Fine Lactose Research Articles

Synergistic effect of magnesium stearate and fine lactose in improving aerosolization performance of fluticasone propionate in dry powder formulation

Magnesium stearate (MgSt) and lactose fines are often used as ternary components in carrier-based dry powder inhalers (DPIs) to improve fine particle fraction (FPF), but whether they act synergistically to improve aerosolization performance of DPI formulations is currently less studied. In addition, the applicability of utilizing powder rheological parameters to predict the FPF needs to be further verified. Thus, in this study, using fluticasone propionate (FP) as a model drug, effect of lactose fines addition in 0.5% MgSt containing DPI formulations on their powder and aerodynamic properties was explored. Influence of MgSt and fines mixing order on the DPIs performance was also investigated. The results showed that addition of lactose fines (1–10%) in 0.5% MgSt containing formulations could further improve flowability and enhance adhesion of the mixtures, and they could act synergistically to improve FPF. Moreover, the presence of 0.5% MgSt can greatly reduce the amount of lactose fines required to achieve the comparable FPF. The mixing order can affect distribution of MgSt on the carrier surface, with higher FPF noted when MgSt was mixed with carrier first, followed by lactose fines. A good linear relationship between powder rheological parameters such as basic flowability energy (BFE), Permeability and FPF was disclosed. In conclusion, in FP based DPIs, MgSt and lactose fines act synergistically to enhance FPF by tuning powder characteristics. Good flowability (27.39%) and strong adhesion (72.61%) contributed to the enhanced drug deposition in the lung.

New theory to explain the effect of lactose fines on the performance of adhesive mixtures for inhalation

A new theory for the dispersibility enhancing effect of excipient fines for adhesive mixtures for inhalation is presented in this paper, while at the same time the shortcomings of current hypotheses are discussed. The proposed mechanism, denoted the ‘viscoelastic damping effect’, states that the presence of fines particles acts to dampen the collisions between carrier particles during mixing. As a consequence, fewer fine particles are ‘irreversibly’ pressed into the carriers, which in turn entails a higher fine particle fraction. The mechanism was demonstrated experimentally at different levels of added lactose fines by studying the influence of processing on fine particle fraction. This approach furthermore enabled quantification of the effect. All fine particles present in the blend (APIs and excipient fines) act together to exert the damping effect. The proposed mechanism is able to explain the main body of published data, including the effect of added excipient fines, the effect of an increased drug load, and the effect of removal of carrier fines. The viscoelastic damping mechanism is general in nature and conveys a broader and more general understanding of the behavior of adhesive mixtures for inhalation.

Elucidation of the using condition and working mechanism of tertiary lactose in dry powder formulations for inhalation

Tertiary lactose has been shown to improve aerosolization performance of carrier-based dry powder inhalation formulations. The working mechanism of the tertiary lactose, however, is still unclear, even the optimal working condition of the lactose fines. Two strategies to incorporate the tertiary lactose were proposed, the “tertiary lactose-carrier-API” and “tertiary lactose-API-carrier”, to decrease the adhesiveness of the drug-carrier by forming different powder aggregates. The effects of the tertiary lactose with different sizes and mass percentages on the aerosolization performance for the two types of formulations were systemically investigated. The results showed that the smaller-sized tertiary lactose is beneficial for powder dispersion and aerosolization, which could be further improved by optimizing its concentration. In terms of the aerosolization performance, the “tertiary lactose-carrier-API” type of ternary formulations obtained highly superior aerosolization performance and significantly enhanced detachment of fine drug particles from large particles in general.

Role of dispersion enhancer selection in the development of novel tratinterol hydrochloride dry powder inhalation formulations

Tratinterol hydrochloride (TH) is a new long-acting bronchodilator with strong β2 adrenoceptor stimulation activity. The aim of this study was to design a new carrier-based dry powder inhalation (DPI) formulation for TH and to investigate the effect of dispersion enhancers on the aerosol performance of TH in vitro. To this end, coarse lactose was used as a carrier. TH was micronized by using a jet mill and blended with the carrier to obtain a reference DPI formulation. Commercial magnesium stearate (MgSt) as received, micronized MgSt (MgSt-M), and fine lactose (FL) were used as the dispersion enhancers and formulated with the micronized TH (TH-M) and the carrier as DPI formulations. The obtained DPI formulations were characterized using dynamic light scattering (DLS), X-ray powder diffraction (XRPD), thermal analysis, powder rheometer, and Raman microscopy. A next generation pharmaceutical impactor (NGI) was used to evaluate the aerodynamic performance of the dry powders. The results showed that TH-M was in an inhalable particle size range, and based on the XRPD and thermal analysis, the solid form of TH-M did not change compared to the starting materials. The NGI results showed that the fine particle fraction (FPF) of TH could be increased with the addition of MgSt and FL as dispersion enhancers in the reference formulation. In addition, the FPF of TH could be increased with a decrease in the particle size of MgSt or an increase in the amount of FL. A combination of MgSt-M and FL could further improve the aerosol performance of TH. Raman spectroscopic imaging confirmed the spatial location of MgSt and TH at the surface of the carrier. This study demonstrates that TH could be formulated into carrier-based dry powder formulation for inhalation using coarse lactose as the carrier. The dual strategy based on using both MgSt and FL as dispersion enhancers improved the aerosol performance of a novel TH dry powder formulation.

Elucidation of the effect of added fines on the performance of dry powder inhalation formulations

Dry powder inhalers (DPIs) are regularly used to treat respiratory diseases. Adding extrinsic fine excipient particles to the blend of active pharmaceutical ingredient (API) and carrier is an established strategy to improve aerosolization efficiency during pulmonary drug delivery. Different amounts and grades of lactose fines may, however, compromise the flowability and downstream processing of the material. Further, given the particle size of the inhaled fine particles (<5.5 µm), also deposition of lactose fines to different lung regions following inhalation cannot be excluded. This study aimed to investigate the impact of commercially available extrinsic lactose fine materials produced using different milling parameters, on physicochemical properties and aerosolization performance of ternary blends, as a factor of time and storage conditions. Further, for the first time, it was attempted to elucidate the effect that the amount of present fines has on the dissolution of the model API from the ternary blends exposed to different storage conditions. We showed that rheological behavior was impacted when a higher amount of fines was present, and this effect was further enhanced by storage at high relative humidity. The aerosolization efficiency was vastly improved with increasing content of fines. Still, initial data indicated that the dissolution of the poorly soluble API was retarded when more fines were present in blends.

The Optimisation of Carrier Selection in Dry Powder Inhaler Formulation and the Role of Surface Energetics

This review examines the effects of particle properties on drug-carrier interactions in the preparation of a dry powder inhaler (DPI) formulation, including appropriate mixing technology. The interactive effects of carrier properties on DPI formulation performance make it difficult to establish a direct cause-and-effect relationship between any one carrier property and its effect on the performance of a DPI formulation. Alpha lactose monohydrate remains the most widely used carrier for DPI formulations. The physicochemical properties of α-lactose monohydrate particles, such as particle size, shape and solid form, are profoundly influenced by the method of production. Therefore, wide variations in these properties are inevitable. In this review, the role of surface energetics in the optimisation of dry powder inhaler formulations is considered in lactose carrier selection. Several useful lactose particle modification methods are discussed as well as the use of fine lactose and force control agents in formulation development. It is concluded that where these have been investigated, the empirical nature of the studies does not permit early formulation prediction of product performance, rather they only allow the evaluation of final formulation quality. The potential to leverage particle interaction dynamics through the use of an experimental design utilising quantifiable lactose particle properties and critical quality attributes, e.g., surface energetics, is explored, particularly with respect to when a Quality-by-Design approach has been used in optimisation.

Elucidation of lactose fine size and drug shape on rheological properties and aerodynamic behavior of dry powders for inhalation

Pulmonary drug delivery has gained great attention in local or systemic diseases therapy, however it is still difficult to scale-up DPI production due to the complexity of interactions taking place in DPI systems and limited understanding between flowability and inter-particle interactions in DPI formulations. Therefore, finding some quantitative parameters related to DPI delivery performance for predicting the in vitro drug deposition behavior is essential. Therefore, this study introduces a potential model for predicting aerodynamic performance of carrier-based DPIs, as well to find more relevant fine powder size and optimal shape to improve aerodynamic performance. Using salbutamol sulfate as a model drug, Lactohale®206 as coarse carrier, Lactohale®300, Lactohale®230, and Lactohale®210 as third fine components individually, the mixtures were prepared at 1% (w/w) drug content accompanied with carriers and the third component (ranging from 3% to 7%), influence of lactose fines size on DPI formulation’s rheological and aerodynamic properties was investigated. The optimum drug particle shape was also confirmed by computer fluid dynamics model. This study proved that pulmonary deposition efficiency could be improved by decreasing lactose fines size. Only fines in the size range of 0–11 μm have a good linear relationship with FPF, attributed to the fluidization energy enhancement and aggregates mechanism. Once exceeding 11 μm, fine lactose would act as a second carrier, with increased drug adhesion. Computational fluid dynamics (CFD) models indicated fibrous drug particles were beneficial to transfer to the deep lung. Furthermore, good correlations between rheological parameters and FPF of ternary mixtures with different lactose fines were established, and it was disclosed that the FPF was more dependent on interaction parameters than that of flowability.

Proof-of-Concept for Adjusted Surface Energies and Modified Fines as a Novel Concept in Particle Engineering for DPI Formulations.

Currently marketed dry powder inhaler (DPI) medicine lacks drug delivery performance due to insufficient powder dispersion. In carrier-based blends, incomplete drug detachment is typically attributed to excessive adhesion forces between carrier and drug particles. Adding force control agents (FCA) is known to increase drug detachment. Several researchers accounted this effect to a decrease in carrier surface energy (SE). In turn, an increase in SE should impede drug detachment. In this proof-of-concept study, we investigated the influence of the SE of the carrier material in binary blends by intentionally inverting the FCA approach. We increased SEs by dry particle coating utilising high-shear mixing, which resulted in decreased respirable fractions of the respective blends. Thus, we confirmed the SE of the carrier influences drug delivery and should be considered in formulation approaches. Complementing engineering techniques on the carrier level, we evaluated a method to modify the SE of extrinsic fines in ternary powder blends for inhalation. By the co-milling of fine lactose and an additive, we tailored the SE and hence the adhesiveness of additional fine excipients. Thus, the extent and the strength of drug–fines agglomerates may be controllable. For ternary DPI formulations, this work highlights the potential benefits of matching the SE of both fines and drugs.

The role of intrinsic fines in the performance change of expired lactose carriers for DPI applications

Dry powder inhalation offers a well-established administration route for either local or systemic drug delivery. Lactose-based powder blends still build the basis of respiratory drug delivery, despite of numerous emerging formulation approaches. The amount of fine lactose excipients, either extrinsic or intrinsic, crucially influences the aerodynamic performance of the corresponding blend. This study highlights the role of intrinsic fines as a fundamental performance affecting parameter during storage and expiry of lactose carrier bulk. We showed that intrinsic fines play an inferior role after expiring compared to fresh batches. If strongly adhering or even merged fines regain their mobility and contribute to the dispersion (by removal and re-addition), it will significantly enhance drug delivery. Furthermore, we provide evidence for decreased mobility of intrinsic fines caused by humidity (e.g., during inappropriate storage) resulting in decreased powder fluidisation.

Effect of pressure drop on the in vitro dispersion of adhesive mixtures of different blend states for inhalation

In this study, the effect of pressure drop (ΔP) on the in vitro dispersion of a series of carrier-based adhesive mixtures of different fines-to-carrier proportions, corresponding to the four different blend states of the blend state model, i.e. S1 to S3, was investigated. Four binary and one ternary adhesive mixture consisting of lactose carrier and budesonide fines and lactose fines were prepared. The dispersion was assessed using a next generation impactor (NGI) at ΔP of 0.5, 2 and 4 kPa. For the S1 mixture, where the fines were located in surface cavities of the carrier, the fine particle fraction (FPF) increased nearly linearly with ΔP. For S2 and S3 mixtures, with adhesion layers on the enveloped carrier surface, the FPF-ΔP relationships were bended and approached a plateau. Examination of powder captured in the pre-separator of the NGI led to the conclusion that the dispersion of these adhesive mixtures occurred by erosion of the adhesion layer, i.e. budesonide was liberated as single particles or micro-agglomerates. It is concluded that the FPF-ΔP relationships were dependent on the blend state and for the S2 and S3 mixtures, a critical pressure drop was identified above which the pressure drop had a limited effect on the FPF.

The Influence of Relative Humidity and Storage Conditions on the Physico-chemical Properties of Inhalation Grade Fine Lactose.

Dry powder inhalers (DPIs) are favorable devices for the delivery of dry formulations to the lungs; still, they largely fail to deliver higher doses of active pharmaceutical ingredient (API) to the lower airways. Addition of fine particles of excipient (fines) to the blend of API and carrier was shown to improve aerosolization performance. Lactose monohydrate is ubiquitous excipient used for this purpose. Lactose exists in a thermodynamically stable crystalline form; however, processes like milling, sieving, or even mixing may induce alteration of crystalline structure and introduce amorphous domains, which could further affect the physico-chemical properties of the material. Therefore, the aim of this work is a detailed characterization of two commercially available types of inhalation grade fine lactose powders (Inhalac 400 and Inhalac 500) prepared using different air-jet milling parameters, with a focus on impact of storage conditions on material properties. We found that the different milling parameters resulted in variable particle size distribution (PSD), and thus surface areas, variable initial amorphous content, cohesivity, flowability, and moisture sorption of materials. In addition, exposure of fine powders to higher humidity reduced the amorphous content present in the materials, but also affected agglomeration tendency and dispersion behavior of both powders. We believe the obtained findings to be important for the aerosolization performance of carrier-based DPIs containing fines and thus need to be duly considered during formulation development.

Surface energy considerations in ternary powder blends for inhalation

The need for optimisation of DPI formulations is a main research motivation in respiratory drug delivery. Well-established formulations like carrier-based blends still show a lack of efficiency. The addition of extrinsic fine excipients is extensively discussed since decades, supported by a wide range of solid-state characteristics to understand their mechanism and classify influencing parameters. The first part of this study aims at comparing the surface energies of lactose fines and their corresponding influence on the aerodynamic performance of the respective ternary blends. Five different fine lactose qualities with varying origins were used, which were distinguishable in terms of surface energy, but comparable regarding particle size, moisture content and chemical composition. It demonstrates the crucial influence of adhesion properties of fines, based on different surface energies. Secondly, one specific fine lactose quality was used on fundamentally different lactose carriers, which highlights the negligible influence of carrier properties if extrinsic fines are preferentially capable of excipient-drug interactions.

Elucidating the Effect of Fine Lactose Ratio on the Rheological Properties and Aerodynamic Behavior of Dry Powder for Inhalation.

Dry powder inhaler (DPI) is recognized as the first choice for lung diseases' treatment. However, it lacks a universal way for DPI formulation development. Fine lactose is commonly added in DPIs to improve delivery performance; however, the fine ratio-dependent mechanism is unclear. Therefore, the objective of this study is to explore the influence of fine lactose ratio on DPI powder properties and aerodynamic behavior, and the fine lactose ratio-dependent mechanism involved during powder fluidization and lung deposition. Here salbutamol sulfate was used as a model drug, Lactohale® 206 as coarse carrier, and Lactohale® 300 as fine component; the mixtures were prepared at 1% drug content, with fine content up to 20%. It was shown that with the fine addition, flowability of the mixtures was improved, interaction among particles was increased, and the presence of fines could help to improve DPI's aerosolization performance. When the fines added were less than 3%, the "active site" hypothesis played a leading role. When the added fines were over 3% but less than 10%, fluidization enhancement mechanism was more important. After the added fines reaching 10%, aggregate mechanism started to dominate. However, FPF cannot be further increased once the fines reached 20%. Moreover, the correlations between FPF and dynamic powder parameters were verified in ternary mixtures, and cohesion had a greater impact on FPF than that of flowability. In conclusion, adding lactose fines is an effective way to improve lung deposition of DPI, with the concrete mechanism lactose fine ratio dependent.

Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?

In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.8, and C-3.7), differing only in type and composition of lactose fines, exhibited median mass aerodynamic diameter (MMAD) of 4.5 μm (A-4.5), 3.8 μm (B-3.8), and 3.7 μm (C-3.7) and varied in dissolution rates (A-4.5 slower than B-3.8 and C-3.7). In vitro total lung dose (TLDin vitro) was determined as the average dose passing through three anatomical mouth-throat (MT) models and yielded dose normalization factors (DNF) for each DPI formulation X (DNFx = TLDin vitro,x/TLDin vitro,A-4.5). The DNF was 1.00 for A-4.5, 1.32 for B-3.8, and 1.21 for C-3.7. Systemic PK after inhalation of 500 μg FP was assessed in a randomized, double-blind, four-way crossover study in 24 healthy volunteers. Peak concentrations (Cmax) of A-4.5 relative to those of B-3.8 or C-3.7 lacked bioequivalence without or with dose normalization. The area under the curve (AUC0-Inf) was bio-IN-equivalent before dose normalization and bioequivalent after dose normalization. Thus, PK could detect differences in pulmonary available dose (AUC0-Inf) and residence time (dose-normalized Cmax). The differences in dose-normalized Cmax could not be explained by differences in in vitro dissolution. This might suggest that Cmax differences may indicate differences in regional lung deposition. Overall this study supports the use of PK studies to provide relevant information on the pulmonary performance characteristics (i.e., available dose, residence time, and regional lung deposition).

Fluidization of fine lactose for dry powder inhalation: A comparison of assisting methods

AbstractFluidization of cohesive pharmaceutical powders is difficult to achieve and typically requires the introduction of external forces. This study investigates the fluidization of the fine inhalation grade of lactose powders (size range from 0.1‐20 μm) that are specifically developed for dry powder inhalation (DPI) applications. The fluidization behaviour of fine lactose powders was evaluated under six conditions: without fluidization aids, with only vertical vibration (VFA), with only a downward‐pointing micro‐jet (MFA), with both vibration and pre‐mixing with coarse particles (VCFA), with both vibration and micro‐jet (VMFA), and with the combined assistance of vibration, micro‐jet, and addition of coarse particles (VMCFA). The enhancement of fluidization due to the use of different assistance methods is reflected by the increase of bed expansion and the decrease in both the minimum fluidization velocity and agglomerate formation. However, applying micro‐jet results in considerable powder losses due to the high fraction of fine particles stuck to the wall. Combining any two assisting methods leads to better fluidization than using a single approach. In particular, the combination of vibration and micro‐jet shows the best performance in improving fluidization. Further addition of coarse particles does not play a significant influence on promoting fluidization. Finally, the analysis of the forces acting on the lactose agglomerates shows the enhancement of separation forces by introducing the fluidization assistance, which leads to a decrease in agglomerate size.

Exploring the impact of extrinsic lactose fines, a USP modified sampling device and modified centrifuge tube on the delivered dose uniformity and drug detachment performance of a fluticasone propionate dry powder inhaler

The present study aimed to probe influences exerted by extrinsic lactose fines on drug detachment and delivered dose uniformity (DDU) of fluticasone propionate (FP) dry powder inhaler (DPI). Extrinsic lactose fines (0–35%) containing lactose pre-blends were formulated using a low shear 3D shaker mixer and systematically analyzed for various physicochemical properties. Moreover, formulated FP DPIs were assessed for drug detachment by force distribution concept and the DDU using two different sampling devices i.e. the Dosage Unit Sampling Apparatus (DUSA) and USP modified glass sampling device (modified DUSA) coupled with Aerolizer® device at 60 L/min. The physicochemical assessment of control and pre-blend lactose samples displayed significant differences in particle size, surface roughness, degree of surface irregularity and powder flow properties. The formulated FP DPIs displayed monolayer-type FP distribution across the lactose particles in laser Raman spectroscopy with acceptable content uniformity (~100%). Drug detachment study using a modified centrifuge tube showed significant differences in drug detachment profile. The FP DPI formulated using 20% of lactose fines showed the lowest drug detachment force (349.45 gf) as compared to the other lactose samples. Moreover, the FP DPI formulated using 20% of lactose fines demonstrated acceptable mean delivered dose (107.76 and 110.62 μg) with the lowest coefficient of variation using DUSA and modified DUSA, respectively. The present study is the first comprehensive summary of delivered dose uniformity using two different USP sampling devices. Accordingly, these observations may be of high significance for both intuitional and industrial formulators.

Linking carrier morphology to the powder mechanics of adhesive mixtures for dry powder inhalers via a blend-state model

The aim of this study was to investigate how the carrier morphology affects the expression of blend states in adhesive mixtures as a function of surface coverage ratio (SCR) and to identify where transitions between the different states occur. Adhesive mixtures of five lactose carriers with varying contents of lactose fines, corresponding to blends with different SCR ranging from 0 to 6, were produced by low-shear mixing. The powder mechanics of the mixtures were characterized by bulk density, compressibility and permeability. The appearance of the carriers and blends was studied by scanning electron microscopy, light microscopy and atomic force microscopy. The size and morphology of the carriers had a crucial impact on the evolution of the blend state, and affected the powder mechanical properties of the mixtures. It was found that smaller carriers with little or no surface irregularities were more sensitive to additions of fines resulting in self-agglomeration of fines at relatively low SCR values. On the contrary, carriers with irregular surface structures and larger sizes were able to reach higher SCR values before self-agglomeration of fines occurred. This could be attributed to an increased deagglomeration efficiency of irregular and larger carriers and to fines predominantly adhering to open pores.

Probing the influence of lactose fines, a USP modified induction port and modified DDU apparatus on the aerodynamic behavior of a fluticasone propionate dry powder inhaler

The objective of the present study is to understand the effects of lactose fines, a USP modified induction port (IP) and USP modified glass sampling apparatus (DDU apparatus) on the aerodynamic behavior of a fluticasone propionate (FP) dry powder inhaler (DPI).

Characterizing the Surface Roughness Length Scales of Lactose Carrier Particles in Dry Powder Inhalers.

Surface roughness is well recognized as a critical physical property of particulate systems, particularly in relation to adhesion, friction, and flow. An example is the surface property of carrier particles in carrier-based dry powder inhaler (DPI) formulations. The numerical characterization of roughness remains rather unsatisfactory due to the lack of spatial (or length scale) information about surface features when a common amplitude parameter such as average roughness ( Ra) is used. An analysis of the roughness of lactose carrier particles at three different length scales, designed for specificity to the study of interactive mixtures in DPI, was explored in this study. Three Ra parameters were used to represent the microscale, intermediate scale, and macroscale roughness of six types of surface-modified carriers. Coating of micronized lactose fines on coarse carrier particles increased their microroughness from 389 to 639 nm while the macroroughness was not affected. Roller compaction at higher roll forces led to very effective surface roughening, particularly at longer length scales. Changes in Ra parameters corroborated the visual observations of particles under the scanning electron microscope. Roughness at the intermediate scale showed the best correlation with the fine particle fraction (FPF) of DPI formulations. From the range of 250 to 650 nm, every 100 nm increase in the intermediate roughness led to ∼8% increase in the FPF. However, the effect of surface roughness was greatly diminished when fine lactose (median size, 9 μm) of comparable amounts to the micronized drug were added to the formulation. The combination of roughness parameters at various length scales provided much discriminatory surface information, which then revealed the "quality" of roughness necessary for improving DPI performance.

Study of a low-dose capsule filling process by dynamic and static tests for advanced process understanding

Precise filling of capsules with doses in the mg-range requires a good understanding of the filling process. Therefore, we investigated the various process steps of the filling process by dynamic and static mode tests. Dynamic tests refer to filling of capsules in a regular laboratory dosator filling machine. Static tests were conducted using a novel filling system developed by us. Three grades of lactose excipients were filled into size 3 capsules with different dosing chamber lengths, nozzle diameters and powder bed heights, and, in the dynamic mode, with two filling speeds (500, 3000 caps/h). The influence of the gap at the bottom of the powder container on the fill weight and variability was assessed. Different gaps resulted in a change in fill weight in all materials, although in different ways. In all cases, the fill weight of highly cohesive Lactohale 220 increased when decreasing the gap. Furthermore, experiments with the stand-alone static test tool indicated that this very challenging powder could successfully be filled without any pre-compression in the range of 5 mg–20 mg with acceptable RSDs. This finding is of great importance since for very fine lactose powders high compression ratios (dosing-chamber-length-to-powder-bed height compression ratios) may result in jamming of the piston. Moreover, it shows that the static mode setup is suitable for studying fill weight and variability.Since cohesive powders, such as Lactohale 220, are hard to fill, we investigated the impact of vibration on the process. Interestingly, we found no correlation between the reported fill weight changes in dynamic mode at 3000 cph and static mode using similar vibration. However, we could show that vibrations during sampling in the static mode dramatically reduced fill weight variability.Overall, our results indicate that by fine-tuning instrumental settings even very challenging powders can be filled with a low-dose dosator capsule filling machine. This study is a further step towards a scientific qualification of dosator nozzles for low-fill weight (1–45 mg) capsule filling.