Evaluation of different techniques for wet granulation and pelletization processes using milk as innovative pharmaceutical excipient for pediatric use.

The present study focused on the use of milk as a novel excipient for the manufacture of pharmaceutical dosage forms specifically designed for the pediatric population. Dairy milks with different fat contents were studied to deliver paracetamol orally. The World Health Organization included milk in the list of GRAS (generally recognized as safe) substances, which together with its taste-masking ability and solubility solving properties, makes it a good candidate as an excipient in formulations containing paracetamol for pediatrics. The influence of the fat content in the milk, the fraction of paracetamol, the type of diluent and drying temperature (considered independent variables) were systematically investigated using a Design of Experiments (DoE) approach for the preparation of granules for oral administration, by wet agglomeration using different processing techniques, enabled the construction of mathematical models reflecting the correlation between the variables. Four different techniques were evaluated: wet granulation by low shear mixer, wet granulation by high shear mixer, wet granulation by fluidized bed, and extrusion and spheronization. The granules and pellets obtained were characterized for size, and size distribution of agglomerates, and complete release of the drug (dependent variables), according to the European Pharmacopoeia. The fraction of fat content in the milk promoted an increase on the dissolution rate of paracetamol. The key finding of the first two process techniques was a migration of paracetamol from powdered agglomerates towards the larger particles, probably due to friction and attrition events, which created a fraction of smaller size granules due to the fragmentation and loss of powder from the larger granules. The study has confirmed the potential of milk to be a novel and efficient excipient that can be used as a liquid binder in various agglomeration techniques to deliver drugs orally.