Scale-Up of pharmaceutical Hot-Melt-Extrusion: Process optimization and transfer.

Hot-Melt-Extrusion on Twin-Screw-Extruders has been established as a standard processing technique for pharmaceutical products. A major challenge is the transfer from a lab to a production level, since the combination of several unit operations within one apparatus leads to complex conditions for such a continuous manufacturing process. Here the residence time distribution is a crucial measure, which reflects the different mechanisms, e.g. dissolution, mixing or degradation, during processing. In the first part of a Scale-Up study, a methodology for the optimization of an extrusion process with respect to the load and throughput is presented. The developed concept was applied for different extruder scales in order to compare the identified processing windows. A deviation of the dominant material heating mechanisms was observed for the different scales, while the constraints for the transfer of a process to a different scale by the developed optimization concept is demonstrated. Finally, a sufficient operating point on a reference extruder is identified and in the second part of this study, different concepts from literature are applied for the transfer of this Hot-Melt-Extrusion process to two larger scales. The focus of the investigations was on the impact of the different approaches on the residence time distribution and the comparison. The determined results revealed a change of the most sufficient approach for the two different extruder sizes. The impact on the location in the time domain and form of the distribution are discussed and additionally evaluated by the fit to a RTD-model. In conclusion, the ratio of the applied energy for transport to mixing is identified as valuable addition in this context.

Investigations Concerning the Residence Time Distribution of Twin-Screw-Extrusion Processes as Indicator for Inherent Mixing.

Over recent years Twin-Screw-Extrusion (TSE) has been established as a platform technology for pharmaceutical manufacturing. Compared to other continuous operation, one of the major benefits of this method is the combination of several unit operations within one apparatus. Several of these are linked to the Residence Time Distribution (RTD), which is typically expressed by the residence time density function. One relevant aspect for pharmaceutical processes is the mixing capacity, which is represented by the width of this distribution. In the frame of this study the influence of the mass flow, the temperature and the screw-barrel clearance were investigated for a constant barrel load (specific feed load, SFL). While the total mass flow as well as the external screw diameter affected the mixing performance, the barrel temperature had no influence for the investigated range. The determined results were additionally evaluated with respect to a fit to the Twin-Dispersion-Model (TDM). This model is based on the superimposition of two mixing functions. The correlations between varied process parameters and the obtained characteristic model parameters proved this general physical view on extrusion.

Inline Determination of Residence Time Distribution in Hot-Melt-Extrusion.

In the framework of Quality-by-Design (QbD), the inline determination of process parameters or quality attributes of a product using sufficient process analytical technology (PAT) is a center piece for the establishment of continuous processes as a standard pharmaceutical technology. In this context, Twin-Screw-Extrusion (TSE) processes, such as Hot-Melt-Extrusion (HME), are one key aspect of current research. The main benefit of this process technology is the combination of different unit operations. Several of these sub-processes are linked to the Residence Time Distribution (RTD) of the material within the apparatus. In this study a UV/Vis spectrophotometer from ColVisTec was tested regarding the suitability for the inline determination of the RTD of an HME process. Two different measuring positions within a co-rotating Twin-Screw-Extruder were compared to an offline HPLC-UV as reference method. The obtained results were overall in good agreement and therefore the inline UV/Vis spectrophotometer is suitable for the determination of the RTD in TSE. An influence of the measuring position on repeatability was found and has to be taken into consideration for the implementation of PATs. An effect of the required amount of marker on process rheology is not likely due to the low Limit-of-Quantification (LoQ).

Inline UV/Vis spectroscopy as PAT tool for hot-melt extrusion.

Hot-melt extrusion on co-rotating twin screw extruders is a focused technology for the production of pharmaceuticals in the context of Quality by Design. Since it is a continuous process, the potential for minimizing product quality fluctuation is enhanced. A typical application of hot-melt extrusion is the production of solid dispersions, where an active pharmaceutical ingredient (API) is distributed within a polymer matrix carrier. For this dosage form, the product quality is related amongst others to the drug content. This can be monitored on- or inline as critical quality attribute by a process analytical technology (PAT) in order to meet the specific requirements of Quality by Design. In this study, an inline UV/Vis spectrometer from ColVisTec was implemented in an early development twin screw extruder and the performance tested in accordance to the ICH Q2 guideline. Therefore, two API (carbamazepine and theophylline) and one polymer matrix (copovidone) were considered with the main focus on the quantification of the drug load. The obtained results revealed the suitability of the implemented PAT tool to quantify the drug load in a typical range for pharmaceutical applications. The effort for data evaluation was minimal due to univariate data analysis, and in combination with a measurement frequency of 1 Hz, the system is sufficient for real-time data acquisition.