Investigation into the effect of varying l-leucine concentration on the product characteristics of spray-dried liposome powders

Objectives Spray-dried formulations offer an attractive delivery system for administration of drug encapsulated into liposomes to the lung, but can suffer from low encapsulation efficiency and poor aerodynamic properties. In this paper the effect of the concentration of the anti-adherent l-leucine was investigated in tandem with the protectants sucrose and trehalose. Methods Two manufacturing methods were compared in terms of their ability to offer small liposomal size, low polydispersity and high encapsulation of the drug indometacin. Key findings Unexpectedly sucrose offered the best protection to the liposomes during the spray drying process, although formulations containing trehalose formed products with the best powder characteristics for pulmonary delivery; high glass transition values, fine powder fraction and yield. It was also found that l-leucine contributed positively to the characteristics of the powders, but that it should be used with care as above the optimum concentration of 0.5% (w/w) the size and polydispersity index increased significantly for both disaccharide formulations. Conclusions The method of liposome preparation had no effect on the stability or encapsulation efficiency of spray-dried powders containing optimal protectant and anti-adherent. Using l-leucine at concentrations higher than the optimum level caused instability in the reconstituted liposomes.     

The effect of water to ethanol feed ratio on physical properties and aerosolization behavior of spray dried cromolyn sodium particles

Cromolyn sodium (CS) was spray dried under constant operation conditions from different water to ethanol feed ratios (50:50-0:100). The spray dried CS samples were characterized for their physicochemical properties including crystallinity, particle size distribution, morphology, density, and water/ethanol content. To determine quantitatively the crystallinity of the powders, an X-ray diffraction (XRD) method was developed using samples with different crystallinity prepared by physical mixing of 100% amorphous and 100% crystalline CS materials. The aerodynamic behavior of the CS samples was determined using an Andersen Cascade Impactor (ACI) with a Spinhaler at an air flow of 60 L/min. Binary mixtures of each spray dried CS powder and Pharmatose 325, a commercial alpha-lactose monohydrate available for DPI formulations, were prepared and in vitro aerosol deposition of the drug from the mixtures was analyzed using ACI to evaluate the effect of carrier on deposition profiles of the spray dried samples. CS spray dried from absolute ethanol exhibited XRD pattern characteristic for crystalline materials and different from patterns of the other samples. The crystallinity of spray dried CS obtained in the presence of water varied from 0% to 28.37%, depending on the ratio of water to ethanol in the feed suspensions. All samples presented different particle size, water/ethanol content, and bulk density values. CS particles spray dried from absolute ethanol presented uniform elongated shape whereas the other samples consisted mainly of particles with irregular shape. Overall, fine particle fraction increased significantly (p < 0.01) with decreasing d50% and water and ethanol content of spray dried CS samples. Significant difference (p < 0.01) in deposition profiles of the drug were observed between corresponding carrier free and carrier blended formulations. The difference in deposition profiles of CS aerosolized from various spray dried samples were described according to the particle size, shape, and water/ethanol contents of the powders. The results of this study indicate that enhanced aerosol performance of CS can be obtained by spray drying of the drug from suspensions containing > or = 87.5% v/v ethanol.     

Microdialysis sampling and the clinical determination of topical dermal bioequivalence

The influence of the deposition pattern and spray characteristics of nasal powder formulations on the insulin bioavailability was investigated in rabbits. The formulations were prepared by freeze drying a dispersion containing a physical mixture of drum dried waxy maize starch (DDWM)/Carbopol^® 974P (90/10, w/w) or a spray-dried mixture of Amioca^® starch/Carbopol^® 974P (25/75, w/w). The deposition in the nasal cavity of rabbits and in a silicone human nose model after actuation of three nasal delivery devices (Monopowder, Pfeiffer and experimental system) was compared and related to the insulin bioavailability. Posterior deposition of the powder formulation in the nasal cavity lowered the insulin bioavailability.

To study the spray pattern, the shape and cross-section of the emitted powder cloud were analysed. It was concluded that the powder bulk density of the formulation influenced the spray pattern. Consequently, powders of different bulk density were prepared by changing the solid fraction of the freeze dried dispersion and by changing the freezing rate during freeze drying. After nasal delivery of these powder formulations no influence of the powder bulk density and of the spray pattern on the insulin bioavailability was observed.     

Spray-dried carrier-free dry powder tobramycin formulations with improved dispersion properties

Tobramycin was spray dried at different temperatures from different water to isopropanol feed ratios (0:100-20:80) in order to obtain dry powder formulations for inhalation. The spray-dried powders were characterized for their physicochemical properties including crystallinity, morphology, density, water content, and particle size distribution using X-ray powder diffraction, scanning electron microscopy, tapped density measurements and laser diffraction. Aerosol performance was studied by dispersing the powders into a Multi-Stage Liquid Impinger with an Aerolizer device. The results indicate that formulations spray dried at temperatures below 200 degrees C exhibited poor powder flow properties and were therefore unlikely to display optimal aerosolization characteristics. Nevertheless, it is interesting to note that the presence of water in the suspensions used for spray-drying markedly enhanced the fine particle fraction, which was about 37% for the raw tobramycin and about 57% for a powder obtained from a suspension containing 2% (v/v) water. Overall, this latter formulation was shown to keep its initial particle size distribution and aerodynamic behaviour for 12 months of storage at 40 degrees C and 75% RH. These new carrier-free formulations provide an attractive alternative for delivering high doses of antibiotics directly to the site of infection while minimising systemic distribution.     

Constant size, variable density aerosol particles by ultrasonic spray freeze drying

This work provides a new understanding of critical process parameters involved in the production of inhalation aerosol particles by ultrasonic spray freeze drying to enable precise control over particle size and aerodynamic properties. A series of highly porous mannitol, lysozyme, and bovine serum albumin (BSA) particles were produced, varying only the solute concentration in the liquid feed, c(s), from 1 to 5 wt%. The particle sizes of mannitol, BSA, and lysozyme powders were independent of solute concentration, and depend only on the drop size produced by atomization. Both mannitol and lysozyme formulations showed a linear relationship between the computed Fine Particle Fraction (FPF) and the square root of c(s), which is proportional to the particle density, ρ, given a constant particle size d(g). The FPF decreased with increasing c(s) from 57.0% to 16.6% for mannitol and 44.5% to 17.2% for lysozyme. Due to cohesion, the BSA powder FPF measured by cascade impaction was less than 10% and independent of c(s). Ultrasonic spray freeze drying enables separate control over particle size, d(g), and aerodynamic size, d(a) which has allowed us to make the first experimental demonstration of the widely accepted rule d(a)=d(g)(ρ/ρ(o))(1/2) with particles of constant d(g), but variable density, ρ (ρ(o) is unit density).     

The impact of drying method and formulation on the physical properties and stability of methionyl human growth hormone in the amorphous solid state

The objective of this work was to investigate the impact of drying method and formulation on the physical stability (aggregation) and selected important physical properties of dried methionyl human growth hormone (Met-hGH) formulations. Solutions of Met-hGH with different stabilizers were dried by different methods (freeze drying, spray drying, and film drying), with and without surfactant. Properties of the dried powders included powder morphology, specific surface area (SSA), protein surface coverage, thermal analysis, and protein secondary structure. Storage stability of Met-hGH in different formulations was also studied at 50 degrees C and at 60 degrees C for 3 months. The dried powders displayed different morphologies, depending mainly on the method of drying and on the presence or absence of surfactant. Film dried powders had the lowest SSA (approximately 0.03 m(2)/g) and the lowest total protein surface accumulation (approximately 0.003%). Surfactant caused a reduction in the SSA of both spray dried and freeze dried powders. Spray dried powders showed greater protein surface coverage and SSA relative to the same formulations dried by other means. Greater in-process perturbations of protein secondary structure were observed with polymer excipients. Formulation impacted physical stability. In general, low molecular weight stabilizers provided better stability. For example, the aggregation rate at 50 degrees C of Met-hGH in a freeze dried trehalose-based formulation was approximately four times smaller than the corresponding Ficoll-70-based formulation. Drying method also influenced physical stability. In general, the film dried preparations studied showed superior stability to preparations dried by other methods, especially those formulations employing low molecular weight stabilizers.     

Aerosolisation of beclomethasone dipropionate using spray dried lactose/polyethylene glycol carriers.

The aim of this study was to characterize the physical properties of spray dried lactose in the presence of different polyethylene glycols (PEG 400, PEG 3000 and PEG 6000) and to evaluate their performance as carriers for dry powder inhaler (DPI) formulations. The efficiency of spray dried lactose/PEG carriers in aerosolisation of beclomethasone dipropionate (BD), a model hydrophobic drug, was compared to Pharmatose 325 M (L325), spray dried lactose alone (SDL), and also a sieved (< 38 microm) fraction of alpha-lactose monohydrate (SL). In vitro deposition analysis was performed using a twin stage liquid impinger at a flow rate of 60 l/min through a Spinhaler. The deposition profiles of the drug from binary formulations composed of BD and spray dried lactose/PEG carriers were also compared to ternary formulations containing large and fine lactose carriers. Differential scanning calorimetry and X-ray diffraction data showed the presence of alpha-anhydrous lactose in spray dried lactose/PEG crystalline powders. Spray drying of lactose in the presence of PEG 400 resulted in the production of a powder (SDL-PEG400) with lower alpha-lactose monohydrate content, and also smaller particle size distribution than those obtained in the presence of PEG 3000 (SDL-PEG3000) or PEG 6000 (SDL-PEG6000). All formulations showed different deposition profiles, except those containing SDL-PEG3000 or SDL-PEG6000 which exhibited similar data. The fine particle fraction of aerosolised BD varied from 6.26 +/- 1.07 (for L325) to 25.87 +/- 5.33 (for SDL-PEG3000). All deposition profiles of BD aerosolised from SDL-PEG3000 were significantly higher (P < 0.01) than those produced by binary and ternary formulations containing L325, a coarse lactose commercially available for DPI formulations. The differences observed in deposition data for various carriers were interpreted according to their physical properties. It was concluded that particle size distribution, morphology and specific surface texture of SDL-PEG3000 and SDL-PEG6000 were important factors influencing their efficiency as small carriers for DPI formulations.     

Characterisation of excipient-free nanoporous microparticles (NPMPs) of bendroflumethiazide.

The purpose of this study was to prepare excipient-free porous microparticles of bendroflumethiazide by spray drying and to characterise the physicochemical properties of the particles produced. Solutions of bendroflumethiazide in ethanol/water, ethanol/water/ammonium carbonate or methanol/water/ammonium carbonate were spray dried using a laboratory spray dryer. Spray dried products were characterised by scanning electron microscopy, X-ray powder diffraction, differential scanning calorimetry, FTIR, laser diffraction particle sizing and density measurement. Nanoporous microparticles (NPMPs) were prepared from the alcoholic solutions containing ammonium carbonate. NPMPs were amorphous in nature, had median particles sizes less than 3mum and densities that were significantly reduced compared to non-porous spray dried bendroflumethiazide powder. The novel process may be used to produce excipient-free amorphous microparticles with desirable physical properties such as amorphous solid state, porosity and low bulk density. This new engineering technology has applications in the design of other therapeutic agents such as those used in pulmonary delivery.     

Effect of Lipidic Excipients on the Particle Properties and Aerosol Performance of High Drug Load Spray Dried Particles for Inhalation

High drug load inhalable particles were prepared by co-spray drying a hydrophobic, crystalline, small molecule drug with various lipid or phospholipid excipients at a 9:1 molar ratio to understand the primary drivers of aerosol performance. The effect of excipient structure on solid-state, surface characteristics, and aerodynamic performance of the co-spray dried particles was studied while keeping the spray drying parameters constant. Spray drying of the drug with lipids produced crystalline drug particles, whereas phospholipids produced partially amorphous drug particles. All of the co-spray dried particles were nearly spherical with a smooth surface, except for the spray dried drug particles without excipients – which showed the presence of rough crystals on the surface. All co-spray dried particles showed surface enrichment of the excipient. The surface enrichment of the phospholipids was higher compared to the lipids. Co-spray dried particles that showed higher surface enrichment of excipients showed improved aerosol performance. In comparing all the excipients studied, distearyolphosphatidylcholine (DSPC) showed maximum enrichment on the particle surface and thereby significantly improved aerosol performance. This study demonstrated that the addition of small amounts of lipid excipients during spray drying can change surface morphology, composition, and cohesion, impacting aerosol performance of drugs.     

Nano spray-dried pyrazinamide-l-leucine dry powders,physical properties and feasibility used as dry powder aerosols

Objective: The aim of this study was to investigate the effect of adding l-leucine and using an ethanolic solvent on the physicochemical properties and aerodynamic behavior of nano spray-dried pyrazinamide (PZA)-l-leucine powders.

Materials and methods: A nano spray dryer was employed to prepare PZA-l-leucine powders. The physicochemical properties were evaluated using a scanning electron microscope (SEM), differential scanning calorimetry and X-ray diffraction. The Andersen cascade impactor was used to evaluate the in vitro aerosolization performance of the sprayed powders.

Results and discussion: The incorporation of l-leucine at 10% improved the percentage fine particle fraction (%FPF) in all ethanolic solvent formulations by up to nearly twofold (20.0–23.4%) compared to the normal spray-dried PZA of (8.8–13.0%). Changes in the particle density and morphology were also observed. The dense solid particles of PZA were completely converted to bulk hollow particles with a thin shell by increasing the l-leucine content up to 50%. Higher ethanol concentration resulted in larger dimensions of the hollow particle but did not directly affect the aerosolization performance. The co-spray dried PZA with 20% l-leucine in a 10% ethanol feed solvent gave the best aerosolization performance (FPF?=?33.0%).

Conclusions: The co-spray dried PZA with a suitable l-leucine content using a nano spray drying technique could be applied to formulate the PZA DPI.     

Particle engineering of materials for oral inhalation by dry powder inhalers. II-Sodium cromoglicate

Sodium cromoglicate is an antiasthmatic and antiallergenic drug used in inhalation therapy and commonly administered by a dry powder inhaler. In the present study we sought to examine the feasibility of producing nanoporous microparticles (NPMPs) of this hydrophilic material by adaptation of a spray drying process previously applied to hydrophobic drugs, and to examine the physicochemical and in vitro deposition properties of the spray dried particles in comparison to a commercial product. The storage stability of successfully prepared NPMPs was assessed under a number of conditions (4°C with dessicant, 25°C at 60% relative humidity and 25°C with dessicant). Spray dried sodium cromoglicate was amorphous in nature. NPMPs of sodium cromoglicate displayed superior aerodynamic properties resulting in improved in vitro drug deposition, as assessed by Andersen Cascade Impactor and twin impinger studies, in comparison to the commercial product, Intal. Deposition studies indicated that porosity and sphericity were important factors in improving deposition properties. The optimum solvent system for NPMP production was water:methanol:n-butyl acetate, as spherical NPMPs spray dried from this solvent system had a higher respirable fraction than non-spherical NPMPs of sodium cromoglicate (spray dried from methanol:n-butyl acetate), non-porous sodium cromoglicate (spray dried from water) and micronised sodium cromoglicate (Intal). While particle morphology was altered by storage at high humidity (60% RH) and in vitro deposition performance deteriorated, it was possible to maintain NPMP morphology and aerosolisation performance by storing the powder with dessicant.     

Optimization of Particle Properties of Nanocrystalline Solid Dispersion Based Dry Powder for Inhalation of Voriconazole

A one-step spray drying based process was employed to generate ready-to-use nanocrystalline solid dispersion (NCSD) dry powder for inhalation (DPI) of voriconazole (VRC). The solid dispersion was prepared by spray drying VRC, MAN (mannitol) and soya lecithin (LEC) from mixture of methanol-water. Various formulation and process related parameters were screened, including LEC, inlet temperature, total solid content and feed flow rate to generate particles of geometric size ≤5 µm. Aerosil® 200 was explored as the quaternary excipient either during spray drying or by physically mixing with the optimized ternary NCSD. The powders were extensively characterized for solid form, primary particle size, assay, embedded nanocrystal size, morphology, porosity, density and moisture content. Aerodynamic properties were studied using next generation impactor (NGI), while surface elemental composition and topography were investigated using SEM-EDS (scanning electron microscopy- energy dispersive spectroscopy) and AFM (atomic force microscopy), respectively. At selected inlet temperature of 120 ?C, total solid content and feed flow rate significantly impacted the size of primary NCSD particles. Size of primary particles increased with increase in total solid content and feed flow rate of the solution. VRC nanocrystals were obtained in polymorphic Form B whereas the matrix of MAN consisted of mixture of polymorphic Forms α, β and δ. SEM-EDS analysis confirmed deposition of Aerosil® 200 on surface of spray dried particles. In addition to increased porosity and reduced density, increase in surface roughness of particles (evident from AFM topographic analysis) contributed to enhanced powder deposition at stages 3 and 4 in NGI. In comparison, physical blending of NCSD with Aerosil® 200 showed improvement in aerosolization due to flow enhancement property.     

Physicochemical properties of amorphous clarithromycin obtained by grinding and spray drying

In order to characterize the amorphous clarithromycin (CAM) obtained by grinding and spray drying, physicochemical properties (crystallinity, thermal behavior, stability and solubility parameters) were evaluated. From powder X-ray diffraction, it was estimated that the crystalline state of CAM was changed into an amorphous state by grinding and spray drying. In differential scanning calorimetry measurements, both broad and sharp peaks for crystallization were observed in ground samples, whereas spray dried samples showed one broad peak due to crystallization. As to the stability test under high humidity, structural difference was confirmed between ground CAMs and spray dried CAM. The heat of dissolution of ground CAMs was greater than that of intact CAM. In the solubility parameter measurement, the increase of the special term, δ_s, indicated that the energy change was due to the polarity of the surface energy of the powder particles by grinding.     

Droplet and particle size relationship and shell thickness of inhalable lactose particles during spray drying

To find means of controlling the size and density of particles intended for inhalation the relationship between droplet and particle size during spray drying was investigated. Lactose solutions were atomized with a two-fluid nozzle and dried in a laboratory spray drier. The effects of nozzle orifice diameter, atomization airflow and feed concentration on droplet and particle size were examined. Mass median diameter of both droplets and particles were analyzed with laser diffraction. In addition, scanning electron microscopy and transmission electron microscopy were used for studies of particle shape and morphology. It was demonstrated that nozzle orifice diameter and airflow, but not feed concentration controlled the droplet size during atomization. Increasing droplet size increased particle size but the effect was also influenced by feed concentration. Particles from solutions of a low concentration (1% w/w) were smaller than those from higher concentrations (5-20% w/w). This may be partly explained by lower yields at higher feed concentrations, but may also be related to differences in drying rate. Spray-dried lactose solutions formed hollow particles, and it was suggested that the shell thickness of the particles increased with increasing feed concentration.     

Freeze-Dried Mannitol for Superior Pulmonary Drug Delivery via Dry Powder Inhaler

Purpose

To show for the first time the superior dry powder inhaler (DPI) performance of freeze dried mannitol in comparison to spray dried mannitol and commercial mannitol.

Methods

Different mannitol powders were sieved to collect 63–90 μm particles and then analyzed in terms of size, shape, surface morphology, solid state, density, flowability. Salbutamol sulphate-mannitol aerosol formulations were evaluated in terms of homogeneity, SS-mannitol adhesion, and in vitro aerosolization performance.

Results

Freeze dried mannitol demonstrated superior DPI performance with a fine particle fraction believed to be highest so far reported in literature for salbutamol sulphate under similar protocols (FPF?=?46.9%). To lesser extent, spray dried mannitol produced better aerosolization performance than commercial mannitol. Freeze dried mannitol demonstrated elongated morphology, α-+β-+δ- polymorphic forms, and poor flowability whereas spray dried mannitol demonstrated spherical morphology, α-+β- polymorphic forms, and excellent flowability. Commercial mannitol demonstrated angular morphology, β- polymorphic form, and good flowability. Freeze dried mannitol demonstrated smoother surface than spray dried mannitol which in turn demonstrated smoother surface than commercial mannitol. FPF of SS increased as mannitol powder porosity increase.

Conclusions

Freeze drying under controlled conditions can be used as a potential technique to generate aerodynamically light mannitol particles for superior DPI performance.     

Particle formation and capture during spray drying of inhalable particles

An investigation of the spray drying process is made in great detail regarding particle formation and capture efficiency with focus on the production of inhalable particles. Mannitol was spray dried as model substance and the spray-dried products were characterized. The resulting products consisted of smooth spheres with a volume median diameter of 2.2-5.5 microm, and narrow size distributions. The investigation was performed in pilot scale of sufficient size to draw general conclusions and make some recommendations. It has been shown that the size of particles is decreased when the feed concentration is decreased, the nozzle gas/feed flow mass ratio increased, and the droplet size decreased. The collection efficiency of the cyclone device used in this study was shown to have a cut-off of 2 microm, i.e., 50% of the particles less than 2 microm are not captured. The data reported indicate that the majority of the single particles formed here, <5 microm, arise from single droplets (of about 10 microm) and are solid, nonporous particles.     

Optimization of a spray drying process to prepare dry powder microparticles containing plasmid nanocomplex

Successful gene delivery to the lung depends not only on precise and effective design of a nanosized nucleic acid delivery system but also on well engineered liquid or solid microparticles. In present work, we tried to statistically optimize spray dried formulations of low molecular weight chitosan-plasmid nanocomplexes via a D-optimal design with respect to five critical responses: yield of the process, microparticle sizes, nanocomplex sizes, DNA stability and relative transfection efficiency. Nonocomplex formulations prepared by different amounts of solid contents and leucine ratio, and spray dried immediately with varying inlet temperature, feed rate and spray air flow rate. Mean results fitted to 2FI models except for relative transfection efficiency, which fitted in a quadratic model. According to the fitted models, the most important pure factors influencing each response determined to be feed rate for yield and DNA stability, feed fluid concentration for microparticle size, inlet temperature for nanoparticle size and leucine concentration for relative transfection efficiency. However, two-factor interactions have more important roles in microparticle size, nanocomplex size and DNA stability. It was concluded that the optimized formulation could be obtained when all the independent variables were at their maximum tested values, except for feed fluid concentration, which should be in its middle point.     

Characterization and aerodynamic evaluation of spray dried recombinant human growth hormone using protein stabilizing agents

The effect of the protein stabilizers on the stability and aerosol performance of spray dried recombinant human growth hormone (SD rhGH) was investigated. rhGH solution was spray dried alone, with polysorbate 20 (at three concentrations of 0.05%, 0.01%, and 0.005%), Zn(2+) (by Zn(2+):rhGH molar ratio of 2:1 and 4:1), and/or lactose (by lactose:rhGH weight ratio of 2:1). Size exclusion chromatography (SEC) analysis of spray dried powders demonstrated that of all the potential protein stabilizers, the combination of polysorbate 20 (0.05%), Zn(2+) (Zn(2+):rhGH molar ratio of 2:1) and lactose (lactose:rhGH weight ratio of 2:1) was the most effective at protecting rhGH against aggregation during spray drying. The results of circular dichroism (CD) analysis revealed that using of polysorbate 20 (in all concentrations) and Zn(2+) (by Zn(2+):rhGH molar ratio of 2:1) together in the formulations would preserve rhGH conformational stability during the process. The particle size distribution data obtained by laser diffraction method showed all SD rhGH formulations had volume median diameter and mean diameter below 5mum. The characterization of the aerosol performance of the spray dried powders by Andersen cascade impactor (ACI) showed that by increasing the concentration of polysorbate 20 in the formulations the aerodynamic efficiency of the resultant particles was reduced. In conclusion, the optimum amounts of polysorbate 20, Zn(2+) and lactose satisfied both physical stability during spray drying process (2.37% aggregation) and good aerosol performance (fine particle fraction; FPF=38.52%).     

Lactose modifications enhance its drug performance in the novel multiple dose Taifun DPI

Drug–carrier particle interactions greatly affect the detachment of drug from the carrier in inhalation powders. In this study, a novel multiple dose, reservoir-based Taifun^® was used as a dry powder inhaler, and the effects of carrier physical properties were evaluated on the pulmonary deposition of budesonide, along with physical stability of the inhalation powder. In this study, untreated commercial preparation of -lactose monohydrate, highly amorphous spray dried lactose, crystallized spray dried lactose, Flowlac-100^® and Flowlac-100^® mixed with crystalline micronized lactose were used as carriers. Dry powder formulations were prepared by the suspension method, where the budesonide–carrier ratio was 1:15.1 (w/w). Carriers and formulations were initially characterized, and again after 1 month’s storage at 40 °C/75% RH. The physical properties of the carriers strongly affected the pulmonary deposition of budesonide and the physical stability of the inhalation powder. Initially, amorphous contents of the carriers were 0–64%, but spontaneous crystallisation of the amorphous lactose occurred during storage and, thus all carriers were 100% crystalline after storage. When compared to an untreated -lactose monohydrate, the highly amorphous spray dried lactose and Flowlac-100^® did not improve aerosol performance of the inhalation powder. When crystalline spray dried lactose was used as a carrier, the highest RF% values were achieved, and RF % values did not alter during storage but the emitted budesonide dose was lower than the theoretical dose. When Flowlac-100^® mixed with crystalline micronized lactose was used as a carrier, the emitted budesonide dose was close to the theoretical dose, and high RF % values were achieved but these changed during storage.     

Spray drying of budesonide, formoterol fumarate and their composites-II. Statistical factorial design and in vitro deposition properties

The aim of this study was to investigate the effect of changing spray drying parameters on the production of a budesonide/formoterol fumarate 100:6 (w/w) composite. The systems were spray dried as solutions from 95% ethanol/5% water (v/v) using a Büchi 191-Mini Spray Dryer. A 2(5-1) factorial design study was undertaken to assess the consequence of altering spray drying processing variables on particle characteristics. The processing parameters that were studied were inlet temperature, spray drier airflow rate, pump rate, aspirator setting and feed concentration. Each batch of the resulting powder was characterised in terms of thermal and micromeritic properties as well as an in vitro deposition by twin impinger analysis. Overall, the parameter that had the greatest influence on each response investigated was production yield - airflow (higher airflow giving greater yields), median particle size - airflow (higher airflow giving smaller particle sizes) and Carr's compressibility index - feed concentration (lower feed concentration giving smaller Carr's indices). A six- to seven-fold difference in respirable fraction can be observed by changing the spray drying process parameters. The co-spray dried composite system which displayed best in vitro deposition characteristics, showed a 2.6-fold increase in respirable fraction in the twin impinger experiments and better dose uniformity compared with the physical mix of micronised powders.