(203i) Downstream Processing of Extrudates: Polymer Platform Development for Hot-Melt Extrusion/Tableting Via in-Line Monitoring of Compaction Properties

As the number of applications for polymers in pharmaceutical development is increasing, there is need for fundamental understanding on how such compounds behave during processing. This research is focussed on the tableting behaviour of polymers used as carriers for solid dispersions manufactured via hot-melt extrusion (HME). Despite the fact that HME has been widely used for solid dispersion technologies there is still limited knowledge on how this processing technique might influence the downstream processing such as the tableting behaviour of pharmaceutical polymers and their formulations (Iyer et al., 2013). Therefore, a novel approach was developed to monitor and analyse ‘in-die’ compaction properties directly on a rotary tablet press during downstream processing of milled extrudates. This is advantageous due to the possibility of performing in-line measurements during the tableting process. During the first part of this research, a polymer platform was developed from which researchers can select the adequate polymer for both HME and tableting purpose by using formulation properties and in-line measured compaction properties (Grymonpré et al., 2017). Afterwards, a promising polymer was selected from this platform and subjected to a quality-by-design (QbD) approach with different active pharmaceutical ingredients (API’s) to understand the influence of process and formulation parameters on the critical quality attributes (CQA) of extrudates and tablets of a hot-melt extruded solid dispersion formulation.

MATERIALS AND METHODS Soluplus (SOL), Kollidon VA 64 (VA 64) and Eudragit EPO (EPO) were selected as amorphous polymers, PVA 4-88 as semi-crystalline polymer, while Celecoxib (CEL) was chosen as BCS class II model drug for development of the polymer platform. Neat polymers and physical mixtures (35% drug load) were processed via HME (Prism Eurolab 16, Thermo Fisher, Germany) using co-rotating twin-screws containing 3 mixing zones.

The extrusion temperature was determined based on the extrudable range of each material as defined via a rheological screening, i.e. the temperature range corresponding to a complex viscosity between 1000 and 10000 Pa.s (Gupta et al., 2015). After cooling the extrudates were milled and sieved to obtain powders with comparable particle sizes as the neat polymer. For each polymer, 3 formulations (neat polymer, neat polymer extrudates and polymer-CEL extrudates) were compressed to tablets (270 ± 10 mg) on a rotary tablet press (MODUL^TM P, GEA Pharma Systems) equipped with cylindrical flat-faced Euro B punches of 10 mm diameter, using 6 main compaction pressures without a pre-compression step. All tablets were analysed for ‘out-of-die’ properties (tabletability, compressibility, compactibility) immediately after ejection. Punch deformation at each compaction pressure was calculated and corrected for during this study. An experimental approach was developed for in-line analysis of the compaction properties (plasticity factor (PF), in-die elastic recovery (IER) and Heckel analysis) on a rotary tablet press using linear variable displacement transducers (LVDT) incorporated inside the turret and clamped onto one pair of punches and a complementary data acquisition analysis system (CDAAS, GEA Pharma Systems). This approach enabled the monitoring of punch stroke movements during a compression cycle directly on a rotary tablet press. Principal component analysis (PCA) was executed on the relevant characterization and compaction data in order to classify the different materials according to their flowability and compaction behaviour using the multivariate data analysing software SIMCA 13.0.3 (Umetrics, Umeå, Sweden).

Furthermore, a statistical Design of Experiments (DoE) was used to evaluate the influence of three HME process parameters: barrel temperature (160-200 °C), screw speed (50-200 rpm), throughput (0.2-0.5 kg/h) and one formulations parameter: drug load (0-20 %) on the CQA’s of extrudates and tablets of the selected SOL-CEL solid dispersion formulation.

RESULTS AND DISCUSSION

Solid state characterization showed that HME yielded stable glassy solutions for all amorphous polymer formulations containing 35 % CEL as these were stable for at least 6 months under stress conditions (40 °C and 75% relative humidity). In general, higher tablet tensile strengths were observed for glassy solutions formulated with all polymers due to higher interparticulate bonding strengths per unit bonding area, while no changes were detected in the interparticulate bonding areas between formulations. There was need for analysing the ‘in-die’ tablet compaction properties of these formulations to understand the mechanisms which modified the mechanical properties such as tablet tensile strength. At higher compaction pressures, glassy solutions of SOL and EPO underwent more plastic deformation which was correlated to a higher compactibility and tabletability of these formulations. Additionally, the formation of stable glassy solutions altered the formulations towards more fragmentary behaviour under compression which was beneficial for the tabletability. No differences in plasticity factor were detected when tableting the neat polymers compared to their extrudates, indicating that HME did not alter the volume reduction mechanism of the amorphous polymers without API. However, this was not the case when using the semi-crystalline polymer (PVA 4-88) as a significant decrease in tabletability was detected after HME of the neat polymer which was linked with a change in crystalline fraction (32 to 21.4%). With the inclusion of amorphous CEL, the tablet tensile strength (TS) was slightly recovered due to similar transition towards a more fragmentary behavior. Principal component analysis (PCA) was applied to summarize the behaviour during HME, milling, feeding and compaction of all formulations, enabling the selection of polymers which have the highest potential as carrier during HME for solid dispersions with CEL in respect of further downstreaming by tableting. By application of PCA on this polymer platform, SOL and VA 64 were selected as more favourable polymers compared to EPO and PVA 4-88 for HME/tableting purpose. The QbD-study on SOL-CEL enabled to evaluate the HME-process as well as the impact of the tableting behaviour on this formulation. Torque was mainly influenced by barrel temperature and drug load since both factors impacted the melt viscosity. In general, drug load had the most significant impact on the extrudate properties compared to the process parameters indicating that for this specific formulation the HME process was very robust. Tabletability was clearly affected by the drug load, while changing the process parameters had no impact on this property. Tablets manufactured from the glassy solutions yielded a significantly higher TS. Drug load also altered the ‘shape’ of the curves (i.e. inflection point), indicating changes in the mechanical properties of the formulations.
Conclusion

Monitoring the punch movement using the described instrumentation and CDAAS-software was an effective tool for in-line measurement of compaction properties on a rotary tablet press. By combining ‘in-die’ and ‘out-of-die’ techniques, it was possible to investigate in a comprehensive way the impact of HME on the tableting behaviour of pharmaceutical polymers and their formulations. While HME had only a limited influence on the compaction properties of the amorphous polymers when no drug was included, HME changed the compaction properties of glassy solutions towards a more fragmentary behaviour, independent of the polymer type. The semi-crystalline PVA 4-88 encountered more impact of HME on tabletability of the neat polymer due to a change in crystalline fraction. In respect to the milling efficiency of the extrudates, the used amorphous polymers were significantly beneficial over the semi-crystalline polymer since they were more brittle. A polymer platform was successfully established using PCA on the large dataset, enabling selection of the most suitable polymers for a specific formulation in respect to HME, milling and further downstream processing towards tablets. Afterwards, a promising polymer was selected from this platform and successfully subjected to a quality-by-design (QbD) approach which emphasized that HME was a robust process for the combination SOL-CEL. However, the quality of extrudates and tablets can be optimized by adjusting specific formulation parameters (e.g. drug load).

REFERENCES

1. 1. Iyer, R., et al. The impact of hot melt extrusion and spray drying on mechanical properties and tableting indices of materials used in pharmaceutical development. J. Pharm. Sci. 102, 3604–3613 (2013).
2. 2. Grymonpré, W., et al. In-line monitoring of compaction properties on a rotary tablet press during tablet manufacturing of hot-melt extruded amorphous solid dispersions. Int. J. Pharm. 517, 348–358 (2017).
3. 3. Gupta, S.S.., et al. Effect of carbamazepine on viscoelastic properties and hot melt extrudability of Soluplus. Int. J. Pharm. 478, 232-239 (2015).