GIT) was established. The influence of selected polymers on CVD properties was defined for the amorphous form regarding the crystalline form of CVD. As a result of grinding (four milling cycles lasting 15 min with 5 min breaks), amorphous CVD was obtained. Its presence was confirmed by the “halo effect” on the diffraction patterns, the disappearance of the peak at 160.5 °C in the thermograms, and the changes in position/disappearance of many characteristic bands on the FT-IR spectra. As a result of changes in the CVD structure, its lower solubility at pH 1.2 and pH 6.8 was noted. While the amorphous dispersions of CVD, especially with Pluronic^® F-127, achieved better solubility than combinations of crystalline forms with excipients. Using the PAMPA-GIT model, amorphous CVD was assessed as high permeable (Papp > 1 × 10⁻⁶ cm/s), similarly with its amorphous dispersions with excipients (hydroxypropyl-β-cyclodextrin, Pluronic^® F-127, and Soluplus^®), although in their cases, the values of apparent constants permeability were decreased. Full article

(This article belongs to the Special Issue Active Pharmaceutical Ingredient (API): Synthetic Strategies and Characterization)

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14 pages, 1699 KiB

Open AccessArticle

Two Crystal Forms of a Hydrated 2:1 β-Cyclodextrin Fluconazole Complex: Single Crystal X-ray Structures, Dehydration Profiles, and Conditions for Their Individual Isolation

by Andrea Sala, Zakiena Hoossen, Alessia Bacchi and Mino R. Caira

Molecules 2021, 26(15), 4427; https://doi.org/10.3390/molecules26154427 - 22 Jul 2021

Cited by 9 | Viewed by 2532

Abstract

Inclusion complexes between cyclodextrins (CDs) and active pharmaceutical ingredients (APIs) have potential for pharmaceutical formulation. Since crystallization of a given complex may result in the isolation of multiple crystal forms, it is essential to characterize these forms with respect to their structures and [...] Read more.

Inclusion complexes between cyclodextrins (CDs) and active pharmaceutical ingredients (APIs) have potential for pharmaceutical formulation. Since crystallization of a given complex may result in the isolation of multiple crystal forms, it is essential to characterize these forms with respect to their structures and physicochemical properties to optimize pharmaceutical candidate selection. Here, we report the preparation and characterization of two crystallographically distinct hydrated forms of an inclusion complex between β-cyclodextrin (β-CD) and the antifungal API fluconazole (FLU) as well as temperature–concentration conditions required for their individual isolation. Determination of crystal water contents was achieved using thermoanalytical methods. X-ray analyses revealed distinct structural differences between the triclinic (TBCDFLU, space group P1) and monoclinic (MBCDFLU, space group C2) crystal forms. Removal of the crystals from their mother liquors led to rapid dehydration of the MBCDFLU crystal, while the TBCDFLU crystal was stable, a result that could be reconciled with the distinct packing arrangements in the respective crystals. This study highlights (a) the importance of identifying possible multiple forms of a cyclodextrin API complex and controlling the crystallization conditions, and (b) the need to characterize such crystal forms to determine the extent to which their physicochemical properties may differ. Full article

(This article belongs to the Special Issue Active Pharmaceutical Ingredient (API): Synthetic Strategies and Characterization)

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11 pages, 2131 KiB

Open AccessArticle

Synthesis of Zinc Oxide Nanoparticles Using Rubus fairholmianus Root Extract and Their Activity against Pathogenic Bacteria

by Naresh Kumar Rajendran, Blassan P. George, Nicolette N. Houreld and Heidi Abrahamse

Molecules 2021, 26(10), 3029; https://doi.org/10.3390/molecules26103029 - 19 May 2021

Cited by 80 | Viewed by 4794

Abstract

Recently, the biosynthesis of zinc oxide nanoparticles (ZnO NPs) from crude extracts and phytochemicals has attracted much attention. Green synthesis of NPs is cost-effective, eco-friendly, and is a promising alternative for chemical synthesis. This study involves ZnO NPs synthesis using Rubus fairholmianus root [...] Read more.

Recently, the biosynthesis of zinc oxide nanoparticles (ZnO NPs) from crude extracts and phytochemicals has attracted much attention. Green synthesis of NPs is cost-effective, eco-friendly, and is a promising alternative for chemical synthesis. This study involves ZnO NPs synthesis using Rubus fairholmianus root extract (RE) as an efficient reducing agent. The UV spectrum of RE-ZnO NPs exhibited a peak at 357 nm due to intrinsic bandgap absorption and an XRD pattern that matches the ZnO crystal structure (JCPDS card no: 36-1451). The average particle size calculated from the Debye–Scherrer equation is 11.34 nm. SEM analysis showed that the RE-ZnO NPs spherical in shape with clusters (1–100 nm). The antibacterial activity of the NPs was tested against Staphylococcus aureus using agar well diffusion, minimum inhibitory concentration, and bacterial growth assay. The R. fairholmianus phytochemicals facilitate the synthesis of stable ZnO NPs and showed antibacterial activity. Full article

(This article belongs to the Special Issue Active Pharmaceutical Ingredient (API): Synthetic Strategies and Characterization)

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11 pages, 2375 KiB

Open AccessArticle

Synthesis, Characterization and HPLC Analysis of the (1S,2S,5R)-Diastereomer and the Enantiomer of the Clinical Candidate AR-15512

by Sergio Rodríguez-Arévalo, Eugènia Pujol, Sònia Abás, Carles Galdeano, Carmen Escolano and Santiago Vázquez

Molecules 2021, 26(4), 906; https://doi.org/10.3390/molecules26040906 - 9 Feb 2021

Cited by 2 | Viewed by 3556

Abstract

AR-15512 (formerly known as AVX-012 and WS-12) is a TRPM8 receptor agonist currently in phase 2b clinical trials for the treatment of dry eye. This bioactive compound with menthol-like cooling activity has three stereogenic centers, and its final structure and absolute configuration, (1 [...] Read more.

AR-15512 (formerly known as AVX-012 and WS-12) is a TRPM8 receptor agonist currently in phase 2b clinical trials for the treatment of dry eye. This bioactive compound with menthol-like cooling activity has three stereogenic centers, and its final structure and absolute configuration, (1R,2S,5R), have been previously solved by cryo-electron microscopy. The route of synthesis of AR-15512 has also been reported, revealing that epimerization processes at the C-1 can occur at specific stages of the synthesis. In order to confirm that the desired configuration of AR-15512 does not change throughout the process and to discard the presence of the enantiomer in the final product due to possible contamination of the initial starting material, both the enantiomer of AR-15512 and the diastereomer at the C-1 were synthesized and fully characterized. In addition, the absolute configuration of the (1S,2S,5R)-diastereomer was determined by X-ray crystallographic analysis, and new HPLC methods were designed and developed for the identification of the two stereoisomers and their comparison with the clinical candidate AR-15512. Full article

(This article belongs to the Special Issue Active Pharmaceutical Ingredient (API): Synthetic Strategies and Characterization)

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15 pages, 3869 KiB

Open AccessArticle

Analysis of a “3-(Naphthalen-1-ylimino)indolin-2-one” Compound and Its Antimicrobial Assessment Using Lipid-Based Self-Nanoemulsifying Formulations

by Saeed Ali Syed, Ahmed Bari, Mohammed S. Aldughaim, Md Abdur Rashid, Mohammad Hossain Shariare and Mohsin Kazi

Molecules 2021, 26(1), 15; https://doi.org/10.3390/molecules26010015 - 22 Dec 2020

Viewed by 2037

Abstract

In recent years, indole derivatives have acquired conspicuous significance due to their wide spectrum of biological activities—antibacterial, antiviral, and anticonvulsant. This compound is derived from naturally grown plants. Therefore, synthesis of a novel “3-(Naphthalen-1-ylimino)indolin-2-one” compound (2) and its analysis using UPLC [...] Read more.

In recent years, indole derivatives have acquired conspicuous significance due to their wide spectrum of biological activities—antibacterial, antiviral, and anticonvulsant. This compound is derived from naturally grown plants. Therefore, synthesis of a novel “3-(Naphthalen-1-ylimino)indolin-2-one” compound (2) and its analysis using UPLC systems along with antimicrobial assessment was the aim of the current study. Isatin was used as a parent drug for synthesizing compound (2). Liquid Chromatographic analysis was performed using a C18 BEH column (1.7 μm 2.1 × 50 mm) by UPLC systems. Degradation studies were carried out to see whether acid, base, thermal, and oxidizing agents had any impact on the synthesized molecule in stress conditions (100 °C). A lipid-based self-nanoemulsifying formulation was developed and selectivity, specificity, recovery, accuracy, and precision were measured as part of the UPLC system’s validation process. Antimicrobial studies were conducted using gram-positive and gram-negative bacteria. The standard samples were run with a concentration range of 5.0–100.0 μg/mL using the isocratic mobile phase comprising of methanol/water (70/30 %v/v) at 234 nm; good linearity (R² = 0.9998) was found. The lower limits of detection (LOD) and quantitation (LOQ) of the method were found to be 0.81 μg/mL and 2.5 μg/mL, respectively. The coefficients of variation were found to be less than 2%. The antimicrobial study suggests that compound (2) has a substantial growth effect against gram-negative bacteria. It was successfully synthesized and applied to measure the concentrations in lipid-based dosage form, along with potent antimicrobial activities. Full article

(This article belongs to the Special Issue Active Pharmaceutical Ingredient (API): Synthetic Strategies and Characterization)

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Review

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16 pages, 1817 KiB

Open AccessReview

Timeline of the Development of Skin-Lightening Active Ingredients in Japan

by Kazuhisa Maeda

Molecules 2022, 27(15), 4774; https://doi.org/10.3390/molecules27154774 - 26 Jul 2022

Cited by 9 | Viewed by 7314

Abstract

Japanese pharmaceutical cosmetics, often referred to as quasi-drugs, contain skin-lightening active ingredients formulated to prevent sun-induced pigment spots and freckles. Their mechanisms of action include suppressing melanin production in melanocytes and promoting epidermal growth to eliminate melanin more rapidly. For example, arbutin and [...] Read more.

Japanese pharmaceutical cosmetics, often referred to as quasi-drugs, contain skin-lightening active ingredients formulated to prevent sun-induced pigment spots and freckles. Their mechanisms of action include suppressing melanin production in melanocytes and promoting epidermal growth to eliminate melanin more rapidly. For example, arbutin and rucinol are representative skin-lightening active ingredients that inhibit melanin production, and disodium adenosine monophosphate and dexpanthenol are skin-lightening active ingredients that inhibit melanin accumulation in the epidermis. In contrast, oral administration of vitamin C and tranexamic acid in pharmaceutical products can lighten freckles and melasma, and these products are more effective than quasi-drugs. On the basis of their clinical effectiveness, skin-lightening active ingredients can be divided into four categories according to their effectiveness and adverse effects. This review discusses academic research and development regarding skin-lightening ingredients in Japan. Full article

(This article belongs to the Special Issue Active Pharmaceutical Ingredient (API): Synthetic Strategies and Characterization)

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43 pages, 48700 KiB

Open AccessReview

An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis

by Matteo Mori, Stefania Villa, Samuele Ciceri, Diego Colombo, Patrizia Ferraboschi and Fiorella Meneghetti

Molecules 2021, 26(23), 7082; https://doi.org/10.3390/molecules26237082 - 23 Nov 2021

Cited by 3 | Viewed by 2366

Abstract

The elucidation of the structure of enzymes and their complexes with ligands continues to provide invaluable insights for the development of drugs against many diseases, including bacterial infections. After nearly three decades since the World Health Organization’s (WHO) declaration of tuberculosis (TB) as [...] Read more.

The elucidation of the structure of enzymes and their complexes with ligands continues to provide invaluable insights for the development of drugs against many diseases, including bacterial infections. After nearly three decades since the World Health Organization’s (WHO) declaration of tuberculosis (TB) as a global health emergency, Mycobacterium tuberculosis (Mtb) continues to claim millions of lives, remaining among the leading causes of death worldwide. In the last years, several efforts have been devoted to shortening and improving treatment outcomes, and to overcoming the increasing resistance phenomenon. The structural elucidation of enzyme-ligand complexes is fundamental to identify hot-spots, define possible interaction sites, and elaborate strategies to develop optimized molecules with high affinity. This review offers a critical and comprehensive overview of the most recent structural information on traditional and emerging mycobacterial enzymatic targets. A selection of more than twenty enzymes is here discussed, with a special emphasis on the analysis of their binding sites, the definition of the structure–activity relationships (SARs) of their inhibitors, and the study of their main intermolecular interactions. This work corroborates the potential of structural studies, substantiating their relevance in future anti-mycobacterial drug discovery and development efforts. Full article

(This article belongs to the Special Issue Active Pharmaceutical Ingredient (API): Synthetic Strategies and Characterization)

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28 pages, 9435 KiB

Open AccessReview

Crystalline Peroxosolvates: Nature of the Coformer, Hydrogen-Bonded Networks and Clusters, Intermolecular Interactions

by Alexander G. Medvedev, Andrei V. Churakov, Petr V. Prikhodchenko, Ovadia Lev and Mikhail V. Vener

Molecules 2021, 26(1), 26; https://doi.org/10.3390/molecules26010026 - 23 Dec 2020

Cited by 25 | Viewed by 5424

Abstract

Despite the technological importance of urea perhydrate (percarbamide) and sodium percarbonate, and the growing technological attention to solid forms of peroxide, fewer than 45 peroxosolvates were known by 2000. However, recent advances in X-ray diffractometers more than tripled the number of structurally characterized [...] Read more.

Despite the technological importance of urea perhydrate (percarbamide) and sodium percarbonate, and the growing technological attention to solid forms of peroxide, fewer than 45 peroxosolvates were known by 2000. However, recent advances in X-ray diffractometers more than tripled the number of structurally characterized peroxosolvates over the last 20 years, and even more so, allowed energetic interpretation and gleaning deeper insight into peroxosolvate stability. To date, 134 crystalline peroxosolvates have been structurally resolved providing sufficient insight to justify a first review article on the subject. In the first chapter of the review, a comprehensive analysis of the structural databases is carried out revealing the nature of the co-former in crystalline peroxosolvates. In the majority of cases, the coformers can be classified into three groups: (1) salts of inorganic and carboxylic acids; (2) amino acids, peptides, and related zwitterions; and (3) molecular compounds with a lone electron pair on nitrogen and/or oxygen atoms. The second chapter of the review is devoted to H-bonding in peroxosolvates. The database search and energy statistics revealed the importance of intermolecular hydrogen bonds (H-bonds) which play a structure-directing role in the considered crystals. H₂O₂ always forms two H-bonds as a proton donor, the energy of which is higher than the energy of analogous H-bonds existing in isostructural crystalline hydrates. This phenomenon is due to the higher acidity of H₂O₂ compared to water and the conformational mobility of H₂O₂. The dihedral angle H-O-O-H varies from 20 to 180° in crystalline peroxosolvates. As a result, infinite H-bonded 1D chain clusters are formed, consisting of H₂O₂ molecules, H₂O₂ and water molecules, and H₂O₂ and halogen anions. H₂O₂ can form up to four H-bonds as a proton acceptor. The third chapter of the review is devoted to energetic computations and in particular density functional theory with periodic boundary conditions. The approaches are considered in detail, allowing one to obtain the H-bond energies in crystals. DFT computations provide deeper insight into the stability of peroxosolvates and explain why percarbamide and sodium percarbonate are stable to H₂O₂/H₂O isomorphic transformations. The review ends with a description of the main modern trends in the synthesis of crystalline peroxosolvates, in particular, the production of peroxosolvates of high-energy compounds and mixed pharmaceutical forms with antiseptic and analgesic effects. Full article

(This article belongs to the Special Issue Active Pharmaceutical Ingredient (API): Synthetic Strategies and Characterization)

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