Effect of chemical conjugation of L-leucine to chitosan on the dispersibility and drug release of a dry powder inhaler nanoparticle formulation

Purpose: This study investigated the effect of chemical conjugation of the amino acid L-leucine to the polysaccharide chitosan on the dispersibility and drug release pattern of a polymeric nanoparticle (NP)-based controlled release dry powder inhaler (DPI) formulation. Methods: A chemical conjugate of L-leucine with chitosan was synthesized and characterized by Infrared (IR) Spectroscopy, Nuclear Magnetic Resonance (NMR) Spectroscopy, Elemental Analysis and X-ray Photoelectron Spectroscopy (XPS). Nanoparticles of both chitosan and its conjugate were prepared by a water-in-oil emulsification – glutaraldehyde cross-linking method using the antihypertensive agent, diltiazem (Dz) hydrochloride as the model drug. The surface morphology and particle size distribution of the nanoparticles were determined by Scanning Electron Microscopy (SEM) and Dynamic Light Scattering (DLS). The dispersibility of the nanoparticle formulation was analysed by a Twin Stage Impinger (TSI) with a Rotahaler as the DPI device. Deposition of the particles in the different stages was determined by gravimetry and the amount of drug released was analysed by UV spectrophotometry. The release profile of the drug was studied in phosphate buffered saline at 37 ⁰C and analyzed by UV spectrophotometry. Results: The TSI study revealed that the fine particle fractions (FPF), as determined gravimetrically, for empty and drug-loaded conjugate nanoparticles were significantly higher than for the corresponding chitosan nanoparticles (24±1.2% and 21±0.7% vs 19±1.2% and 15±1.5% respectively; n=3, p<0.05). The FPF of drug-loaded chitosan and conjugate nanoparticles, in terms of the amount of drug determined spectrophotometrically, had similar values (21±0.7% vs 16±1.6%). After an initial burst, both chitosan and conjugate nanoparticles showed controlled release that lasted about 8 to 10 days, but conjugate nanoparticles showed twice as much total drug release compared to chitosan nanoparticles (~50% vs ~25%). Conjugate nanoparticles also showed significantly higher dug loading and entrapment efficiency than chitosan nanoparticles (conjugate: 20±1% & 46±1%, chitosan: 16±1% & 38±1%, n=3, p<0.05). Conclusion: Although L-leucine conjugation to chitosan increased dispersibility of formulated nanoparticles, the FPF values are still far from optimum. The particles showed a high level of initial burst release (chitosan, 16% and conjugate, 31%) that also will need further optimization.

Preparation and in vitro evaluation of a polymer based controlled release dry powder inhaler formulation for pulmonary delivery

This thesis described the synthesis of an L-leucine conjugate of the biodegradable polymer, chitosan and its potential application for the development of controlled release nanoparticulate dry powder inhaler (DPI) formulations. The study demonstrated that the physicochemical properties of conjugated chitosan nanoparticles had favourable effects on the dispersibility and controlled release profile of a model drug. The toxicity profile of the nanoparticulate formulation revealed promising outcome for its use in pulmonary delivery. The chitosan conjugate produced in this project would be useful for the application of polymer nanoparticulate systems for efficient lung delivery of drugs.

Study on microwave dielectric properties of epoxy resin mixtures used for rapid product development

This paper presents a preliminary study on the dielectric properties and curing of three different types of epoxy resins mixed at various stichiometric mixture of hardener, flydust and aluminium powder under microwave energy. In this work, the curing process of thin layers of epoxy resins using microwave radiation was investigated as an alternative technique that can be implemented to develop a new rapid product development technique. In this study it was observed that the curing time and temperature were a function of the percentage of hardener and fillers presence in the epoxy resins. Initially dielectric properties of epoxy resins with hardener were measured which was directly correlated to the curing process in order to understand the properties of cured specimen. Tensile tests were conducted on the three different types of epoxy resins with hardener and fillers. Modifying dielectric properties of the mixtures a significant decrease in curing time was observed. In order to study the microstructural changes of cured specimen the morphology of the fracture surface was carried out by using scanning electron microscopy.

Implications of precursor chemistry on the alkaline hydrothermal synthesis of titania/titanate nanostructures

A systematic study of four parameters within the alkaline hydrothermal treatment of three commercial titania powders—anatase, rutile, and Degussa P25—was made. These powders were treated with 5, 7.5, 9, and 10 M NaOH between 100 and 220 °C for 20 h. The effects of alkaline concentration, hydrothermal temperature, and precursor phase and crystallite size on the resultant nanostructure formation have been studied through X-ray diffraction, Raman spectroscopy, transmission electron microscopy, and nitrogen adsorption. Through the correlation of these data, morphological phase diagrams were constructed for each commercial powder. Interpretation of the resultant morphological phase diagrams indicates that alkaline concentration and hydrothermal temperature affect nanostructure formation independently, where nanoribbon formation is significantly influenced by temperature for initial formation. The phase and crystallite size of the precursor also significantly influenced nanostructure formation, with rutile displaying a slower rate of precursor consumption compared with anatase. Small crystallite titania precursors formed nanostructures at reduced hydrothermal temperatures.

Vibrational spectroscopy of intercalated kaolinites. Part I

The industrial application of kaolinite is closely related to its reactivity and surface properties. The reactivity of kaolinite can be tested by intercalation, i.e. via the insertion of low molecular weight organic compounds between the kaolinite layers resulting in the formation of a nano-layered organo-complex. Although intercalation of kaolinite is an old and ongoing research topic, there is a limited knowledge available on the reactivity of different kaolinites, the mechanism of complex formation as well as on the structure of the complexes formed. Grafting and incorporation of exfoliated kaolinite in polymer matrices and other potential applications can open new horizons in the study of kaolinite intercalation. This paper attempts to summarize (without completion) the most recent achievements in the study of kaolinite organo-complexes obtained with the most common intercalating compounds like urea, potassium acetate, dimethyl sulphoxide, formamide and hydrazine using vibrational spectroscopy combined with X-ray powder diffraction and thermal analysis.

Development of descriptor tools for the characterization of Australian sugar mill evaporator scale

Cleaning of sugar mill evaporators is an expensive exercise. Identifying the scale components assists in determining which chemical cleaning agents would result in effective evaporator cleaning. The current methods (based on x-ray diffraction techniques, ion exchange/high performance liquid chromatography and thermogravimetry/differential thermal analysis) used for scale characterisation are difficult, time consuming and expensive, and cannot be performed in a conventional analytical laboratory or by mill staff. The present study has examined the use of simple descriptor tests for the characterisation of Australian sugar mill evaporator scales. Scale samples were obtained from seven Australian sugar mill evaporators by mechanical means. The appearance, texture and colour of the scale were noted before the samples were characterised using x-ray fluorescence and x-ray powder diffraction to determine the compounds present. A number of commercial analytical test kits were used to determine the phosphate and calcium contents of scale samples. Dissolution experiments were carried out on the scale samples with selected cleaning agents to provide relevant information about the effect the cleaning agents have on different evaporator scales. Results have shown that by simply identifying the colour and the appearance of the scale, the elemental composition and knowing from which effect the scale originates, a prediction of the scale composition can be made. These descriptors and dissolution experiments on scale samples can be used to provide factory staff with an on-site rapid process to predict the most effective chemicals for chemical cleaning of the evaporators.

Formation of thermodynamically unstable calcium oxalate dihydrate in sugar mill evaporators

Calcium oxalate (CaOX) is the most intractable scale component to remove in sugar mill evaporators by either mechanical or chemical means. The operating conditions of sugar mill evaporators should preferentially favour the formation of the thermodynamically stable calcium oxalate monohydrate (COM), yet analysis of scale deposit from different sugar factories have shown that calcium oxalate dihydrate (COD) is usually the predominant phase, and in some cases is the only hydrate formed. The effects of trans-aconitic, succinic and acetic acids, all of which are present in sugarcane juice, and ethylenediamine tetraacetic acid disodium salt (EDTA) on the growth of CaOX crystals have been examined by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray powder diffraction (XRD) and thermogravimetric analysis (TGA). trans-Aconitic acid, which constitutes two-thirds of the organic acid component in sugarcane juice, in the presence of sugar resulted in the formation of COD and COM in a 3:1 ratio. EDTA was the most effective acid to promote the formation of COD followed by trans-aconitic acid, then acetic acid and lastly succinic acid.