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Crystals
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Multicomponent Pharmaceutical Solids
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Multicomponent Pharmaceutical Solids

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

Deadline for manuscript submissions: closed (10 December 2021) | Viewed by 36820

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

Special Issue Editors

Dr. Duane Choquesillo-Lazarte

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Guest Editor
Laboratorio de Estudios Cristalográficos, IACT, CSIC, Armilla, 18100 Granada, Spain
Interests: crystal engineering; co-crystals; pharmaceutical salts; multicomponent pharmaceutical materials; crystallization; chemical crystallography
Special Issues, Collections and Topics in MDPI journals
Dr. Alicia Dominguez-Martin

E-Mail Website
Guest Editor
Department of Inorganic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
Interests: bioinorganic chemistry; nucleic acids; molecular recognition; multicomponent pharmaceutical materials; co-drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Multicomponent pharmaceutical materials are solids in which at least one component is an active pharmaceutical ingredient (API). The development of this kind of pharmaceutical solids has certainly attracted interest in the past decade as a promising alternative from the laborious and expensive process of traditional pipeline drug development. The application of crystal engineering techniques into the design of pharmaceutical salts, co-crystals, and other multicomponent materials, in addition to the achievement of more environmentally friendly synthetic approaches, has succeeded in modulating the physicochemical, mechanical, and pharmacokinetic properties of drugs, thereby working toward the enhancement of their clinical performance.

Nevertheless, the study of pharmaceutical solids still presents significant challenges. New multicomponent pharmaceutical materials have come to stay, and we will soon see applications on multidrug resistance or co-drug synergy thanks to rational design. For instance, unraveling structure–activity relationships, the preference for supramolecular synthons, and appropriate co-former and/or solvent selection are still issues that need to be thoroughly studied in order to fully understand, and consequently predict, the formation of pharmaceutical solids with tailored properties.

This Special Issue welcomes original research articles and reviews devoted to all aspects related to the field of multicomponent pharmaceutical solids. Our interests include fundamental to applied research, using theoretical and experimental approaches, the development of synthetic methods, screening of multicomponent materials, structure–activity rationale, salt-co-crystal continuum identification, enhancement in physicochemical/mechanical/pharmacokinetic performance, as well as the functionality and applications of multicomponent pharmaceuticals solids.

Dr. Duane Choquesillo-Lazarte
Dr. Alicia Dominguez-Martin
Guest Editors

Manuscript Submission Information

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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

  • Crystal engineering
  • API
  • Multicomponent materials
  • Pharmaceutical solids
  • Co-crystals
  • Mechanochemical methods
  • Solubility
  • Screening
  • Physicochemical properties
  • Co-drugs

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 193 KiB  
Editorial
Multicomponent Pharmaceutical Solids
by Duane Choquesillo-Lazarte and Alicia Domínguez-Martín
Crystals 2023, 13(4), 570; https://doi.org/10.3390/cryst13040570 - 27 Mar 2023
Cited by 2 | Viewed by 1502
Abstract
Multicomponent pharmaceutical solids is a hot topic that brings together the knowledge of crystal engineering and the need to achieve novel and effective drugs at lower costs for the pharmaceutical industry [...] Full article
(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids)

Research

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15 pages, 19336 KiB  
Article
Towards the Development of Novel Diclofenac Multicomponent Pharmaceutical Solids
by Francisco Javier Acebedo-Martínez, Carolina Alarcón-Payer, Helena María Barrales-Ruiz, Juan Niclós-Gutiérrez, Alicia Domínguez-Martín and Duane Choquesillo-Lazarte
Crystals 2022, 12(8), 1038; https://doi.org/10.3390/cryst12081038 - 26 Jul 2022
Cited by 8 | Viewed by 2497
Abstract
Multicomponent pharmaceutical materials offer new opportunities to address drug physicochemical issues and to obtain improved drug formulation, especially on oral administration drugs. This work reports three new multicomponent pharmaceutical crystals of the non-steroidal anti-inflammatory drug diclofenac and the nucleobases adenine, cytosine, and isocytosine. [...] Read more.
Multicomponent pharmaceutical materials offer new opportunities to address drug physicochemical issues and to obtain improved drug formulation, especially on oral administration drugs. This work reports three new multicomponent pharmaceutical crystals of the non-steroidal anti-inflammatory drug diclofenac and the nucleobases adenine, cytosine, and isocytosine. They have been synthesized by mechanochemical methods and been characterized in-depth in solid-state by powder and single crystal X-ray diffraction, as well as other techniques such as thermal analyses and infrared spectroscopy. Stability and solubility tests were also performed on these materials. This work aimed to evaluate the physicochemical properties of these solid forms, which revealed thermal stability improvement. Dissociation of the new phases was observed in water, though. This fact is consistent with the reported observed layered structures and BFDH morphology calculations. Full article
(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids)
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15 pages, 4877 KiB  
Article
Lidocaine Pharmaceutical Multicomponent Forms: A Story about the Role of Chloride Ions on Their Stability
by Cristóbal Verdugo-Escamilla, Carolina Alarcón-Payer, Francisco Javier Acebedo-Martínez, Raquel Fernández-Penas, Alicia Domínguez-Martín and Duane Choquesillo-Lazarte
Crystals 2022, 12(6), 798; https://doi.org/10.3390/cryst12060798 - 6 Jun 2022
Cited by 5 | Viewed by 3761
Abstract
In this investigation, three new crystal forms of lidocaine, and another three of lidocaine hydrochloride with hydroquinone, resorcinol, and pyrogallol were synthetised. All the new forms were characterised using multiple techniques, PXRD, SC-XRD, DSC, and FTIR. The stability of the forms was studied, [...] Read more.
In this investigation, three new crystal forms of lidocaine, and another three of lidocaine hydrochloride with hydroquinone, resorcinol, and pyrogallol were synthetised. All the new forms were characterised using multiple techniques, PXRD, SC-XRD, DSC, and FTIR. The stability of the forms was studied, and, for the more stable forms, i.e., (lidhcl) forms, the solubility was determined through FTIR analysis. The new crystalline forms obtained with (lidhcl) and the three coformers showed an interesting steric stabilisation mechanism of the oxidation of hydroxybenzenes and showed good physicochemical properties with respect to (lidhcl), constituting a mechanism of modulation of the physicochemical properties. Full article
(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids)
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9 pages, 2403 KiB  
Article
Salification Controls the In-Vitro Release of Theophylline
by Laura Baraldi, Luca Fornasari, Irene Bassanetti, Francesco Amadei, Alessia Bacchi and Luciano Marchiò
Crystals 2022, 12(2), 201; https://doi.org/10.3390/cryst12020201 - 29 Jan 2022
Cited by 3 | Viewed by 2677
Abstract
Sustained released formulation is the most used strategy to control the efficacy and the adverse reactions of an API (active pharmaceutical ingredient) with a narrow therapeutic index. In this work, we used a different way to tailor the solubility and diffusion of a [...] Read more.
Sustained released formulation is the most used strategy to control the efficacy and the adverse reactions of an API (active pharmaceutical ingredient) with a narrow therapeutic index. In this work, we used a different way to tailor the solubility and diffusion of a drug. Salification of Theophylline with Squaric Acid was carried out to better control the absorption of Theophylline after administration. Salification proved to be a winning strategy decreasing the dissolution of the APIs up to 54% with respect to Theophylline. Most importantly, this was accomplished in the first 10 min of the dissolution process, which are the most important for the API administration. Two polymorphs were identified and fully characterized. Theophylline squarate was discovered as trihydrate (SC-XRD) and as a metastable anhydrous form. Indeed, during the Variable Temperature-XRPD experiment, the trihydrate form turned back into the two starting components after losing the three molecules of water. On the other hand, the synthesis of the trihydrate form was observed when a simple mixing of the two starting components were exposed to a high humidity relative percentage (90% RH). Full article
(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids)
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Graphical abstract

21 pages, 5658 KiB  
Article
Multicomponent Solids of DL-2-Hydroxy-2-phenylacetic Acid and Pyridinecarboxamides
by Alfonso Castiñeiras, Antonio Frontera, Isabel García-Santos, Josefa M. González-Pérez, Juan Niclós-Gutiérrez and Rocío Torres-Iglesias
Crystals 2022, 12(2), 142; https://doi.org/10.3390/cryst12020142 - 20 Jan 2022
Cited by 5 | Viewed by 2220
Abstract
We prepared cocrystals of DL-2-Hydroxy-2-phenylacetic acid (D, L-H2ma) with the pyridinecarboxamide isomers, picolinamide (pic) and isonicotinamide (inam). They were characterized by elemental analysis, single crystal and powder X-ray, IR spectroscopy and 1H and [...] Read more.
We prepared cocrystals of DL-2-Hydroxy-2-phenylacetic acid (D, L-H2ma) with the pyridinecarboxamide isomers, picolinamide (pic) and isonicotinamide (inam). They were characterized by elemental analysis, single crystal and powder X-ray, IR spectroscopy and 1H and 13C NMR. The crystal and molecular structures of (pic)-(D-H2ma) (1), (nam)-(L-H2ma) (2) and (inam)-(L-H2ma) (3) were studied. The crystal packing is stabilized primarily by hydrogen bonding and in some cases through π-π stacking interactions. The analysis of crystal structures reveals the existence of the characteristic heterosynthons with the binding motif R22(8) (primary amide–carboxilic acid) between pyridinecarboxamide molecules and the acid. Other synthons involve hydrogen bonds such as O-H(carboxyl)···N(pyridine) and O-H(hydroxyl)···N(pyridine) depending on the isomer. The packing of 1 and 3 is formed by tetramers, for whose formation a crystallization mechanism based on two stages is proposed, involving an amide–acid (1) or amide–amide (3) molecular recognition in the first stage and the formation of others, and interdimeric hydrogen bonding interactions in the second. The thermal stability of the cocrystals was studied by differential scanning calorimetry and thermogravimetry. Further studies were conducted to evaluate other physicochemical properties of the cocrystals in comparison to the pure coformers. Density-functional theory (DFT) calculations (including NCIplot and QTAIM analyses) were performed to further characterize and rationalize the noncovalent interactions. Full article
(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids)
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Graphical abstract

15 pages, 3737 KiB  
Article
Oxalic Acid, a Versatile Coformer for Multicomponent Forms with 9-Ethyladenine
by Mónica Benito, Miquel Barceló-Oliver, Antonio Frontera and Elies Molins
Crystals 2022, 12(1), 89; https://doi.org/10.3390/cryst12010089 - 10 Jan 2022
Cited by 3 | Viewed by 3044
Abstract
Six new multicomponent solids of 9-ethyladenine and oxalic acid have been detected and characterized. The salt screening has been performed by mechanochemical and solvent crystallization processes. Single crystals of the anhydrous salts in 1:1 and 2:1 nucleobase:coformer molar ratio were obtained by solution [...] Read more.
Six new multicomponent solids of 9-ethyladenine and oxalic acid have been detected and characterized. The salt screening has been performed by mechanochemical and solvent crystallization processes. Single crystals of the anhydrous salts in 1:1 and 2:1 nucleobase:coformer molar ratio were obtained by solution crystallization and elucidated by single-crystal X-ray analysis. The supramolecular interactions observed in these solids have been studied using density functional theory (DFT) calculations and characterized by the quantum theory of “atoms in molecules” (QTAIM) and the noncovalent interaction plot (NCIPlot) index methods. The energies of the H-bonding networks observed in the solid state of the anhydrous salts in 1:1 and 2:1 nucleobase:coformer are reported, disclosing the strong nature of the charge assisted NH···O hydrogen bonds and also the relative importance of ancillary C–H··O H-bonds. Full article
(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids)
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11 pages, 3864 KiB  
Article
Multicomponent Materials to Improve Solubility: Eutectics of Drug Aminoglutethimide
by Basanta Saikia, Andreas Seidel-Morgenstern and Heike Lorenz
Crystals 2022, 12(1), 40; https://doi.org/10.3390/cryst12010040 - 28 Dec 2021
Cited by 7 | Viewed by 2580
Abstract
Here, we report the synthesis and experimental characterization of three drug-drug eutectic mixtures of drug aminoglutethimide (AMG) with caffeine (CAF), nicotinamide (NIC) and ethenzamide (ZMD). The eutectic mixtures i.e., AMG-CAF (1:0.4, molar ratio), AMG-NIC (1:1.9, molar ratio) and AMG-ZMD (1:1.4, molar ratio) demonstrate [...] Read more.
Here, we report the synthesis and experimental characterization of three drug-drug eutectic mixtures of drug aminoglutethimide (AMG) with caffeine (CAF), nicotinamide (NIC) and ethenzamide (ZMD). The eutectic mixtures i.e., AMG-CAF (1:0.4, molar ratio), AMG-NIC (1:1.9, molar ratio) and AMG-ZMD (1:1.4, molar ratio) demonstrate significant melting point depressions ranging from 99.2 to 127.2 °C compared to the melting point of the drug AMG (151 °C) and also show moderately higher aqueous solubilities than that of the AMG. The results presented include the determination of the binary melt phase diagrams and accompanying analytical characterization via X-ray powder diffraction, FT-IR spectroscopy and scanning electron microscopy. Full article
(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids)
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13 pages, 3538 KiB  
Article
Furosemide/Non-Steroidal Anti-Inflammatory Drug–Drug Pharmaceutical Solids: Novel Opportunities in Drug Formulation
by Francisco Javier Acebedo-Martínez, Carolina Alarcón-Payer, Lucía Rodríguez-Domingo, Alicia Domínguez-Martín, Jaime Gómez-Morales and Duane Choquesillo-Lazarte
Crystals 2021, 11(11), 1339; https://doi.org/10.3390/cryst11111339 - 2 Nov 2021
Cited by 9 | Viewed by 3620
Abstract
The design of drug–drug multicomponent pharmaceutical solids is one the latest drug development approaches in the pharmaceutical industry. Its purpose is to modulate the physicochemical properties of active pharmaceutical ingredients (APIs), most of them already existing in the market, achieving improved bioavailability properties, [...] Read more.
The design of drug–drug multicomponent pharmaceutical solids is one the latest drug development approaches in the pharmaceutical industry. Its purpose is to modulate the physicochemical properties of active pharmaceutical ingredients (APIs), most of them already existing in the market, achieving improved bioavailability properties, especially on oral administration drugs. In this work, our efforts are focused on the mechanochemical synthesis and thorough solid-state characterization of two drug–drug cocrystals involving furosemide and two different non-steroidal anti-inflammatory drugs (NSAIDs) commonly prescribed together: ethenzamide and piroxicam. Besides powder and single crystal X-ray diffraction, infrared spectroscopy and thermal analysis, stability, and solubility tests were performed on the new solid materials. The aim of this work was evaluating the physicochemical properties of such APIs in the new formulation, which revealed a solubility improvement regarding the NSAIDs but not in furosemide. Further studies need to be carried out to evaluate the drug–drug interaction in the novel multicomponent solids, looking for potential novel therapeutic alternatives. Full article
(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids)
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15 pages, 5944 KiB  
Article
Improving the Solubility of Aripiprazole by Multicomponent Crystallization
by Qi Zhou, Zhongchuan Tan, Desen Yang, Jiyuan Tu, Yezi Wang, Ying Zhang, Yanju Liu and Guoping Gan
Crystals 2021, 11(4), 343; https://doi.org/10.3390/cryst11040343 - 28 Mar 2021
Cited by 11 | Viewed by 3995
Abstract
Aripiprazole (ARI) is a third-generation antipsychotic with few side effects but a poor solubility. Salt formation, as one common form of multicomponent crystals, is an effective strategy to improve pharmacokinetic profiles. In this work, a new ARI salt with adipic acid (ADI) and [...] Read more.
Aripiprazole (ARI) is a third-generation antipsychotic with few side effects but a poor solubility. Salt formation, as one common form of multicomponent crystals, is an effective strategy to improve pharmacokinetic profiles. In this work, a new ARI salt with adipic acid (ADI) and its acetone hemisolvate were obtained successfully, along with a known ARI salt with salicylic acid (SAL). Their comprehensive characterizations were conducted using X-ray diffraction and differential scanning calorimetry. The crystal structures of the ARI-ADI salt acetone hemisolvate and ARI-SAL salt were elucidated by single-crystal X-ray diffraction for the first time, demonstrating the proton transfer from a carboxyl group of acid to ARI piperazine. Theoretical calculations were also performed on weak interactions. Moreover, comparative studies on pharmaceutical properties, including powder hygroscopicity, stability, solubility, and the intrinsic dissolution rate, were carried out. The results indicated that the solubility and intrinsic dissolution rate of the ARI-ADI salt and its acetone hemisolvate significantly improved, clearly outperforming that of the ARI-SAL salt and the untreated ARI. The study presented one potential alternative salt of aripiprazole and provided a potential strategy to increase the solubility of poorly water-soluble drugs. Full article
(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids)
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Graphical abstract

21 pages, 9748 KiB  
Article
Entrapped Transient Chloroform Solvates of Bilastine
by Cristina Puigjaner, Anna Portell, Arturo Blasco, Mercè Font-Bardia and Oriol Vallcorba
Crystals 2021, 11(4), 342; https://doi.org/10.3390/cryst11040342 - 28 Mar 2021
Cited by 7 | Viewed by 3410
Abstract
The knowledge about the solid forms landscape of Bilastine (BL) has been extended. The crystal structures of two anhydrous forms have been determined, and the relative thermodynamic stability among the three known anhydrous polymorphs has been established. Moreover, three chloroform solvates with variable [...] Read more.
The knowledge about the solid forms landscape of Bilastine (BL) has been extended. The crystal structures of two anhydrous forms have been determined, and the relative thermodynamic stability among the three known anhydrous polymorphs has been established. Moreover, three chloroform solvates with variable stoichiometry have been identified and characterized, showing that S3CHCl3-H2O and SCHCl3 can be classified as transient solvates which transform into the new chloroform solvate SCHCl3-H2O when removed from the mother liquor. The determination of their crystal structures from combined single crystal/synchrotron X-ray powder diffraction data has allowed the complete characterization of these solvates, being two of them heterosolvates (S3CHCl3-H2O and SCHCl3-H2O) and SCHCl3 a monosolvate. Moreover, the temperature dependent stability and interrelation pathways among the chloroform solvates and the anhydrous forms of BL have been studied. Full article
(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids)
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Review

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18 pages, 3311 KiB  
Review
Recent Advances in the Application of Characterization Techniques for Studying Physical Stability of Amorphous Pharmaceutical Solids
by Yanan Wang, Yong Wang, Jin Cheng, Haibiao Chen, Jia Xu, Ziying Liu, Qin Shi and Chen Zhang
Crystals 2021, 11(12), 1440; https://doi.org/10.3390/cryst11121440 - 23 Nov 2021
Cited by 21 | Viewed by 5364
Abstract
The amorphous form of a drug usually exhibits higher solubility, faster dissolution rate, and improved oral bioavailability in comparison to its crystalline forms. However, the amorphous forms are thermodynamically unstable and tend to transform into a more stable crystalline form, thus losing their [...] Read more.
The amorphous form of a drug usually exhibits higher solubility, faster dissolution rate, and improved oral bioavailability in comparison to its crystalline forms. However, the amorphous forms are thermodynamically unstable and tend to transform into a more stable crystalline form, thus losing their advantages. In order to investigate and suppress the crystallization, it is vital to closely monitor the drug solids during the preparation, storage, and application processes. A list of advanced techniques—including optical microscopy, surface grating decay, solid-state nuclear magnetic resonance, broadband dielectric spectroscopy—have been applied to characterize the physicochemical properties of amorphous pharmaceutical solids, to provide in-depth understanding on the crystallization mechanism. This review briefly summarizes these characterization techniques and highlights their recent advances, so as to provide an up-to-date reference to the available tools in the development of amorphous drugs. Full article
(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids)
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