(T1130-09-56) Impact of Relative Humidity on the Flow Behaviour of Pharmaceutical Materials during Powder Feeding

Purpose: Powder feeding is typically the first unit operation employed during continuous tablet manufacture and is therefore, the first instance where variability may be introduced into the process so ought to be well examined. This process has been selected for this work to study powder flow across a range of relative humidity conditions. Relative humidity is one of several environmental conditions which may impact the flow behaviour of pharmaceutical materials during powder processing. Understanding the impact of relative humidity on bulk powder flow behaviour during feeding operations would enable improved control for manufacturing processes, including continuous manufacture of solid oral dosage. However, without access to environmentally controllable manufacturing areas, such studies have been challenging and as such a mechanistic understanding has to date been based on offline laboratory experiments. In this study, a humidity-controlled manufacturing suite was used to overcome this challenge and to begin developing a better understanding of the impact of relative humidity on powder flow. The main objectives of this work are to investigate the impact of relative humidity on the flow behaviour of excipients of varying hygroscopicity in a loss-in-weight (LIW) feeder system. A secondary aim was to investigate the role of silicon dioxide in silicified microcrystalline cellulose (sMCC) as a flow aid.

Methods: Four pharmaceutical excipients of varying relative hygroscopicity have been selected for this study. These excipients are as follows: lactose, microcrystalline cellulose (MCC), silicified MCC (sMCC), and starch. To ensure equilibrium was maintained throughout handling, experimentation took place within a humidity-controlled manufacturing suite with the excipients being stored and pre-conditioned in a humidity chamber at relative humidity values ranging from 20% to 70%RH. Dynamic vapour sorption (DVS) and loss-on-drying (LOD) were used to characterize the materials before the powder feeding experimentation took place. The excipients were fed through the Coperion K-Tron LIW feeder at a feed rate value of 2.5 kghr^-1. Five repeats of each material at every condition were carried out to ensure reproducibility.

Results: DVS isotherms plots were used to confirm the hygroscopic nature of the selected pharmaceutical excipients. Samples were stored in humidity-controlled chambers prior to manufacture in the environmentally controlled manufacturing suite. LOD was also conducted to verify the moisture content of the excipients was aligned with the expected values from the DVS data. During experimentation, the Coperion K-Tron LIW feeder generated the necessary screw speed to maintain a given feed rate (in this instance, 2.50 kghr^-1). The key findings of this work showed that for the hygroscopic excipients (MCC, sMCC and starch), the average screw speed of the LIW feeder system increased with increasing relative humidity. This suggests that the flow of these excipients is being inhibited by the increase in relative humidity. An analysis of variance (ANOVA) test of each material confirmed statistical significance between the feeding of the excipients at each relative humidity condition. Unlike the hygroscopic excipients, lactose did not flow as freely at low relative humidity for reasons yet to be determined. The presence of silicon dioxide (SiO₂) on MCC is believed to improve the flowability of the material and in this study, an ANOVA test revealed the differences between MCC and its sMCC counterpart to be statistically significant with less variability observed for the sMCC datasets across all three relative humidity conditions.

Conclusion: It may be concluded that relative humidity has a statistically significant impact on the flow behaviour of pharmaceutical excipients of varying hygroscopicities and that the addition of silicon dioxide has a statistically significant impact on the flowability of MCC. For hygroscopic excipients, the flowability is hindered by increasing relative humidity conditions. The next stage of this research is to consider the impact of relative humidity on more challenging materials namely, active pharmaceutical ingredients.

References: 1. Barjat, H. et al. (2020) ‘Demonstration of the Feasibility of Predicting the Flow of Pharmaceutically Relevant Powders from Particle and Bulk Physical Properties’, Journal of Pharmaceutical Innovation, (February). doi: 10.1007/s12247-020-09433-5.
2. Blackshields, C. A. and Crean, A. M. (2018) ‘Continuous powder feeding for pharmaceutical solid dosage form manufacture: a short review’, Pharmaceutical Development and Technology. Informa Healthcare USA, Inc, 23(6), pp. 554–560. doi: 10.1080/10837450.2017.1339197.
3. Ferreira, A. P. et al. (2018) ‘Enhanced Understanding of Pharmaceutical Materials Through Advanced Characterisation and Analysis’, AAPS PharmSciTech, 19(8), pp. 3462–3480. doi: 10.1208/s12249-018-1198-6.
4. Gamble, J. F., Tobyn, M. and Hamey, R. (2015) ‘Application of image-based particle size and shape characterization systems in the development of small molecule pharmaceuticals’, Journal of Pharmaceutical Sciences, 104(5), pp. 1563–1574. doi: 10.1002/ps.24382.
5. Stauffer, F. et al. (2019) ‘Managing active pharmaceutical ingredient raw material variability during twin-screw blend feeding’, European Journal of Pharmaceutics and Biopharmaceutics, 135(March 2018), pp. 49–60. doi: 10.1016/j.ejpb.2018.12.012.

Acknowledgements: Authors acknowledge funding received from the Centre of Doctoral Training in Formulation Engineering via the Engineering and Physical Sciences Research Council and Bristol Myers Squibb. (EPSRC Grant no. EP/S023070/1)