Effect of Air Flow and Acceleration on Particle Size of Dry Powder Aerosols determined by Time-of-Flight Aerosol Beam Spectrometry

The effect of air flow and acceleration on the particle size distributions of two Turbuhalers containing drug loads of 0.5 and 1.3 mg per dose was determined with a time-of-flight aerosol beam spectrometer (Aerosizer®). While the particle size of both inhalers decreased with increasing flow and acceleration, the distributions became narrower and variability was reduced. Simultaneously, a decrease in the number and mass of particles measured was observed which was more pronounced for the 1.3 mg dose. Additionally the count rate for the 1.3 mg dose was lower than for 0.5 mg. These observations were accompanied by a remarkably fine particle size distribution for the high dose Turbuhaler®. It was concluded that the quantity of particles in the DPI aerosols exceeded the resolution of the Aerosizer, erroneously shifting the size distributions towards smaller diameters.

In addition, the DPI aerosols were analyzed with a Four Stage Impinger to evaluate the results. The particle size estimates obtained using the impinger were in the same range as those obtained at an acceleration of 5 L/s2 using the Aerosizer to study the 0.5 mg Turbuhaler. The Aerosizer produced significantly smaller particle sizes than the impinger in all cases evaluating the 1.3 mg Turbuhaler, supporting the theory of distorted particle size distributions due to particle overload.     

Appropriate selection of an aggregation inhibitor of fine particles used for inhalation prepared by emulsion solvent diffusion

Abstract

Context: Dry powder inhaler (DPI) formulations have been developed to deliver large amounts of drugs to the lungs.

Objective: Fine particles of a poorly water-soluble drug, the model drug ONO-2921, were prepared by the emulsion solvent diffusion (ESD) method for use in a DPI.

Methods: The effects of additives on the fine particle formation of ONO-2921 were estimated when droplets of an ethanolic drug solution were dispersed into aqueous media containing various additives. Subsequently, the suspensions were freeze-dried to create powdered samples to estimate the inhalation properties using a twin impinger and an Andersen cascade impactor.

Results: This simple ESD method produced submicron-sized ONO-2921 particles (approximately 600?nm) in combination with suitable additives. In addition, the freeze-dried powder produced using additives exhibited superior in vitro inhalation properties. Among these methods, the freeze-dried powder produced with 0.50% weight/volume one type of polyvinyl alcohol (PVA-205) displayed the most efficient features in the fine particle fraction (FPF). These results could be explained by the stabilization of the ONO-2921 suspension by PVA-205, indicating that PVA-205 acts as an aggregation inhibitor of fine particles.

Conclusions: The ESD method, in combination with appropriate types and amounts of additives, may be useful for preparing a DPI suitable for delivering drugs directly to the lungs without the assistance of carrier particles.     

Crystal engineering of lactose using electrospray technology: carrier for pulmonary drug delivery

Context: Dry powder inhalers (DPIs) consisting of a powder mixture containing coarse carrier particles (generally lactose) and micronized drug particles are used for lung drug delivery. The effective drug delivery to the lungs depends on size and shape of carrier particles. Thus, various methods have been proposed for engineering lactose particles to enhance drug delivery to lungs.

Objective: The objective of current work was to assess suitability of electrospray technology toward crystal engineering of lactose. Further, utility of the prepared lactose particles as a carrier in DPI was evaluated.

Materials and methods: Saturated lactose solutions were electrosprayed to obtain electrosprayed lactose (EL) particles. The polymorphic form of EL was determined using Fourier transform infrared spectroscopy, powder X-ray diffractometry, and differential scanning calorimetry. In addition, morphological, surface textural, and flow properties of EL were determined using scanning electron microscopy and Carr’s index, respectively. The aerosolization properties of EL were determined using twin-stage impinger and compared with commercial lactose particles [Respitose^® (SV003, Goch, Germany)] used in DPI formulations.

Results and discussion: EL was found to contain both isomers (α and β) of lactose having flow properties comparable to Respitose^® (SV003). In addition, the aerosolization properties of EL were found to be significantly improved when compared to Respitose^® (SV003) which could be attributed to morphological (high elongation ratio) and surface characteristic (smooth surface) alterations induced by electrospray technology.

Conclusion: Electrospray technology can serve as an alternative technique for continuous manufacturing of engineered lactose particles which can be used as a carrier in DPI formulations.     

Numerical investigation of powder dispersion mechanisms in Turbuhaler and the contact electrification effect

Powder dispersion in dry powder inhalers (DPI) is affected by factors such as device design and flow rate, but also electrification due to particle–particle/device collisions. This work presented a CFD-DEM study of powder dispersion in Turbuhaler®, aiming to understand the effect of electrostatic charge on the dispersion mechanisms. The device geometry was reconstructed from CT-scan images of commercial Turbuhaler device. Different work functions were applied to the active pharmaceutical ingredient (API) powder and the device wall. Electrostatic charges were accumulated on the API particles due to contact potential difference (CPD) between the particles and the device wall. Results showed that both the chamber and the spiral mouthpiece played an important role in de-agglomeration of powders caused by particle–wall impactions. With increasing flow rates, the performance of the device was improved with higher emitted dose (ED) and fine particle fractions (FPF). The electrostatic charging of the particles was enhanced with higher CPD and higher flow rates, but the electrostatic charging had a minimum effect on powder dispersion and deposition with slight reduction in ED and FPF. In conclusion, the van der Waals force is still the dominant adhesive inter-particle force, and the dispersion efficiency is affected by the flow rate rather than contact electrification of particles. Future work should focus on the effect of highly charged particles emitted from the inhaler on the deposition in the airway.     

Formulation and Evaluation of Insulin Dry Powder for Inhalation

Abstract

Purpose. Dry powder formulation of insulin for pulmonary administration was prepared to obtain increased drug deposition in the alveolar absorptive region. The deposition was studied by investigating the dispersion and deaggregation of insulin from the carrier lactose using an Andersen cascade impactor and twin stage impinger. The subsequent absorption following the deposition was studied by in vivo method. Methods. Insulin in solution with absorption promoters was lyophilized. The powder was incorporated with lactose of different grades and their combinations as carriers to deliver using an inhaler device. Solid-state characteristics of the carrier as well as the drug powder were assessed by particle size and distribution measurement. The flow properties such as moisture content, powder density, angle of repose, and carr's compressibility index of the powder mixture were determined. The aerosol behavior of the powder was studied by dispersion using rotahaler^© connected to a twin-stage impinger (TSI) and an eight-stage Andersen cascade impactor (ACI) operating at different flow rates of 30–90 l/min. The in vivo performance was studied by deliverance to the respiratory tract of guinea pigs. The intratracheal bioavailability with respective to intravenous route was calculated by measuring the blood glucose reduction. Results. The coarser particles of lactose in fractions of carrier containing a wide particle size distribution impacted in the preseperator of cascade impactor, and only the particle less than 10 µm size entered stage 0–stage 7. Formulation containing 1:1 mixture of Respitose ML006 (62%<50 µm) and Respitose ML003 (37.8%<50 µm) as carrier imparts well deaggregation of insulin, and higher deposition leads to 52.3% of fine particle fraction at 60 Lit/min and in vivo bioavailability of 82%. Conclusions. Insulin formulations containing 1:1 mixture of Respitose ML006 and Respitose ML003 as carrier can impart deeper deposition of drug particles and cause higher bioavailability. This suggests that carrier used in the formulation influenced the amount of insulin deposition in the alveolar region of the lung. Hence, it was concluded that the availability of insulin for systemic absorption depends on the particle size of the drug as well as the carrier lactose.     

The Quantitative Evaluation of a Granulation Milling Process III. Prediction of Output Particle Size

Abstract

Regression analysis was performed using comminution data from the previously presented Comil®G/aspirin granulation characterization study. Polynomial models were constructed using mill speed, output screen size and impeller shape as independent variables. The models were used to predict the mean particle size (µ_d) and geometric standard deviation (σ_d) of particle size distributions resulting from the comminution of aspirin using the Comil®G. The predictions were found to compare well with observed values.     

Restructuring of Alumina Particles using a Plasma Torch

ABSTRACT

A new method of modifying ceramics using plasmas was recently revealed in our laboratory. To wit: The size, shape, and phase of alumina particles were dramatically modified by passage through an atmospheric pressure argon plasma. Specifically, irregularly shaped particle of γ-alumina with an average diameter of 15 μm were converted to smaller (6 μm) spherical particles primarily consisting of δ- and corundum phases. The plasma torch was operated with an argon flow rate of 3 slpm, power of 700 watts, and the average particle residence time was 0.1 seconds.     

E-SPART Analysis of Poly (D,L-lactide-co-glycolide) Microspheres Formulated for Dry Powder Aerosols

ABSTRACT

Electrical-single particle aerodynamic relaxation time (E-SPART) analysis was studied as a tool in formulation screening of diy powders for use in aerosol delivery to the lung. The respirable fraction (RF) of drugs delivered by dry powder inhalers (DPIs) can be improved more effectively by using hydrophobic microspheres as carriers. Poly (D,L-lacttde-co-grycolide) microspheres (PLGA) prepared in die respirable size range (3-7 mm) were treated with poryamino acids and isopropanol in order to obtain particles of surface charge suitable for use in DPIs.

The powder formulations were evaluated for their degree of aggregation by cascade impaction following delivery by the Pfeifler® DPI. The IPA treated PLGA microspheres had a significantly higher RF (12.9%) as compared to the PL and PGA treated microspheres (3.3 and 2.4%, respectively), and untreated microspheres (3.8%). Results of electrostatic charge determined by E-SPART analysis suggested that die higher RF for the IPA formulation may be due to hs highly unipolar nature (+ 56.3 mC/g).     

Effect of dual size particle distribution on processing and properties of AZ91D/SiCp magnesium matrix composites prepared by rotation cylinder method

Abstract

Spiral fluidity and hardness and wear experiments were carried out to investigate the effect of dual size (5 and 50 μ m) SiC particle distributions on the fluidity, hardness, and wear resistance of Mg - 9.1Al - 0.7Zn (wt-%) alloy containing 10 vol.-% SiC particles, with the aim of tailoring properties to specific applications. Although a decrease in the fluidity of the composites is observed, as expected, in the presence of SiC particles, the fluidity of the composites with dual size particle distributions was in some instances better than that of composites containing the same volume fraction of single size particles. The hardness and wear resistance of the composites with dual size distributions were weakly dependent on the mixing ratio. In terms of complete molten processing and tailored mechanical properties, the optimum mixing ratio of 5 and 50 μm particles appears to be 1:2.     

FLOW PATTERNS THROUGH TUBE BUNDLES AND PARTICULATE FOULING ONTO CYLINDERS

ABSTRACT

The shear-stress distributions around cylinders in tube bundles were measured by means of the limiting current method and the flow inside the bundle was also visualized. In the case of the staggered bundle, the shear-stress distributions had two peaks by the effect of the jet streams generated at the front row spacing and the adjacent cylinder. While in the bundle with in-line arrangement, the front stagnant point was shifted about 30° downward and the traverse streams among the rows were observed. This traverse streams caused asymmetry of the shear-stress distributions with respect to the main flow axis.

These results were discussed in connection with the fouling experiments investigated in dusty air. Particle deposition around cylinders could be qualitatively predicted from the shear-stress distributions, namely particles tend to deposit at positions where are less shear-stress in both tube arrangements. The size of particle deposited on the wake zone was coarser than that near the stagnant point behind the third row in both arrangements.     

A New Apparatus for the Determination of the Emitted Dose from Pressurized Metered Dose Inhalation Aerosols with Inhalation Devices

Abstract

A new in vitro test apparatus is described in this report to test the emitted dose from the pressurized metered dose inhalation aerosols (MDI) with inhalation devices. Drug deposition from MDIs in conjunction with different inhalation chambers was studied using a new apparatus and compendial apparatuses. The new apparatus is simple and offers an alternate method to determine the small particle fraction delivered from MDI aerosols with inhalation devices.     

Dry powder nasal drug delivery: challenges,opportunities and a study of the commercial Teijin Puvlizer Rhinocort device and formulation

Purpose: To discuss the challenges and opportunities for dry powder nasal medications and to put this in to perspective by evaluating and characterizing the performance of the Teijin beclomethasone dipropionate (BDP) dry powder nasal inhaler; providing a baseline for future nasal products development.

Methods: The aerosol properties of the formulation and product performance of Teijin powder intranasal spray were assessed, with a particular focus on particle size distribution (laser diffraction), powder formulation composition (confocal Raman microscope) and aerosol performance data (British Pharmacopeia Apparatus E cascade impactor, aerosol laser diffraction).

Results: Teijin Rhinocort^® (BDP) dry powder spray formulation is a simple blend of one active ingredient, BDP with hydroxypropylcellulose (HPC) carrier particles and a smaller quantity of lubricants (stearic acid and magnesium stearate). The properties of the blend are mainly those of the carrier (D_v50?=_?98?±?1.3?µm). Almost the totality of the capsule fill weight (96.5%) was emitted with eight actuations of the device. Using the pharmacopeia suggested nasal chamber deposition apparatus attached to an Apparatus E impactor. The BDP main site of deposition was found to be in the nasal expansion chamber (90.2?±?4.78%), while 4.64?±?1.38% of the BDP emitted dose was deposited on Stage 1 of the Apparatus E.

Conclusions: The Teijin powder nasal device is a simple and robust device to deliver pharmaceutical powder to the nasal cavity, thus highlighting the robustness of intranasal powder delivery systems. The large number of actuations needed to deliver the total dose (eight) should be taken in consideration when compared to aqueous sprays (usually two actuations), since this will impact on patient compliance and consequently therapeutic efficacy of the formulation.     

Comparative Evaluation of Surfactant and Hydrophobizing Agent Concentration in Relation to the Optimal Particle Size of Metered-Dose Inhalers

Abstract

The aim of the present study was to formulate stabilized suspension-type metered-dose inhalation aerosols, and to examine the connection between the stabilizing additives and the optimal particle size. For the stabilization of the suspended particles, hydrophilic- and hydrophobic-type additives were applied. Oleil oleate was selected as a hydrophilic anionic surfactant, and the hydrophobizing agent was dimethyl siloxane polymer. The effect of the amount of the applied hydrophilic and hydrophobic additives on the optimal particle size was modeled by a second-order polynomial equation fitted to the data gathered by a face-centered central composite statistical design. We found that if the proper type and amount of additives are selected, it is possible to acquire the therapeutically best composition.     

Preparation and Testing of Cyclosporine Microsphere and Solution Formulations in the Treatment of Polyarthritis in Rats

Abstract

The aim of the present study was to formulate stabilized suspension-type metered-dose inhalation aerosols, and to examine the connection between the stabilizing additives and the optimal particle size. For the stabilization of the suspended particles, hydrophilic- and hydrophobic-type additives were applied. Oleil oleate was selected as a hydrophilic anionic surfactant, and the hydrophobizing agent was dimethyl siloxane polymer. The effect of the amount of the applied hydrophilic and hydrophobic additives on the optimal particle size was modeled by a second-order polynomial equation fitted to the data gathered by a face-centered central composite statistical design. We found that if the proper type and amount of additives are selected, it is possible to acquire the therapeutically best composition.     

Containment aerosol characterization during nuclear power plant severe accident

ABSTRACT

The aerosol size distribution and concentration during a postulated severe accident scenario were simulated using a numerical code NAUA to characterize the aerosols dispersed in the containment under various conditions. The model-predicted aerosol concentration and particle size distribution were in general agreement with the measured data reported in previous studies. A large set of sensitivity tests were conducted to examine the effects of input parameters. The main particle removal mechanism in containment was gravitational sedimentation when wall temperature was assumed to be the same as the air temperature, whereas diffusiophoresis became a more important particle removal mechanism when the difference between the wall temperature and air temperature was significant. The operation of a containment filtered venting system (CFVS) resulted in reduced particle concentration, mass median diameter (MMD), and geometric standard deviation (GSD) because aged larger particles were removed by the CFVS. The particle concentration and GSD of the containment aerosol decreased with increasing emitted particle size owing to the effect of gravitational sedimentation that removes large particles selectively. Non-sphericity of particles reduced the particle removal rate due to gravitational sedimentation, leading to higher particle concentration, MMD, and GSD.     

Aerosol Synthesis and Characterization of Ultrafine Fullerene Particles

Abstract

Aerosol routes were used to produce fullerene particles in the nanometer size range. Particle formation mechanisms at processing temperatures of 400-700°C were studied by measuring particle number and mass size distributions in the gas phase by a differential mobility analyzer and a low-pressure impactor respectively. Subsequently, the foils of the impactor onto which fullerene particles were collected were examined by HPLC.     

Gastrointestinal Transit Time:— An in Vitro Analysis of the Various Parameters Controlling the Critical Flow Velocity of Particles in a Horizontal Tube

Abstract

The factors which affect the critical flow velocity (V_c) of particles of barium sulphate, bismuth subcarbonate, kaolin, sulphadiazine and latex particles has been determined in a horizontal tube. These factors were particle size, particle density, fluid viscosity and tube diameter. V_c was found to increase with increasing particle diameter, particle density and tube diameter but decreases as viscosity of the flowing fluid. The results obtained were found to fit the models of Wicks, Durand and Wasp for the flow conditions of settled beds.     

SIZE AND HYDRATION CHARACTERISTICS OF LABORATORY SIMULATED JET ENGINE COMBUSTION AEROSOLS

ABSTRACT

Size and hydration characteristics for laboratory simulated jet engine combustion aerosols are reported and the validity of these simulated data is discussed. The jet fuels JP4, JP5, JP8 and JET A were burned in laboratory burners designed to simulate the lean pre-mixed, pre-vaporized advanced combustor concept. Significant quantities of aerosols were detected and in most cases their size and hydration properties were similar. Dry particle size distributions were single mode extending over the diameter range 0.014 to 0.200 microns, with peak diameters in the range 0.020 to 0.050 microns. The distributions were observed to vary with combustion stoichiometry, increasing the peak particle diameter as the combustion stoichiometry shifted from leaner to richer conditions. Critical supersaturation spectra for each fuel are presented. A mean ratio of cloud condensation nuclei to condensation nuclei (CCN/CH) has been calculate for each fuel: JP4 = 32%, JP5 = 42%, JET A = 39%, and JP8 = 35% indicating that in general 30 – 40% of the combustion aerosols generated with these laboratory burners can be considered cloud condensation nuclei.     

Some Future Perspectives for Unit Dose Inhalation Aerosols

Abstract

Unit dose inhalation aerosols fail to achieve optimal lung deposition even though this can be achieved by dispersing 1-5 µm aerodynamic diameter particles in air. Dry powder generators require rapid inhalation for actuation and fail to deaggregate and release much of their powder charge because of high particulate adhesion forces. Conversely, pressurized metered dose inhalers (MDIs) fail because emergent propellant droplets are too large and travel too fast. The present unreliable dosimetry associated with the MDI stems from a desire to administer the whole of the metered dose. Rational design should concede on this point and concentrate on reducing primary droplet size and preventing emission of non-respirable large droplets. The loss of a constant proportion of each metered dose in the device and not the patient would be a major achievement. Improved inhalation dosimetry will facilitate future formulation developments designed to sustain local activity in the lung. This may be achieved by reducing particle dissolution rates in the airways.     

Sterile Filtration of NanoCrystal™ Drug Formulations

Abstract

A Nano Crystal? dispersion of the iodinated x-ray contrast agent iodipamide was prepared by wet milling the drug substance in the presence of Pluronic® F127 stabilizer. The mean particle size of the formulation was 98 nm and all drug particles in the formulation were smaller than 220 nm as determined by dynamic light scattering. Approximately 1 liter of dispersion was filtered through a sterile 0.2-μm disposable capsule filter (Supor® 200 DCF?, 0.I m² effective filtration area [EFA], Gelman Sciences) to condition the capsule. No drug concentration or size distribution changes were detected after the filtration process. The microbiological validation tests were performed using Pseudomonas diminuta organisms to challenge the capsule under simulated worst-case process conditions. The results showed that the Supor 200 DCF was able to retain 100% Pseudomonas diminuta organisms (≥10⁷ organisms per cm² of effective filtration area). Thus, this study demonstrated that terminal filtration is a feasible process to sterilize Nano Crystal? drug dispersions that may be chemically or physically unstable at elevated temperatures and thus not amenable to terminal heat sterilization.