Carrier Particle Size Research Articles

Inhalation performance of pollen-shape carrier in dry powder formulation: Effect of size and surface morphology

In a previous study, pollen-shape drug carriers are compared with traditional carriers at different drug mixing ratios and flow rates. It is found that pollen-shape drug carriers can deliver large amount of drug particles and reduce drug losses especially at low flow rates and high drug mixing ratios. In this study, the effect of size and surface morphology of pollen-shape carriers on drug delivery performance is assessed. Pollen-shape carrier particles having various sizes and surface asperities are synthesized. Budesonide (Bd) is used as the model drug. The drug delivery performances of the pollen-shape carrier particles are investigated using an Andersen Cascade Impactor (ACI) equipped with a Rotahaler ® at gas flow rates of 30 and 60 L/min. Three drug mixing ratios are considered. While an increase in the carrier particle size has a mild improvement on the ED, it significantly improves the FPF. A sparse surface asperity has negligible effect on the ED at low flow rates but it improves the FPF compared to a dense surface asperity under all experimental conditions.

Interparticle forces in binary and ternary ordered powder mixes.

An ultracentrifuge technique, previously described by Staniforth et al (1981), has been used to study the adhesion profiles of several binary and ternary ordered powder mixes of pharmaceutical interest. The adhesion profile of an ordered mix provides information about the proportion of drug powder adhering with different forces of attraction to the carrier excipient particle surface. The excipient particle size is shown to affect adhesion between the components of a binary ordered mix-recrystallized lactose formed more stable ordered mixes with drug powder when the carrier particle size was increased. Changes in the adhesion profile of each binary system on adding three different fine-powder excipients to form a ternary ordered mix are also examined. The physical properties of carrier particles and the charge interactions of a third powder component with previously formed binary ordered mixes, are found to influence the physical stability of ternary ordered mixes.

Content uniformity of microdose tablets (dosage 1 μg-10 mg) produced by fluid bed granulation of interactive mixtures

Tablets (100 mg), containing microdose quantities of micronized model drug (1 microgram--10 mg), were produced from interactive powder mixtures which had been fluid bed granulated. Granulation prevents adhesion unit and constituent segregation occurring during compression. Single tablet assays were performed on 100 tablets from each batch. The content of tablets fell within +/- 15% of the mean, and the coefficient of variation was less than 5% (99% confidence) for all batches. Skewness in the content distribution showed little evidence of superpotent tablets and indicated the absence of significant agglomerates of particles of the micronized component. However, there was some indication that the mixtures produced were not totally agglomerate free. These results demonstrate that the true potential of interactive mixing may be realized, provided segregation in the mixture can be eliminated. The distribution of micronized model drug, as a function of carrier particle size, was determined for the different concentration mixtures before and after granulation. When 0.1-2% interactive mixtures were sieved gently, the proportions of micronized material adhering to the different size fractions of carrier were similar. However, the very low concentration mixtures (0.001-0.03%) proved to be relatively unstable, a significant proportion of the micronized component being transferred from the mixtures to the metal surfaces of the sieves. Granulation of the mixtures in a fluidized bed produced a uniform distribution of micronized material throughout the different sized granules. These granules were stable during vibration on the sieves and when compressed. All samples of tablets met the United States Pharmacopeia XXI content uniformity requirements.

Influence of size and surface roughness of large lactose carrier particles in dry powder inhaler formulations

The objective of this study was to determine the effect of both carrier particle size and surface roughness on the aerosol performance of dry powder formulations. Two morphologically distinct grades of lactose, anhydrous (AN) and granulated (GR), were fractionated into 11 discreet sizes up to 300 μm, and separately employed as carriers in 2% (w/w) budesonide blends. In vitro deposition studies were performed at 60 L min −1 with an Aerolizer ® DPI. It was found that large carriers can improve dispersion performance, although the effect is more pronounced with greater surface roughness. AN carriers exhibited minimal surface roughness and generally behaved as predicted from the literature, with the smaller carriers outperforming their larger counterparts. In contrast, GR carriers had a high degree of surface roughness, and the dispersion performance of larger carriers exceeded that of the smaller size fractions. Comparing the two lactose grades, AN carriers deposited a greater fraction of the total dose up to the 90–125 μm size range, when they were surpassed in performance by the GR carriers. These results suggest that the mechanism of drug detachment varies with the physical properties of the carrier particle population, where surface roughness can alter the predominant detachment mechanism to favor larger carrier particle diameters.

Influence of carrier particle size, carrier ratio and addition of fine ternary particles on the dry powder inhalation performance of insulin-loaded PLGA microcapsules

The effects of carrier particle size, carrier ratio and addition of fine ternary agents on dry powder inhalation performance of insulin-loaded PLGA microcapsules were investigated. The use of mannitol with larger particle size in the lower carrier/microcapsules ratio led to higher deposition profiles of the drug. The fine spray dried mannitol and spray dried leucine as the ternary agents both decreased the deposition and dispersibility of microcapsules. It was concluded that addition of ternary component does not always improve aerosolization properties of DPI formulations. Carrier particle size, its flowability and carrier–drug ratio were shown to play an important role in DPI formulations.

Chemical-Looping Combustion of Simulated Synthesis Gas Using Nickel Oxide Oxygen Carrier Supported on Bentonite

Chemical-looping combustion (CLC) is a combustion technology for clean and efficient utilization of fossil fuels for energy production. This process which produces sequestration ready CO2 systems is a promising technology to be utilized with coal gasification systems. In the present work, chemical-looping combustion has been studied with an oxygen carrier, NiO/bentonite (60 wt % NiO) for the gasification systems utilizing simulated synthesis gas. Global reaction rates of reduction and oxidation as a function of conversion were calculated for oxidation-reduction cycles utilizing the thermogravimetric analysis (TGA) data on multicycle tests conducted with NiO/bentonite at atmospheric pressure between 700 and 900 °C. The rate of reduction increased slightly with an increase in temperature, while the rate of oxidation decreased at 900 °C. The effect of particle size of the oxygen carrier on CLC was studied for the particle size between 20 and 200 mesh. The rates of reactions depended on the particle size of the oxygen carrier. The smaller the particle size, the higher the reaction rates. The multicycle CLC tests conducted in a high-pressure flow reactor showed stable reactivity for the production of CO2 from fuel gas at 800 and 900 °C and full consumption of hydrogen during the reaction. Themore » data from a one cycle test on the effect of the pressure on the performance with NiO/bentonite utilizing the tapered element oscillating microbalance (TEOM) showed a positive effect of the pressure on the global rates of reduction-oxidation reactions at higher fractional conversions. The X-ray diffraction (XRD) analysis confirmed the presence of the NiO phase in NiO/bentonite with the oxidized sample in the highpressure reactor and Ni phase with the reduced sample. The presence of a small amount of NiO in the reduced sample detected by X-ray photoelectron spectroscopy (XPS) may be due to its exposure to air during sample transfer from the reactor to XPS. Scanning electron microscopy (SEM) analysis showed no significant changes in morphology of NiO/bentonite reacted in the temperature range 700-800 °C in an atmospheric TGA for 10 oxidation-reduction cycles, but some loss of surface area and porosity was observed at 900 °C. This effect was found to be greater with increase in the particle size of the oxygen carrier.« less

Development and characterisation of interactive mixtures with a fine-particulate mucoadhesive carrier for nasal drug delivery

The aim of this study was to investigate whether mucoadhesive interactive mixtures can be created using carrier particles in a size range appropriate for nasal administration, i.e. 10–50 μm. We also used theoretical models to investigate if homogeneity measurements can be used to evaluate the formation of interactive mixtures containing carrier particles in this size range. Sodium starch glycolate (SSG) was used as carrier material and sodium salicylate (SS) as the model fine-particulate drug. The size ranges of SSG particles and amounts of SS were varied to find the smallest carrier particle size and highest amount of drug that still resulted in an interactive mixture. Visual inspection of the mixtures by scanning electron microscopy showed that interactive mixtures could be formed with carrier particles as small as 30 μm and containing up to 4% (w/w) of SS. Comparisons with theoretical models highlighted the difficulties of using homogeneity measurements to determine if interactive mixtures were formed. The measured coefficients of variation (CV) for the amount of drug in the samples were low and inferior mixtures were associated with only a slight increase. It was thus concluded that mucoadhesive interactive mixtures can be created in an appropriate size range for nasal administration, but that visual inspection of these mixtures is initially necessary to confirm the formation of an interactive mixture.

Ferromagnetic seeding for the magnetic targeting of drugs and radiation in capillary beds

A new implant assisted-magnetic drug targeting approach is introduced and theoretically analyzed to demonstrate its feasibility. This approach uses ferromagnetic particles as seeds for collecting magnetic drug carrier particles at the desired site in the body, such as in a capillary bed near a tumor. Based on the capture cross section ( λ c) approach, a parametric study was carried out using a 2-D mathematical model to reveal the effects of the magnetic field strength ( μ 0 H 0=0.01–1.0 T), magnetic drug carrier particle radius ( R p=20–500 nm), magnetic drug carrier particle ferromagnetic material content ( x fm,p=20–80 wt%), average blood velocity ( u B=0.05–1.0 cm/s), seed radius ( R s=100–2000 nm), number of seeds ( N s=1–8), seed separation ( h=0–8 R s), and magnetic drug carrier particle and seed ferromagnetic material saturation magnetizations (iron, SS 409, magnetite, and SS 304) on the performance of the system. Increasing the magnetic field strength, magnetic drug carrier particle size, seed size, magnetic drug carrier particle ferromagnetic material content, or magnetic drug carrier particle or seed saturation magnetization, all positively and significantly affected λ c, while increasing the average blood velocity adversely affected it. Increasing the number of seeds or decreasing the seed separation, with both causing less significant increases in λ c, verified that cooperative magnetic effects exist between the seeds that enhance the performance. Overall, these theoretical results were encouraging as they showed the viability of this minimally invasive, implant assisted-magnetic drug targeting approach for targeting drugs or radiation in capillary beds.

The Effect of Varying the Particle Size of Beta Tricalcium Phosphate Carrier of Recombinant Human Bone Morphogenetic Protein‐4 on Bone Formation in Rat Calvarial Defects

Beta tricalcium phosphate (beta-TCP) has been developed as one of the carriers of recombinant human bone morphogenetic protein (rhBMP). However, it is not known whether the particle size of beta-TCP is related to its resorption rate and the degree of bone formation. The purpose of this study was to evaluate the effect of using beta-TCP with different particle sizes on the ability of rhBMP-4 to enhance bone formation in the rat calvarial defect model. Calvarial, 8-mm-diameter, critical-size defects were created in 100 male Sprague-Dawley rats. Five groups of 20 animals each received either rhBMP-4 (2.5 microg) using beta-TCP with a particle size of 50 to 150 microm, rhBMP-4 (2.5 microg) using beta-TCP with a particle size of 150 to 500 microm, a beta-TCP control with a particle size of 50 to 150 microm, a beta-TCP control with a particle size of 150 to 500 microm, or a sham-surgery control, respectively, and were evaluated by measuring their histologic and histometric parameters following a 2- and 8-week healing interval. There were no significant differences in the defect closure, new bone area, or augmented area between either the two rhBMP-4/beta-TCP groups or between the two beta-TCP control groups at 2 and 8 weeks. rhBMP-4 combined with either small- or large-particle beta-TCP had a significant effect on the induction of bone formation compared to either a small- or large-particle beta-TCP control or a sham-surgery control. Within the parameters of this study, varying the particle size of beta-TCP did not seem to have a significant effect on bone formation.

Formulation and cytotoxicity of doxorubicin nanoparticles carried by dry powder aerosol particles

Regional drug delivery via dry powder inhalers offers many advantages in the management of pharmaceutical compounds for the prevention and treatment of respiratory diseases. In the present study, doxorubicin (DOX)-loaded nanoparticles were incorporated as colloidal drug delivery system into inhalable carrier particles using a spray-freeze-drying technique. The cytotoxic effects of free DOX, carrier particles containing blank nanoparticles or DOX-loaded nanoparticles on H460 and A549 lung cancer cells were assessed using a colorimetric XTT cell viability assay. The mean geometric carrier particle size of 10 ± 4 μm was determined using confocal laser scanning microscopy. DOX-loaded nanoparticles had a particle size of 173 ± 43 nm after re-dissolving of the carrier particles. Compared to H460 cells, A549 cells showed less sensitivity to the treatment with free DOX. The DOX-nanoparticles showed in both cell lines a higher cytotoxicity at the highest tested concentration compared to the blank nanoparticles and the free DOX. The cell uptake of free DOX and DOX delivered by nanoparticles was confirmed using confocal laser scanning microscopy. This study supports the approach of lung cancer treatment using nanoparticles in dry powder aerosol form.

Fractal and percolation properties of active layer structure at oxygen electrode based on nanocomposite material of dispersed carbon carrier/laccase

The properties of the oxygen electrode active layer with laccase immobilized on highly dispersed colloid graphite (HCG) or carbon black AD 100 are studied. It was assumed that such a composite material provides the optimum conditions for bioelectrocatalytic oxygen reduction and allows enhancing the measured current values referred to the electrode geometric surface. These expectations were not wholly justified: the employment of HCG as a carrier allowed enhancing the specific activity per laccase molecule up to 29.8 μA/pmol of the enzyme, which is five times higher than the specific activity of laccase applied to AD 100 (5.9 μA/pmol of the enzyme); however no success was achieved in forming the active layers of any considerable thickness both in the first and in the second case, as the activity decreased drastically at the increase of the layer thickness. The nature of these problems can be caused by a number of reasons: the physico–chemical and structural characteristics of the carbon materials determining, in their turn, the adsorption value and the orientation of the enzyme molecules towards the carrier and the regularities of the active layer structure consisting of the fractal clusters of carbon particles. With the help of computer modeling, the fractal and percolation properties of the active layer structure are studied. The models of the active layer structure are suggested, in which carbon particles form agglomerates of fractal cluster type. This allows to suggest a number of considerations that can help to explain the fractal and percolation effects and the effect of the carbon carrier particle size on the immobilized enzyme coverage.

Process characteristics and compaction of spray-dried emulsions containing a drug dissolved in lipid

The objective of the present study is to prepare directly compressible powders, containing a poorly water-soluble drug dissolved in medium-chain triglycerides (MCT), by spray drying o/w-emulsions in a pilot plant spray dryer. In addition to the lipid phase, the emulsions contained a water-soluble carrier (a sugar), a water-insoluble carrier (magnesium alumino metasilicate) and a combined emulsifier and film-forming agent (gelatine). A factorial design was used to investigate the effect of formulation variables on the spray drying process and powder properties. The factors varied were soluble carrier type (trehalose or mannitol), insoluble carrier particle size distribution (granular or fine powder) and amount of lipid phase in the emulsion (low or high). Compressibility and compactibility of the spray-dried emulsions were mainly affected by the content of lipid in the powders and decreased on increasing the amount of lipid. Increasing the particle size of the insoluble carrier decreased spray drying process yield and lipid encapsulation efficiency whereas compactibility and handling properties were improved. Incorporation of a soluble carrier becoming amorphous on spray drying resulted in tablets with an increased mechanical strength compared to powders containing a crystalline soluble carrier.

Effect of carrier size on the dispersion of salmeterol xinafoate from interactive mixtures

The objective of this study was to determine the influence of lactose carrier size on drug dispersion of salmeterol xinafoate (SX) from interactive mixtures. SX dispersion was measured by using the fine particle fractions determined by a twin stage impinger attached to a Rotahaler®. The particle size of the lactose carrier in the SX interactive mixtures was varied using a range of commercial inhalation-grade lactoses. In addition, differing size fractions of individual lactose samples were achieved by dry sieving. The dispersion of SX appeared to increase as the particle size of the lactose carrier decreased for the mixtures prepared from different particle size commercial samples of lactose and from different sieve fractions of the same lactose. Fine particles of lactose (<5μm) associated with the lactose carrier were removed from the carrier surface by a wet decantation process to produce lactose samples with low but similar concentrations of fine lactose particles. The fine particle fractions of SX in mixtures prepared with the decanted lactose decreased significantly (analysis of variance, p<0.001) and the degree of dispersion became independent of the volume mean diameter of the carriers (analysis of variance, p<0.05). The dispersion behavior is therefore associated with the presence of fine adhered particles associated with the carriers and the inherent size of the carrier itself has little influence on dispersion.

Binderless granulation of pharmaceutical fine powders with coarse lactose for dry powder inhalation

With the Pressure Swing Granulation (PSG), a fluidized bed binderless granulation method, jet-milled fine model drug powders of roughly 2 μm in diameter were mixed with lactose and successfully agglomerated into spherical soft granules to demonstrate that PSG is an effective granulation method for dry powder inhalation. The effects of both lactose particle size, which is supposed to be of either carriers or excipients for inhalants, and granule formulations on the product properties and their dispersion characteristics were investigated. To strengthen the granule-forming tendency without decreasing the carrier particle size, lactose particles' surface morphology was modified before granulation in a ball-milling pot with balls having their lowest milling size larger than the lactose particle size. By this modification, lactose particles of about 8.8 μm in mean diameter were successfully agglomerated without binders over the full range of mixing ratio with the model drug particles. An excellent dispersion property for inhalation was obtained with the PSG granules produced from the surface modified lactose and the PSG method is expected to add a new freedom in producing dry powder for inhalation.

Lactose as a carrier in dry powder formulations: The influence of surface characteristics on drug delivery

The aim of the study was to investigate the interdependence of carrier particle size, surface treatment of the carrier, and inclusion of fines on the drug delivery from dry power inhaler formulations. Two size fractions (< 63 and 63–90 μm) of α‐lactose monohydrate were subjected to treatment with 95% (v/v) ethanol to introduce small asperities or cavities onto the otherwise smooth surface without substantially changing the particle shape. After blending with albuterol sulfate [ALB; volume median diameter (VMD), 1.9 μm; geometric standard deviation (GSD), 1.5], the solvent‐treated lactose produced a fine particle fraction (FPF; < 6.18 μm) and dispersibility of the drug that was significantly (ANOVA p < 0.01) lower than that which resulted from formulations containing untreated lactose of a similar size fraction, after aerosolization at 60 L min−1 via a Rotahaler. The two size fractions of the treated lactose resulted in similar deposition profiles of ALB. The effects of such surface asperities or cavities of lactose were offset by introducing a small amount (5% w/w) of smaller‐sized lactose (5–10 μm) to the powder formulations. The fine lactose increased the FPF and dispersibility of ALB to such a level that all lactose batches, regardless of particle size or whether solvent treated, produced a similar fraction of aerosolized ALB. The inclusion of recrystallized needle lactose (5–15 μm) was superior to micronized lactose in improving the aerosolization of ALB. The findings of this study indicate that the presence and characteristics of the finer fraction of lactose carrier particles dominate over the particle size and surface smoothness of the carrier particles in determining dispersion and deaggregation of drugs from dry powder formulations for inhalation. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1424–1434, 2001

Experimental studies on pyrolysis of Datong coal with solid heat carrier in a fixed bed

An experimental apparatus was set up for batch simulation of coal pyrolysis with solid heat carrier in a fixed bed. Quartz sand as heat carrier preheated to about 700–800°C was mixed with Datong bituminous coal by an agitator. The thermal history of the coal particle has been followed by a K-type thermocouple. The effects of particle size, pyrolysis time and temperature on the gas yield during pyrolysis of coal with solid heat carrier were examined for different conditions. The experimental results showed that a dominant percentage of the gas product is produced during the first 1–3 min, although gas evolution would last for as long as 10 min. The total gas yield, insensitive to particle size of the heat carrier, depends on carrier temperature and coal particle size under tested conditions. The contact heat transfer of cold and hot particles was analyzed.

The formulation of powder inhalation systems containing a high mass of nedocromil sodium trihydrate

Nedocromil sodium trihydrate is not amenable to conventional methods of dry powder inhaler formulation, including the preparation of coarse carrier systems and aggregation of the pure drug powder. It is considered that the in vitro aerosol performance of such systems is governed by the cohesive drug–drug interactions. Therefore, alternative powder formulation strategies (novel to nedocromil sodium) were developed. By decreasing the particle size of the lactose carrier, the deaggregation and subsequent fine particle drug deposition were significantly improved. Further improvements were made by selecting and then optimizing high‐shear mixing procedures. It was concluded, based on these findings and supportive microscopic studies (low‐temperature and environmental scanning electron microscopy together with energy‐dispersive X‐ray analysis), that the FPL are producing their functional effects by intercalating within the drug self‐agglomerates and physically disrupting the cohesive drug–drug interactions. The use of a smaller‐sized lactose fraction in conjunction with a blending procedure capable of optimally disrupting the drug self‐agglomerates allowed maximal intercalation of the excipient material within the drug self‐agglomerates. The adhesive drug–FPL interactions are considered to be weak compared with the cohesive drug–drug particle interactions, cohesive interactions that would normally govern the aerosol performance of powder systems containing a high mass of nedocromil sodium trihydrate. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:213–223, 2001

Direct measurement of pH profiles in immobilized enzyme carriers during kinetically controlled synthesis using CLSM.

Confocal laser scanning microscopy was applied to measure the pH value in the carrier of immobilized enzymes during the enzyme-catalyzed synthesis. pH profiles with a high resolution are shown, with the pH increasing in the core of the particles. Significant differences occur for different carrier material, particle size, porosity and surface modification. The increased pH value is identified as one of the reasons leading to reduced enzyme selectivity in the penicillin amidase catalyzed synthesis of cephalosporins and penicillins.

In vivo bone formation by human bone marrow stromal cells: effect of carrier particle size and shape.

Successful closure of bone defects in patients remains an active area of basic and clinical research. A novel and promising approach is the transplantation of human bone marrow stromal cells (BMSCs), which have been shown to possess a significant osteogenic potential. The extent and quality of bone formation by transplanted human BMSCs strongly depends on the carrier matrix with which cells are transplanted; to date, hydroxyapatite/tricalcium phosphate (HA/TCP) supports far more osteogenesis than any other matrix tested. In order to further improve the technique of BMSC transplantation, we studied whether commercially available HA/TCP particles, clinically approved as an osteoconductive material and commercially available as particles measuring 0.5-1.0 mm diameter, is an optimum matrix for promoting bone development by BMSCs. HA/TCP and HA particles of varying size were sieved into a variety of size ranges, from <0.044 mm to 1.0-2.0 mm. Transplants were formed by mixing 40 mg aliquots of particles with cultured passaged human BMSCs. They were placed in subcutaneous pockets in immunocompromised Bg-Nu-XID mice and harvested 4 or 10 weeks later. The transplants were examined histologically; the presence of bone within each transplant was evaluated using histomorphometry or blindly scored on a semiquantitative scale. Transplant morphology and the amount of new bone varied in a consistent fashion based on particle size and shape. Transplants incorporating HA/TCP particles of 0.1-0.25 mm size demonstrated the greatest bone formation at both 4 and 10 weeks; larger or smaller particles were associated with less extensive bone formation, while a size of 0.044 mm represented a threshold below which no bone formation could be observed. Flat-sided HA particles measuring 0.1-0.25 mm formed no bone. The differences in bone formation were not attributable to the differences in cell attachment among the groups. Instead, the size and spatial and structural organization of the particles within BMSC transplants appear to determine the extent of bone formation. These findings provide necessary information for the successful clinical application of BMSC transplantation techniques.

Effect of mixing of fine carrier particles on dry powder inhalation property of salbutamol sulfate (SS)

The most commonly used formulations for dry powder inhalations are binary ordered mixes composed of micronized drugs and coarse carriers. An optimal dry powder aerosol formulation should possess an optimal inhalation property and a good flow property. These characteristics are especially important for a multidose dry powder inheler (DPI). In the present study, model powder blend were prepared consisting of synthesized sugar (different particle sized isomalt; IM-PF, IM-FS, IM-F) as a carrier and micronized salbutamol sulfate (SS). These ordered mixtures were aerosolized by the multidose JAGO DPI (SkyePharma AG) and in vitro deposition properties (fine particle fraction, FPF) were evaluated by a twin impinger (TI) at a flow rate of 60 l/min. The separation property between SS and carrier particles was investigated by the centrifuge method and air jet sieve (AJS) method. It was found that FPF decreased with increasing carrier particle size. However, a large carrier particle possesses a good flow property. Therefore, the effect of mixing of fine carrier particles (IM-PF) into the large carrier particles (IM-FS) on dry powder inhalation property was investigated. When the proportion of IM-PF (fine carrier) increase from 0% to 25% of the total carrier powder blend, the FPF also increases from 16.7% to 38.9%. It is concluded that the effect of mixing of fine carrier particles might be a suitable method for improving the dry powder inhalation properties.