Cocrystallization of Febuxostat with Pyridine Coformers: Crystal Structural and Physicochemical Properties Analysis

Abstract

Drug cocrystals and salts have promising applications for modulating the physicochemical properties and solubility of pharmaceuticals. In this study, a cocrystal and two salts of febuxostat (FEB) with pyridine nitrogen coformers, including 4, 4′-bipyridine (BIP), 3-aminopyridine (3AP) and 4-hydroxypyridine (4HP), were designed to improve the solubility of FEB. The single-crystal structures were elucidated, and their physical and chemical properties were investigated by IR, PXRD, and DSC. In addition, drug-related properties, including the solubility and powder dissolution rate were assessed. The solubility and powder dissolution studies showed that the FEB-BIP cocrystal and FEB-3AP salt have superior dissolution compared to FEB.

Febuxostat–p-Toluenesulfonic Acid Multi-Component Crystal: Characterization, Crystal Growth and Elucidation of the Salt/Co-Crystal Nature

“…A total of 500 µL of solvent was added to the solids mixture along with a magnetic stir bar. Initially, a wide range of concentrations (10,15,20,25,90,120,240, and 360 mg/mL) and two solvent systems (2-ethoxyethanol and THF) were tested. Subsequently, the MSZW was determined in 2-ethoxyethanol at low concentrations: 10, 15, 20, and 25 mg/mL.…”

“…In the search for the novel FEB forms with improved solubility and bioavailability, crystal engineering strategies such as co-crystallization [17][18][19][20] and salt formation [20][21][22][23][24] have been reported.…”

“…Various salt forms of FEB with counter-ions such as choline choline [21] 2-methylimidazole, 2-pyridylamine [22], 3-aminopyridine [20], imidazolium [24], and minoxidil [23] have provided novel ways to improve the aqueous solubility of FEB. Notably, to the best of our knowledge, no acidic counter-ions or co-formers were reported in this respect.…”

Evaluation of Pharmacokinetic Feasibility of Febuxostat/L-pyroglutamic Acid Cocrystals in Rats and Mice

“…From physicochemical and pharmacokinetic perspectives, FBX is a poorly water-soluble and highly permeable drug belonging to the biopharmaceutics classification system (BCS) class II [ 1 , 17 , 18 , 19 , 20 , 21 ]. Thus, various formulations of FBX, such as salt formations, solid dispersion formations, and cocrystals, have been developed to improve the solubility of FBX [ 22 , 23 , 24 , 25 ]. Cocrystals of FBX have especially gained attention.…”

“…Although FBX form-A is still used in drug formulation, the co-crystallization of FBX was widely attempted due to the low aqueous solubility and slow absorption rate of FBX as a restriction of BCS class II drugs [ 1 , 14 , 18 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Many cases to enhance the solubility of FBX were reported in numerous FBX cocrystals with isonicotinamide, arginine, pyridine, 4-hydroxy benzoic acid, or salicylic acid as a co-former [ 22 , 24 , 34 ], but these cocrystals of FBX exhibited unstable properties in the buffered solutions of pH 4–7 [ 34 ].…”