Patricia Tang

How Much Particle Surface Corrugation Is Sufficient to Improve Aerosol Performance of Powders

No HeadingPurpose.The current study aimed to quantify the different degree of particle surface corrugation and correlate it to the aerosol performance of powders.Methods.Powders of different degree of surface corrugation were prepared by spray drying under varying conditions. The solid-state properties of the powders including particle size, morphology, crystal form, true density, and moisture content were characterized. The degree of surface corrugation was quantified by the surface fractal dimension (DS) obtained by light scattering. The aerosol performance was studied by dispersing the powders using the Rotahaler at 60 L/min into a multi-stage liquid impinger. Fine particle fraction (FPF) was expressed as the wt% of BSA particles of size ≤5 μm in the aerosol.Results.Four powders of increasing degree of particle surface corrugation were prepared, with DS ranging from 2.06 for the least corrugated to 2.41 for the most corrugated. The powders had a similar size distribution (VMD 3 μm, span 1.4–1.5) and solid-state properties. Increasing the surface corrugation, DS, slightly from 2.06 to 2.18 enhanced the FPF significantly from 27% to 41%. This was explained by the reduced area of contacts and increased separation distance between the particles. Further increase of corrugation (DS ≥ 2.18) did not improve FPF.Conclusion.Powders with varying degrees of corrugation were successfully obtained by spray drying with their surface roughness quantified by fractal analysis. It was shown that only a relatively small degree of surface corrugation was sufficient to accomplish a considerable improvement in the aerosol performance of the powder.

Emerging inhalation aerosol devices and strategies: where are we headed?

Novel inhaled therapeutics including antibiotics, vaccines and anti-hypertensives, have led to innovations in designing suitable delivery systems. These emerging design technologies are in urgent demand to ensure high aerosolisation performance, consistent efficacy and satisfactory patient adherence. Recent vibrating-mesh and software technologies have resulted in nebulisers that have remarkably accurate dosing and portability. Alternatively, dry powder inhalers (DPIs) have become highly favourable for delivering high-dose and single-dose drugs with the aid of advanced particle engineering. In contrast, innovations are needed to overcome the technical constrains in drug-propellant incompatibility and delivering high-dose drugs with pressurised metered dose inhalers (pMDIs). This review discusses recent and emerging trends in pulmonary drug delivery systems.

Micro-particle corrugation, adhesion and inhalation aerosol efficiency.

Atomic force microscopy (AFM) was used to evaluate the particle adhesion and surface morphology of engineered particles for dry powder inhaler (DPI) respiratory therapy to gain a greater understanding of interparticle forces and the aerosolisation process. A series of spherical model drug particles of bovine serum albumin (BSA) was prepared with different degrees of surface corrugation. The particles were evaluated in terms of particle size (laser diffraction) and microscopic morphology (scanning electron microscopy). Conventional tapping mode AFM was used to evaluate the nanoscopic morphology and derive specific roughness parameters, while AFM colloid probe microscopy was used to directly measure the interaction of functionalised probes. The physical characterisation and AFM measurements were evaluated in terms of in vitro aerosolisation performance, using a conventional Rotahaler((R)) DPI and multistage liquid impinger. A direct relationship between the root mean square roughness, particle adhesion and in vitro aerosol performance (measured as fine particle fraction, FPF) was observed suggesting that as the degree of corrugation increased, particle adhesion was reduced which, resulted in a concomitant increase in FPF. This study demonstrates that AFM may be used to predict the aerosolisation performance micron sized particles for inhalation based on their morphological properties.

Modelling the Settling Behaviour of Fractal Aggregates; A Review

Sedimentation is one of the simplest and cheapest methods used for the removal of particulate matter from wastewater. However, the method is only viable for large particles and hence pollutants need to be flocculated to form large aggregates, normally behaving as fractals. Knowledge of the structure of fractal aggregates and their settling behaviour are crucial for optimisation of the sedimentation process. The structure of fractal aggregates can be readily measured using methods such as light scattering. However, the characteristics of the settling behaviour of fractal aggregates are not well understood since these aggregates do not behave as spheres with constant density. The settling behaviour of fractal aggregates depends on various aspects, such as the porosity, size, and buoyant density. The models used in this paper to predict settling velocity of fractal aggregates show that aggregates with particles packed closely together settle more easily than open flocs of particles when the size of aggregates exceeds the transition radius, RT. RT exists due to porosity of the flocs. When the sizes of the flocs are smaller than RT, the passage of fluid through the interior of the aggregates allows the reduction of the drag coefficient, which further results in faster settling of loose aggregates compared to compact aggregates. However, when flocs are bigger than the RT, gravity plays a more important role, which allows compact aggregates to settle faster than loose aggregates. This result suggests that by controlling aggregation processes to ensure aggregates have compact structure and are bigger than RT, sedimentation could be further utilised in pollution control processes. Additionally, the usage of coagulant can be greatly reduced since less coagulant is needed to produce compact aggregates.

Focused-ion-beam Milling: A Novel Approach to Probing the Interior of Particles Used for Inhalation Aerosols

PurposeThe current study aimed to examine the pharmaceutical applications of the focused-ion-beam (FIB) in the inhalation aerosol field, particularly to particle porosity determination (i.e. percentage of particles having a porous interior).Materials and MethodsThe interior of various spray dried particles (bovine serum albumin (BSA) with different degrees of surface corrugation, mannitol, disodium cromoglycate and sodium chloride) was investigated via FIB milling at customized conditions, followed by viewing under a high resolution field-emission scanning electron microscope. Two sets of ten particles for each sample were examined.ResultsFor the spray-dried BSA particles, a decrease in particle porosity (from 50 to 0%) was observed with increasing particle surface corrugation. Spray-dried mannitol, disodium cromoglycate and sodium chloride particles were determined to be 90–100%, 0–10% and 0% porous, respectively. The porosity in the BSA and mannitol particles thus should be considered for the aerodynamic behaviour of these particles.ConclusionsThe FIB technology represents a novel approach useful for probing the interior of particles linking to the aerosol properties of the powder. Suitable milling protocols have been developed which can be adapted to study other similar particles.

Characterisation and aerosolisation of mannitol particles produced via confined liquid impinging jets.

Mannitol particles, produced by spray drying (SD), have been used commercially (Aridol) in bronchial provocation test. In this study, we propose an alternative method to produce inhalable mannitol powders. The elongated mannitol particles (number median length 4.0microm, and axial ratio of 3.5) were prepared using a confined liquid impinging jets (CLIJs) followed by jet milling (JM). Spray dried and jet milled raw mannitol particles were compared in an attempt to assess the performance of the particles produced by the new method. Aerosol performance of the three different powders (CLIJ, SD, and JM) was relatively poor (fine particle fraction or FPF(loaded) below 15%) when dispersed by the Rotahaler. Dispersion through the Aeroliser led to better aerosol performance of the CLIJ mannitol (FPF(loaded) 20.3%), which is worse than the JM (FPF(loaded) 30.3%) and SD mannitol particles (FPF(loaded) 45.7%) at 60 L/min, but comparable (FPF(loaded) 40.0%) with those of the JM (FPF(loaded) 40.7%) and SD (FPF(loaded) 45.5%) powders at 100L/min. Hence, the optimum use of these elongated mannitol particles can be achieved at increased air flow with a more efficient inhaler. In addition to crystallinity, morphology, and particle size distribution, the surface energies of these powders were measured to explain the differences in aerosol performance. A major advantage of using the CLIJ method is that it can be scaled up with a good yield as the precipitate can be largely collected and recovered on a filter, compared with spray drying which has a low collection efficiency for fine particles below 2microm.

Formulation of pH responsive peptides as inhalable dry powders for pulmonary delivery of nucleic acids

Nucleic acids have the potential to be used as therapies or vaccines for many different types of disease, but delivery remains the most significant challenge to their clinical adoption. pH responsive peptides containing either histidine or derivatives of 2,3-diaminopropionic acid (Dap) can mediate effective DNA transfection in lung epithelial cells with the latter remaining effective even in the presence of lung surfactant containing bronchoalveolar lavage fluid (BALF), making this class of peptides attractive candidates for delivering nucleic acids to lung tissues. To further assess the suitability of pH responsive peptides for pulmonary delivery by inhalation, dry powder formulations of pH responsive peptides and plasmid DNA, with mannitol as carrier, were produced by either spray drying (SD) or spray freeze drying (SFD). The properties of the two types of powders were characterised and compared using scanning electron microscopy (SEM), next generation impactor (NGI), gel retardation and in vitro transfection via a twin stage impinger (TSI) following aerosolisation by a dry powder inhaler (Osmohaler™). Although the aerodynamic performance and transfection efficacy of both powders were good, the overall performance revealed SD powders to have a number of advantages over SFD powders and are the more effective formulation with potential for efficient nucleic acid delivery through inhalation.

Method to introduce mannitol powder to intubated patients to improve sputum clearance.

BACKGROUND Poor sputum clearance is a common problem encountered in intubated patients, which may cause airway obstruction, hypoxaemia, and increased risk of lower respiratory tract infection. This may result in longer intensive care unit (ICU) stay or even death. Dry powder mannitol has been shown to improve sputum clearance, and thus we developed a system to deliver it to intubated patients. METHODS This delivery system consists of a standard adult manual ventilation bag, a one-way duck-billed valve, and a dry powder inhaler (Osmohaler™) contained within a delivery chamber to allow positive pressure ventilation, which in turn, is connected in series to an endotracheal or tracheostomy tube. The aerosol is delivered by compressing the ventilation bag in a reproducible manner to generate positive pressure airflow to disperse the powder into the tracheal tube. We tested the powder output and characteristics of the powder in vitro from two endotracheal tubes (7.0 and 8.5 mm in diameter, 300 mm in length), and two tracheostomy tubes (7.0 mm in diameter and 95 mm in length; 90 mm in diameter and 115 mm in length). RESULTS AND CONCLUSIONS Approximately 50 to 60% of the loaded dose of dry powder mannitol is delivered to the distal end of the tracheal tubes for both 4 × 40-mg and 4 × 80-mg capsules. The fine particle fraction (particles smaller than 5 μm) ranges from 20 to 31% of the loaded dose. Powder was emptied from each 40- and 80-mg capsule within 5 ± 1 puffs and 6 ± 1 puffs, respectively. This delivery system has been shown to consistently deliver a very high dose of powder with a favourable fine particle fraction to the distal end of a number of tracheal tubes. This has the potential for a number of clinical therapeutic applications in critically ill patients.

A novel method for the production of crystalline micronised particles.

The aim of this study was to develop a method for converting an amorphous drug to a crystalline form to enhance its stability and inhalation performance. Spray-dried amorphous salbutamol sulphate powder was conditioned with supercritical carbon dioxide (scCO(2)) modified with menthol. The effect of menthol concentration, pressure, temperature and time on the characteristics of the resulting salbutamol sulphate powder was investigated. Pure scCO(2) had no effect on the physical properties of amorphous salbutamol sulphate; however, scCO(2) modified with menthol at 150bar and 50 degrees C was efficient in converting amorphous drug to crystalline form after 12h of conditioning. The average particle size of powders decreased slightly after the conditioning process because of reducing agglomeration between particles by increasing surface roughness. Emitted dose measured by the fine particle fraction (FPF(emitted)) of amorphous salbutamol sulphate was enhanced from 32% to 43% after conditioning with scCO(2)+menthol and its water uptake was significantly decreased. This study demonstrates the potential of scCO(2)+menthol for converting amorphous forms of powders to crystalline, while preserving the particle size.

l-Leucine as an excipient against moisture on in vitro aerosolization performances of highly hygroscopic spray-dried powders

L-Leucine (LL) has been widely used to enhance the dispersion performance of powders for inhalation. LL can also protect powders against moisture, but this effect is much less studied. The aim of this study was to investigate whether LL could prevent moisture-induced deterioration in in vitro aerosolization performances of highly hygroscopic spray-dried powders. Disodium cromoglycate (DSCG) was chosen as a model drug and different amounts of LL (2-40% w/w) were added to the formulation, with the aim to explore the relationship between powder dispersion, moisture protection and physicochemical properties of the powders. The powder formulations were prepared by spray drying of aqueous solutions containing known concentrations of DSCG and LL. The particle sizes were measured by laser diffraction. The physicochemical properties of fine particles were characterized by X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic vapor sorption (DVS). The surface morphology and chemistry of fine particles were analyzed by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and time-of-flight secondary ion mass spectrometry (ToF-SIMS). In vitro aerosolization performances were evaluated by a next generation impactor (NGI) after the powders were stored at 60% or 75% relative humidity (RH), and 25°C for 24h. Spray-dried (SD) DSCG powders were amorphous and absorbed 30-45% (w/w) water at 70-80% RH, resulting in deterioration in the aerosolization performance of the powders. LL did not decrease the water uptake of DSCG powders, but it could significantly reduce the effect of moisture on aerosolization performances. This is due to enrichment of crystalline LL on the surface of the composite particles. The effect was directly related to the percentage of LL coverage on the surface of particles. Formulations having 61-73% (molar percent) of LL on the particle surface (which correspond to 10-20% (w/w) of LL in the bulk powders) could minimize moisture-induced deterioration in the aerosol performance. In conclusion, particle surface coverage of LL can offer short-term protection against moisture on dispersion of hygroscopic powders.