Production of menthol-loaded PCL nanoparticles by solvent displacement

Abstract This Ph.D thesis focuses on the synthesis of menthol-loaded-Poly-ε-caprolactone nanoparticles (NP’s) for transdermal application. Polymers are increasingly needed to produce nanoparticles ready to convey drugs to the tissues or cells of interest. Polymer nanoparticles are submicron-sized colloidal systems.Without doubt, the adequacy of these systems relies upon the structure of the vehicle and, specifically, on the mean size and on the particle size distribution (PSD). The poly-ε-caprolactone (PCL) polymer is chosen to synthesize nanoparticles because of its adaptability and fine tunning of its physico-chemical properties (great biocompatibility and biodegradability) which can be changed to acquire the desired nanoparticle size. Nanospheres have a monolithic type of structure (network) in which drugs are dispersed or absorbed on the surfaces or in the particles. Nano-capsules are vesicular systems in which the drug is kept in a cavity comprising of an inner liquid encompassed by a polymeric layer, which gives a supporting structure to the encapsulated material. For this state the active principle is normally dissolved in the inner core, yet may likewise be absorbed to the capsule surface. Nanosphere or nanocapsule development basically relies upon the production process. Nanoparticles utilized as drug delivery systems ought to be made out of biodegradable, biocompatible and nontoxic polymers. A number of distinctive strategies can be used to integrate polymer nanoparticles. Each has their own particular points of interest and constraints, which normally include blending of two fluid streams, e.g. emulsification-evaporation, emulsification–diffusion and solvent displacement. The solvent displacement strategy is characterized by simplicity of reproducibility, the possibility to utilize solvents with low poisonous potential and above all controlled particle size distribution (PSD). The nano-precipitation system involves dissolving the drug and polymer in the same solvent and afterward blending them with an antisolvent (typically water) in which the drug is immiscible and the nanoparticles are spontaneously framed. In this study, the nanoparticles were produced by utilizing three intensive reactors: a confined impinging jet mixer (CIJM), a two-inlet vortex mixer (VM) and a four-inlet vortex mixer (MIVM), testing their performance in the same operating conditions. Dynamic light scattering was carried out to measure the mean nanoparticle size (dp), particle size distribution (PSD), zeta potential (Z-average) and Polydispersity index (PDI). Nanoparticle separation was carried out by a centrifugation process for Transmission Electron microscope (TEM) analysis and menthol loading evaluation. Menthol quantification was evaluated by Gas chromatography (GC). Differential scanning calorimetry and transmission and scanning electron microscopy techniques were considered for analysing the particle surface morphology and menthol and identification in the nanoparticles and melatonin suspension over textile fabrics. Exceptional micro scale reactors are extremely helpful to get an efficient blend of the considerable number of components present in the solvent solution. High super-saturation can be produced by distinctive micromixers, for example, the Confined Impinging Jets Mixer (CIJM) and the Multi Inlet Vortex Mixer (MIVM), in less time than the required time for nucleation and growth procedures of the precipitating solutes. Super saturation brings the unconstrained development of nanoparticles within the nano estimate limits. The nanoparticles were prepared using the aforementioned intensive mixers (CIJM and MIVM), PCL polymer and diverse internal cores (menthol, melatonin, miglyol etc). The main goal was to investigate the effect of these working parameters on the mean size of the nanoparticles, a reasonable design of Experiment (DoE) was utilized. Furthermore, the effect of the inlet feed speed Vj (Flow rate FR), mass proportion and quench volumetric proportion QR (dilution) on the mean size dp , the zeta potential Zp and poly dispersity index (PDI) of the nanoparticles was also explored. At first poly-ε-caprolactone nanoparticles (nanospheres) were produced under different working conditions. The essential goal of this evaluation was to prepare the nanoparticle synthesis with a wide size range of menthol-loaded –PCL. A further aim to advance the synthesis parameters. After early promising results it was evident that further examinations were required keeping in mind the final goal to optimize the mean size of the nanoparticles. Likewise, quantification of nanoparticles was completed with the specific end goal of estimating drug loaded and encapsulation efficiency. Quantification procedure included various stages followed by centrifugation, extraction and gas chromatography analysis. All nanoparticles studied in this proposition were produced by the solvent displacement technique, utilizing three reactors CIJM, MIVM-4 and VM-2. All trials were performed with a PCL of monolithic-type molecular weight (Mw) 14000 g/mol. Two unique solvents were utilized for the production of the nanoparticles; acetone and acetonitrile. Since these solvents satisfy the following criteria: adequate dissolvability of PCL, water miscibility and low harmfulness. The impact of solvents on the delivered nanoparticles utilizing acetone and acetonitrile was seen: with higher estimations of the inlet feed rate, the nanoparticles became distinctly smaller. In addition, preliminary trials using a third solvent tehtrahydroforan were also done for the sake of comparsion. The impact of the working conditions on the mean size of nanoparticles was explored the underlying polymer concentration, the inlet feed rate and the impacts of the post preparing conditions, for example, the quench (dilution). It was found that the initial polymer concentration, and in addition the inlet feed velocity, has a significant impact on the mean size of nanoparticles. With higher feeding concentrations of PCL polymer, nanoparticles became distinctly greater. When feed velocity was expanded the mean size of nanoparticles diminished. It was also observed that NP size was higher for acetonitrile in contrast with acetone solvent at comparable working conditions in all cases. Moreover, dilution of the solution containing nanoparticles (higher the quench) was found indispensible to obtain stable nanoparticles. In addition, by expanding the inlet feed rate, smaller nanoparticles with lower zeta potential, were acquired. Smaller nanoparticles were created in the MIVM regarding the CIJM. Polydispersity index (PDI, 0.05 ± 0.3) and zeta potential (-30 mV to -40 mV) were observed in all investigated experiments. After nanoparticles were produced, they were quantified. An exact and appropriate measurement of menthol was acquired by a Gas chromatography (GC). Results showed that the incorporation efficiency of menthol in the nanoparticles with expanding menthol content was very nearly 60 % - 80 % in both the CIJM and VM mixers, and this indicates that menthol was adequately exemplified by PCL polymer upon precipitation. Loading was assessed at 35 % - 50 % around, with expanding mass proportion of menthol and PCL, when utilizing both reactors. These results were confirmed through morphologic perceptions of nanoparticles utilizing transmission electronic microscope (TEM) examination. From there on, the work was centered around the synthesis of PCL nanocapsules containing differing internal cores (miglyol, and melatonin). Melatonin nanocapsules were further utilized for the impregnation of cotton fabrics. Furthermore, the synthesis and characterization of the nanocapsules formed by PCL (surface layer) and by melatonin or miglyol (in the core) was investigated. To optimize the nanocapsules production process, the impact of different working conditions was explored i.e. the underlying polymer concentration, the underlying, melatonin or miglyol concentrations and the inlet feed rate, on their mean sizes. Comparative conclusions, were observed for menthol loaded nanoparticles, that is when expanding inlet feed rate the mean size of nanocapsules diminished. Finally, it was also found that when concentrations of all substances was increased larger nanocapsules were shaped.