Direct tableting of formulations containing high percent of active ingredient is often accompanied with poor compactibility properties and consequently low tablet strength. The real formulation containing high percent of active ingredient (75%) from the macrolide antibiotic group and microcrystalline cellulose (15%) as dry binder was studied. The aim of this study was to investigate the three systems: direct tableting system and two dry granulated systems (roller compaction and slugging). Direct tableting of this formulation revealed a poor powder flowability properties and pronounced capping tendency. Both dry granulated systems caused increasing of particle size, better compactibility, higher tablet strength and significant reduction in capping tendency compared to direct tableting. There were no significant differences in tablet properties between roller compaction and slugging. This can indicate that the type of dry granulation is not crucial for tableting, however the parameters during dry granulation, such as compaction pressure, influence on tablet properties. The main volume reduction mechanism for macrolide antibiotic is fragmentation which was confirmed by Heckel analysis, the lubricant sensitivity test, and SEM images. Some plastic deformation also takes place beside fragmentation parallel and after particle fragmentation. Part of plastic deformation can be attributed also to the microcrystalline cellulose which is the typical plastic deforming material. The results of Heckel analysis indicates intensive particle rearrangement at low compaction pressures which was the most expressed at direct tableting system. Lower particle rearrangement at both dry
granulated systems can be attributed to already better settlement and partial fixation of particles in the granules. The yield pressure (Py) of the direct tableting system is lower than the Py of dry granulated systems, which exhibit the lower plasticity of dry granulated systems. These findings do not explain the lower capping tendency of dry granulated systems compared to direct tableting which indicate that change of deformation mechanism or plastic-elastic particle properties is not the main mechanism responsible for lower capping at dry granulated systems. It is obvious that Heckel analysis does not perceive all elements which can attribute to tablet hardness and capping (CC), so it's results must be interpreted with caution, especially when structural changes of material can occur during compression. The main bonding mechanism between particles is attributed to the long distance intermolecular bonds (van der Waals) due to the intensive amorphisation of macrolide antibiotic that occurs due to the physical load during dry granulation. Amorphization leads to a significant increase in surface free energy and consequently stronger long-distance bonding between particles, which is able to withstand the elastic relaxation during decompression and therefore reduce the capping problem. This is considered as a crucial factor which is responsible for reducing capping incidence at dry granulated systems. The level of macrolide antibiotic amorphisation increases with increasing physical load during the process. The biggest influence on lower CC and higher tablet strength at all three systems (direct tableting, roller compaction, slugging) in the group of process parameters at tableting has higher main tableting pressure, while tableting speed has minor effect. The influence of precompression on tablet strength was not evidenced, but it can lead to lower CC. Capping incidence is not so much influenced of main tableting pressure at dry granulated systems as it is at direct tableting system.Based on studying energy differences for plastic-elastic particle deformation, it can be concluded that net energy (NETW) is the highest at direct tableting, followed by roller-compacted and then slugged system. The energy fraction for elastic deformation is lower at direct tableting system compared to both dry granulated systems. These findings are not in accordance to expectations, while higher CC is normally in a correlation to higher elastic deformation energy. This statement confirms the deficiencyof this method, which was pointed out also by other authors, which is that this method considers only deformation differences and neglects the possibility of particle interactions which can significantly influence on energy consumption. The differences in NETW in studied formulation are caused by deformation differences and also by particle interactions which are in our system very significant due to different level of amorphisation. NIR was found as an appropriate method for tablet strength determination. The reference model, which considered the results of all three systems, express satisfying level of certainty of anticipating and represent effective alternative to a classical diametral method for tablet strength determination and step forward in the implementation of contemporary approach, such us PAT (Process Analytical Technology) is, into pharmaceutical industry practice. Artificial intelligence methods - fuzzy logic and artificial neural network are very suitable and successful methods for studying and optimization of tableting process in industrial scale. Both methods stressed the impact of particle size and powder type (direct tableting or dry granulation) and main tableting pressure as crucial factors affecting capping incidence. Both methods have suitable and very comparable results such us identification of significant process parameters of tableting and powder properties, which have an impact to tablet quality and in optimization of process parameters setting in order to get the optimal outcome - no capping incidence, minimal deviation of tablet mass and hardness values at maximal tableting speed.
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