Preparation of Daidzein microparticles through liquid antisolvent precipitation under ultrasonication

In this study, daidzein microparticles (DMP) were prepared using an improved ultrasound-assisted antisolvent precipitation method. Preliminary experiments were conducted using six single-factor experiments, and principal component analysis (PCA) was adopted to obtain the three staple elements of the ultrasonic power, solution concentration, and nozzle diameter. The response surface Box-Behnken (BBD) design was used to optimize the level of the above factors. The optimal preparation conditions of the DMP were obtained as follows: the flow rate was 4 mL/min, the concentration of the daidzein solution was 16 mg/mL, the ratio of antisolvent to solvent (liquid-to-liquid ratio) was 9, the nozzle diameter was 300 μm, the ultrasonic power was 180 W (665 W/L), and the system speed was 760 r/min. The minimum average particle size of DMP was 181 ± 2 nm. The properties of daidzein particles before and after preparation were analyzed via scanning electron microscopy, X-ray diffraction analysis, Differential scanning calorimetry and Fourier transform infrared spectroscopy, no obvious change in its chemical structure was observed, but crystallinity was reduced. Compared with daidzein powder, DMP has a higher solubility and stronger antioxidant capacity. The above results indicate that the improved method of ultrasonication combined with antisolvent can reduce the size of daidzein particles and has a great potential in practical production.     

Ostwald ripening of beta-carotene nanoparticles

Ostwald ripening, the interfacial-energy-driven dissolution and reprecipitation of solutes, becomes an increasingly significant problem for nanoparticle formulations. We present the first quantitative study of Ostwald ripening for nanoparticle dispersions. The Lifshitz-Slyozov-Wagner (LSW) theory of particle growth driven by diffusion is applied to study beta-carotene nanoparticles with sizes of O(100 nm) formed by our block-copolymer protected Flash Nanoprecipitation process. A numerical implementation of the LSW theory that accounts for the original particle size distribution is presented. The predicted particle sizes from the numerical simulation are compared with the experimental results measured by dynamical light scattering. The results show quantitative agreement with no adjustable parameters. The addition of antisolvent results in the reduction of the ripening rate by dramatically decreasing bulk solubility.     

Influence of fractal surface dimension on the dissolution process of sparingly soluble CaCO<Subscript>3</Subscript> microparticles

The dissolution process of sparingly soluble CaCO₃ microparticles and how the fractal surface dimension of the particles changes during dissolution is analyzed. The particles and the dissolution process are studied using scanning electron microscopy, X-ray diffraction, nitrogen adsorption, laser diffraction and conductance measurements. Ball milling of the particles is shown to maintain the particle crystallinity, and to introduce an increased fractal surface dimension in the 1–10 μm size range. Dissolution is found to increase the surface dimension of initially smooth particles and to maintain the fractal surface roughness of milled particles. The dissolution process increases the relative number of small particles (50 nm–1 μm) whereas the larger ones decrease in size. The solubility of the milled fractal particles was ∼1.8 times higher than that for the initially smooth ones. The presented findings show that developing methods for increasing the fractal surface roughness of particles should be of interest for improving the solubility of poorly soluble drug candidates.     

Process optimization studies of 10-Hydroxycamptothecin (HCPT)-loaded folate-conjugated chitosan nanoparticles by SAS-ionic crosslink combination using response surface methodology (RSM)

10-Hydroxycamptothecin (HCPT) is a well-established topoisomerase I inhibitor of a broad spectrum of cancers. However, poor aqueous solubility, low instability, and toxicity to normal tissues have limited its clinical development. A novel HCPT-containing drug carrier system was developed to overcome these disadvantages. The response surface methodology was used to optimize the process of preparing HCPT-chitosan nanoparticles (HCPT-CSNPs) by the SAS-ionic crosslink (supercritical antisolvent SAS) combination method; the resulting HCPT-CSNPs were then conjugated with folate for specific targeting. A central composite design, composed of four independent variables, namely, chitosan concentration, TPP concentration, HCPT nanoparticle concentration, and crosslink time, was applied in the modeling process. The mean particle size and drug entrapment efficiency (DEE) of HCPT-CSNPs were chosen as response variables. The interactive effects of the four independent variables on the response variables were also studied. Nanoparticle characteristics such as morphology, DEE, and mean particle size were investigated. The optimum conditions for preparing HCPT-CSNPs were determined as follows: folate-coupled chitosan concentration 2.46 mg/ml, TPP concentration 7.73 mg/ml, HCPT nanoparticle concentration 0.48 mg/ml, and crosslinking time 47.4 min. Optimum conditions for preparing desired HCPT-CSNPs with a mean particle size of 173.5 nm and entrapment efficiency of 77.3% were obtained. The resulting folate-conjugated HCPT-CSNPs (FA-HCPT-CSNPs) reveal that the amount of folate conjugation was 197.64 mg/g CS. FA-HCPT-CSNPs used in drug carrier systems could have potential value in HCPT-sensitive tumors.     

Moxifloxacin Micronization via Supercritical Antisolvent Precipitation

Supercritical antisolvent (SAS) precipitation is employed for micronization of moxifloxacin (MF), an antibiotic from the fluoroquinolone group, to develop new dosage forms of MF. With this technique, we produced, in a controllable fashion, MF particles with different sizes (0.6–8.0 μm) and morphologies (from polygonal sheets to elongated rectangular prisms). The infrared and circular dichroism spectroscopy data suggest that micronization of MF via SAS does not alter its chemical structure or cause racemization. We demonstrate that micronized forms of MF drug substance exhibit a 20 to 30% increase in the dissolution rate, as compared to the initial MF form, in a physiological medium (pH 7.4). The dissolution rate of the microparticles obtained via SAS micronization depends on their size, morphology, and degree of crystallinity. The various data obtained in this study will be used in formulating new dosage forms of MF for treatment of drug-resistant forms of tuberculoses.     

Anti-solvent precipitation for the preparation of nobiletin nano-particles under ultrasonication-cis/reverse homogenization

In order to address the issue of nobiletin's limited bioavailability, nobiletin nanoparticles (NNP) were created for the first time in this research employing an anti-solvent under ultrasonication-cis/reverse homogenization. Dimethyl sulfoxide (DMSO) was used as the solvent and deionized water as the anti-solvent to create the nobiletin solution. The optimal surfactant dose of surfactant dose of 0.43%; an ultrasonic period of 8.1 min, ultrasonic at a temperature of 64 °C and a solution concentration of 8.33 mg/mL, the method was optimized to obtain the minimum NNP diameter of 199.89 ± 0.02 nm. A dual optimization process of response surface PBD and BBD was used to minimize the size of HNP particles. Additionally, scanning electron microscopy revealed that the specific surface area of the NNP dramatically increased with the reduction of NNP particle size, and dissolving studies indicated the solubility and dissolution studies showed that NNP had substantially greater solubility and dissolution rates than raw nobiletin per unit time; as a result, the NNP produced by anti-solvent precipitation with a twofold homogenization system supported by ultrasound had a realistic potential for growth.     

Fabrication and characterization of iron oxide nanoparticles filled polypyrrole nanocomposites

The effect of iron oxide nanoparticle addition on the physicochemical properties of the polypyrrole (PPy) was investigated. In the presence of iron oxide nanoparticles, PPy was observed in the form of discrete nanoparticles, not the usual network structure. PPy showed crystalline structure in the nanocomposites and pure PPy formed without iron oxide nanoparticles. PPy exhibited amorphous structure and nanoparticles were completely etched away in the nanocomposites formed with mechanical stirring over a 7-h reaction. The thermal stability of the PPy in the nanocomposites was enhanced under the thermo-gravimetric analysis (TGA). The electrical conductivity of the nanocomposites increased greatly upon the initial addition (20 wt%) of iron oxide nanoparticles. However, a higher nanoparticle loading (50 wt%) decreased the conductivity as a result of the dominance of the insulating iron oxide nanoparticles. Standard four-probe measurements indicated a three-dimensional variable-range-hopping conductivity mechanism. The magnetic properties of the fabricated nanocomposites were dependent on the particle loading. Ultrasonic stirring was observed to have a favorable effect on the protection of iron oxide nanoparticles from dissolution in acid. A tight polymer structure surrounds the magnetic nanoparticles, as compared to a complete loss of the magnetic iron oxide nanoparticles during conventional mechanical stirring for the micron-sized iron oxide particles filled PPy composite fabrication.     

纳米氧化锌的过饱和控制生长与大小分布控制.

"在非水介质中合成了纳米氧化锌,测定了纳米氧化锌的紫外吸收光谱,并用有效质量模型计算了粒子大小,开发并命名了一种称之为纳米粒子过饱和控制生长的技术,该技术涉及将小的纳米粒子悬浊液加入到大的粒子悬浊液中,结果因为不同大小粒子间的溶解度差异小的粒子将全部溶解,大的粒子将整体长大,大粒子悬浊液的粒子数将保持不变,大粒子的生长速度显著比Ostwald老化的高．该技术最显著的特征是只要最初两悬浊液粒子大小的差异足够大,分布不是太宽,则粒子大小的分布将会因为粒子如此长大而变窄．"     

Optimization and characterization of ultrasound assisted preparation of curcumin-loaded solid lipid nanoparticles: Application of central composite design,thermal analysis and X-ray diffraction techniques

This study is devoted to preparation of novel solid lipid nanoparticles (SLNs) for the encapsulation of curcumin which is produced by micro-emulsion and ultrasonication using stearic acid and tripalmitin as solid lipids, tween80 and span80 as surfactants. The relation between particle size and entrapment efficiency of the produced SLNs was operated by central composite design (CCD) under response likes surface method (RSM). The variables including the ratio of lipids (X₁), the ratio of surfactants (X₂), drug/lipid ratio (X₃), time of sonication (X₄) and time of homogenization (X₅). Particle size and entrapment efficiency of the loaded curcumin was justified according to the minimum particle size and maximum entrapment efficiency. The curcumin loaded SLNs presented fairly spherical shape with the mean diameter and entrapment efficiency of 112.0 ± 2.6 nm and 98.7 ± 0.3%, respectively. The optimized SLNs were characterized by X-ray diffraction analysis (XRD), differential scanning calorimetry (DSC), photon correlation spectroscopy (PCS) and field emission scanning electron microscopy (FESEM). The drug release profile of the optimal formulated material was examined in aqueous media and almost 30% of the curcumin loaded in SLNs was gradually released during 48 h, which reveals efficient prolonged release of the drug.     

An investigation into the mechanical properties of silicon nanoparticles using molecular dynamics simulations with parallel computing

This study investigates the mechanical properties of cubic silicon nanoparticles with side lengths ranging from 2.7 to 16.3 nm using molecular dynamics (MD) simulation with parallel computing technique. The results reveal that the surface energy of the particles increases significantly as the particle size decreases. Furthermore, having passed the point of maximum compressive load, the phase transformation region of the particles gradually transfers from the core to the surface. The small volume of the current nanoparticles suppresses the nucleation of dislocations, and as a result, the maximum strength and Young’s modulus values of all but the smallest of the current nanoparticles are greater than the corresponding values in bulk silicon. Finally, it is found that the silicon nanoparticles with a side length of 10.86 nm exhibit the greatest maximum strength (24 GPa). In nanoparticles with shorter side lengths, the maximum strength decreases significantly as the volume of the nanoparticle is reduced.     

Effect of solvent type and concentration on size and morphology of arbidol microparticles obtained by supercritical antisolvent precipitation

The capability of arbidol microparticle preparation by supercritical antisolvent (SAS) precipitation was demonstrated. A nonmonotonic dependence of the average particle size on the concentration was found, while the position of the minimum is dependent on the type of solvent used. It is possible to prepare Arbidol particles of various morphology and size from several microns to several hundred microns depending on the conditions.     

Improvements in azithromycin recrystallization using ultrasound for size reduction

The primary motive of the current work is to achieve smaller mean particle size with narrow size distribution that can enhance the bioavailability of azithromycin (ARZ), an essential requirement due to its poor water solubility. Recrystallization of ARZ was evaluated using cooling as well as antisolvent crystallization approaches in the presence of ultrasonic irradiation with detailed study into effect of different parameters such as ultrasonic power, time and temperature. Ultrasound assisted antisolvent crystallization at low temperatures (<10℃) yielded best size reduction up to 80% with narrower distribution and also gave better yield of the product, that too within 5 min of sonication. With scale up considerations, recirculation mode of operation was also evaluated which offered promising results for the size reduction. Images captured using optical microscope and SEM revealed a nearly uniform rod/plate-shaped geometry. Increase in amorphous nature of ARZ was confirmed based on XRD analysis. FTIR analysis showed no significant changes in the functional groups when compared to the original sample. Overall, the work demonstrated an improved reprocessing approach based on the use of ultrasound with insights into effect of operating parameters and effect of ultrasound on various characteristics.     

Formulation and physiochemical study of α-tocopherol based oil in water nanoemulsion stabilized with non toxic,biodegradable surfactant: Sodium stearoyl lactate

The unique properties such as high optical clarity, stability and enhanced bioavailability of nanoemulsion make them useful for food, cosmetic and pharmaceutical industries. In this work, sodium stearoyl lactate and Tween 80 surfactants were collectively used to fabricate alpha tocopherol based oil in water nanoemulsion using high energy ultrasonication method. The spherical nature of pure and drug loaded nanoemulsion has been confirmed with transmission electron microscopy (TEM). The influence of pH, dilution, surfactant concentration and ionic strength on average particle size of pure and nutraceutical (benzylisothiocyanate and curcumin) encapsulated emulsion was examined. The prepared emulsion exhibited good stability up to 90 days in salt solution (50–200 mM) and different pH conditions. The cumulative release % of benzylisothiocyanate and curcumin was found to be 50.29% in 36 h and 89.15% in 150 h respectively. The antioxidant activity of pure, benzylisothiocyanate, curcumin and cocktail (benzylisothiocyanate and curcumin) nanoemulsion was calculated with 2,2-diphenyl-1-picrylhydrazyl radical. The IC₅₀ value of different antioxidant showed that benzylisothiocyanate nanoemulsion acted as better antioxidant as compared to pure and curcumin encapsulated nanoemulsion. Also the cell viability of pure nanoemulsion was found to be 24% on hep G2 cell. The effect of UV light irradiation on curcumin and benzylisothiocyanate stability was carried out in different solvent conditions (water/ethanol and nanoemulsion). The degradation of curcumin by the impact of UV light was successfully controlled by trapping in NEm.     

Effect of surrounding gas temperature on the morphological evolution of TiO2 nanoparticles generated by laser ablation in tubular furnace

Titanium oxide nanoparticles are synthesized by laser ablation of Ti target in oxygen atmosphere under well-controlled temperature profiles in a tubular furnace. The size and the shape of generated nanoparticles are varied by changing the temperature of furnace. The mobility-based size distributions of generated air-borne nanoparticles are measured using a scanning mobility particle sizer, and the size distributions of primary particles are analyzed by a scanning electron microscope. When the particles are generated by laser ablation at the room temperature, the particles are agglomerates in gas phase with the average mobility diameter of 117 nm and the mean diameter of primary particles of 11 nm. The primary particle diameter increases from 11 to 24 nm by raising the furnace temperature up to 800 °C. Since the mass of Ti vapor ablated from a target is found to be constant regardless of the furnace temperature, this particle growth may be attributed to the reduction in nuclei number as a result of mild quenching at higher temperatures. As the temperature reaches higher than 1,000 °C, the mobility diameter suddenly drops and the primary particle diameter increases due to sintering, and at 1,200 °C the mobility diameter coincides with the primary particle diameter. Since the laser oven method offers an independent control of vapor concentration and the temperature of surrounding atmosphere, it is an effective tool to study the formation process of nanoparticles from primary particles with a given size.     

SCF micronization of poly-3-hydroxybutyrate using supercritical antisolvent

Micronization of poly-3-hydroxybutyrate (PHB) by the supercritical fluid antisolvent precipitation (SAS) technique using supercritical carbon dioxide as an antisolvent was studied experimentally. The possibility of preparing particles of varying morphology (including hollow spheres) and specified size from 100 nm to 20 μm was demonstrated. The influence of different mechanisms of solid phase formation during SAS micronization on the size and morphology of PHB microparticles under different experimental conditions was considered.     

Preparation of hydroxypropylmethylcellulose microparticles using supercritical antisolvent precipitation

Micronization of hydroxypropylmethylcellulose using supercritical antisolvent (SAS) method is studied. The influence of various parameters, such as solvent type, polymer concentration, pressure, solution to supercritical CO₂ flow rate ratio on morphology of particles is discussed. The possibility of obtaining spherical or elliptical shape hydroxypropylmethylcellulose particles of submicron size (190–620 nm) that depends on the process parameters is demonstrated.     

Ultrasound influence on the solubility of solid dispersions prepared for a poorly soluble drug

Solid dispersions have been successfully used to enhance the solubility of several poorly water soluble drugs. Solid dispersions are produced by melting hydrophilic carriers and mixing in the poorly water soluble drug. Supersaturation is obtained by quickly cooling the mixture until it solidifies, thereby entrapping the drug. The effects of using ultrasound to homogenize the molten carrier and drug mixture were studied. In particular, the increase in drug solubility for the resulting solid dispersions was analyzed. Piroxicam, which has very low water solubility, was used as a model drug. A full factorial design was used to analyze how sonication parameters affected the solubility and in vitro release of the drug. The results show that the use of ultrasound can significantly increase the solubility and dissolution rate of the piroxicam solid dispersion. Pure piroxicam presented a solubility of 13.3 μg/mL. A maximum fourfold increase in solubility, reaching 53.8 μg/mL, was observed for a solid dispersion sonicated at 19 kHz for 10 min and 475 W. The in vitro dissolution rate test showed the sonicated solid dispersion reached a maximum rate of 18%/min, a sixfold increase over the piroxicam rate of 2.9%/min. Further solid state characterization by thermal, X-ray diffraction and Fourier transform infrared analyses also showed that the sonication process, in the described conditions, did not adversely alter the drug or significantly change its polymorphic form. Ultrasound is therefore an interesting technique to homogenize drug/carrier mixtures with the objective of increasing the solubility of drugs with poor water solubility.     

Pure drug nanoparticles in tablets: what are the dissolution limitations?

There has been increasing interests for drug companies to incorporate drug nanoparticles into their existing formulations. However, technical knowledge in this area is still in its infancy and more study needs to be done to stimulate growth in this fledging field. There is a need to scrutinize the performance of pure drug nanoparticles in tablets, particularly relating formulation variables to their dissolution performance. Application of the pure form, synthesized without the use of surfactants or stabilizers, is often preferred to maximize drug loading and also to minimize toxicity. Cefuroxime axetil, a poorly water-soluble cephalosporin antibiotic, was used as the model drug in the formulation development. Drug release rate, tablet disintegration time, tensile strength and energy of failure were predominantly influenced by the amount of super-disintegrant, amount of surfactant, compression force and diluent species, respectively. The compression rate had minimal impact on the responses. The main hurdle confronting the effective use of pure drug nanoparticles in tablets is the difficulty in controlling aggregation in solution, which could potentially be aggravated by the tabletting process. Through the use of elevated levels of surfactants (8 w/w% sodium dodecyl sulphate), drug release from the nanoparticle preparation was enhanced from 58.0 ± 2.7% to 72.3 ± 0.7% in 10 min. Hence, it is recommended that physical formulations for pure drug nanoparticles be focused on the particle de-aggregation step in solution, if much higher rates are to be desired. In conclusion, even though pure drug nanoparticles could be easily synthesized, limitations from aggregation may need to be overcome, before successful application in tablets can be fully realized.     

Micronization of levofloxacin by supercritical antisolvent precipitation

The process of micronization of levofloxacin (LF, an antibacterial agent of the fluoroquinolone group) by the supercritical antisolvent precipitation technique (SAS) was investigated. It was shown that LF particles of different sizes (from 1 to 10 μm) and of various morphologies (from thin plates to elongated parallelepipeds) can be produced depending on the type of solvent used for conducting micronization. Investigation of the micronized LF preparations using the methods of IR-Fourier spectroscopy, Raman scattering, and circular dichroism showed that the LF micronization caused neither changes in its chemical structure nor racemization. Micronization of LF significantly affects the rate of its dissolution in model systems exhibiting effects dependent on the type of the solvent used for micronization. For example, the highest rate of dissolution at pH 4 was observed for LF preparations micronized with the help of chlorohydrocarbons. It was shown that the rate of dissolution of all micronized LF preparations was higher by 15–30% in comparison with the initial LF, which likely was related to the changes in the degree of crystallinity/amorphousness, as well as of morphologies of microparticles formed in the SAS process.     

Microflow reactor synthesis of palladium nanoparticles stabilized with poly(benzyl ether) dendron ligands

A simple glass capillary microflow reactor system has been applied for the synthesis of palladium nanoparticles by thermal decomposition of palladium acetate (Pd(OAc)₂) in diphenyl ether in the presence of poly(benzyl ether) dendron ligands (PBED Gn-NH₂, n = 1–3) as a stabilizer. Effect of hydrodynamic parameters (capillary diameter, linear flow rate, volume flow rate, and reaction temperature) and concentrations (precursor and stabilizer) on the particle size was investigated. The particle size can be controlled by varying linear flow rate and temperature as well as ligand/precursor concentration ratio. Volume flow rate does not affect the particle size when the linear flow rate is held constant for different capillary diameters (150–320 μm). Unlike batch systems, in this microreactor system, smaller particles are produced at low ligand concentrations when the molar ratio of the ligand to metal precursor ranged from 1 to 5. As another characteristic of the microreactor synthesis, the concentration of the Pd precursor can be increased (up to 27 mM) with maintaining a constant particle size (3.1 ± 0.2 nm) and a good monodispersity, while in the batch system a significant increase and broadening in the particle size are observed with increasing precursor concentration.