Crystal engineering of ionic cocrystals comprising Na/K salts of hesperetin with hesperetin molecules and solubility modulation
Hesperetin (HES) is a weakly acidic flavonoid of topical interest owing to its antiviral properties. Despite the presence of HES in many dietary supplements, its bioavailability is hindered by poor aqueous solubility (1.35 µg ml−1) and rapid first-pass metabolism. Cocrystallization has evolved as a...
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| Format: | Article |
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International Union of Crystallography
2023-05-01
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| Series: | IUCrJ |
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| Online Access: | http://scripts.iucr.org/cgi-bin/paper?S205225252300266X |
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| author | Shasha Jin Molly M. Haskins Cheng-Hua Deng Catiúcia R. M. O. Matos Michael J. Zaworotko |
| author_facet | Shasha Jin Molly M. Haskins Cheng-Hua Deng Catiúcia R. M. O. Matos Michael J. Zaworotko |
| author_sort | Shasha Jin |
| collection | DOAJ |
| description | Hesperetin (HES) is a weakly acidic flavonoid of topical interest owing to its antiviral properties. Despite the presence of HES in many dietary supplements, its bioavailability is hindered by poor aqueous solubility (1.35 µg ml−1) and rapid first-pass metabolism. Cocrystallization has evolved as a promising approach to generate novel crystal forms of biologically active compounds and enhance the physicochemical properties without covalent modification. In this work, crystal engineering principles were employed to prepare and characterize various crystal forms of HES. Specifically, two salts and six new ionic cocrystals (ICCs) of HES involving sodium or potassium salts of HES were studied using single-crystal X-ray diffraction (SCXRD) or powder X-ray diffraction and thermal measurements. Structures of seven of the new crystalline forms were elucidated by SCXRD, which revealed two families of isostructural ICCs in terms of their crystal packing and confirmed the presence of phenol...phenolate (PhOH...PhO−) supramolecular heterosynthons. Diverse HES conformations were observed amongst these structures, including unfolded and folded (previously unreported) conformations. One ICC, HES with the sodium salt of HES (NESNAH), was scalable to the gram scale and found to be stable after accelerated stability testing (exposure to elevated heat and humidity). HESNAH reached Cmax after 10 min in PBS buffer 6.8 compared with 240 min in pure HES. In addition, relative solubility was observed to be 5.5 times greater, offering the possibility of improved HES bioavailability. |
| first_indexed | 2024-04-09T14:15:33Z |
| format | Article |
| id | doaj.art-c4199a6be2c24571bdd0ba5e30cb0511 |
| institution | Directory Open Access Journal |
| issn | 2052-2525 |
| language | English |
| last_indexed | 2024-04-09T14:15:33Z |
| publishDate | 2023-05-01 |
| publisher | International Union of Crystallography |
| record_format | Article |
| series | IUCrJ |
| spelling | doaj.art-c4199a6be2c24571bdd0ba5e30cb05112023-05-05T11:31:33ZengInternational Union of CrystallographyIUCrJ2052-25252023-05-0110332934010.1107/S205225252300266Xlq5051Crystal engineering of ionic cocrystals comprising Na/K salts of hesperetin with hesperetin molecules and solubility modulationShasha Jin0Molly M. Haskins1Cheng-Hua Deng2Catiúcia R. M. O. Matos3Michael J. Zaworotko4Department of Chemical Sciences and Bernal Institute, University of Limerick, Limerick V94 T9PX, IrelandDepartment of Chemical Sciences and Bernal Institute, University of Limerick, Limerick V94 T9PX, IrelandDepartment of Chemical Sciences and Bernal Institute, University of Limerick, Limerick V94 T9PX, IrelandDepartment of Chemical Sciences and Bernal Institute, University of Limerick, Limerick V94 T9PX, IrelandDepartment of Chemical Sciences and Bernal Institute, University of Limerick, Limerick V94 T9PX, IrelandHesperetin (HES) is a weakly acidic flavonoid of topical interest owing to its antiviral properties. Despite the presence of HES in many dietary supplements, its bioavailability is hindered by poor aqueous solubility (1.35 µg ml−1) and rapid first-pass metabolism. Cocrystallization has evolved as a promising approach to generate novel crystal forms of biologically active compounds and enhance the physicochemical properties without covalent modification. In this work, crystal engineering principles were employed to prepare and characterize various crystal forms of HES. Specifically, two salts and six new ionic cocrystals (ICCs) of HES involving sodium or potassium salts of HES were studied using single-crystal X-ray diffraction (SCXRD) or powder X-ray diffraction and thermal measurements. Structures of seven of the new crystalline forms were elucidated by SCXRD, which revealed two families of isostructural ICCs in terms of their crystal packing and confirmed the presence of phenol...phenolate (PhOH...PhO−) supramolecular heterosynthons. Diverse HES conformations were observed amongst these structures, including unfolded and folded (previously unreported) conformations. One ICC, HES with the sodium salt of HES (NESNAH), was scalable to the gram scale and found to be stable after accelerated stability testing (exposure to elevated heat and humidity). HESNAH reached Cmax after 10 min in PBS buffer 6.8 compared with 240 min in pure HES. In addition, relative solubility was observed to be 5.5 times greater, offering the possibility of improved HES bioavailability.http://scripts.iucr.org/cgi-bin/paper?S205225252300266Xcrystal engineeringionic cocrystalsphenol–phenolate synthonsnutraceuticalsmolecular crystals |
| spellingShingle | Shasha Jin Molly M. Haskins Cheng-Hua Deng Catiúcia R. M. O. Matos Michael J. Zaworotko Crystal engineering of ionic cocrystals comprising Na/K salts of hesperetin with hesperetin molecules and solubility modulation IUCrJ crystal engineering ionic cocrystals phenol–phenolate synthons nutraceuticals molecular crystals |
| title | Crystal engineering of ionic cocrystals comprising Na/K salts of hesperetin with hesperetin molecules and solubility modulation |
| title_full | Crystal engineering of ionic cocrystals comprising Na/K salts of hesperetin with hesperetin molecules and solubility modulation |
| title_fullStr | Crystal engineering of ionic cocrystals comprising Na/K salts of hesperetin with hesperetin molecules and solubility modulation |
| title_full_unstemmed | Crystal engineering of ionic cocrystals comprising Na/K salts of hesperetin with hesperetin molecules and solubility modulation |
| title_short | Crystal engineering of ionic cocrystals comprising Na/K salts of hesperetin with hesperetin molecules and solubility modulation |
| title_sort | crystal engineering of ionic cocrystals comprising na k salts of hesperetin with hesperetin molecules and solubility modulation |
| topic | crystal engineering ionic cocrystals phenol–phenolate synthons nutraceuticals molecular crystals |
| url | http://scripts.iucr.org/cgi-bin/paper?S205225252300266X |
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