Particle interactions in complex dry powder inhaled formulations and single particle aerosol mass spectrometry

Jetzer, Martin. Particle interactions in complex dry powder inhaled formulations and single particle aerosol mass spectrometry. 2018, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_13010

Downloads: Statistics Overview


Pharmaceutical aerosols are an effective method to deliver therapeutic agents to the respiratory tract. Among aerosol generation systems, dry powder inhalers (DPIs) have been an attractive technology for both local and systemic delivery of drugs. DPIs combine several advantages compared to metered dose inhalers (MDIs) and other inhalation devices: DPIs are breath-actuated (patients do not require hand-lung coordination), no need for environmentally damaging chlorofluorocarbon (CFC) propellants or solvents, improved product stability, DPIs deliver a wide range of drugs (e.g. traditional anti-asthmatics, proteins) in high doses via one short inhalation and increased respirable fractions compared to MDIs. Furthermore, DPIs often have only low inspiratory flow resistances, which is beneficial for patients suffering from respiratory diseases [1, 2]. Inhalation devices are designed to deliver a reproducible predefined dose of drug to the small airways and alveolar regions of the human lung. It has been reported that particles with a mass median aerodynamic diameter (MMAD) of <5 μm are effectively deposited at these sites [3, 4]. The MMAD of an aerosol particle depends on its geometrical diameter, density, and morphology with these properties generally being optimized during the manufacturing process [5]. Most commercial DPI formulations (adhesive mixtures) consist of micronized drug blended with coarser carrier particles (usually alpha lactose monohydrate; ca. 20-300 μm), which is used to aid the handling, metering and dosing of the formulation. These components are usually combined in a manufacturing process with high- or low-shear blending, which is used primarily to distribute the cohesive drug particles throughout the bulk excipient of the formulation to create a homogeneous mixture. The interactions between drug and carrier are a major determinant of DPI performance. Due to interparticulate forces, such as mechanical interlocking, capillary, electrostatic, and van der Waals, micronized powders exhibit very adhesive and cohesive behavior and form spontaneously agglomerates [6, 7]. The extent of the combined forces is dependent on powder properties such as particle size, morphology, shape, and material characteristics (e.g. amorphous content, hydrophilicity, electrical resistivity) [8], as well as on environmental factors, such as relative humidity and temperature [9]. Since the extent of agglomeration negatively affects the fraction of the inhaled powder within the respirable range [10], these agglomerates must be deagglomerated effectively prior to or during the processes of aerosolization and inhalation [11].
In recent years, there has been great interest in the development of ternary mixing systems because the addition of a ternary component into carrier-based DPI formulations can lead to improved aerosol performance due to drug-carrier interaction modifications [12-19]. In lactose-based DPI formulations, ternary components can be either lactose fines [20], sugars (e. g. micronized glucose) [21], or a variety of force control agents (FCAs) such as magnesium stearate (MgSt) or leucine [13, 15, 16, 18, 22]. Blending lactose together with MgSt prior to adding the active pharmaceutical ingredient (API) has been shown to modify the performance of pharmaceutical inhaled products [14, 15]. Also pre-treatment of APIs with different FCAs has been shown to alter the performance and improve the drug deposition in the lowest impactor stages [23]. Various application processes such as mechanofusion, high- or low-shear mixing and particle smoothing have been used to apply different FCAs on carrier particles as very thin coating layers (<10 nm) [16, 22, 24, 25].
The current pharmacopoeial standard method for determining the aerodynamic particle size distribution (APSD) of APIs delivered from inhaled pharmaceutical products is to generate a size-segregated sample of the particles in a cascade impactor, typically the Next Generation Impactor (NGI) [26-28], followed by the dissolution of each size-fractionated particle sample into a solvent which is then analyzed by high-performance liquid chromatography (HPLC). While highly quantitative for the total concentration of API delivered, this technique does not yield any information regarding the relationships and interactions between the various product components (API(s), excipients) within the formulation. Cascade impaction testing also requires mastery of a complex technique before consistent results can be achieved and results in a large demand on resources in terms of laboratory personnel and solvents, and the measurements are very time-consuming [29, 30]. The development of more rapid techniques as application for routine product quality testing or in product development is therefore highly desired [31]. Mass spectrometry based aerosol analytical techniques have been undergoing continuous development since the 1970s [32, 33]. Aerosol-specific mass spectrometers are capable of providing both aerodynamic particle size distribution (APSD) profiles and the chemical composition of particles by using a statistical sample of a high number of single particles in a very short timeframe (minutes). The single particle aerosol mass spectrometry (SPAMS) technique can be used to evaluate particle interactions/co-associations between drug product components in a way that is inaccessible via cascade impactor techniques. Importantly, since in recent years more complex inhaled products have become available on the market that deliver two (or even three) APIs within a single dose (e. g. Ultibro® Breezhaler®, Foster® NEXThaler®, Trelegy® Ellipta®) using highly sophisticated engineered formulation approaches with fine lactose and/or magnesium stearate [34-36]. Clinical research has shown that such combination inhalers provide an enhanced clinical effect beyond that achieved when the two drugs are administered concurrently from two separate inhalers. Preliminary tests using aerosol time-of-flight mass spectrometry and SPAMS determined that the respirable fraction can be composed of co-associated API particles, which could be the reason behind the increased effects of the combination drug inhalers [30, 37, 38].
This thesis focuses on the investigation of the complex mechanisms that affect the dispersion of drug particles during aerosolization and ultimately the in vitro aerosol performance of inhalation. Particular attention was paid to combinations of two APIs and formulations containing magnesium stearate as force control agent. Specifically prepared model dry powder inhaled formulations and commercial products were used. High- and low-shear blending techniques of lactose and magnesium stearate were explored and the effect of different storage regimes on physicochemical properties and performance of such dry powder inhaled formulations was assessed. Advanced powder characterization techniques such as single particle aerosol mass spectrometry (SPAMS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) were employed to improve the mechanistic understanding of particle interactions, drug detachment and dispersion during impaction analysis.
In a first study, aerodynamic particle size distribution profiles (APSD) of commercial metered dose inhaler (MDI) and dry powder inhaler (DPI) were obtained using single particle aerosol mass spectrometry (SPAMS; Livermore Instruments Inc., USA) and then compared to those obtained by the Aerodynamic Particle Sizer (APS; TSI Incorporated, USA) and Next Generation Impactor (NGI, Copley Scientific, USA). In addition, the transmission efficiency of SPAMS as well as potential size bias of APSD measurements that might result from a size dependent transmission profile were evaluated. It was demonstrated that the SPAMS can generate useful APSD measurements with both pMDI and DPI products. However, a consistent difference of particle transmission in the SPAMS in the region of 2-3 μm was found compared to NGI measurements.
In a second study, measurements of Advair® Diskus® and Seretide® using the SPAMS technique showed that a significant fraction of the emitted drug particles can form co-associated particles with other drugs (and likely excipients) in the same DPI or pMDI formulation. For this, unique mass spectral fragmentation patterns could be recognized and assigned for each API using the SPAMS data analysis software. SPAMS also revealed which particle size fractions are most likely forming these co-associations. In a third study it could be demonstrated that for example in Foster® NEXThaler® the degree of particle co-association was manipulated by the choice of formulation and manufacturing approach for DPIs. It is possible that in the manufacturing process APIs or carrier can be processed together with the force control agent magnesium stearate to improve dispersion mechanics. An explanation may be that the drug or the carrier receive an MgSt-coating that would prevent the co-association or agglomeration of the particles and moreover facilitate detachment from carrier. This results in high in vitro performance (and furthermore high extra fine particle fraction of particles <2 μm), as well as a relatively fine APSD profile compared to products not engineered in this way. Particle co-associations of API-MgSt were detected in the commercially available DPI product Foster® NEXThaler®.
The intensity of the blending technique is demonstrated in a fourth study in this work to affect the distribution of MgSt covering the lactose carrier. This coverage of lactose by MgSt as evidenced using the ToF-SIMS technique was shown to significantly influence the in vitro aerosol performance. The underlying mechanism of particle interaction between API and the carrier seems to be substantially different for high- and low-shear formulations. This provides the basis for a modification in particle interactions from drug-lactose to drug-MgSt (in high-shear), which then is responsible for the improved performance by enhanced particle detachment from carrier due to lower interaction forces.
In a fifth study, the conditioning of DPI capsules at controlled temperature and humidity settings also showed to have a significant effect on the separation of drug and carrier particles. Significant differences were observed between adhesive and cohesive model compounds (with respect to lactose). This study highlights that electrostatic forces and interactions play a significant role in dry powder inhaled formulations. Large differences in the electrostatic charging behavior were observed. Fluticasone propionate seems to have a high propensity to electrostatic charging, while salmeterol xinafoate only showed negligible performance consequences as a result of its electrostatic charging behavior. Most of the common excipients used in DPI formulations, such as lactose monohydrate, do not seem to experience significant charge accumulation in stark contrast to MgSt, which tends to acquire high amounts of electrostatic charge. Other DPI drug product components such as HPMC capsules did not tend to charge significantly. Conditioning of certain APIs was found to be helpful to dissipate electrostatic charge which in turn increased aerosol performance.
In summary, this thesis combines improvements to the analytical methodologies such as SPAMS with the systematic investigation of dry powder inhalation formulations to advance the understanding of in vitro aerosol characteristics of drug product formulations at a fundamental mechanistic level.
Advisors:Imanidis, Georgios and Huwyler, Jörg
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmazeutische Technologie (Huwyler)
UniBasel Contributors:Imanidis, Georgios and Huwyler, Jörg
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13010
Thesis status:Complete
Number of Pages:1 Online-Ressource (162 Seiten)
Identification Number:
edoc DOI:
Last Modified:03 May 2019 04:30
Deposited On:02 May 2019 09:52

Repository Staff Only: item control page