Cocrystals of Nitrofurantoin: How Coformers Can Modify Its Solubility and Permeability Across Intestinal Cell Monolayers

Solubility and permeability of nitrofurantoin (NITRO) were compared with those of its cocrystals containing isoniazid (ISO), bipyridyl (BIP), or phenanthroline (PHE) as coformers, and their parent mixtures. NITRO dissolution profiles were evaluated via HPLC; we resorted to molecular dynamics (MD) si...

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Bibliographic Details
Published inCrystal growth & design Vol. 22; no. 5; pp. 3090 - 3106
Main Authors Segalina, Alekos, Pavan, Barbara, Ferretti, Valeria, Spizzo, Federico, Botti, Giada, Bianchi, Anna, Pastore, Mariachiara, Dalpiaz, Alessandro
Format Journal Article
LanguageEnglish
Published American Chemical Society 04.05.2022
Subjects
Chemical Sciences
or physical chemistry
Theoretical and
Permeability
Mixtures
Granular materials
Dissolution
Monolayers
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Summary:Solubility and permeability of nitrofurantoin (NITRO) were compared with those of its cocrystals containing isoniazid (ISO), bipyridyl (BIP), or phenanthroline (PHE) as coformers, and their parent mixtures. NITRO dissolution profiles were evaluated via HPLC; we resorted to molecular dynamics (MD) simulations to rationalize the experimental data on the basis of nitrofurantoin–coformers and nitrofurantoin–water intermolecular interactions. Permeation studies were performed by using an in vitro model of the small intestine based on IEC-6 cells. The NITRO water solubility was reduced by its mixture with PHE and BIP but not with ISO. Cocrystallization with BIP induced a slight increase of NITRO solubility; cocrystallization with PHE induced its solubility decrease, even if lower than the physical mixture. The solubility changes were attributed to NITRO solvation shell alterations (MD simulations). Cocrystallization with ISO allowed an increase of the NITRO solubility in the first 30 min of the dissolution pattern. Permeation measurements showed that the NITRO–PHE mixture was detrimental for the monolayer integrity, whereas no alterations were induced by the cocrystal. No effects on NITRO permeability and monolayer integrity were observed either for NITRO–ISO or for NITRO–BIP mixtures. The NITRO–ISO cocrystal increased the NITRO permeability across the monolayer without reducing its integrity.
ISSN:1528-7483
1528-7505
DOI:10.1021/acs.cgd.2c00007