Good flow and mechanical properties of compression mixtures are of key importance in manufacturing of quality solid oral pharmaceutical forms, including sustained release matrix tablets that are most frequently based on high-molecular weight hypromellose (HPMC). Importance of these properties is even more pronounced when scaling up from smaller laboratory to pilot and further to larger production scale, and when using higher tableting speeds. Understanding of the impact of the above mentioned properties, scale-up and critical process parameters on compression mixture behavior is therefore essential, and requires necessary attention already during research and development phase of the medicine. However, despite the wide use of HPMC polymers there is still a profound lack of studies with holistic assessment of their flow and mechanical properties, especially their differences between different producers. It is well known that HPMC polymers, due to their poor flow and/or mechanical properties, are not always suitable for direct compression, i.e. the technology of choice for manufacturing of tablets from industry perspective. Thus, wet agglomeration of dry powder mixture containing higher amount of HPMC polymers is often required to improve these properties. However, wet agglomeration is one of the more complex processes, where it is especially challenging to study and elucidate the effect of difficulty to achieve the same process conditions during scale-up and effect of process parameters on properties of produced granules that contain high amount of HPMC in their composition. The aim of our work has therefore been 1) to investigate flow and mechanical properties (compaction) of different grades of HPMC (substitution type 2208 polymers, including three different suppliers and two second generation directly compressible grades), 2) to investigate the effects of wet granulation process parameters on flow and compaction of produced granules that contain high amount of HPMC in their composition, 3) to investigate the effect of scale-up of granulation and tableting process on the properties of produced granules and tablets, 4) and to investigate the effect of tableting speed on deformation and compaction of HPMC polymers. All studies were performed in the context of optimization of the flow and mechanical properties of experimental, but realistic industrial compression mixture based on high-molecular weight HPMC. For this reason, we feel the results of our work have even bigger value and industrial application. The flow properties were determined using flow time, angle of repose, mass and hardness variation of produced tablets, Carr index, Hausner ratio, constant B from initial part of Heckel profile, and shear cell. Intra-granular porosity was determined using micro-computer tomography. The compaction properties were quantified using the ‘out-of-die’ Heckel, modified Walker and Kuentz-Leuenberger model, as well as two tensile strength profiles (tabletability and compactibility), and elastic recovery. Compaction was performed by both an instrumented single-punch tablet press and a high-speed rotary press simulator, and high-shear wet granulation was performed at different scales: 4 L, 300 L and 600 L. We used statistical approach to analyze the results. High-shear granulation scale-up and critical process parameters study showed the scale itself had larger effects on the granule properties than the process parameters for the formulation studied, which demonstrated high robustness of our formulation on the individual scale level. Granulation scale-up has again been found to be a very complex and non-linear process, and negative properties of formulations, especially those based on high-molecular weight HPMC polymers, are not easily compensated with the process parameters during the scale-up. Nevertheless, out of all the process parameters studied water addition volume had the largest effect, despite its more or less non-significant direct effect on flow and compaction properties of granules on bulk level. More statistically significant was its indirect effect through the effect on properties of primary granules, e.g. granule size. Results also showed both new direct compression HPMC grades had better flow properties in comparison to other more established grades, and represent additional options in the toolbox for optimization of flow properties of HPMC polymers and their formulations. Still, their flowability was poor to very poor according to pharmacopoeian classification, and at the same time their compaction properties (especially tabletability) was worse in comparison to other samples. Benecel K4M from Ashland also had slightly better flow properties, comparable with both direct compression grades. All other samples had worse flowability without significant differences between them, with Metolose K100M from Shin-Etsu having the worst flow properties. Methocel K15M from Dow Chemical Company had the best compaction properties, followed by Methocel K100 LV from the same producer and Benecel K100M from Ashland and Metolose K100M from Shin-Etsu. Based on all results both direct compression grades from Dow Chemical Company and Benecel K4M from Ashland had the worst compaction properties. All the studied HPMC samples exhibited some sensitivity to changes in the compression speed, however, not all the samples were susceptible to the same extent. The reason for these differences lays in their viscoelastic mechanical properties. Methocel K4M from Dow Chemical Company was the least sensitive to changes in compression speed and consequently the least viscoelastic. Methocel K100M DC and both samples from Ashland (Benecel K4M and K100M) followed, without significant differences among them. On the other hand, both samples from Shin-Etsu (Metolose K4M and K100M) showed to be the most sensitive and consequently the most viscoelastic. When transferring the tableting technology from a single punch press to a rotary press by using a compact simulator, the compaction properties of all studied samples were poorer, despite keeping the contact time constant. Hence, we believe not only contact time, but matching the relative contribution of consolidation times, dwell time and decompression time also has a crucial impact on the success of the scale-up, among other factors. However, not all materials were susceptible to the change of the equipment to the same extent, and the results showed similar trend as in the case of the compression speed sensitivity results.
At the end we studied also the effect of exposing HPMC polymers to moisture followed by drying to initial levels of moisture on their compaction properties. After drying the samples back to the initial water content level the bulk volume and porosity were found to be higher than initial values before exposure to moisture, and higher porosity also maintained to be elevated during compaction. Therefore, most of the studied samples’ compaction properties got worse after the moisturing and drying cycle, with this effect being most profound for Benecel K4M from Ashland. For the rest of the samples this effect was less profound, rarely also opposite. The results of this thesis in our opinion present one of the most holistic assessments of flow and mechanical properties of HPMC polymers as basic powder materials so far, especially the studied differences among the three different producers, and also of flow and mechanical properties of produced granules containing high amount of these polymers in their composition.
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