(W1030-08-51) Microdosing with Vibrating Capillary – Influence of Dosing Time on Precision

Purpose: A lot of powder in pharmaceutical development show complex rheological properties, e.g., micronized APIs, engineered particles, tertiary blends. Additionally, they need to be filled in a precise way with a lot of flexibility in terms of primary container and dosing weight. Filling by vibrating capillary is an option to cover both versatile powder properties and different container closure systems.

Especially for clinical samples it is necessary to find a GMP-conform, 100% controlled and validated dosing system which can be used with disposable product contact parts, and to be easily installed within a containment. Additionally, it is important to have very low powder residues in the system after filling to save resources or to save expensive developmental powders.

Methods: Two different powders with different flowing properties were used: Respitose® ML001 (milled lactose by DFE Pharma), Carr’s Index of 32, Flow Factor of 3 and d₅₀ of 40 µm – very poor flowability; MM3 (micronized lactose by MicroSphere), Carr’s Index of 36, Flow Factor of 1.6 and d₅₀ of 1.8 µm – extremly poor flowability. Vibrating capillary: The vibrating capillary (MicroVibe®) is driven by a piezo. The powder is fed from the top and it uses vibration for fluidization of the powder for dosing. Upon vibration the powder starts to flow through the dosing nozzle. Stopping the vibration leads to an intended arching of powder, causing the stop of flow of material. The vibration is controlled by a load cell (see fig. 1). The critical process parameters are vibration amplitude and frequency. The vibrating capillary dosing system is available as a semi-automatic stand-alone equipment for any primary packaging or integrated in a fully automatic capsule filler. This study used the semi-automatic stand-alone equipment. For every powder 100 dosings were filled into a container.

Results: The target fill weight is met in any case with a max. deviation of 4.0%, e.g., 0.96 mg for ML001 (see table 1). RSD is below 9% in every case, but it depends on the dosing time and the intended target fill weight. Generally spoken, with increasing target fill weight, RSD is decreasing. If RSD is more important than dosing time, which is typical for clinical supplies of Phase I, it can be optimized by slower dosing rates. Increased frequency and amplitude are reducing the dosing rate. This results in smaller portions of powder. The smaller the incremental portions of powder, the more precise the dosing. This is valid for both types of powders regardless from the powder flow characteristics. However, powder flow characteristics seem to have an influence on the level of improvement possible for an individual powder. In case of 1 mg dosing of ML001 the RSD improved from 8.5% to 3.5% by almost tripling the dosing time from 1.4 s to 3.7 s. The optimization of 1 mg MM3 dosing improved only the RSD from 6.7% to 3.6% by adjusting the dosing rate with increased timing from 2.9 s to 5.2 s. The example of ML001 and MM3 demonstrates that both powders can be dosed with the technology of vibrating capillary at acceptable precision with improved but lower powder dosing rates. In any case the RSD could be lowered by min. factor 2 with optimized dosing rates. The dosing time can be kept stable regardless of the intended target fill weight. The vibrating capillary achieved the target fill weight of 1 mg, 5 mg and 20 mg at < 1.7 s for ML001 and < 3.1 s for MM3. The very high dosing rates compromise on RSD and acceptable dosing accuracy is observed for fill weights >5mg. Overall a higher dosing rates (i.e. shorter dosing time) can be achieved for ML001 because of the slightly improved flowability of ML001.

Conclusion: The vibrating capillary is a useful tool in dosing poorly flowing powders precisely in very low amounts. The focus of dosing in terms of dosing speed or dosing precision can be defined with variation of CPP of frequency and amplitude. The flow characteristics of a specific powder influence the possible dosing rate and the potential level of improving the dosing accuracy in terms of RSD.

References: 1. Sternberger-Ruetzel E, Mikrodosierung mittels vibrierender Kapillare, TechnoPharm 10, Nr. 2, 84-91 (2020)
2. Sternberger-Ruetzel E, Vollautomatische Dosierung unterschiedlicher Pulver mittels vibrierender Kapillare, TechnoPharm 13, Nr. 2, 68-74 (2023)

Figure 1: Dosing scheme for vibrating capillary

Table 1: Results of dosing; in yellow optimized results for dosing time (the faster the better), in blue optimized results for RSD (the lower the better)

Fig. 2: Dosing diagram, e.g. “mean weight [time]” means the mean weight with optimized dosing time