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Expanding the Crystal Structure Landscape of Pravastatin Complexes: Tuning Solubility, Diffusion, and Pharmacokineticsстатья
Статья опубликована в высокорейтинговом журнале
Статья опубликована в журнале из списка Web of Science и/или Scopus- Авторы: Richu Bagya Varsa S., Priya Katukam Lasya, Kole Goutam Kumar, Dhotre Anant V., Chella Naveen, Ramanujan Ganesh Muruswamy, Chernyshev Vladimir V., Sanphui Palash
- Журнал: Crystal Growth and Design
- Том: 24
- Номер: 12
- Год издания: 2024
- Издательство: American Chemical Society
- Местоположение издательства: United States
- Первая страница: 5309
- Последняя страница: 5323
- DOI: 10.1021/acs.cgd.4c00542
- Аннотация: Pravastatin (PRV), a lipid-lowering medication, isprescribed to treat cardiovascular disease and dyslipidemia. Due toits low permeability and high solubility, the biopharmaceuticsclassification system (BCS) class III drug exhibits poorbioavailability. To overcome the bottlenecks of PRV, novelcomplexes with Zn and Cu along with a zwitterionic cocrystalwith L-proline (PRO) were synthesized. These new solid formswere characterized by SC-XRD, PXRD, DSC, TGA, FT-IR, DVS,and SEM images. Rietveld refinement was used to obtain the 3Dcoordinates of the PRV−Na−PRO ionic cocrystal hydrate fromhigh-resolution PXRD data. PRV−Cu and Zn complexes wereobtained by substituting PRV sodium salt with a Cu/Zn metal. InPRV−Na−PRO cocrystal hydrate, each Na metal is coordinatedfrom carboxylates of PRV (2) and zwitterionic PRO (1) and three water molecules result in an octahedron geometry. Cu iscoordinated with two carboxylate anions of PRV (2) and three water molecules, forming a square pyramidal geometry. The PRV−Zn complex maintains an octahedral geometry using four coordination from two carboxylate anions of PRV (2) and two watermolecules. The PRV−Na−PRO cocrystal hydrate exhibited higher solubility (1.7-fold) and diffusion profile (1.1-fold) compared tothe commercial PRV−Na salt hydrate, whereas PRV−Cu/Zn complexes showed controlled drug release. Surprisingly, the PRV−Na−PRO cocrystal hydrate enhanced peak plasma concentration Cmax (50 fold) and AUC (14.4 fold) compared to the commercialPRV−Na salt during pharmacokinetics study in rats. The stability of the PRV complexes was supported by ground-state optimizationenergy calculations. Unlike the moisture-sensitive PRV−Na salt hydrate and PRV−Na−PRO cocrystal hydrate, PRV−Zn/Cucomplexes exhibited far superior moisture stability and may offer extended drug release. On the other hand, the PRV−Na−PROcocrystal hydrate with significantly improved bioavailability can be commercialized following proper formulation that offers moisturestability.
- Добавил в систему: Чернышев Владимир Васильевич
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