Kyrre Thalberg

Particle Formation and Capture During Spray Drying of Inhalable Particles

An investigation of the spray drying process is made in great detail regarding particle formation and capture efficiency with focus on the production of inhalable particles. Mannitol was spray dried as model substance and the spray‐dried products were characterized. The resulting products consisted of smooth spheres with a volume median diameter of 2.2–5.5 µm, and narrow size distributions. The investigation was performed in pilot scale of sufficient size to draw general conclusions and make some recommendations. It has been shown that the size of particles is decreased when the feed concentration is decreased, the nozzle gas/feed flow mass ratio increased, and the droplet size decreased. The collection efficiency of the cyclone device used in this study was shown to have a cut‐off of 2 µm, i.e., 50% of the particles less than 2 µm are not captured. The data reported indicate that the majority of the single particles formed here, < 5 µm, arise from single droplets (of about 10 µm) and are solid, nonporous particles.

Modeling dispersion of dry powders for inhalation. The concepts of total fines, cohesive energy and interaction parameters

A range of carrier based dry powder formulations consisting of micronized drug, carrier lactose and, in some formulations, lactose fines were produced and tested for dispersibility, i.e. fine particle fraction (FPF). Two different drugs were used, budesonide (BUD) and beclomethasone dipropionate (BDP). A model based on the total amount of fines (TF) and the cohesive energy (CE) of the formulation is proposed, where TF is the sum of added drug, lactose fines and the fines inherent to the carrier. The expression for CE is derived from regular solutions theory and allows calculation of interparticle interaction parameters. The model was able to describe experimental data well, such as the decrease in FPF when the proportion of drug is increased at a constant TF level and the non-linear effects seen when a cohesive drug is added to carrier. BDP and BUD were found to be 5.3 times and 1.8 times more cohesive than lactose fines respectively. The model hence provides a link between the macroscopic behavior of a dry powder formulation and the interaction between the different species at the particulate level.

The Stability of Insulin in Solid Formulations Containing Melezitose and Starch. Effects of Processing and Excipients

ABSTRACT Solid insulin formulations obtained by different methods of preparation were compared with respect to chemical stability and morphology. Spray- and freeze-drying, solution enhanced dispersion by supercritical fluids (SEDS) and precipitation into starch microspheres were the methods used for preparation of solid powders. The excipients applied were melezitose, starch, and sodium taurocholate. The stability of the samples was evaluated after storage in open containers at 25°C and 30% RH for 6 months. All samples were amorphous after processing and storage as detected by XRD, except for the starch microspheres which were semi-crystalline. The spray- and freeze-dried samples containing melezitose and sodium taurocholate experienced a significant water uptake during storage, resulting in changes in morphology and disappearance of Tg. However, the chemical stability of these samples did not seem to be affected by the water uptake. Changes in morphology were not observed for the SEDS powders and the starch microspheres. The chemical stability of the samples was assessed by HPLC. In general, conventional spray- and freeze drying resulted in samples with higher chemical stability compared to SEDS powders and starch microspheres. Nevertheless, the excipients applied were observed to be of major importance, and further optimization of the formulation as well as processing conditions may lead to slightly different conclusions.

Mechanistic time scales in adhesive mixing investigated by dry particle sizing

This study exploits the mechanisms governing blending of adhesive mixtures, i.e. random mixing, de-agglomeration and adhesion, and their relative importance to achieve mixing homogeneity. To this end, blending of micronized particles (fines) with carrier particles was carried out using a high shear mixer. Dry particle sizing using laser diffraction coupled with a strong powder dispersion unit was employed to measure the fines content in samples collected during mixing, and hence to assess blend homogeneity. The method was also employed to evaluate the relative strength of the agglomerates present in the fines. Particle sizing using a non-destructive imaging technique was used to monitor changes in particle size during blending. It could be shown that the de-agglomeration of the fine-particle agglomerates is the slowest mechanism and hence the rate-limiting step as regards achieving a homogeneous adhesive mixture. Consequently, a longer mixing time is needed for blending of larger agglomerates. Being fast, simple and reproducible, the laser diffraction technique was shown to be an efficient method for measurement of fine particle content and homogeneity of a mixture, while the non-destructive image analysis was able to give relevant information on the rate of de-agglomeration of the fine-particle agglomerates as well as on the size of the resulting carrier-fine particle assemblies.

Development of a Rational Design Space for Optimizing Mixing Conditions for Formation of Adhesive Mixtures for Dry-Powder Inhaler Formulations

The purpose of the present study was to develop guidance toward rational choice of blenders and processing conditions to make robust and high performing adhesive mixtures for dry-powder inhalers and to develop quantitative experimental approaches for optimizing the process. Mixing behavior of carrier (LH100) and AstraZeneca fine lactose in high-shear and low-shear double cone blenders was systematically investigated. Process variables impacting the mixing performance were evaluated for both blenders. The performance of the blenders with respect to the mixing time, press-on forces, static charging, and abrasion of carrier fines was monitored, and for some of the parameters, distinct differences could be detected. A comparison table is presented, which can be used as a guidance to enable rational choice of blender and process parameters based on the user requirements. Segregation of adhesive mixtures during hopper discharge was also investigated.

Dispersibility of lactose fines as compared to API in dry powders for inhalation

This work investigates the dispersion performance of fine lactose particles as function of processing time, and compares it to the API, using Beclomethasone Dipropionate (BDP) as model API. The total load of fine particles is kept constant in the formulations while the proportions of API and lactose fines are varied. Fine particle assessment demonstrates that the lactose fines have higher dispersibility than the API. For standard formulations, processing time has a limited effect on the Fine Particle Fraction (FPF). For formulations containing magnesium stearate (MgSt), FPF of BDP is heavily influenced by processing time, with an initial increase, followed by a decrease at longer mixing times. An equation modeling the observed behavior is presented. Surprisingly, the dispersibility of the lactose fines present in the same formulation remains unaffected by mixing time. Magnesium analysis demonstrates that MgSt is transferred to the fine particles during the mixing process, thus lubrication both BDP and lactose fines, which leads to an increased FPF. Dry particle sizing of the formulations reveals a loss of fine particles at longer mixing times. Incorporation of fine particles into the carrier surfaces is believed to be behind this, and is hence a mechanism of importance as regards the dispersion performance of dry powders for inhalation.

Relationships between surface coverage ratio and powder mechanics of binary adhesive mixtures for dry powder inhalers

The aim of this paper was to study relationships between the content of fine particles and the powder mechanics of binary adhesive mixtures and link these relationships to the blend state. Mixtures with increasing amounts of fine particles (increasing surface coverage ratios (SCR)) were prepared using Lactopress SD as carrier and micro particles of lactose as fines (2.7 µm). Indicators of unsettled bulk density, compressibility and flowability were derived and the blend state was visually examined by imaging. The powder properties studied showed relationships to the SCR characterised by stages. At low SCR, the fine particles predominantly gathered in cavities of the carriers, giving increased bulk density and unchanged or improved flow. Thereafter, increased SCR gave a deposition of particles at the enveloped carrier surface with a gradually more irregular adhesion layer leading to a reduced bulk density and a step-wise reduced flowability. The mechanics of the mixtures at a certain stage were dependent on the structure and the dynamics of the adhesion layer and transitions between the stages were controlled by the evolution of the adhesion layer. It is advisable to use techniques based on different types of flow in order to comprehensively study the mechanics of adhesive mixtures.

Towards quantitative prediction of the performance of dry powder inhalers by multi-scale simulations and experiments

Graphical abstract Figure. No caption available. ABSTRACT This work demonstrates the use of multi‐scale simulations coupled with experiments to build a quantitative prediction tool for the performance of adhesive mixtures in a dry powder inhaler (DPI). Using discrete element model (DEM), the behaviour of fine‐carrier particle assemblies upon different mechanisms encountered during dose entrainment and dispersion can be described at the individual particle level. Combining these results with computational fluid dynamics (CFD) simulations, the complete dosing event from a DPI can be captured and key performance measures can be extracted. A concept of apparent surface energy, ASE, was introduced to overcome challenges associated with the complex particle properties, e.g. irregular particle shapes and surface roughness. This approach correctly predicts trends observed experimentally regarding API adhesivity, flow rate and device geometry. By incorporating the effects of drug load, critical adhesion and surface energy distributions to the simulation tool, the fine particle fraction could be predicted with good agreement to experiments for two different formulations in two different devices at two flow rates. It is concluded that multi‐scale simulations provide a useful tool to support device and formulation development, as well as to gain further insight into the physical mechanisms governing dispersion from DPIs.

Mechanistic investigation of mixing and segregation of ordered mixtures: experiments and numerical simulations

Abstract Pulmonary delivery of cohesive and micronized drugs through dry powder inhalers (DPIs) is traditionally achieved through the formation of ordered mixtures. In order to improve the mechanistic understanding of formation of ordered mixtures, the system consisting of micronized lactose (AZFL, representative of an active pharmaceutical ingredient) and a coarse particle carrier (LH100) is investigated as a function of different process and material variables in a high shear mixer (HSM) and in a low shear double cone (DCN) blender, using both experimental and numerical methods. Process insight is developed using a Discrete Element Method (DEM) based numerical model which could predict the formation of ordered mixtures in the two blenders and was verified against experimental determinations. Spatial and temporal evolution of granular flow are visualized and quantified in silico to reveal distinguishing features of both blenders to aid in rational selection of blenders and process parameters.