A Proposal for an Alternative Approach to Particle Size Method Development During Early-Stage Small Molecule Pharmaceutical Development.

Particle size analysis in the pharmaceutical industry has long been a source of debate regarding how best to define measurement accuracy; the degree to which the result of a measurement or calculation conforms to the true value. Defining a "true" value for the size of a particle can be challenging as the output of its measurement will differ because of variations in measurement approaches, instrumental differences and calculation methods. Consequently, for "real" particles, a universal "true" value does not exist and accuracy is therefore not a definable characteristic. Accordingly, precision is then a measure of the ability to reproducibly achieve a measurement of unknown relevance. This article proposes, in place of accuracy, a means to define the "appropriateness" of a measurement in line with the critical quality attributes (CQA) of the material being characterized. The decision as to whether the measurement is correct should involve a link to the CQA; that is, correlation should be demonstrated, without which the measured particle size cannot be defined as a critical material attribute. Correspondingly, methods should also be able to provide sufficient precision to demonstrate discrimination relating to variation in the CQA. The benefits and challenges of this approach are discussed.

Insight into pressure drop dependent efficiencies of dry powder inhalers.

PURPOSE: The purpose of this study was to assess the effectiveness of three commercial capsule-based dry powder passive inhalers [Rotahaler® (RH), Monodose Inhaler® (MI) and Handihaler® (HH)] in de-agglomerating salbutamol sulphate (SS) and micronized lactose (LH300) powders and their sensitivity to air flow rate changes and air flow resistance. METHODS: Aerosolisation was assessed in real-time using a laser diffraction method: this approach was possible as only single-component formulations were tested. Volume percent of the aerosolised particles with diameter less than 5.4 µm at air flow rates from 30 to 180 l min−1 was obtained with the RH, MI and HH and provided a parameter, relative de-agglomeration (RD), as a measure of de-agglomeration. The pressure drops across the device at various flow rates were obtained from a differential pressure meter. RESULTS: The relationship between RD of SS and LH300 and air flow rate appeared substantially different between the devices. It was surprisingly found that in some cases RD dropped at the highest air flows: this indicates a device specific maxima in RD occurs, and this may in part be attributed to changes in capsule motion. It is proposed that this relationship between RD and pressure drop provides a patient focussed simple way to assess RD performance. This assessment indicated that MI was the most efficient relative de-agglomerator at lower pressure drops, while HH increases its effectiveness at higher pressure drops. CONCLUSION: The approach of measuring RD as a function of pressure drop revealed instructive variations in the aerosolisation performances of different devices. This new approach helps compare device performances with different powders, and hence improve optimisation and consistency of performance.

The kinetics of cohesive powder de-agglomeration from three inhaler devices.

PURPOSE: The purpose of the current investigation is to understand the kinetics of de-agglomeration (k(d)) of micronised salbutamol sulphate (SS) and lactohale 300 (LH300) under varying air flow rates (30-180l min(-1)) from three dry powder inhaler devices (DPIs), Rotahaler (RH), Monodose Inhaler (MI) and Handihaler (HH). RESULTS: Cumulative fine particle mass vs. time profiles were obtained from the powder concentration, emitted mass and volume percent <5.4 µm, embedded in the particle size distributions of the aerosol at specific times. The rate of de-agglomeration (k(d)), estimated from non-linear least squares modelling, increased with increasing air flow rates. The k(d)vs. air flow rate profiles of SS and LH300 were significantly different at high air flow rates. The k(d) was highest from RH and lowest from MI. Differences in k(d) between the devices were related to device mode of operation while the differences between the materials were due to the powder bed structure. CONCLUSION: This approach provided a methodology to measure the rate constant for cohesive powder de-agglomeration following aerosolisation from commercial devices and an initial understanding of the influence of device, air flow rate and material on these rate constants.

Structural influence of cohesive mixtures of salbutamol sulphate and lactose on aerosolisation and de-agglomeration behaviour under dynamic conditions.

PURPOSE: The purpose of this study was to understand the behaviour of cohesive powder mixtures of salbutamol sulphate (SS) and micronized lactose (LH300) at ratios of SS:LH300 of 1:1, 1:2, 1:4 and 1:8 under varying air flow conditions. METHODS: Aerosolisation of particles less than 5.4µm at air flow rates from 30 to 180 l min(-1) was investigated by determining particle size distributions of the aerosolised particles using laser diffraction and fine particle fractions of SS using the twin stage impinger modified for different air flow rates using a Rotahaler(®). The de-agglomeration data were best fitted by a 3-parameter sigmoidal equation using non-linear least squares regression and characterised by the estimated parameters. RESULTS: De-agglomeration air flow rate profiles showed that SS:LH300 mixtures with increased lactose content (1:4 and 1:8) improved powder aerosolisation, but lactose had negligible effect on SS aerosolisation at the higher and lower limits of air flow rates studied. De-agglomeration flow rate profiles of SS-LH300 mixtures with increased lactose content (1:4 and 1:8) were greater than theoretically expected based on weighted individual SS and LH300 profiles. This indicated that interactions between the cohesive components led to enhanced de-agglomeration. The composition of the aerosol plume changed with air flow rate. CONCLUSION: This approach to characterising aerosolisation behaviour has significant applications in understanding powder structures and in formulation design for optimal aerosolisation properties.

Influence of realistic airflow rate on aerosol generation by nebulizers.

Mathematical models are available which predict aerosol deposition in the respiratory system assuming that the aerosol concentration and size are constant during inhalation. In this study, we constructed a sinusoidal breathing model to calculate the aerosol concentration produced by a nebulizer as a function of inhalation time. The laser diffraction technique (Spraytec, Malvern Instruments Ltd., Malvern, UK) was used to validate this model as it allows the aerosol concentration and particle size to be measured in real time. Each nebulizer was attached to a special glass measurement cell and a sine-wave pump. Two standard jet nebulizers (Mistyneb and Microneb), two breath-enhanced jet nebulizers (Pari LC+ and Atomisor NL9M) and three mesh nebulizers (Eflow, Aeroneb Go and Aeroneb Pro with Idehaler) were characterized. Results obtained were consistent in terms of curve profile between the proposed model and the laser diffraction measurements. The standard jet and mesh nebulizers produced significant variations in aerosol concentration during inhalation, whereas the breath-enhanced jet nebulizers produced a constant aerosol concentration. All of the nebulizers produced a relatively constant particle size distribution. Our findings confirm that the concentration observed during inhalation is often not constant over time. The laser diffraction method allows the concentration and size of particles for each unit volume of air inhaled to be measured and could therefore be used to predict the aerosol deposition pattern more precisely.

The role of force control agents in high-dose dry powder inhaler formulations.

The aim of this study was to determine the aerosolisation and aerodynamic properties of model inhalation particles (salbutamol sulphate and budesonide) upon coprocessing with force control agents (FCAs)-leucine, lecithin and magnesium stearate. Coprocessing of the drug particles with FCAs (5%, w/w) was conducted using mechanofusion-a novel dry mechanical fusion process. The influence of mechanofused FCAs on the entrainment and deaggregation behaviour of the drug-only formulations was investigated using a next generation impactor (NGI) and an in-line Spraytec laser diffraction particle sizer. In vitro measurements of salbutamol sulphate coprocessed with FCAs indicated a significant (p < 0.001) improvement of the fine particle fraction (FPF). The coprocessing of salbutamol sulphate with magnesium stearate produced the highest FPF, with an increase from 29.18% to 79.42% of the emitted dose. Coprocessing of budesonide particles only led to a small increase in fine particle delivery but a greater reduction in device retention. Aerosolisation analysis of the aerosolised powders indicated more effective aerosolisation and a considerable time reduction in powder bed fluidisation and entrainment upon coprocessing of the APIs with FCAs. From these data, it can be postulated that processing of drug actives with FCAs using mechanofusion is an effective means of improving the deagglomeration and aerosolisation properties of cohesive powders in DPI systems.