(T1030-02-13) Investigating Granule Temperature Dynamics and Its Impact on Granule Properties during Long TSMG Runs

Purpose: The commercialization of Eucreas, Orlissa, Oriahnn and the successful scale-up of fevipiprant showcase the potential of twin-screw melt granulation (TSMG) as a continuous manufacturing platform¹. The high-energy environment at the kneading zone causes local heat generation leading to an increase in granule temperature. A strong correlation between granule temperature and drug degradation was previously established by Kittikunakorn et al.². Similarly, Van Steene et al. demonstrated use of granule temperature to elucidate granulation mechanisms during TSMG³. Based on these studies, granule temperature was a superior indicator of thermal history at the kneading zone during granule growth. However, the studies monitored granule temperature for a short interval and assumed uniformity across the entire discharge frame (Figure 1). Granule temperature is influenced by frictional heat generation at kneading zone which could vary during a long run. Therefore, this study aimed to investigate the uniformity and dynamics of granule temperature across the discharge during a long TSMG run and its correlation with drug degradation and granule properties. During measurements, the maximum temperature within the discharge frame was defined as peak granule temperature whereas the average temperature within the discharge frame was defined as average granule temperature (Figure 1).

Methods: Long TSMG runs (1 hr) were done with gabapentin (GABA) as the model drug and mannitol as the primary filler. GABA was chosen due to its thermolabile nature and ability to degrade immediately upon melting. GABA and Gabalactam (GABA-L), the primary degradant was quantified using HPLC with sample concentration of 5 mg/mL and GABA-L limit of quantification at 0.01%. Klucel™ (Hydroxypropylcellulose) was chosen as thermal binder and binder level was fixed at 10 % based on previous studies¹. The drug load was varied at 4 levels i.e. 0, 20, 40, 90% to elucidate its impact on granule temperature dynamics during long runs. Granulation trials were conducted on Leistritz ZSE-18 twin-screw corotating extruder with a 25 L/D barrel configuration equipped with 30 mm kneading block (Staggering angle 60°). Processing conditions were kept consistent at a barrel temperature of 130 °C, screw speed of 200 rpm and a feed rate of 3 kg/h. Granules were collected for a 2-minute interval at 2m, 20m, 40m, 60m during the TSMG run. Kittikunakorn et al. observed a strong correlation between granule temperature and drug stability². Granule temperature was measured at discharge using a Thermodyne FLIR E54 camera.

Results: Peak and average granule temperatures were calculated from video frames using the Thermal Studio Software (Figure 1). The difference in peak and average granule temperature (δT_granule) was observed for all TSMG runs across various drug loads, confirming the non-uniform thermal history during the granulation process (Figure 2). This non-uniform thermal history could result from friction and the local hot spots generated at the kneading zone during granule growth. This was confirmed as δT_granule was higher for runs where visible granule growth was observed i.e. 20, 40, 90% GABA load and lower for runs with no granule growth i.e. 0% GABA load. An increase in peak granule temperature was observed until 10 minutes, after which no further δT_granule deviations were observed during the TSMG run at 20% GABA load. This initial drift can be attributed to the time required to reach a steady state (Figure 2). The initial increase in peak granule temperature corresponded to increased % GABA-L, highlighting it as a superior indicator of thermal history during TSMG process (Figure 3). Conversely, a consistent δT_granule was observed during longer TSMG runs for 40 and 90% GABA load (Data not shown) implying that steady state was achieved within 2 minutes at these drug loads. A consistent δT_granule during the entirety of run indicates process robustness and facilitates easier process control. % GABA-L remained consistent around 0.06% at all the four sampling intervals with no change observed in peak granule temperature over the entire 1h run. Further studies are needed to investigate any changes in drug crystal size with respect to granule temperature during longer runs.

Conclusion: Granule temperature is a superior indicator of thermal history at the kneading zone and is influenced by granule growth and strength. Peak granule temperature strongly correlated with % GABA-L during long runs and its impact of granule size distribution and tensile strength needs to be investigated for the longer run. A consistent δT_granule after steady state is promising and can be a sign of good process control. δT_granule also highlighted the non-uniform thermal history of the granulation process and can be used as an early indicator of drug stability concerns during TSMG, especially in case of deviations during the run.

References: 1. Pradhan, Adwait, Fengyuan Yang, Kapish Karan, Thomas Durig, Quyen Schwing, Brian Haight, Mark Costello, Mark Anderson, and Feng Zhang. "Material-sparing degradation-kinetics model for thermolabile drug stability assessment during twin-screw melt granulation–Insights with gabapentin." International Journal of Pharmaceutics 674 (2025): 125421.
2. Kittikunakorn, N., Paul, S., Koleng III, J. J., Liu, T., Cook, R., Yang, F., ... & Zhang, F. (2021). How does the dissimilarity of screw geometry impact twin-screw melt granulation ?. European Journal of Pharmaceutical Sciences, 157, 105645.
3. Van de Steene, S., Van Renterghem, J., Vanhoorne, V., Vervaet, C., Kumar, A., & De Beer, T. (2023). Visualization of the granule temperature using thermal imaging to improve understanding of the granulation mechanism in continuous twin-screw melt granulation. International Journal of Pharmaceutics, 645, 123423.


Figure 1. Radiometric image analysis on the FLIR Thermal Studio software to measure peak and average granule temperature. The hot spot and average spot in the discharge frame is measured and extrapolated to all the other radiometric frames in the video.


Figure 2. Granule temperature (Peak vs average) for a long TSMG run of 20% GABA drug load. Gray area indicates the sampling period at 2,20,40,60 minutes.


Figure 3. % GABA-L (Degradant) at the four sampling points (2,20,40,60 minutes) for a TSMG run with 20% GABA drug load. Increase in granule temperature correlated well to increase in % GABA-L during the long run.