(M1130-06-33) Continuous Manufacturing of Inhalation Powders: Effects of Processing Parameters

Purpose: This work presents the original preparation of inhalation powders using the twin-screw corotating extruder. Currently, dry powder inhaler (DPI) blends are manufactured via low or high shear batch mixing processes [1, 2]. The use of twin screw mixing for dry granulation has been studied, but the application of continuous mixing to produce inhalation powders has not been considered [3]. The objective was to demonstrate that twin screw mixing can produce inhalation blends and determine how varying processing parameters affects critical quality attributes. In addition, powders were prepared using standard batch mixing techniques for comparison to the novel approach.

Methods: 10% micronized budesonide, 3% magnesium stearate, and 87% lactose were mixed in a V blender for 10 minutes and fed in parallel with lactose into the Nano-16 twin screw mixer (Leistritz). The final formulation obtained was 1% drug and 0.3% lubricant in lactose. Figure 1 details the screw profiles used in this study. The three screw profiles evaluated consisted of mainly conveying elements and one GFM mixing (profile 1), one 30° kneading (profile 2), or one 60° kneading (profile 3). One powder sample was passed through the mixer multiple times to analyze effect on uniformity. The same formulation was prepared using a low shear mixer (Turbula, Glen Mills, 46 rpm, 240 mL) for 60 minutes and a high-shear mixer (R402V high-shear mixer, RobotCoupe, 500 rpm, 1400 mL) for 32 minutes. Each blend was sampled at specific timepoints and locations to analyze uniformity using HPLC. 30 mg of each powder was loaded into a size 3 HPMC capsule and actuated using a single-dose inhaler (RS01, Plastiape) connected to an abbreviated impactor and vacuum pump (Copley) operated at 4 kPa pressure drop. Each section of the impactor was assayed for drug deposition and fine particle fraction (FPF) reported as a performance metric.

Results: Torque remained low and stable ( < 5%) for all mixing runs performed using profiles 1 and 2. Torque overload and machine shut down occurred when using profile 3, which is attributed to the presence of the 60 °neutral kneading element, which has no conveying capability. The mixing uniformity data in Figure 2 indicates that profile 2 produces more uniform powders than those produced using profile 1. The 30° offset discs in the kneading element generate higher shear mixing in comparison to the GFM elements which are primarily intended for conveying [4]. %RSD of FPF decreases with increasing number of passes through the mixer when processed using profile 1 at 40 g/min feed rate and 200 rpm screw speed. The mean FPF value did not change significantly, indicating that particle size of drug fines can be made more consistent without drastically changing FPF by increasing mixing time. Figure 3 reveals that FPF of the low shear powder was significantly lower than that of powders produced using high shear and twin-screw mixing. We hypothesize that twin screw and high shear mixing processes have sufficient energy input to break up drug agglomerates and evenly distribute on the carrier surface, whereas low shear mixing does not.

Conclusion: In this study we have demonstrated the ability to tune aerosol properties of powders prepared with twin screw mixing by adjusting mixing elements and processing conditions. We have also shown that twin screw can produce powders with better inhalation performance that low shear and comparable to high shear batch mixing. Twin screw mixing is a robust, promising method for developing uniform DPI blends with good aerosol performance.

References: 1. Alyami, H., et al., An investigation into the effects of excipient particle size, blending techniques and processing parameters on the homogeneity and content uniformity of a blend containing low-dose model drug. PLoS One, 2017. 12(6): p. e0178772.
2. Jones, M.D., et al., The relationship between drug concentration, mixing time, blending order and ternary dry powder inhalation performance. Int J Pharm, 2010. 391(1-2): p. 137-47.
3. Mateo-Ortiz, D., et al., Dry Powder Mixing is Feasible in Continuous Twin Screw Extruder- Towards Lean Extrusion Process for Oral Solid Dosage Manufacturing. 2018.
4. Martin, C., Twin Screw Extruders as Continuous Mixers for Thermal Processing: a Technical and Historical Perspective. AAPS PharmSciTech, 2016. 17(1): p. 3-19.

Acknowledgements:The author(s) received no financial support for the research, authorship, and/or publication of this article. Ren, Spahn, Smyth and Zhang are co-inventors on IP related to this work.


Figure 1. Illustrations of the screw profiles used for twin screw mixing. All three profiles consist of wide and narrow pitch conveying elements followed by a GFM combed mixing element (top), a 30° kneading element (middle), or a 60° kneading element (bottom).


Figure 2. Mixing uniformity of powders produced using twin screw mixing profiles 1 and 2.


Figure 3. Aerosol performance for powders produced using low and high shear batch and twin-screw mixing.