Prediction of the tablet strength: development of the unified compaction curve model for wet granulation

The complexity of tablet is often overlooked. A simple compressed mass of active and inactive ingredients hides the complex relationship between achieving the desired drug potency, the tablet strength and the tablet dissolution. The resulting tablet properties, particularly the tablet strength, are driven by the wet granulation process, an up-stream particle size enlargement process. Studies on the influence of the wet granulation process on the tablet properties show that there is still confusion over the influence of the wet granulation on the final tablet strength due to the lack of investigation in the direct impact between wet granulation and tabletting, which paves the path for the objective of this thesis. The influence of the wet granulation process on the final tablet strength was investigated by conducting wet granulation case studies looking at the effects of the liquid level, wet massing time, impeller speed and binder flow rate on a standard formulation of 1:1 lactose and microcrystalline cellulose granulated with polyvinyl pyrrolidine polymer in various solutions. A model called the “Unified Compaction Curve” was adopted from the dry roller compaction process and applied to the wet granulation case studies to see the feasibility of the model and understand how the model bridges the relationship between the wet granulation operating conditions and the final tablet strength. To understand this, granules from selected granulation batches were analysed to determine the granule properties including the circularity factor, surface roughness and granule porosity. The effect of the wet massing process, presence of moisture, liquid binder acidity and the presence of hydrogen-bonding in the granule liquid bridges on the microcrystalline cellulose properties was also investigated. The Unified Compaction Curve model was also extended to investigate the effect of the granulator scale on the final tablet strength to explore the possibility of a new up-scale guideline. The results demonstrate that the wet granulation process can have a direct effect on the subsequent tablet strength. As the liquid level, wet massing time and impeller speed increases, the tablet strength decreases from a maximum tablet hardness of approximately 45kp (from direct compaction) to lowest tablet hardness of 23.5kp after 10 minutes of wet massing time. Therefore there is a “loss of compactability” when the formulation is exposed to processing conditions in wet granulation and even in dry roller compaction (Kochhar et al., 1995; Bultmann, 2002; Freitag and Kleinebudde, 2003; Shi et al., 2011; Shi et al., 2011). The loss of compactability in the formulation by the processing compaction forces sets up the fundamental conditions for the Unified Compaction Curve model to be applied. The Unified Compaction Curve model was found to be a feasible model for the wet granulation process in which the model was able to translate the wet granulation compaction curves for various liquid levels, wet massing times, impeller speeds and binder flow rates and overlap them onto the master direction compaction curve, which allows the prediction of the resulting tablet strength. The Unified Compaction Curve is able to quantify the amount of compaction pressure exerted on the granules during wet granulation through the “effective wet granulation compaction pressure”, PWGC. When the PWGC is coupled with the cumulative number of impeller revolutions, the liquid level, wet massing time, impeller speed and binder flow-rate wet granulation data all coincide onto a first-order exponential curve. This makes the Unified Compaction Curve a potentially powerful tool in visually seeing the magnitude of deterioration in the tablet strength by the wet granulation process, which allows the prediction of the final tablet strength. The deterioration in the tablet strength with increasing wet granulation processing time is attributed to the decrease in the granule surface and rounding of the granule structure. This was evident by the increase in the circularity factor with increasing number of impeller revolutions and SEM images. The granulator impeller consolidates the granules, consequently destroying the granule surface roughness and decreases the granule porosity. If the granule porosity is seen as a function of the cumulative number of impeller revolutions, it can be seen that the relationship is the inverse relationship of the PWGC and the cumulative number of impeller revolutions. This demonstrates that the granule porosity is one of the main driving factors for the deterioration of the tablet strength with increasing residence time in the granulator. The transition of the granule morphology and porosity during wet granulation can be attributed to the irreversible plastic deformation of microcrystalline cellulose particles, which wrap and encase the lactose particles during the consolidation and densification of the granules during the wet granulation process. This destroys the mechanical inter-locking ability of the granules during the tabletting process, hence leading to the “loss of compactability” and reduction in the final tablet strength. However, the Unified Compaction Curve model will only be valid for granulation formulations comprising at least 30% liquid level and with at least 50% microcrystalline cellulose in the formulation used in this study, to effectively translate the kinetic forces from the impeller into compaction forces for significant deformation to occur. This was evident in granulation case studies where a liquid level less than 30% leads to the compaction data not conforming to the Unified Compaction Curve model. A recent study into the Unified Compaction Curve model found that a formulation comprising of 49% of microcrystalline cellulose (Avicel Ph-101) was not successful for the model to be valid (Dave and Dudhat, 2013). Investigations into the presence or absence of intra-granular hydrogen bonding in the granule liquid bridges can influence the final tablet. When hydrogen bonding is present (by using water-based liquid binder) between the granules, the granule strength increases which in turn compromises the table strength. The inverse trend was found for the absence of hydrogen-bonding (by using an ethanol-based liquid binder). Therefore strength of the liquid bridges can play a part in controlling the final tablet strength. The exploration of the effect of the liquid binder on the microcrystalline cellulose properties revealed that microcrystalline cellulose swells upon exposure to liquid binder. The swelling of the cellulose would increase the bonding area and confer strength to the tablet. The acidity of the liquid binder appears to influence the crystallite size of microcrystalline cellulose granules. The crystallite size was found to be larger for granulation experiments using a liquid binder with a neutral pH level (such as calcium oxide liquid binders), compared to the crystallite size in granules produced with more acidic liquid binders (such as PVP or hydrochloric acid). The wet massing time did not have any significant effect on the crystalline or amorphous regions of microcrystalline cellulose. The effects of the wet granulator scale was also investigated which revealed that Unified Compaction Curve demonstrates different mixing intensities between the 1litre and 5 litre granulator bowls in the relationship between the wet granulation compaction pressure (denoted as χ ) and the cumulative number of impeller revolutions. The compaction pressure per revolution was found to be greater for the 1L granulator in comparison to the 5L granulator scale. This formed the basis for the proposal of a new wet granulation scale-up rule which looks at maintaining ‘constant compaction pressure’ during the wet granulation scale-up process. This scale-up rule is a function of the compaction pressure per revolution and the cumulative number of impeller revolutions. The compaction pressure per revolution, χ, is able to compensate for the differences in the granulator bowl geometry and impeller design between the two granulator scales. The proposed rule is anticipated to be a useful tool to help maintain constant granule properties during wet granulation scale-up but also to target the desired tablet. The studies in this thesis will allow a deeper insight into the mechanisms in the relationship between the wet granulation process and the final tablet strength, which would enable the wet granulation to be tailored for optimisation and target tablet specifications, make trouble-shooting easier to carry out and reduce resources for wet granulation case studies. This is of great importance and benefit to the pharmaceutical industry