Process understanding on high shear granulated lactose agglomerates during and after drying

Abstract

In 2001 the FDA launched the Process Analytical Technology initiative as a response to the growing public and industrial awareness that there is a lack of process understanding required to have an optimal control of pharmaceutical manufacturing. The current research project was initiated based upon the insight that critical process and product attributes can only be acknowledged upon a thorough process understanding. This thesis can be seen as a follow up on earlier research done on wet high shear granulation; key process parameters that are involved in the wet high shear granulation process, including granule breakage and growth were determined. Although the relevance of these critical process parameters towards the formation of inhomogeneous granules was reported extensively, the consequences of the described in-homogeneity phenomena in granules in further processing were not elaborated. After the wet granulation process, a drying step is always necessary to obtain a basis for the final drug product. After the wet granulation process, a drying step is always necessary to obtain a basis for the final drug product but the drying of wet granules often involves an unwanted and uncontrolled size reduction. The aim of this thesis was to investigate the behavior of the granules throughout the drying process and the consequences of granule heterogeneity during and after the drying process. In this thesis it was shown that granular composition, size heterogeneity and water content are the critical process and product quality parameters during drying. Granule characterization revealed that the change in granule size of (partially) dried granules follows a three phase system characterized by a growth, plateau and breakage phase. The growth phase is based upon available surface water enabling layering growth and coalescence upon consolidation. Below a minimum liquid bridge volume the presence of very small amounts of water or the formation of solid bridges cannot prevent abundant size reduction. In the plateau phase above minimum water content, behavior of granules can be described with Rumpfs’ dynamic granule strength. More specific, in fluid bed drying the granular bed, the granule size, the inter-granular composition and water content are totally heterogeneous throughout the drying process. This heterogeneity differentiates the drying rate and extent of size increase and reduction of the different granule size classes in relation to the dynamic granule strength. Near infrared spectroscopy (NIR) is shown to be a versatile method to further determine the critical process and product factors by in-line monitoring of water content of granule and monitoring of granule size and attrition effects. By NIR it was shown that different drying parameters led to significantly different compositions of granules (non-crystalline and crystalline lactose) with a direct influence on the functionality of the granules such as compactibility. Finally, based upon the granule composition specific degradation of a steroid in lactose granules it is concluded that the heterogeneous composition of high shear granulated lactose granules dictates both the critical chemical and physical stability and quality aspects of the granules.