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.
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.
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