Solid-State Diversity of Fenofibric Acid: Synthon Polymorphs and Salts with Altered Solubility and Dissolution

Richu Bagya, V.S.; Ramanujan, G.M.; Prajapati, A.K.; Chernyshev, V.V.; Sanphui, P.

Авторы: Richu Bagya Varsa S., Ramanujan Ganesh Munuswamy, Prajapati Aditya Kumar, Chernyshev Vladimir V., Sanphui Palash
Журнал: Crystal Growth and Design
Том: 25
Номер: 3
Год издания: 2025
Издательство: American Chemical Society
Местоположение издательства: United States
Первая страница: 720
Последняя страница: 733
DOI: 10.1021/acs.cgd.4c01513
Аннотация: Fenofibric acid (hereafter FFA) is a lipid-loweringagent used to treat dyslipidemia, hyperlipidemia, and cardiovasculardiseases. The drug belongs to the biopharmaceutical classificationsystem (BCS) Class II category with poor aqueous solubility andhigh permeability, resulting in improved bioavailability (81%)compared to its prodrug fenofibrate (69%). FFA is marketed in itsactive form as well as prodrug formulations (fenofibrate andcholine fenofibrate) as a sustained-release formulation, because ofpoor absorption. In order to expand the structural landscape ofFFA, solid-form screening resulted in a novel polymorph (FFA-2)along with a reported commercial form (FFA-1). While the crystalstructure of FFA-1 maintains an unusual acid···carbonyl hetero-synthon-mediated dimer, FFA-2 offers a more robust carboxylic acid dimer, and thus they are designated as synthon polymorphs.Moreover, the novel polymorph (FFA-2) improved its dissolution profile (4-fold) compared to FFA-1 in a neutral pH medium. Inorder to enhance the aqueous solubility of FFA, further salt screening was carried out that resulted in two ionized forms withheterocyclic amines, specifically piperidine (PPD) and piperazine (PPZ). The crystal structure of the PPZ salt was confirmed bysingle-crystal XRD, while that of PPD salts was obtained from PXRD data. The FFA-PPZ (1:0.5) salt maintains zigzag packingsimilar to that of FFA-1, while FFA-PPD (1:1) salt sustains layered packing similar to that of FFA-2. The PPZ salt facilitated much-controlled release, while the PPD salt exceptionally enhanced the solubility and dissolution rate of the drug. Both salts demonstratedexceptional stability in moist environments. Similar to FFA-1, both salts maintained identical cell viability in the human monocyteTHP-1 cell line. To summarize, a novel polymorph (FFA-2) and PPD salt can be formulated to improve bioavailability and potentially decrease the required dosage.
Добавил в систему: Чернышев Владимир Васильевич

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Solid-State Diversity of Fenofibric Acid: Synthon Polymorphs and Salts with Altered Solubility and Dissolutionстатья

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