Simultaneous Measurement of Granule Disintegration and API Dissolution Profiles As a Tool for Maintaining Product Quality during Process Scale-up

The release rate of an active pharmaceutial ingridient (API) is a crucial atribute of a solid dosage form. In vitro dissolution tests with clearly defined conditions are used to assess quality of the solids. A dissolution profile provides information about the amount of dissolved API from the solid dosage form in time. Comparison of the different profiles could serve as a tool to assess a success of a transfer or scale-up of a given process. Granulation proces is a key step during the manufacture of solid dosage forms, therefore the granules are tested by in vitro dissolution experiments. However, single dissolution profile of API from the granules does not provide deep insight into dissolution process. While classical in vitro dissolution tests are not always discriminatory, their combination with the simultaneous monitoring of other variables, such as the mechanical propertier of disintegrating granules before and during dissolution, may be more sensitive to in consisitncies in the product quality – either between batches or during scale-up or transfer.

The aim of this work is to investigate the dissolution mechanism of the granules consisted of 6-component formulation with a high load of API (58 % wt.) and produced at qualitatively different conditions of the granulation process (various main impeller speed, expressed by Froude number ranging from 0.26 to 2.04) and on different scales (granulator volume: 4, 25 and 400 L). A novel metodology which combines granule disintegration online monitoring with a measurement of API dissolution profile was developed. An evolution of a granule size distribution is analyzed online using a laser particle size analyzer (Horiba Partica LA950) by static light scattering. A 300ml circuit with flow cell and input cone for load and to take the samples for offline measurement on UV spectrophotometer in order to obtain dissolution profile coupled with information about granule disintegration. The inner structure of the granules was investigated using x-ray micro-CT tomography and their mechanical properties were analyzed by CT3 Texture Analyzer. Three possible mechanisms of API release from granules were proposed: leaching, surface erosion and granule breakage. These mechanisms were identified in different stages of the dissolution process and different contribution of each mechanism was observed for granules produced at different Froude number granulation set-up. In a more detailed part of study, where granules sieved into coarse (over 400 µm) and fine (under 400 µm) fractions were investigated, breakage of the coarse granules into considerably stable sub-granules was observed, where the prevailing mechanism of release was leaching of API. This demonstrates that a sub-population of granules exists in each batch regardelss of the process conditions, which shows very robust and repeatable properties. The challenge for future QbD research will be to identify mechanisms that lead to the formation of this sub-population.