Various researchers have found that the inclusion of excipient fines in a formulation enhances Dry Powder Inhaler drug delivery. Jagdeep Shur and Robert Price from the University of Bath and Tim Freeman of Freeman Technology believe they can explain the reasons why
Quality by Design (QbD) is encouraging the pharmaceutical industry to gain sufficient knowledge to specify, formulate and manufacture more effectively than it has in the past. Widespread interest in pulmonary drug delivery means that for many researchers, this involves a detailed understanding of relatively new technologies, such as dry powder inhalation. Since the demands of the dry powder inhaler (DPI) are very different from those of the tablet press, even experienced powder formulators face a steep learning curve.
With a DPI, delivery of the defined dose to the lung, relies on control of the aerosolisation process initiated by the inhaling patient. The inclusion of excipient fines in a formulation is an established way of enhancing delivery, but the mechanisms involved are not yet fully understood. Here, the impact of fines on powder properties is explored with reference to the effect this has on behaviour within the DPI. A key focus is the direct correlation between specific powder characteristics and DPI performance.
With a passive dry powder inhaler the motive force for delivery of the drug is supplied by the patient. During inhalation, air is drawn through a dose causing it to fluidise and aerosolise to form a cloud of particles that is drawn into the body. Effective fluidisation releases the entire dose to the user. Very fine particles deposit in the lung while coarser particles are retained in the throat and subsequently ingested. The fraction of a dose that deposits in the lungs, because of its size, is often referred to as the fine particle fraction (FPF), or fine particle dose (FPD), if expressed in terms of mass.
Relatively coarse excipient particles, typically lactose, are often used to improve the flow properties of a formulation. The fine active pharmaceutical ingredient (API) attaches to these particles during blending, subsequently detaching during aerosolisation. If this elutriation process is inefficient, then the API does not detach from the coarser particle and will therefore be deposited in the oropharynx leading to the API being ingested rather than inhaled.
Various researchers have found that the inclusion of excipient fines in a formulation increases FPD, enhancing drug delivery.1,2,3 The active site theory1 suggests that this is because excipient fines bind to the most active sites on the coarse carrier, blinding them from interaction with the API particles. The API consequently attaches more weakly at lower energy sites. The agglomerate theory,2 on the other hand, attributes the behaviour to the formation of excipient-drug aggregates that form weaker bonds with the carrier.
While these theories both have their merits, there has been relatively little investigation of the impact of the addition of fines on powder properties and fluidisation behaviour, which may critically affect DPI performance. Fines can change the shear, bulk and dynamic properties of a powder: could this explain why they increase the efficiency of drug delivery?
Powders are complex two- or even three-phase (when moist) systems that can easily transition from solid to fluid-like behaviour. Particle size is one of the variables that affects properties, which is why fines content can be critical, but many other parameters are also influential. Other primary variables include particle shape, hardness, porosity and surface texture; external parameters include humidity and air content.
As a result, measuring powder properties is challenging and there are many characterisation techniques in use. Methods that try to define a powder with a single number capture just one aspect of behaviour, but multi-faceted characterisation can be highly informative, giving fuller insight into the complexities of a given sample.
The strength of interaction between particles in a powder has a marked effect on properties. If the forces of attraction between particles are strong, relative to the downward pull exerted by gravity, then the powder will tend to be cohesive while if gravitational forces are dominant, the powder may be termed free-flowing (non-cohesive). For each powder, the relative strength of these forces will determine where on the spectrum of cohesivity the material lies.
In general finer particles, particularly those with a mean diameter of less than 30µm, are more cohesive. This is because the relative strength of interparticle forces increases with decreasing particle size, although shape and surface texture also have an impact. Stronger forces of attraction between the particles provide resistance to the downward pull of gravity allowing cohesive particles to pack in open structures that hold air. The larger particles of non-cohesive powders, in contrast, pack more efficiently, with much lower free volume.
Differences in interparticle bond strength and packing influence bulk, shear and dynamic powder properties, all of which can be used to characterise the degree of cohesivity of a material. For industrial applications the key is to measure properties that reflect how the material will perform during processing, so the best way of defining cohesivity will vary depending on the application. With DPIs, flowability and fluidisation behaviour are particularly important, so measuring properties that quantify cohesivity in terms of its impact on these characteristics will be advantageous.
Because powders are affected by so many variables, reproducible measurement can be difficult. Conditioning the powder prior to measurement, by gently agitating it in a prescribed way to break up loose agglomerates and release excess air, provides a consistent baseline state for analysis enhancing reproducibility.
Powder rheometers measure the dynamic properties of powders, the properties of materials in motion, and are, uniquely, able to accurately characterise aerated materials. The best systems also incorporate shear and bulk property measurement, giving the fullest possible analysis. For DPI studies, these instruments are extremely valuable, allowing direct investigation of aerated flow behaviour and fluidisation, as well as bulk properties such as permeability.
The impact of fines on the properties of batches of surface-etched lactose powder containing 0, 2.5, 5 and 10% fines (Sorbolac 400, Meggle, Germany) was investigated experimentally using the FT4 Powder Rheometer from Freeman Technology, of Welland, UK. Bulk density, permeability, compressibility and aerated flow energy were all measured using the standard methodology for the instrument.4
As fines content increases bulk density falls from 0.741 +/-0.009g/ml (0% fines) to 0.659 +/-0.007g/ml (10% fines). Permeability also falls with increasing fines, but compressibility increases (Figure 1). With more co-hesive powders the air held in their relatively open structure is squeezed out when normal stress is applied.
Although conditioned bulk density is therefore low, compression has a marked effect. Less cohesive powders, because they are better packed with little free volume, are left relatively unchanged by the application of normal stress. These bulk density and compressibility data therefore suggest that the inclusion of fines is increasing the cohesivity of the formulation.
More cohesive powders also have lower permeability, a greater resistance to air flow. The combination of small void spaces and strong interparticle forces makes it difficult for air to flow between the individual particles, creating a greater air pressure drop over the bed. Permeability is of direct relevance when considering fluidisation behaviour, which relies on the separation and suspension of individual particles in an upward air flow. These results suggest that with increasing fines, the bed will be less easy to fluidise, a trend echoed by aerated flow energy measurements.
Aerated flow energy is usually measured at increasing air velocity until the powder fluidises. Figure 2 shows values for aerated flow energy for each of the four samples, measured at an air velocity of 8mm/s. The results show that aerated flow energy increases with increasing fines content i.e. samples containing more fines provide greater resistance to flow when fluidised. It is difficult for air to separate and lubricate particles in a cohesive powder bed, so such materials tend to fluidise poorly; non-uniform fluidisation and channelling are commonplace. This makes them less free-flowing, even when aerated.
This work highlights how fines influence powder parameters that are important for DPI development/operation. In summary, they increase the cohesivity of the material, make it more resistant to air flow and less easy to fluidise.
To understand the impact of fines content on DPI performance, the lactose samples used in the previous study were turbula blended with 1.6% fluticasone propionate to produce an API-containing formulation. The dispersion behaviour of these samples was then assessed using a Cyclohaler DPI. FPD was determined from aero-dynamic particle size data.
The results show that FPD increases with fines content and that there is a direct correlation between aerated flow energy and fine particle dose (see figure 3). Increasing fines increases the resistance of the bed to flow, which enhances drug delivery. A more detailed examination of the aerosolisation process highlights why.
The pressure drop across a packed bed is directly proportional to the velocity of fluid flowing upwards through it, up until the point of fluidisation (see figure 4). At a certain velocity, the upward force induced by the fluid becomes equal to the downward force on the particles caused by gravity and, provided there are no forces of attraction between particles, the bed begins to fluidise. This is the point of incipient fluidisation and the velocity at which it occurs is referred to as the minimum fluidisation velocity (MFV). In reality, there are always some interparticle forces and the velocity rises above the MFV before the bed fluidises. Fluidisation is marked by a sharp fall in pressure drop.
The work done here indicates that formulations with more fines provide greater resistance to fluidisation. Increasing the level of fines, increases cohesivity giving the powder bed greater tensile strength. A consequence of this is that the pressure drop and velocity through beds of these materials will rise higher prior to fluidisation.
At the point of incipient fluidisation, the formulation particles are subjected to the greatest differential velocity between the moving air and static bed, and aerodynamic drag hits a peak. These forces drive aerosolisation, promoting the particle-particle and particle-device collisions that strip API from the carrier. In a more cohesive bed such forces are higher, giving more energetic dispersion.
Visual studies of aerosolisation, gathered using high-speed photography,5 support this finding. This work shows that the mechanism of fluidisation can change depending on the tensile strength of the bed. With cohesive powders the bed fractures at a certain velocity, the powder lifting as a plug, which then ruptures to form a dense cloud of particles. In this high energy process, flow in the cloud is chaotic and dispersion is highly effective.
Fluidisation of the less cohesive formulations, on the other hand, proceeds via a gradual process of erosion, pockets of powder being dragged from the surface once velocity through the bed exceeds a certain value.
Formulations for use in DPIs need to fluidise and aerosolise in an appropriate way to ensure effective drug delivery to the lung. Fines change the response of a formulation to air increasing cohesivity and the tensile strength of the powder bed. This promotes more energetic aerosolisation, increasing FPD. Since this behaviour is reflected in the direct correlation between aerated flow energy and FPD, powder rheometers are proving to be a useful tool for DPI formulators. Offering bulk, shear and dynamic measurements that give maximum insight into powder characteristics - these systems provide understanding that accelerates and optimises product development.