We hypothesize that the USP induction port may de-agglomerate carrier-free powder emitting from dry powder inhalers (DPIs).

There has been increasing interests for drug companies to incorporate drug nanoparticles into their existing formulations. However, technical knowledge in this area is still in its infancy and more study needs to be done to stimulate growth in this fledging field. There is a need to scrutinize the performance of pure drug nanoparticles in tablets, particularly relating formulation variables to their dissolution performance. Application of the pure form, synthesized without the use of surfactants or stabilizers, is often preferred to maximize drug loading and also to minimize toxicity. Cefuroxime axetil, a poorly water-soluble cephalosporin antibiotic, was used as the model drug in the formulation development. Drug release rate, tablet disintegration time, tensile strength and energy of failure were predominantly influenced by the amount of super-disintegrant, amount of surfactant, compression force and diluent species, respectively. The compression rate had minimal impact on the responses. The main hurdle confronting the effective use of pure drug nanoparticles in tablets is the difficulty in controlling aggregation in solution, which could potentially be aggravated by the tabletting process. Through the use of elevated levels of surfactants (8 w/w% sodium dodecyl sulphate), drug release from the nanoparticle preparation was enhanced from 58.0 ± 2.7% to 72.3 ± 0.7% in 10 min. Hence, it is recommended that physical formulations for pure drug nanoparticles be focused on the particle de-aggregation step in solution, if much higher rates are to be desired. In conclusion, even though pure drug nanoparticles could be easily synthesized, limitations from aggregation may need to be overcome, before successful application in tablets can be fully realized.

We developed a computational method to predict aerodynamic diameter of particles with corrugated surfaces. The surface corrugation was quantified using a parameter called surface fractal dimension (DS) which ranges from 2 (very smooth) to 3 (very rough). Three different drag coefficient expressions, which include the use of skin factor and/or shape factor to incorporate the effect of surface roughness, were employed in the computational method. We validated our computational method by comparing the aerodynamic diameters to the values measured with a Particle Size Distribution Analyser (PSDA) 3603 (TSI, Shoreview, MN, USA), which measures the time taken for a particle to accelerate between two laser beams to give the aerodynamic diameter. We prepared spherical bovine serum albumin (BSA) particles with DS of 2.06, 2.18, 2.35, and 2.41. For corrugated particles with DS of 2.35 and 2.41, the calculated aerodynamic diameters agreed with the measured values. For smoother particles with DS of 2.18 and 2.06 the maximum differences were 17% and 20%, respectively. Better agreement was reached for particles with more corrugated surfaces because these particles are less cohesive and consequently they are easier to disperse.

The application of nanoparticles in the pharmaceutical industry has particular benefits for poorly water-soluble drugs. The increase in specific surface area that comes with a decrease in particle size offers an enhanced dissolution rate for these valuable drugs. Present methods for elucidating the dissolution rate-change due to size reduction have been inadequate. Furthermore, there have been very little studies on the dissolution kinetic behaviour of drug nanoparticles and their relations to the current dissolution models. When incorporated into tablets, in view of their small size and high aggregation tendency, there have been significant challenges involved in effectively utilizing these particles. Experimental data showed the flow-through cell to be unequivocally the most robust dissolution method for the nanoparticulate system whereby the dissolution profiles conformed most closely to the classic Noyes-Whitney model. This indicated that the increase in dissolution rate of the nanoparticles results from an increase in surface area and solubility. A modified negative-two-thirds-root diffusion model was also shown to be effective in describing the dissolution behaviour of these particles. In tablets, the amount of surfactant was found to be the limiting factor in achieving full dispersion of nanoparticles in solution.

Most pharmaceutical compounds can benefit from being produced with a small particle size to enhance processing or therapeutic performance. Confined liquid impinging jets (CLIJ) were employed in this study to evaluate the feasibility and limitations in the production of nanodrugs (i.e., particle size in the nanorange). Four drugs from different pharmaceutical classes and water solubilities - salbutamol sulfate, mannitol, ibuprofen, and cyclosporine - were examined. Particles of salbutamol sulfate and cyclosporine with diameters of approximately 300 nm were successfully achieved. The use of CLIJ thus shows potential in the production of nanopharmaceuticals for certain compounds.

This paper reviews the concept of filter quality (q(F)) for dust filtration media composed of different structures: metal fiber beds (MFB), fabric filters (BF), and fly ash filters (FAF). Filter quality is a useful index of the filtration performance, which incorporates both pressure drop and filtration efficiency. Major parameters affecting the filter quality are filtration velocity in the range of 0.06-0.19 m/s, dust loading, porosity of the medium in the range of 75-93%, and internal structure of the medium. The experimental observation showed that filter quality decreased with increasing filtration velocity or dust concentration. A unique increase in filter quality during the initial stage of filtration appeared with the FAF as a result of the predominately surface filtration with less pore clogging. Nevertheless, the filter quality cannot be taken as an absolute indicator of filter performance, but rather it should be used just as a reference parameter depending on operating conditions. The results of this work show that fly ash filters are capable of providing more stable performance, particularly during the initial stage of filtration, and thereafter of a certain time filter quality initiates to decline as other filters. (c) 2007 Elsevier B.V. All rights reserved.

Advances in nanomedicine are expected to escalate in the coming years, particularly related to the availability and delivery of optimum dosage. It is crucial that the dissolution behavior of such novel dosage forms be adequately scrutinized to maximize their therapeutic benefits. In this work, the dissolution behavior of irregularly shaped nanoparticles was analyzed using a modified negative-two-thirds-root diffusion model (with shape factor, sigma, incorporated into the equation to describe shape evolution). The model was shown to be effective in describing the transition from peanut-shape nanoparticles (connected by bridges) to discrete spheres during the dissolution process. Due to the eventual aggregation of the discrete spheres in solution, description of the dissolution behavior was limited to the aggregate as a whole. Scanning electron microscopy, diffusion layer thickness calculations, and sonication studies provide information to show that, during dissolution, the bridges dissolve, yielding discrete spheres which then aggregate randomly in solution. Viscosity experiments reveal that the dissolution behavior was predominantly diffusion-controlled. The dissolution behavior of irregularly shaped nanoparticles in solution is described as going from bridged particles to discrete particles, to aggregates, and finally to full dissolution.

PURPOSE:Many existing and new drugs fail to be fully utilized because of their limited bioavailability due to poor solubility in aqueous media. Given the emerging importance of using nanoparticles as a promising way to enhance the dissolution rate of these drugs, a method must be developed to adequately reflect the rate-change due to size reduction. At present, there is little published work examining the suitability of different dissolution apparatus for nanoparticles.METHODS:Four commonly-used methods (the paddle, rotating basket and flow-through cell from the US Pharmacopia, and a dialysis method) were employed to measure the dissolution rates of cefuroxime axetil as a model for nanodrug particles.RESULTS:Experimental rate ratios between the nanoparticles and their unprocessed form were 6.95, 1.57 and 1.00 for the flow-through, basket and paddle apparatus respectively. In comparison, the model-predicted value was 7.97. Dissolution via dialysis was rate-limited by the membrane.CONCLUSIONS:The data showed the flow-through cell to be unequivocally the most robust dissolution method for the nanoparticulate system. Furthermore, the dissolution profiles conform closely to the classic Noyes-Whitney model, indicating that the increase in dissolution rate as particles become smaller results from the increase in surface area and solubility of the nanoparticles.

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.

Two instruments, namely the Aerosizer LD and the Particle Size Distribution Analyser (PSDA) 3603, were used to measure aerodynamic diameters of spray dried bovine serum albumin (BSA) particles with different surface corrugation (DS). The measured aerodynamic diameters were compared with the values calculated using the theoretical model previously developed by our group. The model-calculated aerodynamic diameters have been shown to agree with the measured values for corrugated and less cohesive BSA particles with DS varying between 2.18 and 2.41. For smoother and more cohesive BSA particles with DS of 2.06 the measured and calculated values differed by 27% (compared to the value measured by PSDA 3603) and 115% (compare to the value measured by Aerosizer). This variation resulted from the difficulty to completely disperse the more cohesive particles during measurement. Hence, the model can be used to estimate aerodynamic diameter in situations when direct measurement fails due to unavailability of equipment, limitations or difficulty in dispersing powders into their individual particles in the aerosol.

The aim of this work is to evaluate and optimise aerosol performance of precipitated cyclosporine A (CsA) powders as a model peptide for inhalation drug delivery. Confined liquid impinging jets (CLIJ) was used to precipitate CsA with stabilisers (lecithin and lactose), followed by spray drying to produce dry powders. Minimum concentrations of each stabiliser were determined from a matrix design of nine experimental conditions (i.e. 32 corresponding to 2 additives at 3 concentration levels). Suspensions of CsA particles of 180–700nm were produced by CLIJ precipitation and powders comprising approximately 1μm agglomerates of CsA particles were obtained following spray drying. The internal structure of the agglomerates was not hollow. The aerosol performance of the CLIJ-spray dried powders was initially screened using a dry powder attachment on a laser diffractometer to identify the optimal CLIJ experimental conditions. The optimal aerosol performance was then confirmed using the Aeroliser® dry powder inhaler with a multi-stage liquid impinger operating at 60 and 100L/min. The powder produced from spray drying of the suspension using CLIJ at 1% w/v lactose and 0.025% w/v lecithin showed the best dispersion behaviour and the corresponding aerosol performance shows a fine particle fraction of 54–56%. These results showed the potential of CLIJ precipitation with spray drying in the production of peptides for inhalation.

The growing use of the inhalation route for the delivery of new types of drugs, such as proteins for both local and systemic effects, and the need to manufacture and deliver fine particles to the targeted parts of the respiratory tract have led to more interest in the characterization of not only the size of the aerosol particles, but also their morphology and how they are dispersed by inhaler devices. These devices are most commonly dry powder inhalers. A fractal object, as defined by Mandelbrot, has a dimension greater than the geometric or physical dimension but less than or equal to the embedding dimension in an enclosed space. Characterization of particle surface is important because surface roughness is recognized to affect physicochemical properties of pharmaceutical products and is therefore a crucial factor in the manufacturing process and product performance.

Commercial dry powder dispersers needed in conjunction with particle size measurement equipment are usually quite expensive (of the order of thousands of dollars). We have found that a simple vacuum generator can be used as a cost-effective disperser (US$50). Comparison with other commercial dispersers, small scale powder disperser (SSPD) model 3433 (TSI, Shoreview, USA) and Scirocco dry powder disperser (Malvern, Worcs, UK), showed that our disperser worked as efficiently as these expensive dispersers. Crystalline mannitol (less than 1% moisture content) and amorphous BSA (8.5-9.2% moisture content) smooth spherical particles were used to test the dispersion capability of the unit. Smooth spherical particles were chosen because they are more cohesive than corrugated particles due to increased contact points. Therefore, sufficient dispersions of other less cohesive particles should be able to be achieved using the optimum conditions reported here. The effects of air pressure, sample weight, and nozzle size of the disperser were investigated. Comparison of the particle size distributions between wet and dry measurements were used to determine the dispersion efficiency. Quantitative comparisons were made using the values of D(v,0.5) and span. The best dispersion was found using a 1.00 mm nozzle and the maximum percentage differences in D(v,0.5) and span are 23% and 19%, respectively, with more than 200 mg mannitol powder dispersed with pressures of 50, 70, 90 psi. Using BSA powders, the maximum percentage differences of D(v,0.5) and span are 37% and 25%, respectively. As was the case for the commercial devices, the dispersion of BSA particles could not be improved even when the pressure of the compressed air was increased. (C) 2008 Elsevier B.V. All rights reserved.

This study investigates the effect of air inlet size on (i) the flowfield generated in a dry powder inhaler, and (ii) the device-specific resistance, and the subsequent effect on powder deagglomeration. Computational fluid dynamics (CFD) analysis was used to simulate the flowfield generated in an Aerolizer with different air inlet sizes at 30, 45, and 60 l/min. Dispersion performance of the modified inhalers was measured using mannitol powder and a multistage liquid impinger at the same flow rates. The air inlet size had a varying effect on powder dispersion depending on the flow rate. At low flow rates (30 and 45 l/min), reducing the air inlet size increased the inhaler dispersion performance by increasing the flow turbulence and particle impaction velocities above their critical levels for maximal powder dispersion. At 60 l/min, reducing the air inlet size reduced the inhaler dispersion performance by releasing a large amount of powder from the device before the turbulence levels and particle impaction velocities could be fully developed. The results demonstrate that the maximal inhaler dispersion performance can be predicted if details of the device flowfield are known.

The aims of the study are to analyze the influence of air flow on the overall performance of a dry powder inhaler (Aerolizer®) and to provide an initial quantification of the flow turbulence levels and particle impaction velocities that maximized the inhaler dispersion performance.