CORRELATION BETWEEN PHYSICOCHEMICAL PROPERTIES AND COHESIVE BEHAVIOR OF FUROSEMIDE CRYSTAL MODIFICATIONS

This study reports the influence of changes in crystal form, with subsequent changes in physico-chemical properties, on the cohesive properties of furosemide powders. Two known polymorphs and three crystal habits were prepared by changing the crystallisation solvent and velocity. Crystallised products were characterised by their XRD profiles. Powder properties including solid-state photochemical reactivity, particle size and distribution, density, wettability and dissolution were measured. Fine particles of form I, mean size 3 mu m, were extremely cohesive, mean size of agglomerates 108 mu m, and poorly wettable, contact angle > 90 degrees. Changes in the crystal habit of form I led to the crystallisation of large (mean size > 50 mu m) tabular and rod shape, less cohesive but also poorly wettable (contact angle > 90 degrees) particles. These large particles although not cohesive had poor dissolution properties. Milled particles with a mean size of smaller than 10 mu m, obtained from the large crystals were again cohesive. The method of preparation of form II produced small plate like crystals, mean size 8 mu m, fractionally more wettable, contact angle 75 degrees, and not as cohesive, mean size agglomerates 25 mu m. Milling to a mean size of 4 mu m increased the cohesive properties because the mean size of agglomerates was then 53 mu m. Different crystal habits of form I did not show a difference in degradation during the nucleation period, mean rate constant 1.4x10(-2) h(-1) and the growth period, mean rate constant 2.4x10(-2) h(-1). In summary crystal modification improved the wettability and cohesive properties of furosemide particles without changing the solid-state stability of the drug. The dissolution properties of larger less cohesive particles were however poor and milling, to increase the surface area available for dissolution, increased the cohesive properties of particles.