Crystals

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11 pages, 3193 KiB

Open AccessArticle

Salts of S-(+)-Ibuprofen Formed via Its Reaction with the Antifibrinolytic Agents Aminocaproic Acid and Tranexamic Acid: Synthesis and Characterization

by Hannah M. Frösler, Humbelani S. Ramulumo, Cesarina Edmonds-Smith and Mino R. Caira

Crystals 2023, 13(8), 1222; https://doi.org/10.3390/cryst13081222 - 8 Aug 2023

Cited by 1 | Viewed by 1706

Abstract

The paucity of multi-component compounds containing the non-steroidal anti-inflammatory drug (NSAID) S-(+)-ibuprofen (S-IBU) in combination with other drugs prompted the present study, which describes 1:1 salts of this active pharmaceutical ingredient (API) with the two most widely used antifibrinolytic APIs, namely 6-aminohexanoic acid [...] Read more.

The paucity of multi-component compounds containing the non-steroidal anti-inflammatory drug (NSAID) S-(+)-ibuprofen (S-IBU) in combination with other drugs prompted the present study, which describes 1:1 salts of this active pharmaceutical ingredient (API) with the two most widely used antifibrinolytic APIs, namely 6-aminohexanoic acid (aminocaproic acid, ACA) and tranexamic acid (TXA), which are zwitterions in the solid state. Since NSAIDs are known to cause adverse side effects such as gastrointestinal ulceration, the presence of ACA and TXA in the salts with S-(+)-ibuprofen might counter these effects via their ability to prevent excessive bleeding. The salts were prepared by both the liquid-assisted grinding method and co-precipitation and were characterized by X-ray powder diffraction and single-crystal X-ray diffraction, thermal analysis, Fourier transform infrared spectroscopy, and solubility measurements. The X-ray analyses revealed a high degree of isostructurality, both at the level of their respective asymmetric units and in their extended crystal structures, with charge-assisted hydrogen bonds of the type N-H⁺⋅⋅⋅O⁻ and O-H⁺⋅⋅⋅O⁻ featuring prominently. The thermal analysis indicated that both salts had significantly higher thermal stability than S-(+)-ibuprofen. Solubility measurements in a simulated biological medium showed insignificant changes in the solubility of S-(+)-ibuprofen when tested in the form of the salts (S-IBU)⁻(ACA)⁺ and (S-IBU)⁻(TXA)⁺. Full article

(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids (2nd Edition))

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15 pages, 4427 KiB

Open AccessArticle

Febuxostat–p-Toluenesulfonic Acid Multi-Component Crystal: Characterization, Crystal Growth and Elucidation of the Salt/Co-Crystal Nature

by Doriana T. Ungur, Gustavo Santiso-Quinones, Mihaela M. Pop, Tudor L. Tamas, Carmen Guguta, Danny Stam, Alice Mija and Coca A. Iordache

Crystals 2023, 13(5), 836; https://doi.org/10.3390/cryst13050836 - 18 May 2023

Cited by 1 | Viewed by 2272

Abstract

The multi-component solid form of febuxostat (FEB) with p-toluenesulfonic acid was synthesized by solvent-drop grinding and cooling-evaporative crystallization and characterized by powder X-ray diffraction (XRPD), thermogravimetry (TGA), differential scanning calorimetry (DSC), and infrared spectroscopy (FT-IR). The multi-component form was stable after exposure [...] Read more.

The multi-component solid form of febuxostat (FEB) with p-toluenesulfonic acid was synthesized by solvent-drop grinding and cooling-evaporative crystallization and characterized by powder X-ray diffraction (XRPD), thermogravimetry (TGA), differential scanning calorimetry (DSC), and infrared spectroscopy (FT-IR). The multi-component form was stable after exposure at elevated temperature and relative humidity and powder dissolution measurements revealed five-fold aqueous solubility improvement relative to FEB. Additionally, the decrease in pH after dissolution suggests a potential for enhancing the drug absorption in the lower stomach. In the context of the regulatory requirements, the salt/co-crystal nature of the form was elucidated by a combination of crystallization process development and crystal growth, followed by SC-XRD and FT-IR. Despite the very weak basicity of the drug, crystal structure determination combined with spectroscopy analysis revealed salt formation by the transfer of the acidic proton from p-toluenesulfonic acid to FEB. Our study emphasizes the importance of the crystal structure knowledge in understanding the type of interactions present in multi-component crystals as well as complying with the specific regulatory requirements. Full article

(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids (2nd Edition))

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15 pages, 4396 KiB

Open AccessEditor’s ChoiceArticle

From Liquid to Solid: Cocrystallization as an Engineering Tool for the Solidification of Pyruvic Acid

by Camila Caro Garrido, Koen Robeyns, Damien P. Debecker, Patricia Luis and Tom Leyssens

Crystals 2023, 13(5), 808; https://doi.org/10.3390/cryst13050808 - 12 May 2023

Viewed by 1912

Abstract

Pyruvic acid is an organic compound used in various fields (e.g., the pharmaceutical, cosmetic, food, and chemical industries) and subject to constantly growing demand. Pyruvic acid is liquid at room temperature, rendering manipulation less straightforward. Furthermore, in the liquid phase, pyruvic acid is [...] Read more.

Pyruvic acid is an organic compound used in various fields (e.g., the pharmaceutical, cosmetic, food, and chemical industries) and subject to constantly growing demand. Pyruvic acid is liquid at room temperature, rendering manipulation less straightforward. Furthermore, in the liquid phase, pyruvic acid is air-sensitive. We here present a multi-component crystal engineering strategy to render pyruvic acid solid under ambient conditions, focusing on cocrystallization and salt formation. Out of 73 screened cocrystal and salt formers, eight were found to form novel crystalline forms with pyruvic acid. Four of these were studied in detail, with pyruvic acid stable in a solid phase at temperatures up to 120 °C. These results illustrate the effectiveness of cocrystallization as a tool to convert unstable liquid compounds into stable crystalline solid forms. Full article

(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids (2nd Edition))

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15 pages, 7913 KiB

Open AccessArticle

Drug Repurposing of the Antiviral Drug Acyclovir: New Pharmaceutical Salts

by Paulo Nunes, Pedro Henrique de Oliveira Santiago, Cecilia Carolina Pinheiro da Silva and Javier Ellena

Crystals 2023, 13(5), 782; https://doi.org/10.3390/cryst13050782 - 8 May 2023

Cited by 2 | Viewed by 7210

Abstract

Drug repurposing is becoming interesting in terms of offering advantages over the traditional drug development, once drug discovery is a costly, time-consuming, and highly risky process. In particular, with the coronavirus disease (COVID-19) declared by World Health Organization as a global pandemic, there [...] Read more.

Drug repurposing is becoming interesting in terms of offering advantages over the traditional drug development, once drug discovery is a costly, time-consuming, and highly risky process. In particular, with the coronavirus disease (COVID-19) declared by World Health Organization as a global pandemic, there has emerged a considerable need to develop therapeutic agents capable of preventing viral outbreaks. Concomitantly, well-known and long-used drugs such as acyclovir (Acv) have been tested against COVID-19. Acv is a guanosine analogue that acts as an antiviral drug, commonly used to treat herpes simplex virus (HSV), genital herpes, and varicella zoster virus (VZV). Acv showed to inhibit viral proteases, multiple viral genes expression, and RNA-Dependent RNA Polymerase, helping to recover COVID-19 patients. However, ACV is a BCS class III/IV drug, with low permeability and/or slight water solubility (concentration-dependent). Given the repurposing eligibility of Acv, in this work, two new salts of this drug are presented (nitrate and sulfate), with the aim of improving its pharmacokinetic properties. The new salts were evaluated by X-ray diffraction, and thermal and spectroscopic analyses. A third salt, a chloride one, was also characterized and used for comparison. Full article

(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids (2nd Edition))

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15 pages, 3578 KiB

Open AccessArticle

Solubility and Crystallization Studies of Picolinic Acid

by Diogo S. Baptista, M. Fátima M. Piedade and Catarina V. Esteves

Crystals 2023, 13(3), 392; https://doi.org/10.3390/cryst13030392 - 24 Feb 2023

Cited by 1 | Viewed by 2183

Abstract

Solubility and crystallization studies of a monocarboxylic derivative of pyridine, picolinic acid (2-pyridinecarboxylic acid), were undertaken as a need for new data in the literature was identified. Moreover, comparative studies of structurally related small molecules, such as these pyridinecarboxylic acid isomers (picolinic acid [...] Read more.

Solubility and crystallization studies of a monocarboxylic derivative of pyridine, picolinic acid (2-pyridinecarboxylic acid), were undertaken as a need for new data in the literature was identified. Moreover, comparative studies of structurally related small molecules, such as these pyridinecarboxylic acid isomers (picolinic acid (PA), nicotinic acid (NA, also known as Niacin or vitamin B₃), and isonicotinic acid (IA)), can contribute to a larger goal of identifying optimal crystallization conditions. Indeed, vitamin B₃ has been thoroughly explored in literature, whilst IA and, particularly, PA have received less attention. Hence, results on both the solubility (obtained through the gravimetric method) and solid-state structure (investigated by means of PXRD) of PA, at different temperatures, in three polar solvents: water, ethanol (both protic solvents) and acetonitrile (aprotic solvent) are presented in this work. These results indicate that PA is very soluble in water (for T ≈ 293 K, C_PA ≈ 862.5 g·kg⁻¹), way less soluble in ethanol (C_PA ≈ 57.1 g·kg⁻¹), and even less in acetonitrile (C_PA ≈ 17.0 g·kg⁻¹). The crystallization outcome was analyzed in comparison with its family of compounds data, revealing that two polymorphic forms were identifiable for PA, and that no hydrates or solvates were found. Full article

(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids (2nd Edition))

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14 pages, 4247 KiB

Open AccessEditor’s ChoiceArticle

Structural Origin of Anisotropic Thermal Expansion of Molecular Crystals and Implication for the Density Rule Probed with Four ROY Polymorphs

by Sayantan Chattoraj and Changquan Calvin Sun

Crystals 2023, 13(2), 270; https://doi.org/10.3390/cryst13020270 - 4 Feb 2023

Cited by 1 | Viewed by 2368

Abstract

The objective of this work was to investigate the molecular origin of the differences in the thermal expansivity of four ROY polymorphs (Y, R, OP, and ON) using variable temperature single crystal X-ray diffractometry (VT-SCXRD). Thermal expansivity was found to be directly influenced [...] Read more.

The objective of this work was to investigate the molecular origin of the differences in the thermal expansivity of four ROY polymorphs (Y, R, OP, and ON) using variable temperature single crystal X-ray diffractometry (VT-SCXRD). Thermal expansivity was found to be directly influenced by the crystal packing and the number and type of directional interactions, such as hydrogen bonds, involved in packing. Polymorphs with layered molecular packing, i.e., ON, OP, and R, show higher volume expansivity, where the axial component of the expansion is the largest in the directions perpendicular to the hydrogen-bonded layers and the smallest along the layers. Polymorph Y shows the least volume expansivity, which corresponds to the presence of a denser hydrogen-bonded network structure in the crystal, and absence of apparent molecular layers. The largest overall expansivity is observed for polymorph ON that lacks intermolecular hydrogen bonds and exhibits a layered packing pattern along two axes. The differences in the thermal expansivity of the ROY polymorphs lead to violations of the density rule in polymorph stability prediction due to crossover in crystal density with change in temperature, which means the rank order of crystal density of polymorphs is temperature-dependent. Thus, at absolute zero, the most thermodynamically stable polymorph Y is predicted to not have the highest density, which violates the density rule. Likewise, for all enantiotropic polymorphs undergoing the density crossover phenomenon, the density rule is valid only within the temperature range bracketed by the temperatures of density crossover (T_d) and thermodynamic transition (T_t). For all monotropic polymorphs, the density rule is valid only above T_d. Full article

(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids (2nd Edition))

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11 pages, 3714 KiB

Open AccessArticle

New Metformin–Citric Acid Pharmaceutical Molecular Salt: Improving Metformin Physicochemical Properties

by Cristóbal Verdugo-Escamilla, Carolina Alarcón-Payer, Francisco Javier Acebedo-Martínez, Alicia Domínguez-Martín and Duane Choquesillo-Lazarte

Crystals 2022, 12(12), 1748; https://doi.org/10.3390/cryst12121748 - 2 Dec 2022

Cited by 2 | Viewed by 2062

Abstract

Crystal engineering and, more specifically, the development of multicomponent materials has become an effective technique to rationally modify important physicochemical properties of solids, such as solubility and thermal stability. In this work, in order to overcome some of the problems that metformin has [...] Read more.

Crystal engineering and, more specifically, the development of multicomponent materials has become an effective technique to rationally modify important physicochemical properties of solids, such as solubility and thermal stability. In this work, in order to overcome some of the problems that metformin has as a pharmaceutical, a new metformin base salt with citric acid (MTF–CIT) has been developed, which improves the thermal stability and solubility (two-fold) compared to metformin base (MTF). A complete characterization of the new crystalline form through PXRD, DSC, SCXRD, and FT–IR was conducted to ensure the purity of the new phase and provide a comprehensive view of its physicochemical behavior, thus correlating the improvement in stability and solubility with the crystal structure. The MTF–CIT salt crystallizes in the monoclinic P2₁/c1 spacegroup with z′ = 1. Intermolecular interactions found in MTF–CIT structure and simulated crystal morphology suggest a steric protection effect on the metformin ion that leads to the enhancement of stability in several orders of magnitude compared with MTF, as well as an improvement in solubility due to the exposition of polar groups in the biggest facets, making this new multicomponent salt a promising pharmaceutical solid. Full article

(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids (2nd Edition))

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11 pages, 5519 KiB

Open AccessArticle

Swelling and Salt Formation in Ibuprofen and Tranexamic Acid-Containing Tablets during High-Temperature Storage

by Yuto Kawano, Yoshiharu Tanaka, Nanami Hata, Yuki Yoshiike, Masato Nakajima, Etsuo Yonemochi and Nobuhiro Ishihara

Crystals 2022, 12(10), 1420; https://doi.org/10.3390/cryst12101420 - 8 Oct 2022

Viewed by 2708

Abstract

Ibuprofen (IBP)- and Tranexamic acid (TXA)-containing tablets are known to swell when stored at high temperatures, but the mechanism of swelling is unknown. In this study, we investigated the possible mechanism of swelling with high-temperature storage. Differential scanning calorimetry (DSC) and powder X-ray [...] Read more.

Ibuprofen (IBP)- and Tranexamic acid (TXA)-containing tablets are known to swell when stored at high temperatures, but the mechanism of swelling is unknown. In this study, we investigated the possible mechanism of swelling with high-temperature storage. Differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD) analyses showed that a new complex was formed in swollen tablets, when stored at 50 °C for 60 days. Additionally, we prepared single crystals of IBP and TXA, and analyzed them using single crystal X-ray diffractometry (SCXRD), to identify the new complex formed during storage. This revealed that the single crystal was a salt consisting of IBP and TXA. The PXRD peak of the salt simulated by SCXRD matched that of the PXRD peak of the swollen tablet after storage. These results suggest a close relationship between the swelling and crystal structures of IBP and TXA. Full article

(This article belongs to the Special Issue Multicomponent Pharmaceutical Solids (2nd Edition))

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