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Crystals
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Computational and Experimental Approaches in Pharmaceutical Crystals
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Computational and Experimental Approaches in Pharmaceutical Crystals

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

Deadline for manuscript submissions: closed (16 December 2022) | Viewed by 17466

Special Issue Editors

Prof. Dr. Patrizia Rossi

E-Mail Website
Guest Editor
Department of Industrial Engineering, University of Firenze, 50121 Firenze, Italy
Interests: solid-state structure–properties relationship of different classes of compounds; XRPD; polymorphism and pseudopolymorphism; API
Dr. Martina Lippi

E-Mail Website
Guest Editor
Department of Industrial Engineering, University of Firenze, 50121 Firenze, Italy
Interests: crystallography; supramolecular chemistry; material chemistry; cocrystal; drug design

Special Issue Information

Dear Colleagues,

It’s a real pleasure for me to invite you to contribute to the Crystals Special Issue entitled: Computational and Experimental Approach in Pharmaceutical Crystals.

It is well known as solid-state analysis plays a key role in the study of compounds of pharmaceutical interest. In fact, it helps to understand a multiplicity of phenomena like polymorphism and pseudo-polymorphism, intermolecular interactions, solvation and desolvation just to name a few. On the other hand, an experimental approach alone may sometimes not be sufficient to deeply rationalize particular behavior of a pharmaceutical compound; in this case, the possibility to perform theoretical calculations is of great importance. 

In addition to this, a computational approach may help in in the design of compounds having desired properties, in other words this kind of analysis is of fundamental importance for the crystal engineering of well performing APIs (Active pharmaceutical ingredients). 

The special issue on ‘‘Computational and Experimental Approach in Pharmaceutical Crystals’’ is intended to cover both the fields of design and solid-state analysis, by an experimental and computational point of view, of compounds of pharmaceutical interest.

Prof. Dr. Patrizia Rossi
Dr. Martina Lippi
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 2100 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

  • Active Pharmaceutical Ingredients (API)
  • computational methods
  • crystal engineering
  • complementary techniques
  • X-ray diffraction

Published Papers (6 papers)

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Research

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11 pages, 3008 KiB  
Article
A Fast, Low-Cost and Simple Method for Predicting Atomic/Inter-Atomic Properties by Combining a Low Dimensional Deep Learning Model with a Fragment Based Graph Convolutional Network
by Peng Gao, Zonghang Liu, Jie Zhang, Jia-Ao Wang and Graeme Henkelman
Crystals 2022, 12(12), 1740; https://doi.org/10.3390/cryst12121740 - 1 Dec 2022
Cited by 2 | Viewed by 2428
Abstract
Calculations with high accuracy for atomic and inter-atomic properties, such as nuclear magnetic resonance (NMR) spectroscopy and bond dissociation energies (BDEs) are valuable for pharmaceutical molecule structural analysis, drug exploration, and screening. It is important that these calculations should include relativistic effects, which [...] Read more.
Calculations with high accuracy for atomic and inter-atomic properties, such as nuclear magnetic resonance (NMR) spectroscopy and bond dissociation energies (BDEs) are valuable for pharmaceutical molecule structural analysis, drug exploration, and screening. It is important that these calculations should include relativistic effects, which are computationally expensive to treat. Non-relativistic calculations are less expensive but their results are less accurate. In this study, we present a computational framework for predicting atomic and inter-atomic properties by using machine-learning in a non-relativistic but accurate and computationally inexpensive framework. The accurate atomic and inter-atomic properties are obtained with a low dimensional deep neural network (DNN) embedded in a fragment-based graph convolutional neural network (F-GCN). The F-GCN acts as an atomic fingerprint generator that converts the atomistic local environments into data for the DNN, which improves the learning ability, resulting in accurate results as compared to experiments. Using this framework, the 13C/1H NMR chemical shifts of Nevirapine and phenol O–H BDEs are predicted to be in good agreement with experimental measurement. Full article
(This article belongs to the Special Issue Computational and Experimental Approaches in Pharmaceutical Crystals)
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17 pages, 5082 KiB  
Article
Synthesis and Computational and X-ray Structure of 2, 3, 5-Triphenyl Tetrazolium, 5-Ethyl-5-phenylbarbituric Acid Salt
by Ahmed H. Bakheit, Hazem A. Ghabbour, Hadayt Hussain, Rashad Al-Salahi, Essam A. Ali and Gamal A. E. Mostafa
Crystals 2022, 12(12), 1706; https://doi.org/10.3390/cryst12121706 - 24 Nov 2022
Cited by 7 | Viewed by 1428
Abstract
The title compound triphenyl tetrazolium (TPT) of phenobarbital, 5-Ethyl-5-phenylbarbituric acid triphenyl tetrazolium salt (4) was prepared by the reaction of 5-Ethyl-5-phenyl-2,4,6(1H, 3H, 5H)-pyrimidinetrione, monosodium salt (1) with triphenyl tetrazolium chloride (3) in deionized water at an ambient temperature through a cation [...] Read more.
The title compound triphenyl tetrazolium (TPT) of phenobarbital, 5-Ethyl-5-phenylbarbituric acid triphenyl tetrazolium salt (4) was prepared by the reaction of 5-Ethyl-5-phenyl-2,4,6(1H, 3H, 5H)-pyrimidinetrione, monosodium salt (1) with triphenyl tetrazolium chloride (3) in deionized water at an ambient temperature through a cation exchange reaction. Colorless crystals of compound four suitable for an X-ray structural analysis were obtained by slow evaporation from acetonitrile. Compound four had crystallized in the monoclinic space group, P21/c, with a = 15.3678 (9) Å, b = 12.2710 (7) Å, c = 21.8514 (13) Å, β = 109.867 (2)°, V = 3875.5 (4) Å3, and Z = 4. A Through density functional theory (DFT) calculations, the probable molecular association structure in the phenobarbitone -triphenyl tetrazolium solution was studied. With the 6-311G-(d,p) basis set, the gas phase features of the phenobarbital-triphenyl tetrazolium clusters with a phenobarbitone dimer and water molecules, including an optimum structure and intermolecular hydrogen bonding, were investigated in detail. In addition, the positions and strengths of the intermolecular hydrogen bond interactions between the phenobarbitone and triphenyl tetrazolium molecules were analyzed using atoms in molecule (AIM) analysis, reduced density gradient (RDG) methods, the XRD method, and the non-covalent interaction (NCI) index method. In addition, the molecular electrostatic potential (MEP) surfaces were analyzed to determine the electrophilic and nucleophilic centers. Full article
(This article belongs to the Special Issue Computational and Experimental Approaches in Pharmaceutical Crystals)
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9 pages, 871 KiB  
Article
Fast and Efficient Synthesis of Racemic Baloxavir Catalyzed by Strong Solid Acid under Microwave Conditions
by Yiyun Wang, Xiaofang Lv, Zihui Meng, Zhibin Xu, Zhonghui Zheng, Jiarong Li and Min Xue
Crystals 2022, 12(7), 891; https://doi.org/10.3390/cryst12070891 - 23 Jun 2022
Viewed by 1856
Abstract
The compound (±)-12aR-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione is the intermediate of baloxavir marboxil. In the literature, traditional heating methods and common acid catalysts are used, which result in long reaction times and a low yield. Therefore, finding an efficient and environmentally friendly synthetic route is necessary. In [...] Read more.
The compound (±)-12aR-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione is the intermediate of baloxavir marboxil. In the literature, traditional heating methods and common acid catalysts are used, which result in long reaction times and a low yield. Therefore, finding an efficient and environmentally friendly synthetic route is necessary. In this study, (±)-12aR-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-7-benzyloxy-3,4,12,12a-tetrahydro-1h-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 3) was synthesized using a sulfonate resin solid acid catalyst (HND-580) under microwave conditions. The benzyl group was removed without further purification, and an intermediate, racemic baloxavir, was obtained under microwave irradiation. The total yield of the two steps was 78%. This method greatly reduces the reaction time and improves production efficiency. Full article
(This article belongs to the Special Issue Computational and Experimental Approaches in Pharmaceutical Crystals)
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12 pages, 3173 KiB  
Article
A Solid-Solid Phase Transformation of Triclabendazole at High Pressures
by Imran Ali, Jiequn Tang, Yanqiang Han, Zhiyun Wei, Yongli Zhang and Jinjin Li
Crystals 2022, 12(2), 300; https://doi.org/10.3390/cryst12020300 - 21 Feb 2022
Cited by 4 | Viewed by 1738
Abstract
Triclabendazole is an effective medication to treat fascioliasis and paragonimiasis parasitic infections. We implemented a reliable quantum mechanical method which is density functional theory at the level of ωB97XD/6-31G* along with embedded fragments to elucidate stability and phase transition between two forms of [...] Read more.
Triclabendazole is an effective medication to treat fascioliasis and paragonimiasis parasitic infections. We implemented a reliable quantum mechanical method which is density functional theory at the level of ωB97XD/6-31G* along with embedded fragments to elucidate stability and phase transition between two forms of triclabendazole. We calculated crystal structure parameters, volumes, Gibbs free energies, and vibrational spectra of two polymorphic forms of triclabendazole under different pressures and temperatures. We confirmed form I was more stable than form II at atmospheric pressure and room temperature. From high-pressure Gibbs free energy computations, we found a pressure-induced phase transformation between form I (triclinic unit cell) and form II (monoclinic unit cell). The phase transition between forms I and II was found at a pressure and temperature of 5.5 GPa and ≈350 K, respectively. In addition, we also studied the high-pressure polymorphic behavior of two forms of triclabendazole. At the pressure of 5.5 GPa and temperature from ≈350 K to 500 K, form II was more stable than form I. However, at temperatures lower than ≈350 K, form I was more stable than form II. We also studied the effects of pressures on volumes and Raman spectra. To the best of our knowledge, no such research has been conducted to determine the presence of phase transformation between two forms of triclabendazole. This is a case study that can be applied to various polymorphic crystals to study their structures, stabilities, spectra, and phase transformations. This research can assist scientists, chemists, and pharmacologists in selecting the desired polymorph and better drug design. Full article
(This article belongs to the Special Issue Computational and Experimental Approaches in Pharmaceutical Crystals)
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14 pages, 4282 KiB  
Article
Improved Solubility and Dissolution Rate of Ketoprofen by the Formation of Multicomponent Crystals with Tromethamine
by Lili Fitriani, Wahyu Alfath Firdaus, Wahyu Sidadang, Henni Rosaini, Okky Dwichandra Putra, Hironaga Oyama, Hidehiro Uekusa and Erizal Zaini
Crystals 2022, 12(2), 275; https://doi.org/10.3390/cryst12020275 - 17 Feb 2022
Cited by 8 | Viewed by 3094
Abstract
This study aims to improve the dissolution rate of ketoprofen by preparing multicomponent crystals with tromethamine. The multicomponent crystals (equimolar ratio) of ketoprofen and tromethamine were prepared by the solvent co-evaporation method. The solid-state properties of the resulting powder were characterized by powder [...] Read more.
This study aims to improve the dissolution rate of ketoprofen by preparing multicomponent crystals with tromethamine. The multicomponent crystals (equimolar ratio) of ketoprofen and tromethamine were prepared by the solvent co-evaporation method. The solid-state properties of the resulting powder were characterized by powder X-ray diffraction, DSC thermal analysis, FT–IR spectroscopy, solubility, and in vitro dissolution rate. The crystal structure of the multicomponent crystal was determined by single-crystal X-ray diffraction analysis. The results showed that the powder X-ray diffraction pattern of the ketoprofen–tromethamine binary system was different from that of the starting materials. This difference indicates the formation of a new crystalline phase between ketoprofen and tromethamine (equimolar ratio). The DSC thermogram of the ketoprofen–tromethamine binary system exhibited a single and sharp endothermic peak at 128.67 °C, attributed to the melting point of a multicomponent crystal of ketoprofen–tromethamine. A single-crystal X-ray analysis revealed that ketoprofen–tromethamine formed a layered structure, salt-type multicomponent crystal. The solubility and dissolution rate of the multicomponent crystal were notably enhanced compared to the intact ketoprofen. The ketoprofen–tromethamine binary system forms salt-type multicomponent crystals, which can significantly increase the solubility and dissolution rate. Full article
(This article belongs to the Special Issue Computational and Experimental Approaches in Pharmaceutical Crystals)
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Review

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21 pages, 5279 KiB  
Review
A Critical Review on Engineering of d-Mannitol Crystals: Properties, Applications, and Polymorphic Control
by Yuxin Yang, Jia Liu, Anna Hu, Ting Nie, Zeneng Cheng and Wenjie Liu
Crystals 2022, 12(8), 1080; https://doi.org/10.3390/cryst12081080 - 1 Aug 2022
Cited by 11 | Viewed by 6170
Abstract
d-mannitol is a common six-carbon sugar alcohol, which is widely used in food, chemical, pharmaceutical, and other industries. Polymorphism is defined as the ability of materials to crystallize into different crystal structures. It has been reported for a long time that d [...] Read more.
d-mannitol is a common six-carbon sugar alcohol, which is widely used in food, chemical, pharmaceutical, and other industries. Polymorphism is defined as the ability of materials to crystallize into different crystal structures. It has been reported for a long time that d-mannitol has three polymorphs: β, δ, and α. These different polymorphs have unique physicochemical properties, thus affecting the industrial applications of d-mannitol. In this review, we firstly introduced the characteristics of different d-mannitol polymorphs, e.g., crystal structure, morphology, molecular conformational energy, stability, solubility and the analytical techniques of d-mannitol polymorphisms. Then, we described the different strategies for the preparation of d-mannitol crystals and focused on the polymorphic control of d-mannitol crystals in the products. Furthermore, the factors of the formation of different d-mannitol polymorphisms were summarized. Finally, the application of mannitol polymorphism was summarized. The purpose of this paper is to provide new ideas for a more personalized design of d-mannitol for various applications, especially as a pharmaceutical excipient. Meanwhile, the theoretical overview on polymorphic transformation of d-mannitol may shed some light on the crystal design study of other polycrystalline materials. Full article
(This article belongs to the Special Issue Computational and Experimental Approaches in Pharmaceutical Crystals)
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