title: A new cocrystal and salts of itraconazole: comparison of solid-state properties, stability and dissolution behavior.
abstract: Cocrystallization and salt formation have been shown to entail substantial promise in tailoring the physicochemical properties of drug compounds, in particular, their dissolution and hygroscopicity. In this work, we report on the preparation and comparative evaluation of a new cocrystal of itraconazole and malonic acid and two new hydrochloric salts (dihydrochloride and trihydrochloride) of itraconazole. The intrinsic dissolution rate, hygroscopicity, and thermodynamic stability were determined for the obtained solid-state forms and compared to itraconazole-succinic acid (2:1) cocrystal. The results show that the solid-state forms with higher intrinsic dissolution rate are less stable. Both itraconazole salts exhibited the highest dissolution rate, but also demonstrated high hygroscopicity at relative humidity above 70%. The new cocrystal, in contrast, were found to increase the dissolution rate of the parent drug by about 5-fold without compromising the hygroscopicity and the stability. This study demonstrates that, for dissolution rate enhancement of poorly water-soluble weak bases, cocrystallization is a more suitable approach than hydrochloric salt formation.
authors: Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, FI-00014, Finland. anna.shevchenko@helsinki.fi
authors: Anna
authors: A
authors: Shevchenko
authors: Luis M
authors: LM
authors: Bimbo
authors: Inna
authors: I
authors: Miroshnyk
authors: Jorma
authors: J
authors: Haarala
authors: Kristýna
authors: K
authors: Jelínková
authors: Kaisa
authors: K
authors: Syrjänen
authors: Bert
authors: B
authors: van Veen
authors: Juha
authors: J
authors: Kiesvaara
authors: Hélder A
authors: HA
authors: Santos
authors: Jouko
authors: J
authors: Yliruusi
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry*; D002712:Chlorides / Q000737:chemistry*; D003460:Crystallization; D004355:Drug Stability; D017964:Itraconazole / Q000737:chemistry*; D008314:Malonates / Q000737:chemistry*; D033362:Powder Diffraction; D012492:Salts / Q000737:chemistry; D012995:Solubility; D014961:X-Ray Diffraction
chemical_list: D000935:Antifungal Agents; D002712:Chlorides; D008314:Malonates; D012492:Salts; D017964:Itraconazole; C030290:malonic acid