The relationship between the physicochemical properties of dry powder aerosols and the aerodynamic aerosolization performance efficiency could be rather complex because a myriad of influencing factors described above. Real pharmaceutical fine powders are affected by both their intrinsic characteristics and environmental factors. They are susceptible to change over time. Each change will result in a formulation with new physicochemical properties that may influence performance.[95] Unique inhaler devices and aerosolization conditions further confound the aerosol performance evaluation and limit the potential to predict behavior. The aerosolization performance prediction remains a challenge due to the limited fundamental understanding of interparticulate interactions in heterogeneous condition and how they can be related to the deaggregation processes even in the simplest dry powder aerosol system. It is imperative to extend qualitative observations to obtain quantitative reproducible measurements. Currently, the performance prediction can be roughly classified into two categories: The correlation of performance data with 1) formulation properties and 2) airflow properties.
Performance prediction of a DPI formulation is, to a large extent, achieved by correlation of performance data (such as ED, FPF, MMAD) with formulation properties. The performance is generally evaluated at fixed airflow condition (e.g. fixed airflow rate,
pressure drop, etc). A straightforward approach frequently used is the correlation of performance with interparticulate interactions. Traditional techniques for interparticulate force measurement include particle detachment following centrifugation, vibration, impact separation, and the rapidly developed atomic force microscopy (AFM) technique.[96] The AFM colloid probe and pull-off force techniques allow interparticulate force measurement at single particle level. It is well known that geometric and energetic heterogeneity often cause log-normal distribution of the pull-off forces.[97] However, practically, it has been observed that dry powder formulations having similar adhesion/cohesion do not necessarily result in similar aerodynamic behavior of the drug when lactose monohydrate based formulations were studied.[52, 98] This deviation may be attributed to different sites of adhesion.[52]
Moreover, increased cohesion was correlated with decreased FPF[99, 100] or increased FPF
[101] when using drug-only formulation. These paradoxical correlation results can possibly be explained by variation in the fluidization and the effectiveness of aerodynamic deaggregation exerted on the agglomerates.[101] It is clear that the pull-off force alone may not be a reliable parameter for performance prediction. There are reports of the influence of the contribution of individual interparticulate forces (van der Waals, capillary, electrostatic forces) on performance. However, the correlation of formulation performance with individual component of these fundamental forces was rare.
In recent years, for the purpose of performance efficiency optimization, indirect correlations of performance data with particle size,[102-104] carrier type,[105, 106] particle morphology,[107] surface roughness,[92, 100, 108] surface energy,[109-112] ternary component,[104, 113, 114] relative humidity (RH%) [115, 116] have been explored. These parameters have a great influence on the particulate interaction. Caution should still be
exercised when applying some of these parameters. For example, the correlation of performance with the increasing surface roughness, was known to either increase [35, 108] or decrease [92, 100, 117] the interparticulate forces depending on the true area of contact. Different surface analytical techniques have been applied to evaluate the change in correlation between particle parameters and performance. AFM is a powerful and versatile technique that is playing an important role in surface characterization of various components related to the fundamental forces and geometrical features that contribute to adhesion/cohesion under a variety of environmental conditions.[118] This technique has been used extensively for formulation screening and performance prediction. It is worth mentioning that performance efficiency of micronized drug particles is dependent on the drugs’ cohesive and adhesive properties and optimum performance is achieved when the ratio of cohesion to adhesion is balanced. An approach, designated the cohesive-adhesive balance (CAB) method has been described [119, 120] and the aerosol performance was correlated with the ratio of cohesive and adhesive forces.[101, 105] Although factors such as surface roughness can significantly influence the performance, this method avoids the need for measurement of the area of contact, by a normalization technique. Overall this method has been useful for formulation screening [121] and correlation with the results of aerosolization performance mechanism studies in the more sophisticated ternary blending system.[113] A slightly cohesive drug-carrier CAB ratio was suggested for optimum formulation performance.[121] Although rapid development of the AFM technique has occurred, it should be noted that the correlation using one technique may not always be reliable. AFM substrates are usually prepared by recrystallization or high-pressure compaction, which may not be a true representation of a relevant pharmaceutical formulation.
Other surface analytical techniques such as inverse gas chromatography (IGC) and contact angle measurement can provide complementary data for surface energy analysis.
Other correlations have been explored for performance data with respect to alternative aerosol powder properties such as milling effect,[104] Hildebrand solubility parameter,[122] drug-carrier ratio,[123] Carr’s flowability index,[124] elongation ratio,[35]
avalanche time,[98] and the amount of particle surface coating.[125, 126] These parameters are more or less indirectly related to the fundamental interparticulate forces or surface energetics.
Conversely, the correlation of performance with the airflow properties (e.g. shear stress) is much less frequently reported than the relationship to formulation properties. This may be attributed to: 1) the requirement for a performance study to control a variety of influencing factors, and the airflow is the easiest to fix once the inhaler devices and airflow rate are determined; 2) The performance efficiency among different formulations is usually compared qualitatively and categorically (i.e. rank order comparison); 3) Many of the studies of aerodynamic behavior under various air flow conditions focus on the inhaler device development. (For example, the computation fluid dynamics (CFD) aided inhaler device design); 4) The formulation effect is often confounded by the inhaler device effect. More than twenty inhalers [43, 66] are currently marketed with a variety of mechanisms of drug aerosolization, the results and findings in one system cannot be extrapolated directly to another system. Nevertheless, the formulation performance as a function of airflow parameters is very important because the optimum formulation cannot be determined unless its performance under the airflow conditions within a relevant inspiratory range is evaluated. For example, the optimized formulation used in Inhalator® (high shear stress) may not
necessarily disperse efficiently in Rotahaler® (low shear stress) at the same airflow rate. Moreover, most of the commercial DPIs require patients’ inspiration for pulmonary drug delivery. The airflow parameters are dependent on the airflow rate (patients’ maneuver) which may vary greatly. Performance reproducibility in a wide respirable range is a key to the successful formulation development and FDA approval for pulmonary delivery. Currently, the conventional formulation optimization and reproducibility study remains an empirical estimation based on iteration by trial and error.
Performance efficiency is directly related to specific resistance (RD), which is
dependent on the geometry and dimension of the inhaler devices.[127] At given airflow rate, inhaler devices with higher RD are expected to generate greater turbulence and result in
higher FPF.[128] However, higher RD will result in lower volumetric airflow rate due to the
capability of patients’ maneuver. Powder flow is correlated directly with ease of particle separation and aerosol performance at given RD (same inhaler device).[129] This indicates
that increasing inspiratory effort corresponds to increase in FPF. More recently, Chan et al
[130] studied the influence of airflow at 8 different airflow rates on the performance using mannitol powder. They observed that an increase in “FPFImpinger” (FPFImpinger represents FPF
that separate from the influence of capsule, device and throat retention) occurred at lower airflow rate between 30 and 75 L/min but reached a plateau at higher airflow rate. They also applied a CFD approach to track the fate of 1000-5000 particles through the airstream generated inside the Aerolizer®, and concluded that device flow field generated from simpler geometry is necessary for deaggregation mechanism studies such as turbulence and impaction levels.[130, 131] It should be noted that the airflow rate based on a patient’s inhalation covers a very narrow range of inspiratory capacity, while RD tolerates a wider
range which can be achieved by device innovation.[128] Recently, a CFD approach was used to model airflow path and particle trajectories using ~1000 particles. The particles were assumed to deaggregate when the fluid based torque exceeded the separation torque.[59]
Both fluid-based and impact-based effects were evaluated.[59] Due to the complexity of the deaggregation process, the CFD approach is only capable of describing a small population of particles but not the entire pharmaceutical powder. In 2006, de Boer et al [132] evaluated the relationship of FPF and pressure drop (ΔP) using four commercial inhaler devices with distinct mechanisms of deaggregation upon which the performance was highly dependent. The complexity of deaggregation makes it difficult to separate the effects of formulation heterogeneity and the confounding airflow conditions other than ΔP. A global nonideality of the experimental system was observed instead of attempting to deconvolute the confounded separate effects.[132] Also in 2006, Louey et al [56] described standardized entrainment tubes (SETs). These SETs were characterized using four airflow parameters including pressure drop (ΔP), power, Reynold’s number (Re), and shear stress (τs) at airflow rates of
28.3 and 60 L/min. An increase in these parameters across the device at the same airflow rate corresponds to increased drug deaggregation. The airflow conditions of these SETs encompass those of commercial inhalers, and the application of well-defined SETs for performance studies eliminates the confounding factors caused by inhaler devices and allows focus on formulation effect. A semi-quantitative correlation of performance data including fine particle mass (FPM) and mass median aerodynamic diameter (MMAD) with these airflow parameters was then evaluated. For VentolinTM rotacaps (a lactose based albuterol sulfate formulation), hyperbolic relationship and exponential decay were suggested for FPM- airflow parameters and MMAD-airflow parameters correlation, respectively.[56] Yet, no
regression analyses were performed to further quantify these relationships due to the limited quantity of initial data.