Special Issue "Pharmaceutical Crystals"

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

Deadline for manuscript submissions: closed (30 September 2019).

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Etsuo Yonemochi
E-Mail Website
Guest Editor
School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Tokyo 142-8501, Japan
Interests: physicochemimcal properties; physical propertiy analysis; crystal form; polymorph prediction
Special Issues and Collections in MDPI journals
Prof. Hidehiro Uekusa
E-Mail Website
Guest Editor
Department of Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8551, Japan
Interests: crystallography; structure analysis; pharmaceutical crystals; phase transition
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

We are delighted to invite you to submit an article to the “Pharmaceutical Crystals” Special Issue of Crystals.

Needless to say, the crystalline state is the most used and the most important form of solid active pharmaceutical ingredients (APIs). The characterization of pharmaceutical crystals encompasses numerous scientific disciplines, and its center is crystal structure analysis, which reveals the molecular structure of important pharmaceutical compounds, and also affords key structural information that relates to the broadly variable physicochemical properties of the APIs, e.g., solubility, stability, tablet ability, color, and hygroscopicity.

The Special Issue on “Pharmaceutical Crystals” aims to publish novel molecular and crystal structures of pharmaceutical compounds. We especially encourage the submission of works of new crystal structures of APIs including polymorphs and solvate crystals, and of multi-component crystals of APIs including co-crystals and salts, which would be related to changes of the physicochemical properties of pharmaceutical crystals.

This Special Issue demonstrates the importance of crystal structure information in many sectors of pharmaceutical science and engineering, and thus contributions from both industry and academia are welcome.

Prof. Etsuo Yonemochi
Prof. Hidehiro Uekusa
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 papers will be 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 1800 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

  • Pharmaceutical crystals
  • Co-crystals
  • Salts
  • Solvates
  • Physicochemical properties
  • Crystal engineering

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Published Papers (11 papers)

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Editorial

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Editorial
Preface of the Special Issue “Pharmaceutical Crystals”
Crystals 2020, 10(2), 89; https://doi.org/10.3390/cryst10020089 - 05 Feb 2020
Viewed by 506
Abstract
Dear Colleagues, [...] Full article
(This article belongs to the Special Issue Pharmaceutical Crystals)

Research

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Article
Impact of Crystal Habit on Solubility of Ticagrelor
Crystals 2019, 9(11), 556; https://doi.org/10.3390/cryst9110556 - 24 Oct 2019
Cited by 4 | Viewed by 939
Abstract
Drugs with poor biopharmaceutical performance are the main obstacle to the development and design of medicinal preparations. The anisotropic surface chemistry of different surfaces on the crystal influences its physical and chemical properties, such as solubility, tableting, etc. In this study, the antisolvent [...] Read more.
Drugs with poor biopharmaceutical performance are the main obstacle to the development and design of medicinal preparations. The anisotropic surface chemistry of different surfaces on the crystal influences its physical and chemical properties, such as solubility, tableting, etc. In this study, the antisolvent crystallization and rapid-cooling crystallization were carried out to tune the crystal habits of ticagrelor (TICA) form II. Different crystal habits of ticagrelor (TICA) form II (TICA-A, TICA-B, TICA-C, TICA-D, and TICA-E) were prepared and evaluated for solubility. The single-crystal diffraction (SXRD) indicated that TICA form II belongs to the triclinic P1 space group with four TICA molecules in the asymmetric unit. The TICA molecules are generated through intermolecular hydrogen bonds along the (010) direction, forming an infinite molecular chain, which are further stacked by hydrogen bonds between hydroxyethoxy side chains, forming molecular circles composed of six TICA molecules along bc directions. Thus, in the case of TICA form II, hydrogen bonds drive growth along one axis (b-axis), which results in the formation of mostly needle-shape crystals. Morphology and face indexation reveals that (001), (010) and (01-1) are the main crystal planes. Powder diffractions showed that five habits have the same crystal structure and different relative intensity of diffraction peak. The solubility of the obtained crystals showed the crystal habits affect their solubility. This work is helpful for studying the mechanism of crystal habit modification and its effect on solubility. Full article
(This article belongs to the Special Issue Pharmaceutical Crystals)
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Article
Comparative Evaluation of the Photostability of Carbamazepine Polymorphs and Cocrystals
Crystals 2019, 9(11), 553; https://doi.org/10.3390/cryst9110553 - 24 Oct 2019
Cited by 2 | Viewed by 984
Abstract
Carbamazepine (CBZ), a widely used antiepileptic, is known to be sensitive to light. The aim of this study was to evaluate the photostabilities of three cocrystals of CBZ (CBZ–succinic acid (SUC), CBZ–saccharin (SAC) form I, and CBZ–SAC form II) illuminated with a D [...] Read more.
Carbamazepine (CBZ), a widely used antiepileptic, is known to be sensitive to light. The aim of this study was to evaluate the photostabilities of three cocrystals of CBZ (CBZ–succinic acid (SUC), CBZ–saccharin (SAC) form I, and CBZ–SAC form II) illuminated with a D65 fluorescent lamp compared with those of the conventional solid forms: CBZ polymorphs (forms I, II, and III). The order of discoloration determined using a colorimetric measurement was almost consistent with that of the degradation rates estimated using Fourier-transform infrared reflection–absorption spectroscopy, and these parameters of CBZ polymorphs increased in the order of form III, form I, and form II. CBZ–SUC and CBZ–SAC form I significantly suppressed the discoloration and degradation of CBZ compared with the raw CBZ, while CBZ–SAC form II facilitated the discoloration and degradation of CBZ. These results were supported by the results from the low-frequency Raman spectroscopy. The molecular mobility estimated using solid-state nuclear magnetic resonance 1H spin–lattice relaxation time strongly correlated with the degradation rate constant, indicating that molecular mobility significantly decreased following the formation of CBZ–SUC and CBZ–SAC form I and resulted in higher photostability. Overall, CBZ–SUC and CBZ–SAC form I are photostable forms and cocrystallization was proven to be an effective approach to improving the photostability of a photolabile drug. Full article
(This article belongs to the Special Issue Pharmaceutical Crystals)
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Article
Structural and Reactivity Analyses of Nitrofurantoin–4-dimethylaminopyridine Salt Using Spectroscopic and Density Functional Theory Calculations
Crystals 2019, 9(8), 413; https://doi.org/10.3390/cryst9080413 - 09 Aug 2019
Cited by 3 | Viewed by 1346
Abstract
Pharmaceutical salt, nitrofurantoin–4-dimethylaminopyridine (NF-DMAP), along with its native components NF and DMAP are scrutinized by FT-IR and FT-Raman spectroscopy along with density functional theory so that an insight into the H-bond patterns in the respective crystalline lattices can be gained. Two different functionals, [...] Read more.
Pharmaceutical salt, nitrofurantoin–4-dimethylaminopyridine (NF-DMAP), along with its native components NF and DMAP are scrutinized by FT-IR and FT-Raman spectroscopy along with density functional theory so that an insight into the H-bond patterns in the respective crystalline lattices can be gained. Two different functionals, B3LYP and wB97X-D, have been used to compare the theoretical results. The FT-IR spectra obtained for NF-DMAP and NF clearly validate the presence of C33–H34⋅⋅⋅O4 and N23–H24⋅⋅⋅N9 hydrogen bonds by shifting in the stretching vibration of –NH and –CH group of DMAP+ towards the lower wavenumber side. To explore the significance of hydrogen bonding, quantum theory of atoms in molecules (QTAIM) has been employed, and the findings suggest that the N23–H24⋅⋅⋅N9 bond is a strong intermolecular hydrogen bond. The decrement in the HOMO-LUMO gap, which is calculated from NF → NF-DMAP, reveals that the active pharmaceutical ingredient is chemically less reactive compared to the salt. The electrophilicity index (ω) profiles for NF and DMAP confirms that NF is acting as electron acceptor while DMAP acts as electron donor. The reactive sites of the salt are plotted by molecular electrostatic potential (MEP) surface and calculated using local reactivity descriptors. Full article
(This article belongs to the Special Issue Pharmaceutical Crystals)
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Article
Synthesis, X-Ray Crystal Structure, Hirshfeld Surface Analysis, and Molecular Docking Study of Novel Hepatitis B (HBV) Inhibitor: 8-Fluoro-5-(4-fluorobenzyl)-3-(2-methoxybenzyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one
Crystals 2019, 9(8), 379; https://doi.org/10.3390/cryst9080379 - 24 Jul 2019
Cited by 5 | Viewed by 2164
Abstract
A method for the synthesis of 8-fluoro-5-(4-fluorobenzyl)-3-(2-methoxybenzyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one has been developed and the electronic and spatial structure of a new biologically active molecule has been studied both theoretically and experimentally. The title compound was crystallized from acetonitrile and the single-crystal X-ray analysis has revealed [...] Read more.
A method for the synthesis of 8-fluoro-5-(4-fluorobenzyl)-3-(2-methoxybenzyl)-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one has been developed and the electronic and spatial structure of a new biologically active molecule has been studied both theoretically and experimentally. The title compound was crystallized from acetonitrile and the single-crystal X-ray analysis has revealed that it exists in a monoclinic P21/n space group, with one molecule in the asymmetric part of the unit cell, a = 16.366(3) Å, b = 6.0295(14) Å, c = 21.358(4) Å, β = 105.21(2)°, V = 2033.7(7) Å3 and Z = 4. Hirshfeld surface analysis was used to study intermolecular interactions in the crystal. Molecular docking studies have evaluated the investigated compound as a new inhibitor of hepatitis B. Testing for anti-hepatitis B virus activity has shown that this substance has in vitro nanomolar inhibitory activity against Hepatitis B virus (HBV). Full article
(This article belongs to the Special Issue Pharmaceutical Crystals)
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Article
Synthesis, Crystal Structure, and Solubility Analysis of a Famotidine Cocrystal
Crystals 2019, 9(7), 360; https://doi.org/10.3390/cryst9070360 - 15 Jul 2019
Cited by 5 | Viewed by 1460
Abstract
A novel cocrystal of the potent H2 receptor antagonist famotidine (FMT) was synthesized with malonic acid (MAL) to enhance its solubility. The cocrystal structure was characterized by X-ray single crystal diffraction, and the asymmetry unit contains one FMT and one MAL connected [...] Read more.
A novel cocrystal of the potent H2 receptor antagonist famotidine (FMT) was synthesized with malonic acid (MAL) to enhance its solubility. The cocrystal structure was characterized by X-ray single crystal diffraction, and the asymmetry unit contains one FMT and one MAL connected via intermolecular hydrogen bonds. The crystal structure is monoclinic with a P21/n space group and unit cell parameters a = 7.0748 (3) Å, b = 26.6502 (9) Å, c = 9.9823 (4) Å, α = 90, β = 104.2228 (12), γ = 90, V = 1824.42 (12) Å3, and Z = 4. The cocrystal had unique thermal, spectroscopic, and powder X-ray diffraction (PXRD) properties that differed from FMT. The solubility of the famotidine-malonic acid cocrystal (FMT-MAL) was 4.2-fold higher than FMT; the FAM-MAL had no change in FMT stability at high temperature, high humidity, or with illumination. Full article
(This article belongs to the Special Issue Pharmaceutical Crystals)
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Article
Preparation of Theophylline-Benzoic Acid Cocrystal and On-Line Monitoring of Cocrystallization Process in Solution by Raman Spectroscopy
Crystals 2019, 9(7), 329; https://doi.org/10.3390/cryst9070329 - 27 Jun 2019
Cited by 6 | Viewed by 1452
Abstract
Pure theophylline-benzoic acid cocrystal was prepared via slurry and cooling crystallization in solution to overcome the disadvantages of existing preparation methods. The target cocrystal was characterized by powder X-ray diffraction (PXRD), thermalgravimetric analysis (TGA), differential scanning calorimetry (DSC) and Raman spectroscopy. The slurry [...] Read more.
Pure theophylline-benzoic acid cocrystal was prepared via slurry and cooling crystallization in solution to overcome the disadvantages of existing preparation methods. The target cocrystal was characterized by powder X-ray diffraction (PXRD), thermalgravimetric analysis (TGA), differential scanning calorimetry (DSC) and Raman spectroscopy. The slurry and cooling cocrystallization process in solution was monitored via on-line Raman spectroscopy. The results obtained from on-line Raman monitoring can exhibit the transformation process from raw materials (theophylline and benzoic acid) to cocrystal and show the cocrystal formation rate. Comparing each transformation process under different conditions in slurry crystallization, we found that suspension density of raw materials and temperature both have an impact on the theophylline-benzoic acid cocrystal formation rate. It could be concluded that the cocrystal formation rate increased with the increase of suspension density of raw materials. Further under the same suspension density, higher temperature will accelerate theophylline-benzoic acid cocrystal formation. Meanwhile, various data from the cocrystallization process in cooling crystallization, including nucleation time, nucleation temperature and suitable cooling ending point can be gained from results of on-line Raman monitoring. Full article
(This article belongs to the Special Issue Pharmaceutical Crystals)
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Article
Elucidation of the Crystal Structures and Dehydration Behaviors of Ondansetron Salts
Crystals 2019, 9(3), 180; https://doi.org/10.3390/cryst9030180 - 26 Mar 2019
Cited by 2 | Viewed by 1329
Abstract
In drug development, it is extremely important to evaluate the solubility and stability of solid states and to immediately determine the potential for development. Salt screening is a standard and useful method for obtaining drug candidates with good solid state properties. Ondansetron is [...] Read more.
In drug development, it is extremely important to evaluate the solubility and stability of solid states and to immediately determine the potential for development. Salt screening is a standard and useful method for obtaining drug candidates with good solid state properties. Ondansetron is marketed as a hydrochloride dihydrate, and its dehydration behavior was previously reported to transition to an anhydrate via a hemihydrate as an intermediate by heating. Here, we synthesized ondansetron hydrobromide and hydroiodide and examined their dehydration behaviors. Single-crystal structure analysis confirmed that like ondansetron hydrochloride, ondansetron hydrobromide formed a dihydrate. Moreover, the crystal lattice parameters and hydrogen bonding networks were similar and isomorphic. While single-crystal structure analysis showed that ondansetron hydroiodide also formed a dihydrate, the crystal lattice parameters and hydrogen bonding networks were different to those of ondansetron hydrobromide and hydrochloride. Additionally, the dehydration behavior of ondansetron hydrobromide differed from that of the hydrochloride, with no hemihydrate intermediate forming from the hydrobromide, despite similar anhydrate structures. Given that it is difficult to predict how a crystal structure will form and the resulting physical properties, a large amount of data is needed for the rational design of salt optimization. Full article
(This article belongs to the Special Issue Pharmaceutical Crystals)
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Article
Solvent-Mediated Polymorphic Transformation of Famoxadone from Form II to Form I in Several Mixed Solvent Systems
Crystals 2019, 9(3), 161; https://doi.org/10.3390/cryst9030161 - 20 Mar 2019
Cited by 4 | Viewed by 1285
Abstract
This paper discloses six polymorphs of famoxadone obtained from polymorph screening, which were characterized by XRPD, DSC, and SEM. A study of solvent-mediated polymorphic transformation (SMPT) of famoxadone from the metastable Form II to the stable Form I in several mixed solvent systems [...] Read more.
This paper discloses six polymorphs of famoxadone obtained from polymorph screening, which were characterized by XRPD, DSC, and SEM. A study of solvent-mediated polymorphic transformation (SMPT) of famoxadone from the metastable Form II to the stable Form I in several mixed solvent systems at the temperature of 30 °C was also conducted. The transformation process was monitored by Process Analytical Technologies. It was confirmed that the Form II to Form I polymorphic transformation is controlled by the Form I growth process. The transformation rate constants depended linearly on the solubility difference value between Form I and Form II. Furthermore, the hydrogen-bond-donation/acceptance ability and dipolar polarizability also had an effect on the rate of solvent-mediated polymorphic transformation. Full article
(This article belongs to the Special Issue Pharmaceutical Crystals)
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Article
(2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(2-chlorophenyl)hydrazine carboxamide: Synthesis, X-ray Structure, Hirshfeld Surface Analysis, DFT Calculations, Molecular Docking and Antifungal Profile
Crystals 2019, 9(2), 82; https://doi.org/10.3390/cryst9020082 - 04 Feb 2019
Cited by 2 | Viewed by 1234
Abstract
Life-threatening fungal infections accounts for a major global health burden especially for individuals suffering from cancer, acquired immune deficiency syndrome (AIDS), or autoimmune diseases. (2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(2-chlorophenyl)hydrazinecarboxamide has been synthesized and characterized using various spectroscopic tools to be evaluated [...] Read more.
Life-threatening fungal infections accounts for a major global health burden especially for individuals suffering from cancer, acquired immune deficiency syndrome (AIDS), or autoimmune diseases. (2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(2-chlorophenyl)hydrazinecarboxamide has been synthesized and characterized using various spectroscopic tools to be evaluated as a new antifungal agent. The (E)-configuration of the imine moiety of the title molecule has been unequivocally identified with the aid of single crystal X-ray analysis. The molecular structure of compound 4 was crystallized in the monoclinic, P21/c, a = 8.7780 (6) Å, b = 20.5417 (15) Å, c = 11.0793 (9) Å, β = 100.774 (2)°, V = 1962.5 (3) Å3, and Z = 4. Density functional theory computations have thoroughly explored the electronic characteristics of the title molecule. Moreover, molecular docking studies and Hirshfeld surface analysis were also executed on the title compound 4. The in vitro antifungal potential of the target compound was examined against four different fungal strains. Full article
(This article belongs to the Special Issue Pharmaceutical Crystals)
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Article
Melting Diagrams of Adefovir Dipivoxil and Dicarboxylic Acids: An Approach to Assess Cocrystal Compositions
Crystals 2019, 9(2), 70; https://doi.org/10.3390/cryst9020070 - 30 Jan 2019
Cited by 3 | Viewed by 1173
Abstract
Pharmaceutical cocrystallization is a useful method to regulate the physical properties of active pharmaceutical ingredients (APIs). Since the cocrystals may form in various API/coformer ratios, identification of the cocrystal composition is the critical first step of any further analysis. However, the composition identification [...] Read more.
Pharmaceutical cocrystallization is a useful method to regulate the physical properties of active pharmaceutical ingredients (APIs). Since the cocrystals may form in various API/coformer ratios, identification of the cocrystal composition is the critical first step of any further analysis. However, the composition identification is not always unambiguous if cocrystallization is performed in solid state with unsuccessful solution crystallization. Single melting point and some new X-ray diffraction peaks are necessary but not sufficient conditions. In the present study, the use of melting diagrams coupled with the X-ray diffraction data was tested to identify cocrystal compositions. Adefovir dipivoxil (AD) was used as a model API, and succinic acid (SUC), suberic acid (SUB), and glutaric acid (GLU) were coformers. Compositions of AD/SUC and AD/SUB had been previously identified as 2:1 and 1:1, but that of AD/GLU was not unambiguously identified because of the difficulty of solution crystallization. Melting diagrams were constructed with differential scanning calorimetry, and their interpretation was assisted by powder X-ray diffraction. The cocrystal formation was exhibited as new compositions with congruent melting in the phase diagrams. This method correctly indicated the previously known cocrystal compositions of AD/SUC and AD/SUB, and it successfully identified the AD/GLU cocrystal composition as 1:1. The current approach is a simple and useful method to assess the cocrystal compositions when the crystallization is only possible in solid state. Full article
(This article belongs to the Special Issue Pharmaceutical Crystals)
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