Dry granulation via roller compaction

Abstract

Granulation processes for solid oral dosage forms are commonly used in the pharmaceutical industry to enhance the quality of the final product, i.e. tablets. Today, roller compaction is one of the most common granulation techniques for solid oral dosage forms as it provides advantages like simple operation, due to integrated process control mechanisms, suitability for water- or heat-sensitive APIs and opportunity for an implementation in a continuous manufacturing process. Although roller compaction was intensively investigated, the impact of upscaling from a small to a larger roller compactor or vice versa is not fully understood. <br /> To account for this knowledge gap, in this thesis the effect of a scale up on the quality attributes of intermediate- and final products, was investigated. Therefore, the controversially discussed topic of reduced tabletability of roller compacted granules caused by work hardening phenomena, particle size enlargement effect, porosity of granules and lubricant sensitivity was investigated. Two formulations, one predominantly plastic deforming and the other predominantly brittle deforming, were used. Both had been previously characterised in respect to their compressibility, tabletability and compactibility and processed at both scales to differentiate between material and scale dependent effects on the intermediate- and final product. Finally, a successful scale up strategy was developed to achieve the same product quality for all scales.<br /> Solid fraction of the ribbons is well known as key intermediate critical quality attribute for downstream processing of a roller compaction process. Different established analytical methods were compared for the measurement of the solid fraction of ribbons. The GeoPycnometer method (volume displacement) turned out as the most reliable and most robust method. <br /> Subsequently, both formulations were dry granulated at both scales with equal process settings. A higher solid fraction of the ribbons was obtained for both formulations at the larger scale. For the predominantly plastic deforming formulation the particle size distribution of the granules was similar for both scales, resulting in a lower tensile strength of the tablets of the large scale, which was mainly impacted by the work hardening effect and sensitivity towards lubricant. The increased solid fraction of the ribbon produced by the large scale compared to the small scale correlated with a lower tensile strength of the tablets. In contrast, negligible differences of the tensile strength of the tablets between both scales were observed for the predominantly brittle deforming formulation, although the particle size distribution of the granules differed at higher specific compaction forces of the large scale. This was driven by the impact of the brittle deforming component, which enhances the fracturing behaviour of the granules and resulted in a negligible susceptibility towards work hardening, lubricant and particle size enlargement effect. In conclusion, even though differences existed between ribbons produced at both scales, these could be balanced if the formulation contains a high proportion of a brittle component. This strategy will allow enhancing the robustness of the scalability of the process and the final product quality.<br /> Previously it was demonstrated that a different solid fraction of the ribbon resulted in a different tensile strength of the tablets between scales for the predominantly plastic formulation. This formulation however, is commonly used to counteract the main disadvantage of the roller compaction; the reduced tabletability of granules of tablets (loss of tensile strength). To account for this, a new approach (Scale Model) was developed for the predominantly plastic formulation to achieve the same solid fraction of the ribbon at both scales. Same solid fraction at both scales resulted in a same porosity of the granules, compressibility and tensile strength of the tablets, although a different particle size distribution of the granules was obtained. This demonstrated that the particle size distribution of granules should not to be considered as the main intermediate quality attribute to achieve a successful scale up for a roller compaction process, because the porosity and the compressibility of the granules defining the microstructure of a tablet during tableting and subsequently the resulting tensile strength of the tablets. The Scale Model approach demonstrated a practicable solution for the pharmaceutical industry to scale the process from small development batches to commercial batches and still achieve equal quality of the tablets.<br /> In order to investigate the observed higher solid fraction at the large scale at equal process settings for both scales a new analytical method via NIR was developed to measure the solid fraction distribution along the roll width. It was possible to predict the solid fraction of unknown samples by acquiring the NIR spectra comprising reduction of analysis time compared to the GeoPycnometer method, which measured the “total” solid fraction of the ribbon. The effect of the cheek plates (lower solid fraction at the edges) decreased with increased distance to the cheek plates, which was especially the case for the larger scale with a broader roll width. This led to a higher “total” solid fraction of the ribbons produced by the large scale compared to the small scale at equal process settings. These results explained the previously observed different quality attributes of intermediate- and final products. The proposed scale up approach showed that the differences of resulting granules and tablets between scales can be balanced for a predominantly plastic deforming formulation through the adaption of the specific compaction force. Thus, adapting the specific compaction force by measurements of the “total” solid fraction (GeoPycnometer) is a suitable scale up strategy for a roller compaction process. <br /> Moreover, the solid fraction of a tablet (compressibility) was an important impact factor, which reinforced the development of theoretical models to predict the solid fraction for unknown powder mixtures based on single component compression analysis. A new theoretical developed Percolation and a modified Kawakita model were evaluated for model application. An exponential model was added to elucidate whether the two-parametrised models with theoretical background are superior in terms of predictability of solid fraction compared to a model without parametrised variables. Four mixtures were compressed over a wide pressure range at various fractions of a plastic and brittle deforming component. Based on single compression analysis of the pure excipients and application of these models, it was possible to predict the solid fraction of all mixtures. The Kawakita model showed overall superior prediction accuracy, whereas the Percolation model resulted in the best fit for mixtures containing the plastic deforming component in a range of 72%–48%. Both models were in good agreement at residuals below 3%. The prediction could serve as a systematic guidance for the formulator to select appropriate excipients depending on the active pharmaceutical ingredient to build quality into the drug product according to the Quality by Design approach. <br /> In summary, this thesis provides a new profound knowledge and an appropriate guidance for the scale up of a roller compaction process. An effect of a scale up of a roller compaction process on the quality attributes of intermediate- and final products was demonstrated. This effect can be balanced by applying the proposed scale up strategy or by diminishing the formulation susceptibility to scale dependent effects with an increased proportion of a predominantly brittle deforming component in the formulation.