Steam as a challenging binder for pharmaceutical wet granulation

Granulation is a process of particle size enlargement during which powder particles agglomerate through agitation or compression mechanisms. Today, granulation technology is used by a wide range of industries, including chemical, pharmaceutical, agrochemical, and also in the production of fertilizers and detergents. There are several reasons why granulation could be necessary during a manufacturing process: to prevent powder segregation, improve the uniformity of the content of the final products, and also to increase the flow and the compaction properties of the mix. Another advantage is the reduction of toxic dust production that leads to the prevention of cross-contamination and to benefits for operator health. Finally, granulate manufacturing is convenient for the storage and shipment of materials, since they are characterized by a bulk density that is greater than the parent powder mixture. Among the different granulation techniques, wet granulation is the most used, and for this reason, the aim of this research project was to compare two different approaches to perform wet granulation: traditional wet granulation and unconventional steam granulation. In the first case, the liquid binder consists of simple water that is nebulized on the powder bed; in the second case, a stream of steam is used as a liquid binder. The literature reports that steam granulation allows for the reduction of the amount of liquid binder necessary and the process as a result of the gaseous properties of the steam. However, there are few published data reporting the effect of steam on the technological characteristics of granules and tablets. Different granulating equipment can be used for granules manufacturing, among them high shear granulators are very common in the pharmaceutical industry, and thus are selected for this study. To also evaluate the effect of composition of the quality attributes of granules produced with the two different techniques, five different formulations were selected. All the formulations contain 20% (w/w) of caffeine as model drug, 50% (w/w) of microcrystalline cellulose as granulating aid, and 30% (w/w) of diluent. The diluents selected were: dicalcium phosphate anhydrous, corn starch, lactose monohydrate, maltodextrin and sorbitol. The five diluents are characterized by different solubility in water, thickening power and particle size. Before starting the granulation experiments, a rheological analysis of the wet masses was performed using the mixer torque rheometer to establish the amount of water or steam necessary for the granulation process and to hypothesize the growth regime followed by the granules during the massing phase. The results demonstrated that steam granulation requires a lower amount of liquid binder than traditional wet granulation, allowing a reduction in the drying phase. Moreover, steam granulation generally allows better control of granule growth because it occurs more slowly than wet granulation. The granulation experiments were performed using a standardized experimental procedure, and the granules, after drying in a ventilated oven, were characterized by sieve analysis to evaluate the particle size distribution, and by measurement of the tensile strength and uniformity of the content. A compression study was also performed to identify the compression mechanism (rupture or deformation). Granules with a particle size lower then 500 μm were mixed with a lubricant and a glidant and compressed in a single punch tablet machine using different compression forces. Tablets characterized by a tensile strength between 1 and 2 MPa were selected and analysed by mass and content uniformity tests, disintegration and dissolution tests. The results demonstrate that the granules manufactured through steam granulation produce tablets with a shorter disintegration time and faster caffeine release than those achieved through the wet technique.