The influence of model drugs on the preparation of pellets by extrusion/spheronization: II spheronization parameters

Abstract

Five drug-models, 4-parahydroxybenzoic acid (4HBA), methyl (MBA), propyl (PBA) and butyl (BBA) paraben and propyl gallate (PG), all of similar chemical nature, were mixed in different proportions (50–73.7%) with microcrystalline cellulose (MCC) (26.3–50%) plus various levels of water (26.9–50.0%). The wet powder mass was extruded and spheronized under standard conditions. The pellets produced were evaluated in terms of their median diameter, their modal size range, the % within a given size range (0.7–1.7 mm) and their shape factor. For the majority of formulations, all drug models, except 4HBA, produced pellets. This material only had two combinations of excipients that produced acceptable pellets. For all the model drugs, two combinations of formulations could be identified; (1) a combination, which produced pellets from all the model drugs and (2) a combination, which was too wet to produce pellets with any of the model drugs. Between these two extremes, whether pellets could be made and their quality varied with the model drug. Cluster analysis was able to divide the formulations into 4 clusters. In cluster 1 all the model drugs produced pellets except 4HBA; in cluster 2 all drugs produced pellets except MBA; in cluster3, pellets were produced with PBA, BBA and PG while MBA produced agglomerates and 4HBA was too dry; in cluster 4, MBA and BBA produced pellets, PBA produced agglomerates while 4HBA was too dry to pelletise and PG too dry to extrude. The five drug models showed different relationships between the median pellet size and drug-load and initial water content in the formulation. Cluster analysis indicated that, the level of water and type of model drug were the most significant factors in determining the pellet size. Three clusters could be identified, but the response to water content was drug dependent. It was not possible to identify a relationship between the force required to extrude the wet mass and the ability to produce good pellets nor their median size. All the products, which could be classified as good pellets, when produced, had a shape factor that can be considered to be indicative of a spherical shape. The most consistent material, in terms of spheronization, as represented by median diameter, size range and roundness, was propyl gallate (PG), which throughout all the formulations produced an almost constant value for shape factor and median pellet size, which in the majority of cases fell within a limited pellet size.