Polymorphic Conversion of Furosemide after Crystallization in Aqueous Polymeric Solution: Crystallite Analysis Using Scherrer vs. Williamson-Hall Equation and Drug Dissolution.

Abstract

Purpose: Furosemide (FUR) is a potent loop diuretic, practically water-insoluble drug and also known to exhibit polymorphic form I (most stable), form II (metastable), and form III (metastable), and also a poorly stable amorphous form. FUR was crystallized using aqueous polymeric solutions and the effect of crystallite properties on polymorphic transformation and dissolution was studied.

Methods: FUR crystal was prepared using aqueous solution of HPMC, CMC, MC, or, PVA as non-solvent (as FH, FC, FM, and FP respectively), and spectral analysis and in vitro dissolution was performed.

Results: FTIR study of FH and FM exhibited only two peaks (3342.99 and 3250.43 cm-1), considering form II, whereas, FP and FC presented three distinct peaks between 3400-3200 cm-1 (3397.95, 3348.78, and 3280.32 cm-1) corresponding to asymmetric sulfonamide-NH, secondary amine-NH, and symmetric sulfonamide-NH stretching, confirming the presence of form-I. Further, XRD and DSC also confirmed the polymorphic identity of the crystal forms. Crystallite size analysis using the Scherrer equation and Williamson-Hall plot revealed a significant reduction in the size of all crystal products compared to pure FUR, with an associated increase in dislocation density, suggesting enhanced structural imperfections. All prepared crystals demonstrated markedly improved dissolution profile relative to the pure drug. Furthermore, stability studies under accelerated condition (40 °C/75% RH, 3 mo) confirmed the retention of respective polymorphic forms without any noticeable changes (FH and FM stayed in form II and FC and FP stayed in form I).

Conclusion: This study concluded that the stable polymorphic form of furosemide crystal was produced using aqueous polymeric solution with improved dissolution.