Role of Structure, Microenvironmental pH, and Speciation To Understand the Formation and Properties of Febuxostat Eutectics

Abstract

Cocrystallization studies were undertaken to improve the solubility of a highly water-insoluble drug, febuxostat (FXT), used in the treatment of gout and hyperuricemia. A liquid-assisted grinding (LAG) method was successfully employed, starting with the screening of various coformers for obtaining cocrystals. However, in this process, three eutectic systems with coformers (probenecid, adipic acid, and α-ketoglutaric acid) were formed. Affinities of the different functional groups to form a hydrogen bond and ΔpK a differences, leading to the eutectic formation, were discussed. The eutectic systems thus formed were further characterized and analyzed using a differential scanning calorimeter (DSC) and powder X-ray diffraction (PXRD). Binary thermal phase diagrams were plotted using different ratios of the systems to confirm the formation of eutectics, and pH-dependent solubility studies exhibited a significant decrease in the solubility in comparison to that of the drug for all three eutectic systems. The solubility of FXT reduced from 46.53 μg/mL (pH 5.63) to 46.03 μg/mL, 28.53 μg/mL, and 18.88 μg/mL; 770.58 μg/mL (pH 8.21) to 307.574 μg/mL, 116.63 μg/mL, 113.40 μg/mL; and from 13165.97 μg/mL (pH 10.13) to 1409.737 μg/mL, 854.51 μg/mL, and 1218.99 μg/mL for FXT-probenecid, FXT-adipic acid, and FXT-α-ketoglutaric acid eutectic systems, respectively. Furthermore, the microenvironmental pH studies were carried out to understand the effect of the microenvironment on the solubility of these eutectic systems. The contribution to solubility from lattice and nonlattice forces considering the microenvironment was also discussed.

Study on Sulfamethoxazole–Piperazine Salt: A Mechanistic Insight into Simultaneous Improvement of Physicochemical Properties

“…Previous works have demonstrated the impact of microenvironmental pH on the solubility and dissolution behavior of salts, 54 cocrystals, 55 and eutectics. 56 In the present study, the impact of PIP on the microenvironmental pH of the SMX−PIP salt and its effect on speciation profile, solubility, and IDR of SMX from the SMX− PIP salt in comparison to pure SMX was investigated. Table 1 captures the microenvironmental pH of SMX and SMX−PIP salt in different aqueous buffers (pH 1.2, 4.5, 6.8, 7.4) and water (pH 7.03).…”

Polymer-Assisted Aripiprazole–Adipic Acid Cocrystals Produced by Hot Melt Extrusion Techniques

“…Unlike eutectics, where a diffraction pattern represents the combination of individual parent components, cocrystals are characterized by the presence of distinct peaks due to formation of new crystalline material. Hence, the presence of distinct peaks in the PXRD pattern of ARP-ADP cocrystals rules out the formation of eutectics . Diffraction peaks of cocrystals processed at different screw speeds showed no difference in the intensity and 2θ values, which indicates the formation of cocrystals was complete.…”

“…Hence, the presence of distinct peaks in the PXRD pattern of ARP-ADP cocrystals rules out the formation of eutectics. 46 Diffraction peaks of cocrystals processed at different screw speeds showed no difference in the intensity and 2θ values, which indicates the formation of cocrystals was complete. These results were in line with the previous literature.…”

Evolution of Cocrystals from Solid Solutions in Benzoic Acid–Mono/poly-fluorobenzoic Acid Combinations

“…This conjecture is corroborated by the formation of a cocrystal-type entity for BA–345TFBA and authentic cocrystals for BA–2345TFBA and BA–23456PFBA, respectively, wherein additional fluorine atoms facilitate heteromolecular interactions in other directions. Lately, eutectics have been identified to be alternate cocrystallization products for combinations featuring steric misfit, discontinuous/finite heteromeric interactions, and less favorable energetics. ,,,− On this basis, we speculated that BA–26DFBA and BA–246TFBA combinations can make eutectics due to the likelihood of finite/discrete heteromeric motifs (e.g., acid heterodimers) between the components upon cocrystallization. At the same time, we ruled out mere mixtures where no interactions exist.…”