Micro/nanonisation du naproxène et du dipropionate de béclométhasone en milieu aqueux par fragmentation laser femtoseconde

RESUME Reduire la taille des particules est une approche simple pouvant ^etre utilisee an d'ameliorer la biodisponibilite, surtout pour les medicaments administres par inhalation et par voie orale. Cependant, les techniques existantes de micro/nanonisation ne sont pas adaptees a la phase de decouverte, ou la quantite d'actif disponible est restreinte. Nous proposons une nouvelle approche, la fragmentation laser, pour micro/nanoniser les medicaments en faible quantit e disponible. Notre hypothese est que le procede laser peut produire des micro/nanocristaux de deux medicaments modeles, le dipropionate de beclomethasone (medicament pulmonaire) et le naproxene (medicament oral), avec des transformations physico-chimiques minimes. La fragmentation laser consiste a focaliser une radiation laser dans une suspension de medicament agitee magnetiquement. Un laser femtoseconde a ete utilise. La taille des particules a ete caracterisee par la diusion de lumiere et par la microscopie electronique a balayage. La degradation a ete evaluee par la chromatographie liquide a haute performance. Les proprietes physico-chimiques des micro/nanocristaux lyophilises ont ete evaluees par la spectrometrie infrarouge, la diraction de rayons X, l'analyse elementaire et la calorimetrie dierentielle. La cinetique de dissolution in vitro des nanoparticules a aussi ete etudiee. Des nanocristaux de naproxene et des microcristaux de dipropionate de beclomethasone (DPB) ont ete produits par fragmentation laser avec succes. Des particules de tailles dierentes variant de 500 nm a quelques microns peuvent ^etre produites en modiant les param etres de fabrication. La nanonisation a ete accompagnee d'une degradation chimique 2 3 fois plus elevee que la micronisation. Apres le traitement laser, la composition chimique est majoritairement conservee (65% 100%), et le changement est d^u a une oxydation possible lors de l'interaction laser-matiere dans l'eau. La phase cristalline a ete conservee, mais une forme amorphe peut appara^tre (possiblement a la surface des particules). La vitesse de dissolution in vitro du naproxene nanonise par laser est amelioree de 10 fois et plus. La fragmentation par laser femtoseconde permet de microniser des medicaments en petite quantite avec une degradation et des transformations physico-chimiques limitees. La nanonisation par laser, bien que possible, induit plus de degradation et de transformations physico-chimiques. La fragmentation laser est donc une technique adaptee pour la micronisation (et dans certains cas la nanonisation) de medicament pendant la phase de decouverte, et est particulierement interessante pour les medicaments pulmonaires peu solubles dans l'eau.----------ABSTRACT Reducing the particle size of drugs is a simple approach that may be used to improve their bioavailability, especially for compounds delivered by inhalation and orally. However, current micro/nanonization techniques are not well adapted to the drug discovery stage, where the availability of the actives is scarce. We propose a novel approach, laser fragmentation, to perform micro/nanonization of drugs using small quantities. Our hypothesis is that the laser process can produce micro/nanocrystals of two drug models, beclomethasone dipropionate (BDP) (pulmonary drug) and naproxen (oral drug), with minimal physico-chemical transformations. Laser fragmentation consists in focusing a laser radiation into a magnetically agitated drug suspension. In this study, a femtosecond laser was used. The drugs particle size was characterized by dynamic light scattering and scanning electron microscopy. The degradation was evaluated by high performance liquid chromatography. The physicochemical properties of the lyophilized micro/nanocrystals were evaluated by Fourier transform infrared spectroscopy, x-ray diraction, elemental analysis and dierential scanning calorimetry. The in vitro dissolution kinetics of nanoparticles was also studied. Nanocrystals of naproxen and microcrystals of BDP were successfully produced by laser fragmentation. Particles of dierent sizes (from 500 nm to several micrometers) could be obtained by adjusting the process parameters. Nanonization was accompanied by 2 3 times more chemical degradation than micronization. After the laser process, the chemical composition was mainly conserved (65% 100%), and the change may be attributed to a moderate oxidation occured during laser-drug interaction in water. Drug crystallinity was maintained, but an amorphous form may appear (possibly on the particle surface). The in vitro dissolution rate of laser-nanonized naproxen showed considerable improvements (at least 10 times faster) compared to the untreated drug powder. Laser fragmentation enables the micronization of small quantities of drugs with limited degradation and polymorphic transformation. The nanonization presents more degradation and physico-chemical transformations. The process therefore represents a suitable micronization (and in some cases nanonization) technique for the drug discovery phase, and is of particular interest for poorly water-soluble pulmonary drugs

Role of iodine oxoacids in atmospheric aerosol nucleation

Iodic acid (HIO₃) is known to form aerosol particles in coastal marine regions, but predicted nucleation and growth rates are lacking. Using the CERN CLOUD (Cosmics Leaving Outdoor Droplets) chamber, we find that the nucleation rates of HIO₃ particles are rapid, even exceeding sulfuric acid–ammonia rates under similar conditions. We also find that ion-induced nucleation involves IO₃⁻ and the sequential addition of HIO₃ and that it proceeds at the kinetic limit below +10°C. In contrast, neutral nucleation involves the repeated sequential addition of iodous acid (HIO₂) followed by HIO₃, showing that HIO₂ plays a key stabilizing role. Freshly formed particles are composed almost entirely of HIO₃, which drives rapid particle growth at the kinetic limit. Our measurements indicate that iodine oxoacid particle formation can compete with sulfuric acid in pristine regions of the atmosphere

Acid-Resistant Catalysis without Use of Noble Metals: Carbon Nitride with Underlying Nickel

A nanocomposite able to function as a hydrogenation catalyst under strongly acidic conditions without the presence of noble metals is synthesized and thoroughly studied. This specially designed catalyst possesses a unique structure composed of carbon nitride (CN) with underlying nickel, in which the nickel endows the CN with new active sites for hydrogen adsorption and activation while it itself is physically isolated from the reactive environment and protected from poisoning or loss. The CN is inert for hydrogenation without the help of nickel. The catalyst shows good performance for hydrogenation of nitro compounds under strong acidic conditions, including the one-step hydrogenation of nitrobenzene in 1.5 M H₂SO₄ to produce <i>p</i>-amoniophenol, for which the acid in the reaction system has restricted the catalyst only to noble metals in previous studies. Further characterization has demonstrated that the nickel in the catalyst is in an electron-deficient state because some of its electron has been donated to CN (HRTEM, PES); thus, the hydrogen can be directly adsorbed and activated by the CN (HD exchange, in situ IR and NMR). With this structure, the active nickel is protected by inert CN from the corrosion of acid, and the inert CN is activated by the nickel for catalytic hydrogenation. The assembly of them gives a new catalyst that is effective and stable for hydrogenation even under a strongly acidic environment

Nanotubular Gamma Alumina with High-Energy External Surfaces: Synthesis and High Performance for Catalysis

Inorganic nanocrystals catalysts with a high proportion of high-energy surfaces can bring about high performance for catalysis and has been an important research topic in the past decades. Gamma alumina is one of the most important inorganic oxides used as solid acids or catalytic support for many more industrial catalysts. However, the preparation of gamma alumina mainly with high-energy external surfaces has never been reported because it has a complicated crystal structure. We demonstrate here in depth a new-type γ-alumina material from a systematic investigation, which is controllably synthesized as regular nanotubes with high-energy {111} facets as main external surfaces. The new-type material shows much better performance as acid catalyst or catalytic support for metals, as compared with common γ-alumina whose main exposed surface is stable {100} or {110} facets in irregular morphology. As an example, palladium loaded on the new-type γ-alumina is easily prepared in higher dispersion and unique electronic states upon the stronger interaction with the support, giving rise to better catalytic performance for semihydrogenation of alkynes, without any assistance of other metals. The systematic investigation should open opportunities of catalyst innovation for new chemical reactions