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ABSTRACT: The sublimation kinetics of amino acid l-leucine is studied with the isothermal thermogravimetric (TG) analysis at temperatures between 400.7 and 517.5 K. Sublimation of l-leucine follows zero order kinetics. l-leucine begins to sublime around 423.2 K and sublimation rate increases exponentially with increasing temperature. The vapour pressure of l-leucine is determined based on the mass loss rate showing a good correlation with literature values. Using the Arrhenius equation, the activation energy and pre-exponential factor are determined. The sublimation enthalpy and entropy are obtained using the Clausius–Clapeyron equation.
Thermochimica Acta 01/2009; 482:17-20. · 1.80 Impact Factor
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ABSTRACT: Combined gas phase synthesis and coating of sodium chloride (NaCl) and lactose nanoparticles has been developed using an aerosol
flow reactor. Nano-sized core particles were produced by the droplet-to-particle method and coated insitu by the physical
vapour deposition of L-leucine vapour. The saturation of L-leucine in the reactor determined the resulting particle size and
size distribution. In general, particle size increased with the addition of L-leucine and notable narrowing of the core particle
size distribution was observed. In addition, homogeneous nucleation of the vapour, i.e. formation of pure L-leucine particles,
was observed depending on the saturation conditions of L-leucine as well as the core particle characteristics. The effects
of core particle properties, i.e. size and solid-state characteristics, on the coating process were studied by comparing the
results for coated NaCl and lactose particles. During deposition, L-leucine formed a uniform coating on the surface of the
core particles. The coating stabilised the nanoparticles and prevented the sintering of particles during storage.
Journal of Nanoparticle Research 11/2008; 10:121-130. · 3.29 Impact Factor
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ABSTRACT: Aerosolization behavior of carrier-free l-leucine coated salbutamol sulphate inhalable powders has been studied. L-Leucine coatings were formed by physical vapour deposition (PVD) on the surface of the spherical particles in the gas phase. While depositing L-leucine formed pointy crystalline asperities whose size and density increased with the increased content of L-leucine in the gas phase. The asperity size changed from few nanometers to hundreds of nanometers. Due to the rough surface, all these coated fine powders were well-flowable and could be fed without the aid of coarser carriers. The aerosolization characteristics of the powders were studied with 'Inhalation Simulator' under ascending and fast inhalation profiles. When detected on-line by infrared light attenuation, the emission of the coated powders from an inhaler (Easyhaler) was distinctively dependent on the inhalation flow rate less than 30 l/min whereas that of micronized salbutamol sulphate powder solely depended on the studied inhalation flow rate range up to 100 l/min. Gravimetric measurements showed that emitted doses (ED) and fine particle fractions (FPF) of the coated powders were 5.1-7.1 mg/dose and 42-47%, respectively, which were 3-4 times higher than those of the micronized powder. The ED and FPF of the coated powders decreased as the surface roughness increased which is hypothesized as mechanical interlocking between the surface asperities.
International Journal of Pharmaceutics 09/2008; 365(1-2):18-25. · 3.35 Impact Factor
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ABSTRACT: Salbutamol sulphate nanoparticles have been simultaneously prepared and coated with L-leucine in the gas phase. Three different ways of coating can be separated based on the operation temperatures used in an aerosol flow reactor. Below the temperature of L-leucine sublimation, formation of the L-leucine layer on the core particle surface takes place via diffusion of L-leucine molecules on the droplet surfaces during droplet drying. At intermediate temperatures, the extent of sublimation of L-leucine depends notably on the concentration, and thus partial evaporation was expected. The L-leucine coating was solely formed via vapor deposition at high reactor temperatures when complete sublimation of L-leucine was obtained. The geometric mean diameter of the core salbutamol particles was approximately 65 nm. In general, particle size increased with the addition of L-leucine. The size distribution remained the same or broadened when the coating layer of the particles was formed via surface diffusion whereas notable narrowing of the distribution was observed when the coating was formed via vapor deposition. Upon desublimation and heterogeneous nucleation on the surfaces of smooth, spherical core particles, L-leucine formed a discontinuous coating with leafy crystals a few nanometers in size.
International Journal of Pharmaceutics 07/2008; 358(1-2):256-62. · 3.35 Impact Factor
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ABSTRACT: The crystallization and structural integrity of micron-sized inhalable salbutamol sulphate particles coated with L-leucine by different methods are investigated at different humidities. The influence of the L-leucine coating on the crystallization of salbutamol sulphate beneath the coating layer is explored.
The coated particles are prepared by an aerosol flow reactor method, the formation of the L-leucine coating being controlled by the saturation conditions of the L-leucine. The coating is formed by solute diffusion within a droplet and/or by vapour deposition of L-leucine. The powders are humidified at 0%, 44%, 65% and 75% of relative humidity and the changes in physical properties of the powders are investigated with dynamic vapour sorption analysis (DVS), a differential scanning calorimeter (DSC), and a scanning electron microscope (SEM).
Visual observation show that all the coated particles preserve their structural integrity whereas uncoated salbutamol sulphate particles are unstable at 65% of relative humidity. The coating layer formed by diffusion performs best in terms of its physical stability against moisture and moisture-induced crystallization. The degree of crystallization of salbutamol in the as-prepared powders is within the range 24-35%. The maximum degree of crystallization after drying ranges from 55 to 73% when the salbutamol crystallizes with the aid of moisture. In addition to providing protection against moisture, the L-leucine coating also stabilizes the particle structure against heat at temperatures up to 250 degrees C.
In order to preserve good flowability together with good physical stability, the best coating would contain two L-leucine layers, the inner layer being formed by diffusion (physical stability) and the outer layer by vapour deposition (flowability).
Pharmaceutical Research 07/2008; 25(10):2250-61. · 4.09 Impact Factor
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ABSTRACT: A novel aerosol flow reactor method for the combined gas phase synthesis and coating of particles for drug delivery has been developed.
As an example, micron-sized salbutamol sulfate particles were produced via droplet-to-particle conversion and in-situ coated by the physical vapor deposition (PVD) of L-leucine vapor.
During the deposition, L-leucine vapor crystallized on the surfaces of amorphous salbutamol particles. The size of L-leucine crystallites increased with increasing vapor concentration of L-leucine. The salbutamol particles with rough L-leucine surfaces exhibited good flowability enabling to them to be dispersed into air flow without the delivery aid of coarse lactose carriers.
The fraction of particles smaller than 5 micrometers varied between 0.35 and 0.48 when dispersed into 60 l/min air flow having a jet Reynolds number of 30700. When the coated fine particles were blended with lactose carriers, the fine particle fraction was as high as 90%. The L-leucine coating also improved the stability of salbutamol particles when stored at 45% relative humidity atmosphere.
Pharmaceutical Research 02/2008; 25(1):242-5. · 4.09 Impact Factor
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ABSTRACT: Coating of micrometer-sized particles of salbutamol sulphate or sodium chloride with the amino acid L-leucine in the gas phase is described. A novel method to synthesize core particles and coat them with L-leucine simultaneously was carried out in an aerosol flow reactor. The coating was prepared via temperature-induced heterogeneous nucleation of L-leucine vapor on the 0.6–1.0 µm core particles, and subsequent growth of L-leucine crystals by physical vapor deposition. The core salbutamol particles were amorphous, whereas the NaCl core particles were crystalline. The L-leucine sublimation that took place at 140–195 °C depended on the identity of the core material due to (i) molecular interaction and (ii) phase mixing. The former was dominant with salbutamol/L-leucine particles and the latter was dominant with NaCl/L-leucine particles. During the vapor deposition, L-leucine formed a discontinuous coating layer of leafy-looking crystallites, with sizes from a few nanometers to hundreds of nanometers, pointing out from the core particle surface. The L-leucine deposition properties depended on the core morphology: L-leucine crystallites were distributed more evenly on salbutamol core surfaces than on salt core surfaces, where the crystallites were localized mainly on edges. The stability of coated salbutamol particles was retained during storage under humid conditions.
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ABSTRACT: Preparation of L-leucine nanoparticles by a process based on physical vapor deposition has been presented. In an aerosol flow reactor method, aqueous L-leucine droplets were first dried followed by the sublimation of L-leucine to produce vapor that upon vapor deposition resulted in L-leucine nanoparticles with size ranging from 40 to 200 nm. Onset temperature for the sublimation of L-leucine at concentrations from 0.02 to increased from 135 to , respectively. The formation of nanoparticles was initiated in three different ways: (i) via droplet drying, (ii) via heterogeneous nucleation of L-leucine vapor on solid L-leucine particles, and (iii) via homogeneous nucleation of L-leucine vapor to form new-born nanoparticles. Consequently, the saturation conditions of L-leucine vapor in the reactor determined the resulting particle size, size distribution and number concentration, those depending very much on nucleation mode. In general, the both nucleation modes produced narrow size distributions, that is, geometric standard deviation (GSD) was <1.8 although the number concentration increased with the increased amount of L-leucine vapor. Upon desublimation and vapor deposition, L-leucine formed leafy crystals whose size was the largest when produced from the heated section at the vicinity of the onset temperature and the smallest far above the onset temperature. All the particles prepared in the conditions (i)–(iii) were crystalline. However, X-ray diffraction analysis showed preferential direction for crystal growth according to the way of particle formation.
Journal of Aerosol Science.
