Solubility prediction of salicylic acid in water-ethanol-propylene glycol mixtures using the Jouyban-Acree model.

To show the applicability of a solution model, i.e. the Jouyban-Acree model, for predicting the solubility of a solute in ternary solvent systems based on model constants computed using solubility data of the solute in binary solvent systems, the solubility of salicylic acid in water-ethanol, water-propylene glycol, ethanol-propylene glycol mixtures was determined. A minimum number of three data points from each binary system was used to calculate the binary interaction parameters of the model. Then the solubility in other binary solvent compositions and also in a number of ternary solvents was predicted, and the mean percentage deviation (MPD) was calculated as an accuracy criterion. The overall MPD (+/-SD) was 7.3 (+/-7.3)% and those of a similar predictive model was 15.7 (+/-11.5)%. The mean difference between the proposed and a previous model was statistically significant (paired t-test, p < 0.004).

Use of solid corrugated particles to enhance powder aerosol performance.

PURPOSE: To study the dispersion performance of non-porous corrugated particles, with a focus on the effect of particle surface morphology on aerosolization of bovine serum albumin (BSA) powders. METHODS: The solid-state characteristics of the spray-dried BSA powders, one consisting of smooth spherical particles and another corrugated particles, were characterized by laser diffraction, X-ray powder diffraction, scanning electron microscopy, confocal microscopy, thermogravimetric analysis, surface area analyzer, and buoyancy method. The powders were dispersed using the Rotahaler and the Dinkihaler coupled to a four-stage liquid impinger operating at 30 to 120 L/min. Fine particle fraction (FPF) was expressed as the wt. % of BSA particles of size < or =5 microm collected from the liquid impinger. RESULTS: Apart from the morphology and morphology-related properties (specific surface area, envelope density), the corrugated particles and spherical particles of BSA had very similar solid-state characteristics (particle size distribution, water content, true density, amorphous nature). Using the Dinkihaler, the FPFs of the corrugated particles were 10-20 wt. % higher than those of the smooth particles. Similar FPF differences were found for the powders dispersed by the Rotahaler, but the relative changes were larger. In addition, the differences were inversely proportional to the air flows (17.3% at 30 L/min, 25.2% at 60 L/min, 13.8% at 90, 8.5% at 120 L/min). Depending on the inhaler, capsule and device retention and impaction loss at the impinger throat were lower for the corrugated particles. CONCLUSIONS: Enhanced aerosol performance of powders can be obtained by surface modification of the particles. The surface asperities of the corrugated particles could lower the true area of contact between the particles, and thus reduce the powder cohesiveness. A distinct advantage of using corrugated particles is that the inhaler choice and air flow become less critical for these particles.

In vitro aerosol performance and dose uniformity between the Foradile Aerolizer and the Oxis Turbuhaler.

Dry powder inhalers for eformoterol fumarate dihydrate, a long-acting beta-2 agonist for bronchodilation, are currently available as the Foradile Aerolizer and the Oxis Turbuhaler. The two products are different in the formulation, the aerosol production mechanism, and the device resistance to air flow. These disparities are likely to lead to different aerosol characteristics. Our objective was to compare the in vitro performance of these two inhalers in producing eformoterol aerosols. Emitted dose uniformity was measured using a sampling apparatus described in the British Pharmacopaeia. Ten individual doses (dose number 2, 3, 15, 16, 30, 31, 45, 46, 59, and 60) of the entire content (60 doses) were collected from the Aerolizer and the Turbuhaler (six inhalers each). Particle size distribution of the aerosols generated by the two inhalers were measured by a multiple stage liquid impinger at four different air flows (30-120 L/min). Eformoterol collected from the sampling devices was measured by HPLC. Fine particles are those of < or = 1.7-5.0 microm in size in the aerosols obtained by interpolation of the data at the specified air flow. The Aerolizer showed a slight dependence of the emitted dose on the air flow, with the average emitted dose increased from 80% (at 30 L/min) to 90% (at higher flows) of the 12-microg label claim as compared with 60% for the Turbuhaler. When the emitted dose was normalized by the average emitted dose value, the Aerolizer showed less variation in the normalized emitted dose uniformity than the Turbuhaler. At high air flows, 90 and 120 L/min, both inhalers produced similar amounts (4 microg) of fine particles in the aerosol per dose discharged. As the flow as decreased to 30 and 60 L/min, both inhalers produced significantly less fine particles (p < 0.05), with the Oxis Turbuhaler producing lesser amounts than the Foradile Aerolizer. However, due to the different device resistance, comparing the inhaler performance at the same inspiratory effort may be more appropriate. At a comfortable effort of 40 cm H2O, the Foradile Aerolizer would produce a significantly higher fine particle mass in the aerosols. We conclude that the two inhalers were dissimilar in the emitted dose uniformity. The fine particle mass of eformoterol produced by the two inhalers was equivalent at high but not at low air flows. The disparities may be due to the difference in the formulation and the aerosol generation mechanism of the inhalers.

Effect of particle size, air flow and inhaler device on the aerosolisation of disodium cromoglycate powders.

Recently, the dispersion of mannitol powders has demonstrated the importance of particle size, air flow and inhaler device (Chew and Chan, 1999). The aim of the present study is to extend our investigation to a different compound, disodium cromoglycate (DSCG) powders. Solid state characteristics of the powders were assessed by particle sizing, scanning electron microscopy, X-ray powder diffraction, moisture content, particle density determination and freeze fracture. The aerosol behaviour of the powders was studied by dispersion using Rotahaler(R) and Dinkihaler(R), connected to a four-stage liquid impinger operating at 30-120 l/min. Three amorphous powders with a mass median diameter (MMD) of 2.3, 3.7, 5.2 microm and a similar polydispersity were prepared. The particles were nearly spherical with a particle density of 1.6 g/cm(3) and moisture content of 6.6 wt.%. Using Rotahaler(R), the maximum fine particle fraction (FPF(max)) for all three powders was only 15 wt.%, attained at the highest flow of 120 l/min. Using Dinkihaler(R), the FPF(max) was two to four times higher, being 36 and 29 wt.% for the 2.3 and 3.7 microm powder, respectively, at 60 l/min; and 18 wt.% for the 5.2 microm powder at 120 l/min. Hence, the study shows that the FPF in the DSCG powder aerosols was determined by the interaction of the particle size, air flow and inhaler design. The attribution of the amorphous nature and the different physico-chemical properties of the powder may explain the incomplete and low dispersibility of DSCG.

The effect of spacers on the delivery of metered dose aerosols of nedocromil sodium and disodium cromoglycate.

The effect of the spacers (Fisonair, Breath-A-Tech, Volumatic and Nebuhaler) on the in vitro aerosol characteristics of two propellant-driven metered dose inhalers (MDIs), Tilade (nedocromil sodium) and Intal (disodium cromoglycate), was studied. The measurement was carried out on a Marple-Miller impactor operating at 30 l/min. Five actuations were collected for the drug assay. The results showed that Tilade (label claim 2 mg active per actuation) and Intal (label claim 5 mg active per actuation) generated aerosols with a fine particle mass (FPM, i.e. mass of particles 5 microm in the aerosol) of 0.34 mg (S.D. 0.01, n = 4) and 0.02 mg (S.D. 0.01, n = 4) per actuation, respectively. For both inhalers, large volume spacers increased (Fisonair > Nebuhaler > Volumatic) while small volume spacer (Breath-A-Tech) decreased the FPM. The FPM (per actuation) for Tilade with Fisonair, Nebuhaler, Volumatic and Breath-A-Tech was 0.52 (0.03), 0.45 (0.03), 0.41 (0.04) and 0.09 (0.04) mg, respectively, while for Intal the corresponding values were 0.41 (0.02), 0.32 (0.04), 0.28 (0.03) and 0.08 (0.01) mg. Thus, the fine particle mass can be either increased or decreased, depending on the spacer selected. In addition, all spacers significantly reduced the coarse particle (> or = 10 microm) mass, with Fisonair, Breath-A-Tech, Nebuhaler and Volumatic producing only 7.6, 0.4, 5.2 and 2.6, respectively of that from Tilade alone and 15.6, 0.7, 5.4 and 4.1%, respectively of that from Intal alone. The general trends for Tilade and Intal were similar but not quantitatively identical. The proper choice of spacers is therefore important for the optimal delivery of Tilade and Intal.

Influence of particle size, air flow, and inhaler device on the dispersion of mannitol powders as aerosols.

PURPOSE: To study the effect of particle size, air flow and inhaler type on the dispersion of spray dried mannitol powders into aerosols. METHODS: Mannitol powders were prepared by spray drying. The solid state properties of the powders were determined by laser diffraction, X-ray powder diffraction, scanning electron microscopy, freeze fracture, Karl Fischer titration and gas pycnometry. The powders were dispersed using Rotahaler and Dinkihalerg, connected to a multistage liquid impinger at different air flows. RESULTS: Three crystalline mannitol powders with primary particle size (MMD) 2.7, 5.0, 7.3 microm and a similar polydispersity were obtained. The particles were spherical with a density of 1.5 g/cm3 and a moisture content of 0.4 wt.%. At an air flow of 30 L/min all the powders were poorly dispersed by both inhalers. With the Rotahaler increasing the flow (60-120 L/min) increased the fine particle fraction (FPF) in the aerosols for the 2.7 microm powder, and decreased the FPF for the 7.3 microm powder; whereas the FPF for 5.0 microm powder was unaffected. With the Dinkihaler, all the powders were near complete dispersion at > or = 60 L/min. CONCLUSIONS: The FPF in the mannitol powder aerosols was determined by an interplay of the particle size, air flow and inhaler design.