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Crystals
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Structural Studies in Drug Discovery and Development: From the Lead...
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Structural Studies in Drug Discovery and Development: From the Lead to the Pharmaceutical Form

A special issue of Crystals (ISSN 2073-4352). This special issue belongs to the section "Crystal Engineering".

Deadline for manuscript submissions: 20 July 2024 | Viewed by 7859

Special Issue Editors

Dr. Matteo Mori

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, Italy
Interests: diffraction techniques; structure elucidation; conformation of bioactive compounds; antitubercular and anticancer agents; metal complexes, protein–protein interaction inhibitors; enzymatic inhibitors; multi-target drugs
Special Issues, Collections and Topics in MDPI journals
Dr. Fiorella Meneghetti

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, Italy
Interests: diffraction techniques; structure elucidation; conformation of bioactive compounds; antitubercular and anticancer agents; metal complexes, protein–protein interaction inhibitors; enzymatic inhibitors; multi-target drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to announce that submissions for the Special Issue of Crystals, entitled “Structural studies in drug discovery and development: from the lead to the pharmaceutical form”, are now open.

Crystallography is an invaluable tool in the pharmaceutical field for the study of both ligands and biological targets. In the early stages of the drug discovery process, single-crystal X-ray diffraction (SC-XRD) is a necessary resource for the synthesis of many compounds. For instance, it supports the correct identification of isomers when the results provided by other techniques prove inconclusive. Even more importantly, it provides a definition for the absolute configuration of stereoisomers. The study of atropisomers or the investigation of the coordination chemistry of metallodrugs constitute other notable examples of the several applications of SC-XRD in drug discovery. Furthermore, the important contribution of structural biology to the definition of the binding mode of compounds to their molecular targets should also be acknowledged. However, the relevance of crystallography is not limited to the lead selection and development phases. An extensive analysis of solid states, especially when focused on the study of the intermolecular interactions and crystal packing, is fundamental for the examination of polymorphic forms and co-crystals. These data are often pivotal for the identification of the most suitable pharmaceutical forms and for determining information based on their solubility and stability.

For this Special Issue, we would be delighted to receive research contributions based on these premises, either in the form of an original research paper, a short communication, or a focus review.

Dr. Matteo Mori
Prof. Dr. Fiorella Meneghetti
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Crystals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • single-crystal x-ray diffraction
  • structural analysis
  • spectroscopic methods
  • spectrometric methods
  • pharmaceutical compounds
  • biologically active molecules
  • organic molecules
  • metal complexes
  • synthetic intermediates
  • atropisomers
  • absolute configuration
  • asymmetric synthesis
  • catalysis
  • mechanistic investigations
  • polymorphism
  • co-crystals
  • solubility

Published Papers (6 papers)

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Research

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16 pages, 3683 KiB  
Article
Mechanochemical Synthesis of Praziquantel Hemihydrate in the Presence of Five Solvents with Different Water Miscibility
by Ilenia D’Abbrunzo, Dario Voinovich and Beatrice Perissutti
Crystals 2024, 14(4), 374; https://doi.org/10.3390/cryst14040374 - 16 Apr 2024
Viewed by 331
Abstract
In this study, we report the mechanochemical synthesis of praziquantel hemihydrate in the presence of five solvents with different water miscibility. The commercially available praziquantel Form A (a racemic anhydrate structure) was ground in the presence of several water–solvent mixtures using two grinding [...] Read more.
In this study, we report the mechanochemical synthesis of praziquantel hemihydrate in the presence of five solvents with different water miscibility. The commercially available praziquantel Form A (a racemic anhydrate structure) was ground in the presence of several water–solvent mixtures using two grinding procedures (i.e., direct liquid-assisted grinding and neat grinding plus liquid-assisted grinding). Five organic solvents (i.e., acetic acid, 2-pyrrolidone, ethanol, ethyl acetate and hexane) were chosen considering their different miscibility with water and their capability to form solvates with praziquantel (documented for acetic acid and 2-pyrrolidone). The results suggested that the use of a second solvent has a detrimental effect on the formation of the hemihydrate. The inclusion of water in the solid is even worse in the case of water-miscible solvents, probably due to the favored interactions between the liquids. In fact, hexane is the only solvent permitting the mechanochemical crystallization of praziquantel hemihydrate to a limited extent. Importantly, interconversion studies between the hydrate/monosolvate/anhydrous forms revealed a preferential inclusion of solvents over water in the crystal lattice when using acetic acid or 2-pyrrolidone and complete dehydration of the hemihydrate and conversion in the most thermodynamically stable polymorph A of praziquantel with ethanol, ethyl acetate and hexane. Full article
(This article belongs to the Special Issue Structural Studies in Drug Discovery and Development: From the Lead to the Pharmaceutical Form)
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10 pages, 7444 KiB  
Article
Use of X-ray Microscopy for Confirmation of Crystallinity Detection in Amorphous Formulations by Electrospray Laser Desorption Ionization Mass Spectrometry Imaging
by Kelsey K. Ramp, Noah R. Dierckman, Margaret A. Sperry, Matthew E. Reuter, Yongan Tang, Gregory K. Webster and Patrick A. McVey
Crystals 2023, 13(10), 1418; https://doi.org/10.3390/cryst13101418 - 24 Sep 2023
Viewed by 757
Abstract
The use of mass spectrometry imaging for crystallinity detection offers improved matrix selectivity and sensitivity over the techniques, such as X-ray microscopy and Raman spectrometry, that are traditionally used with this work. Crystallinity is observed in electrospray laser desorption ionization mass spectrometry imaging [...] Read more.
The use of mass spectrometry imaging for crystallinity detection offers improved matrix selectivity and sensitivity over the techniques, such as X-ray microscopy and Raman spectrometry, that are traditionally used with this work. Crystallinity is observed in electrospray laser desorption ionization mass spectrometry imaging (ELDI-MSI) as a high-intensity agglomeration of the analyte in a spatially resolved image. As this is an indirect method of crystallinity detection, confirmation of this method’s ability to detect crystallization in amorphous formulations is needed by directly correlating observations of tablet crystallinity by ELDI-MSI to those of an established detection technique. Micro-computed tomography (micro-CT) has the necessary sensitivity for this investigation and is ideal for use in evaluating the correlation with crystallinity detection by ELDI-MSI. In this work, micro-CT followed by ELDI-MSI, in the same location on tablets of amorphous formulations of miconazole spiked with trace levels of crystalline miconazole, were analyzed. Crystals detected by ELDI-MSI as an agglomeration spatially matched with the detected crystals but were chemically unidentified by micro-CT. The results of this correlation study and a conclusion about the effectiveness of ELDI-MSI as a complimentary technique to indirectly detect crystallinity in enabling formations of an amorphous API are presented. Full article
(This article belongs to the Special Issue Structural Studies in Drug Discovery and Development: From the Lead to the Pharmaceutical Form)
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22 pages, 5750 KiB  
Article
Glycine Dissolution Behavior under Forced Convection
by Cornelia Eder, Simon A. Schiele, Frederik Luxenburger and Heiko Briesen
Crystals 2023, 13(2), 315; https://doi.org/10.3390/cryst13020315 - 14 Feb 2023
Cited by 1 | Viewed by 1346
Abstract
The integration of a flow-through cell into a Mach–Zehnder interferometer offers the possibility to study the dissolution of crystals in detail. The influence of flow on the displacement velocity of a specific crystal facet and the distribution of the solute concentration around the [...] Read more.
The integration of a flow-through cell into a Mach–Zehnder interferometer offers the possibility to study the dissolution of crystals in detail. The influence of flow on the displacement velocity of a specific crystal facet and the distribution of the solute concentration around the crystal are measured simultaneously in a time-resolved manner. The disintegration from the crystal surface and the mass transfer into the solvent can be separated. We aim to establish an in vitro experiment that improves the quality of prediction for the bioavailability of active pharmaceutical ingredients. In the presented feasibility study, glycine was used as a model substance. It was successfully demonstrated that the set-up is suitable for observing disintegration and mass transfer separately. The description of the dissolution rate in terms of the Sherwood number as a function of Reynolds, Schmidt and Grashof numbers clearly shows that with increasing flow rate there is a transition from natural to forced convection as the dominant mass transfer mechanism. Temporal and spatial resolved concentration fields visualize the convective mass transfer and also show the influence of convection on the diffusive boundary layer. No limitation of the dissolution by surface disintegration could be found in the examined range of flow rates. Full article
(This article belongs to the Special Issue Structural Studies in Drug Discovery and Development: From the Lead to the Pharmaceutical Form)
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21 pages, 5010 KiB  
Article
Crystal Structure, Hirshfeld Surface Analysis, In-Silico and Antimycotic Investigations of Methyl 6-methyl-4-(4-nitrophenyl)-2-oxo-1,2-dihydropyrimidine-5-carboxylate
by Alakbar Huseynzada, Matteo Mori, Fiorella Meneghetti, Aygun Israyilova, Elif Guney, Koray Sayin, Laurent R. Chiarelli, Mustafa Demiralp, Ulviyya Hasanova and Vagif Abbasov
Crystals 2023, 13(1), 52; https://doi.org/10.3390/cryst13010052 - 27 Dec 2022
Cited by 1 | Viewed by 1883
Abstract
Herein, we report the preparation of methyl 6-methyl-4-(4-nitrophenyl)-2-oxo-1,2-dihydropyrimidine-5-carboxylate 2, obtained by the regioselective oxidative dehydrogenation of the dihydropyrimidine derivative 1 in the presence of cerium ammonium nitrate. The structure of compound 2 was investigated by single-crystal X-ray diffraction (SC-XRD), which allowed the [...] Read more.
Herein, we report the preparation of methyl 6-methyl-4-(4-nitrophenyl)-2-oxo-1,2-dihydropyrimidine-5-carboxylate 2, obtained by the regioselective oxidative dehydrogenation of the dihydropyrimidine derivative 1 in the presence of cerium ammonium nitrate. The structure of compound 2 was investigated by single-crystal X-ray diffraction (SC-XRD), which allowed the determination of its tautomeric form. Moreover, the presence of non-covalent interactions and their impact on the crystal structure were analyzed. To better characterize the intermolecular contacts, the Hirshfeld surface and enrichment ratio analyses were performed. Furthermore, the antimycotic activity of compounds 1 and 2 was investigated against Candida albicans, Aspergillus flavus, and Aspergillus niger, and their efficacy was compared to that of fluconazole. Computational investigations on the putative target of the compounds provided insights to explain the better activity of 2 with respect to its synthetic precursor. Full article
(This article belongs to the Special Issue Structural Studies in Drug Discovery and Development: From the Lead to the Pharmaceutical Form)
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13 pages, 2212 KiB  
Article
Antioxidant Quercetin 3-O-Glycosylated Plant Flavonols Contribute to Transthyretin Stabilization
by Lidia Ciccone, Nicolò Tonali, Carole Fruchart-Gaillard, Lucia Barlettani, Armando Rossello, Alessandra Braca, Elisabetta Orlandini and Susanna Nencetti
Crystals 2022, 12(5), 638; https://doi.org/10.3390/cryst12050638 - 29 Apr 2022
Cited by 3 | Viewed by 1896
Abstract
Plants are rich in secondary metabolites, which are often useful as a relevant source of nutraceuticals. Quercetin (QUE) is a flavonol aglycone able to bind Transthyretin (TTR), a plasma protein that under pathological conditions can lose its native structure leading to fibrils formation [...] Read more.
Plants are rich in secondary metabolites, which are often useful as a relevant source of nutraceuticals. Quercetin (QUE) is a flavonol aglycone able to bind Transthyretin (TTR), a plasma protein that under pathological conditions can lose its native structure leading to fibrils formation and amyloid diseases onset. Here, the dual nature of five quercetin 3-O-glycosylated flavonol derivatives, isolated from different plant species, such as possible binders of TTR and antioxidants, was investigated. The crystal structure of 3-O-β-D-galactopyranoside in complex with TTR was solved, suggesting that not only quercetin but also its metabolites can contribute to stabilizing the TTR tetramer. Full article
(This article belongs to the Special Issue Structural Studies in Drug Discovery and Development: From the Lead to the Pharmaceutical Form)
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Review

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30 pages, 11194 KiB  
Review
Exploring Various Crystal and Molecular Structures of Gabapentin—A Review
by Justyna Baranowska and Łukasz Szeleszczuk
Crystals 2024, 14(3), 257; https://doi.org/10.3390/cryst14030257 - 06 Mar 2024
Viewed by 1047
Abstract
Novel antiepileptic drugs have been developed at an unparalleled rate during the past 15 years. Gabapentin (GBP), which was approved for the treatment of refractory localization-related epilepsies in the U.K. and Europe in 1993, was one of the first drugs to come out [...] Read more.
Novel antiepileptic drugs have been developed at an unparalleled rate during the past 15 years. Gabapentin (GBP), which was approved for the treatment of refractory localization-related epilepsies in the U.K. and Europe in 1993, was one of the first drugs to come out of this era. Since then, GBP has become well-known across the world, not only for its antiepileptic qualities but also for its effectiveness in the treatment of chronic pain disorders, particularly neuropathic pain. In this review, the crystal structures of GBP and GBP-related compounds have been analyzed and compared. Particular attention has been paid to the polymorphism of GBP and its hydrates, their thermodynamic stability, and conformational differences. In addition, the puckering parameters for the cyclohexane ring of a total of 118 molecules of GBP found in the analyzed crystal structures have been calculated and analyzed. The results of recent high-pressure crystallization studies and quantum chemical calculations indicate that the entire landscape of GBP has not been revealed yet. Full article
(This article belongs to the Special Issue Structural Studies in Drug Discovery and Development: From the Lead to the Pharmaceutical Form)
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