Novel Co-crystals and Eutectics of Febuxostat: Characterization, Mechanism of Formation, and Improved Dissolution.

Co-crystallization studies were undertaken to improve the solubility of a highly water-insoluble drug febuxostat (FXT), used in the treatment of gout and hyperuricemia. The selection of co-crystal former (CCF) molecules such as 1-hydroxy 2-naphthoic acid (1H-2NPH), 4-hydroxy benzoic acid (4-HBA), salicylic acid (SAC), 5-nitro isophthalic acid (5-NPH), isonicotinamide (ISNCT), and picolinamide (PICO) was based on the presence of complementary functional groups capable of forming hydrogen bond and the ΔpKa difference between FXT and CCF. A liquid-assisted grinding (LAG) method was successfully employed for the rapid screening of various pharmaceutical adducts. These adducts were characterized based on their unique thermal (differential scanning calorimetry) and spectroscopic (Fourier transform infrared and Raman spectroscopy) profiles. Binary phase diagrams (BPD) were plotted to establish a relationship between the thermal events and adduct formed. Powder X-ray diffraction (PXRD) studies were carried out to confirm the formation of eutectic/co-crystal. Thermogravimetric analysis (TGA) was also performed for the novel co-crystals obtained. The propensity for strong homo-synthons over weak hetero-synthons and strong hetero-synthons over weak homo-synthons during supramolecular growth resulted in the formation of eutectics and co-crystals respectively. FXT:1H-2NPH (1), FXT:4-HBA (1), FXT:SAC (1, 2), and FXT:5-NPH (2-1) gave rise to pure eutectic systems, while FXT:ISNCT (2-1) and FXT:PICO (1) gave rise to novel co-crystals with characteristic DSC heating curves and PXRD pattern. Additionally, the impact of microenvironmental pH and microspeciation profile on the improved dissolution profile of the co-crystals was discussed. Graphical Abstract.

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

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 ΔpKa 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.

To Evaluate the Effect of Solvents and Different Relative Humidity Conditions on Thermal and Rheological Properties of Microcrystalline Cellulose 101 Using METHOCEL™ E15LV as a Binder.

The solvent used for preparing the binder solution in wet granulation can affect the granulation end point and also impact the thermal, rheological, and flow properties of the granules. The present study investigates the effect of solvents and percentage relative humidity (RH) on the granules of microcrystalline cellulose (MCC) with hydroxypropyl methyl cellulose (HPMC) as the binder. MCC was granulated using 2.5% w/w binder solution in water and ethanol/water mixture (80:20 v/v). Prepared granules were dried until constant percentage loss on drying, sieved, and further analyzed. Dried granules were exposed to different percentage RH for 48 h at room temperature. Powder rheometer was used for the rheological and flow characterization, while thermal effusivity and differential scanning calorimeter were used for thermal analysis. The thermal effusivity values for the wet granules showed a sharp increase beginning 50% w/w binder solution in both cases, which reflected the over-wetting of granules. Ethanol/water solvent batches showed greater resistance to flow as compared to the water solvent batches in the wet granule stage, while the reverse was true for the dried granule stage, as evident from the basic flowability energy values. Although the solvents used affected the equilibration kinetics of moisture content, the RH-exposed granules remained unaffected in their flow properties in both cases. This study indicates that the solvents play a vital role on the rheology and flow properties of MCC granules, while the different RH conditions have little or no effect on them for the above combination of solvent and binder.

Characterization and Thermodynamic Relationship of Three Polymorphs of a Xanthine Oxidase Inhibitor, Febuxostat.

Febuxostat (FXT), a xanthine oxidase inhibitor, is an interesting and unique molecule, which exhibits extensive polymorphism, with over 15 polymorphic forms reported to date. The primary purpose of the study was to characterize the three polymorphic forms with respect to their thermodynamic quantities and establish thermodynamic relationship between them. The polymorphs were characterized by thermal and powder X-ray diffraction methods. Three different methods were used to calculate the transition temperatures (Ttr) and thereby their thermodynamic relationships. Although the first and second method used calorimetric data (melting point and heat of fusion), the third method employed the use of configurational free energy phase diagram. The onset melting points of three polymorphic forms were found to be 482.89 ± 0.37 K for form I, 476.30 ± 1.21 K for form II, and 474.19 ± 0.11 K for form III. Moreover, the powder X-ray diffraction patterns for each form were also unique. The polymorphic pair of form I and II and of form I and III was found to be enantiotropic, whereas pair of form II and III was monotropic. Besides the relative thermodynamic aspects (free energy differences, enthalpy, entropy contributions) using different methods, the pharmaceutical implications and phase transformation aspects have also been covered.