Polymorphic conversion of furosemide after crystallization in aqueous polymeric solution: Crystallite analysis using Scherrer vs. Williamson-Hall equation and drug dissolution

Background and Purpose: Furosemide (FUR) is a potent diuretic, practically water-insoluble drug and also known to exhibit polymorphic form I (most stable), and metastable form II and form III. FUR was crystallized using aqueous polymeric solution and the effect of crystallite properties on polymorphic transformation and dissolution was studied. Methods: FUR was crystallized using aqueous solution of HPMC, CMC, MC, or, PVA as non-solvent (FH, FC, FM, and FP respectively). Crystallite properties were analyzed using Scherrer and Williamson-Hall equation. Effect of crystal on drug dissolution were also studied. 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 (3397.95, 3348.78, and 3280.32 cm-1) corresponding to asymmetric sulfonamide-NH, secondary amine-NH, and symmetric sulfonamide-NH stretching respectively, confirming the presence of form-I. Further, XRD and DSC also established 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: Furosemide form I has been transformed to stable form II after crystallization in aqueous polymeric solution of HPMC and MC, and not by CMC and PVA. A comparative analysis was undertaken using Scherrer vs. Williamson-Hall equation. Improved dissolution was also witnessed with all the crystals.