New Multicomponent Solid Forms of the Antitumor Drug Ripretinib: The Role of Conformations in Dictating Dissolution and Photostability

Muthaiyan, M.; K, S.F.; Kenguva, G.; Prajapati, A.K.; Dandela, R.; Chernyshev, V.V.; Sanphui, P.

Авторы: Muthaiyan Muthukumari, K S.Fayaz T, Kenguva Gowtham, Prajapati Aditya Kumar, Dandela Rambabu, Chernyshev Vladimir V., Sanphui Palash
Журнал: Crystal Growth and Design
Том: 24
Номер: 18
Год издания: 2024
Издательство: American Chemical Society
Местоположение издательства: United States
Первая страница: 7617
Последняя страница: 7631
DOI: 10.1021/acs.cgd.4c00855
Аннотация: Ripretinib (RIP), a medication to treat gastrointestinalstromal tumors, possesses very poor aqueous solubility and bioavailabilityand is prone to degrade under sunlight. In order to overcome thebottlenecks of the drug, salt screening was performed that resulted inhydrochloride, acetate, 2−6-dihydroxybenzoate, and ferulate salts, alongwith a solvate with formic acid and an unexpected methanol solvate. Thenew multicomponent solids were characterized by PXRD, DSC, TGA, FT-IR, and SC-XRD. In all these RIP multicomponent solids, the N−H···Ohydrogen-bonded centrosymmetric dimer involving urea NH groups andthe carbonyl group of the naphthyridine ring is consistent with thepolymorphs and solvates reported above. In RIP salts, a proton istransferred from the acid to the N-methyl pyridine fraction of the RIP.Even though formic acid is a stronger acid than acetic acid, RIP-formicacid (1:2) is crystallized as a cocrystal (solvate), whereas the RIP acetate acetic acid salt hydrate (1:1:2:1) is crystallized as a mixedionized state. RIP-2−6-dihydroxybenzoate is crystallized as a solvate (or hydrate), whereas RIP-ferulate forms an anhydrous phase.Solubility experiments in 75% EtOH-water medium indicated that the HCl salt improved up to 4-fold solubility, whereas the RIP-2,6-dihydroxybenzoate and ferulate salts exhibited comparable solubility as the native drug. Similarly, RIP-HCl salt offered 1.5-foldimproved chemical stability during photolysis compared to the native drug. The improved solubility and chemical stability of the RIPmulticomponent solids are partially correlated to the extended conformation of the native drug and the acidity of the coformers.
Добавил в систему: Чернышев Владимир Васильевич

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New Multicomponent Solid Forms of the Antitumor Drug Ripretinib: The Role of Conformations in Dictating Dissolution and Photostabilityстатья

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