Agglomeration state and migration of drugs in wet granulations during drying.

Migration of drugs was studied during drying of wet granules, agglomerated at pendular and funicular state (S(3) and S(4)). Granulating liquids of different viscosity (2.5 and 7.5 mPa s) and drugs and diluents of different solubility and wettability were employed and correlation was sought between distribution of the liquid, wet kneading parameters (torque and liquid consumption S%), solid-liquid interactions (work of adhesion and spreading coefficients) and the migration of drugs. It was found that drug migration, expressed as CV% of its content, was strongly dependent on the type of diluent. Also, the type of diluent exerted the strongest effect on torque and liquid consumption during wet kneading and a significant one on moisture content of the final granulations. Viscosity of the granulating liquid and molecular weight of the binder had no effect on liquid consumption but viscosity had a significant one on drug migration. Significant linear relationships were found between spreading coefficients and the liquid consumption (S%) at the mid-state of funicular agglomeration (S(3)+S(4))/2 or the torque at the capillary state S(5). Migration of drug was remarkably lower for drying in the microwave oven and increased from the pendular (S(3)) to the funicular (S(4)) agglomeration state when drying in conventional oven was applied. Linear relationships were found between migration (CV%) and the spreading coefficient of liquid on solid, lambda(LS), for the low and the high viscosity levels of the granulating liquid, with r=0.965, P=0.05 and r=0.901, P=0.10, respectively. Also, a general linear relationship (r=0.903 and P=0.002) accommodating all experimental data was found between migration (CV%) and the ratio lambda(LS)/viscosity. Drug migration increases with solubility and may become a problem in a range higher than 1 g in 148-400 ml of granulating liquid.