Synthesis of 5-Fluorouracil nanoparticles via supercritical gas antisolvent process

The micronization of an anticancer compound (5-Fluorouracil) by supercritical gas antisolvent (GAS) process was investigated. 5-Fluorouracil was dissolved in dimethyl sulfoxide (DMSO) and subsequently carbon dioxide as an antisolvent was injected into this solution thus, the solution was supersaturated and nanoparticles were precipitated. The influence of antisolvent flow rate (1.6, 2 and 2.4 mL/min), temperature (34, 40 and 46), solute concentration (20, 60 and 100 mg/mL) and pressure (9, 12 and 15 MPa) on particle size and particle size distribution were studied. Particle analyses were performed by scanning electron microscopy (SEM) and Zetasizer Nano ZS. The mean particle size of 5-Fluorouracil was obtained in the range of 260–600 nm by varying the GAS effective parameters. The High performance liquid chromatography (HPLC) and Fourier transforms infrared spectroscopy (FTIR) analyses indicated that the 5-Fluorouracil nanoparticles were pure and the nature of the component did not change. The experimental results indicated that increasing the antisolvent flow rate and pressure, while decreasing the temperature and initial solute concentration, led to a decrease in 5-Fluorouracil particle size.     

Dense CO2 antisolvent precipitation of levothyroxine sodium: A comparative study of GAS and ARISE techniques based on morphology and particle size distributions

Morphology and particle size distribution of levothyroxine sodium are experimentally investigated by comparing gas antisolvent (GAS) and atomized rapid injection for solvent extraction (ARISE) techniques using dense CO₂. Precipitation of levothyroxine sodium from ethanol was carried out at 25, 40 and 50 °C, with pressure in the 90–120 bar range and different concentrations of the organic solution. Particles produced by the GAS process are nanospheres whereas ARISE processed particles are either spherical or rod-like micro and nanoparticles. Particle size and size distributions of GAS processed levothyroxine sodium are in the 370–500 nm range, while the ARISE process produced particles in the 360–1200 nm range. In most cases, both techniques produced bimodal size distributions, due to particle agglomeration. The different morphological characteristics and particle size distributions of levothyroxine sodium obtained using GAS and ARISE at different operating conditions can be useful depending on the type of drug formulation chosen, as well as the route of drug administration and delivery system.     

Kinetic Modeling of the Gas Antisolvent Process for Synthesis of 5‐Fluorouracil Nanoparticles

Mathematical modeling for 5‐fluorouracil (5‐FU) nanoparticle synthesis via gas antisolvent (GAS) process was investigated. 5‐FU was precipitated from a dimethyl sulfoxide (DMSO) solution using CO₂ as antisolvent. The particle size was controlled by nucleation and growth rates, therefore, the kinetic modeling study is essential. Thermodynamic modeling was applied to determine optimal operating conditions for experimental 5‐FU synthesis. Kinetic parameters were evaluated by fitting the particle size distribution predicted by the model to experimental data. The experimental and modeling results indicated that the particle size decreased with increasing the antisolvent addition rate.     

Controlled liquid antisolvent precipitation using a rapid mixing device

Particle formation by the liquid antisolvent (LAS) process involves two steps: mixing of solution–antisolvent streams to generate supersaturation and precipitation (which includes nucleation and growth by coagulation and condensation) of particles. Uniform mixing conditions ensure rapid and uniform supersaturation, making it a precipitation controlled process where the particle size is not further affected by mixing conditions and results in precipitation of ultra-fine particles with narrow particle size distribution (PSD). In this work, we demonstrate that the use of an ultrasonically driven T-shaped mixing device significantly improves mixing of solution and antisolvent streams for precipitation of ultra-fine particles in a continuous operation mode. LAS precipitation of ultra-fine particles of multiple active pharmaceutical ingredients (APIs) such as itraconazole (ITZ), ascorbyl palmitate (ASC), fenofibrate (FNB), griseofulvin (GF), and sulfamethoxazole (SFMZ) in the size range 0.1–30 μm has been carried out from their organic solutions in acetone, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), and ethanol (EtOH). Classical theory of homogeneous nucleation has been used to analyze the result, which suggests that higher nucleation rate results in finer particle size. Interestingly, experimental determination of degree of supersaturation indicates that higher supersaturation does not necessarily result in higher nucleation rate and nucleation rates can be correlated to solvent polarity.     

Precipitation kinetics of PMMA sub-micrometric particles with a supercritical assisted-atomization process

Sub-micrometric particles of PMMA were successfully prepared via a supercritical assisted-atomization (SAA) process using acetone as a solvent and supercritical carbon dioxide as a spraying medium. The effects of several key factors on the particle size were investigated. These factors included the concentration of polymer solution, temperature in saturator and volumetric flow rate ratio of carbon dioxide to polymer solution. The shape of the polymer's primary particles is spherical with the arithmetic mean size ranging from 82 nm to 176 nm and the mass-weighted mean size ranging from 127 nm to 300 nm. As evidenced from the experimental results, the lower concentrations of polymer solution, optimized volumetric flow rate ratios, and higher temperatures in saturator can effectively reduce the mean particle size. The precipitation kinetic parameters were determined from the particle size distributions with the aid of the population balance theory. This study found the primary nucleation to be dominant in the precipitation and diffusion may govern particle growth.     

Crystallization of silibinin from organic solutions using supercritical and aqueous antisolvents

Silibinin, an anticancer drug, was crystallized from organic solutions using supercritical and aqueous antisolvents. Silibinin was dissolved in acetone and ethanol at concentration range of 0.01–0.04 g/mL, and the drug solutions were placed in contact with two different antisolvents, carbon dioxide and water. The mixing of the drug solutions and antisolvents led to the prompt precipitation of silibinin in a solid crystal form. The experimental variables, such as temperature, solution concentration, mixing rate and solution/antisolvent volume ratio were manipulated. When the experiments were conducted with a supercritical antisolvent, the effects of external additives on the crystal habit were examined. α-d-Glucose penta acetate, triton X-100 and urea were added to the solution at concentration range of 0.001–0.003 g/mL as external additives. The temperature increase of 20 °C induced 25% increase in particle size. As the solution concentration was increased from 0.01 to 0.04 g/mL, the average particle size decreased from 35.5 to 22.0 μm in supercritical antisolvent experiments, while the particle size increased from 8.9 to 30.4 μm in aqueous antisolvent experiments. The use of different kinds of external additives resulted in different modifications of the particle shape and structures.     

Kinetics of magnetite nanoparticles formation in a one step low temperature hydrothermal process

In the present study, a one step hydrothermal process was employed to synthesize magnetite nanoparticles using oleic acid as surfactant agent at 140 °C. Effects of reaction time and alkalinity were studied on particles size and morphology. By changing these parameters, some monodisperse spherical nanoparticles with mean particle size between 2.71 and 13.88 nm were synthesized and characterized via TEM, XRD, VSM, TGA and FT-IR techniques. Assuming the Avrami behavior of particles formation, a kinetics equation was proposed for the transformation rate at 140 °C. Using some simplifying assumptions, nucleation and growth rates were calculated for the hydrothermal formation of magnetite nanoparticles at 140 °C.     

Generation and precipitation of paclitaxel nanoparticles in basil seed mucilage via combination of supercritical gas antisolvent and phase inversion techniques

In recent years, plant derived polymers have evoked tremendous interest in the field of drug delivery. In this work, a promising anticancer drug, paclitaxel, was precipitated in the basil seeds mucilage (BSM) using supercritical carbon dioxide (SC-CO₂). The employed SC-CO₂ process in this research is a combination of gas antisolvent and phase inversion techniques and consists of two steps: (1) casting solution preparation, a uniform mixture of BSM, water, paclitaxel and dimethyl sulfoxide (DMSO), (2) simultaneous generation and precipitation of nanoparticles in BSM structure using SC-CO₂ as antisolvent. The effect of DMSO/water ratio (4 and 6 (v/v)), pressure (10–16 MPa) and CO₂ addition rate (1–3 mL/min) on mean particle size (MPS), particle size distribution (PSD) and drug loading efficiency (DLE) were studied. Particle analyses were performed by scanning electron microscopy (SEM) and Zetasizer. High performance liquid chromatography was utilized for studying DLE. Nanoparticles of paclitaxel (MPS of 117–200 nm depending on process variables) with narrow PSD were successfully precipitated in BSM structure with DLE of 56.8–78.2%. The FTIR spectra confirmed that paclitaxel actually precipitated in basil seeds mucilage. Experimental results indicated that higher DMSO/water ratio, pressure and CO₂ addition decreased MPS and DLE.     

Polymethylmethacrylate (PMMA) sub-microparticles produced by Supercritical Assisted Injection in a Liquid Antisolvent

A recently developed supercritical assisted process, called Supercritical Assisted Injection in a Liquid Antisolvent (SAILA) is proposed to produce polymer micro and nanoparticles in water stabilized suspensions. Polymethylmethacrylate (PMMA) has been selected as the model polymer for a systematic study of the influence of the SAILA operating parameters on particle morphology and diameter. The effect of expanded liquid injection pressure on particle size and distribution was studied and different expanded liquid temperatures and compositions were also explored. Successful precipitation of the polymer in a water stabilized suspension was obtained and narrow particle size distributions were obtained using 70 and 90 bar injection pressures. PMMA particles controlled diameter were produced ranging between 0.2 ± 0.04 μm and 0.9 ± 0.2 μm. Particles are formed from the expanded liquid solution as a consequence of very fast supersaturation produced by spraying it the liquid antisolvent.     

A new approach to select solvents and operating conditions for supercritical antisolvent precipitation processes by using solubility parameter and group contribution methods

A new approach is proposed to select operating temperature and pressure for supercritical antisolvent particle precipitation based on solubility parameter calculated by group contribution methods and using only the critical properties of the solvent. Solubility parameters are also used to choose the most suitable organic solvent for a given application. Supercritical antisolvent precipitation operating conditions of 36 systems are investigated including 8 organic solvents (methanol, ethanol, acetone, DMSO, DCM, chloroform, NMP and acetic acid) and 6 solid solutes (atenolol, tartaric acid, flunisolide, paracetamol, amoxicillin and cholesterol) in the temperature and pressure ranges of 25⿿85 °C and 50⿿250 bar. The results show a good agreement between the experimental and calculated data for these systems. Although particle precipitation depends on several parameters such as mass-transfer rates and hydrodynamics, the focus of this work is on the role of thermodynamics to indicate the preliminary conditions for a successful antisolvent precipitation process. Validation and results of this new approach suggest that it can be a useful tool for a qualitative and completely predictive evaluation of supercritical antisolvent particle precipitation in a cheaper way than carrying out experimental runs.     

Aerosol synthesis of silicon nanoparticles with narrow size distribution—Part 1: Experimental investigations

A study on the feasibility of aerosol processing of nearly monodisperse silicon nanoparticles via pyrolysis of monosilane in a hot wall reactor is presented. For optimal conditions silicon nanoparticles with a geometric standard deviation of 1.06 were synthesized at a production rate of 0.7 g/h. The size of the particles could be precisely controlled in the range of 20–40 nm, whilst maintaining a geometric standard deviation in the range of 1.06–1.08, by proper choice of the governing parameters temperature, residence time and precursor concentration. The results show that narrow particle size distributions can only be obtained in the temperature range between 900 and 1100 °C, as long as both the initial silane concentration (1 mbar silane partial pressure) and the reactor total pressure are low (25 mbar). This regime for the production of narrow particle size distributions has not been identified in prior work on the thermal decomposition of silane. Narrowly distributed particles can be obtained under conditions where nucleation and particle growth are separated and the agglomeration rates are negligible.     

Nanoparticle formation in spray pyrolysis under low-pressure conditions

The formation of zirconia particles prepared by low-pressure spray pyrolysis (LPSP) was studied experimentally and numerically. A numerical model was developed, and it is the first to quantitatively explain the phenomena occurring in the LPSP system. Under certain operational conditions, particle formation was based on a one-droplet to one-particle conversion, as found in the spray pyrolysis process under atmospheric pressure conditions. On the other hand, nanoparticles were generated at higher temperatures and under conditions of lower pressure. Zirconia nanoparticles were successfully produced under experimental conditions of 1600 °C, 30 Torr with 10 l/min nitrogen as a carrier gas. The mass and heat transport calculation indicated that the evaporation rate would increase rapidly with increasing temperature and decreasing pressure in the furnace. The model considered flow regimes, and accounted for the regime range from continuum to free-molecular, depending on the Knudsen number. A very high evaporation rate led to the assumption that droplets were ruptured instantaneously, resulting in the production of monomers. Nanoparticles were then formed by the nucleation of monomers to form clusters, and then by the coagulation between clusters and surface condensation of monomers onto clusters. To predict the size distribution of nanoparticles, a population balance analysis called the nodal method was used. The simulation results showed reasonable agreement with the experimental results.     

Estimating nucleation rates from apparent particle formation rates and vice versa: Revised formulation of the Kerminen–Kulmala equation

Connections between observed particle formation rates (typically at diameter 3 nm or larger) and the actual nucleation rates have important applications in atmospheric science. First, nucleation theories can be evaluated and second, semi-empirical particle formation rates can be developed for large scale models that neglect the cumbersome initial steps of formation and growth. Kerminen and Kulmala, by estimating the particle formation rate, nucleation mode growth rate and scavenging rate onto background particles (coagulation sink) from measured size distribution evolution, derived a simple yet rather accurate formula for this purpose [Kerminen V.-M., Kulmala, M. (2002). Analytical formulae connecting the “real” and the “apparent” 25 nucleation rate and the nuclei number concentration for atmospheric nucleation events, Journal of Aerosol Science 33, 609–622]. The present work reformulates the original theory in a way that two drawbacks are eliminated: (1) the original expression was derived using a slightly inaccurate coagulation sink dependence on particle size and (2) was based on knowing the condensation sink which requires knowledge of the condensing vapors.     

Co-precipitation of amoxicillin and ethyl cellulose microparticles by supercritical antisolvent process

Microparticles of ethyl cellulose (EC) and amoxicillin (AMC) have been precipitated by a supercritical antisolvent process (SAS) using CO₂ as the antisolvent and a mixture of dichloromethane (DCM) and dimethyl sulfoxide (DMSO) as solvents. Combinations of three temperatures (308, 323 and 333 K) and four pressures (100, 150, 200 and 250 bar) were assessed in the vessel and the rest of the variables were held constant (i.e. CO₂ flow rate, sample flow rate, washing time, nozzle diameter and the amoxicillin:ethyl cellulose ratio). Scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and elemental analysis (EA) were used to determine the particle size and shape and to confirm the presence of both compounds in the resulting precipitates. In most cases, mixed amoxicillin and ethyl cellulose particles were produced with sizes in the micrometer range. Pressure and temperature effects on the co-precipitation were investigated. The release behaviour of the microparticles precipitated by the SAS process was evaluated in two biological fluids – simulated gastric and simulated intestinal fluids. Co-precipitated materials allowed a slower drug release rate than pure drug.     

Processing naproxen with supercritical CO2

Naproxen has been processed with supercritical fluids in order to improve the dissolution rate and bioavailability. Microparticles of naproxen have been obtained by a Rapid Expansion of Supercritical Solutions (RESS) process in which carbon dioxide has been used as a solvent and methanol as a cosolvent. The influence of extraction pressure (200–300 bar) and extraction temperature (60 °C and 100 °C) on the naproxen precipitation has also been investigated. In general, the morphology of the precipitated particles improved and particle size (PS) decreased in comparison to the raw material. Lower extraction pressure and higher extraction temperature led to a smaller particle size. On the other hand, a supercritical antisolvent (SAS) process has been applied due to the relative medium solubility values of naproxen in supercritical carbon dioxide, with precipitation obtained successfully in all cases. The initial concentration of the solution and the solvent effect has both been analysed. Morphologies and mean diameter ranges have been analysed by scanning electron microscopy (SEM) and the influence on crystallinity of both supercritical processes has been evaluated by X-ray diffraction (XRD) measurements.     

Numerical simulation of particle formation in the rapid expansion of supercritical solution process

In this paper, we numerically study particle formation in the rapid expansion of supercritical solution (RESS) process in a two dimensional, axisymmetric geometry, for a benzoic acid + CO₂ system. The fluid is described by the classical Navier–Stokes equation, with the thermodynamic pressure being replaced by a generalized pressure tensor. Homogenous particle nucleation, transport, condensation and coagulation are described by a general dynamic equation, which is solved using the method of moments. The results show that the maximal nucleation rate and number density occurs near the nozzle exit, and particle precipitation inside the nozzle might not be ignored. Particles grow mainly across the shocks. Fluid in the shear layer of the jet shows a relatively low temperature, high nucleation rate, and carries particles with small sizes. On the plate, particles within the jet have smaller average size and higher geometric mean, while particles outside the jet shows a larger average size and a lower geometric mean. Increasing the preexpansion temperature will increase both the average particle size and standard deviation. The preexpansion pressure does not show a monotonic dependency with the average particle size. Increasing the distance between the plate and the nozzle exit might decrease the particle size. For all the cases in this paper, the average particle size on the plate is on the order of tens of nanometers.     

Some novel aspects of nanocrystalline diamond nucleation and growth by direct current plasma assisted chemical vapor deposition

Some novel aspects of nanocrystalline diamond (NCD) film nucleation and growth by DC-PACVD were investigated, which focused on the effect of methane injection timing at ramp stage (see discussion in the text) and cathode temperature as well. NCD films were deposited for 4 h on a 4 in. Si wafer which was ultrasonically seeded in a methanol slurry of diamond powder with a 5 nm average diameter. The H₂/CH₄/N₂ gas mixture with a composition of 96.7%/3%/0.3% was used as precursor gas. The total gas flow rate and chamber pressure were 150 sccm and 150 Torr, respectively. Discharge voltage and current of 500 V and 45 A were used respectively at a substrate temperature of 800 °C. The nucleation density, microstructure, growth rate and crystallinity of the obtained NCD films were characterized by SEM, XRD, NEXAFS and Raman spectroscopy. The nucleation density was found to be sensitive to methane injection timing in the ramp stage. In addition, the cathode temperature greatly affected the nucleation density, grain size and growth rate.     

Effect of operating parameters on PVP/tadalafil solid dispersions prepared using supercritical anti-solvent process

Supercritical anti-solvent (SAS) process was employed to produce tadalafil solid dispersion sub-micron particles. Three independent variables for the SAS process (temperature, pressure, and drug concentration) were varied in order to investigate the effects on particle size and morphology of PVP/tadalafil solid dispersion (drug to polymer ratio 1:4). The mean particle size decreased with decreasing temperature (50 → 40 °C) and concentration (15 → 5 mg/mL) and increasing pressure (90 → 150 bar). Depending on the experimental variable, the mean particle size varied from 200 nm to 900 nm, and the dominant experimental variable was determined to be the drug concentration. Moreover, at a concentration of 15 mg/mL with any other process conditions, tadalafil tended to partially aggregate in crystalline form with irregular particle shapes. The results of in vitro dissolution experiments showed good correlation with mean particle size and crystallinity of the SAS-processed particles, in that the highest drug concentration showed the least dissolution rate and vice versa. Therefore, among the three variables studied, the drug concentration is the major factor that produces sub-micron particles in the SAS process.     

Parameterizing the formation rate of new particles: The effect of nuclei self-coagulation

The study is based on the work of Lehtinen et al. (2007) [Lehtinen, K. E. J., Dal Maso, M., Kulmala, M., & Kerminen, V.-M. (2007). Estimating nucleation rates from apparent particle formation rates and vice versa: Revised formulation of the Kerminen–Kulmala equation. Journal of Aerosol Science, 38, 988–994] who derived formulae connecting “real” and “apparent” nucleation rates. The parameterization neglected self-coagulation of newly formed particles and clusters, however, and here we have extended the previous work to include the effects of the self-coagulation. Our main focus was on calculating the “apparent” nucleation rate, i.e. the rate at which particles appear at sizes larger than the critical cluster size, as a function of the “real” nucleation rate. The revised parameterization was comprehensively tested against an explicit aerosol dynamic model at diverse atmospheric conditions. It was found out that nuclei self-coagulation has importance to new particle formation when J_nuc/Q>10^?2 where J_nuc is the nucleation rate and Q is the production rate of condensable vapours. This corresponds to the nucleation rates ranging from >10 cm^?3 s^?1 (free troposphere) to >10⁴ cm^?3 s^?1 (polluted boundary layer) depending on the atmospheric conditions. In terms of the particle number concentration, the calculations performed with the explicit model and the predictions of revised parameterization were generally within an order of magnitude. Several issues related to applications in large-scale models were also discussed.     

Supercritical antisolvent micronization of PVP and ibuprofen sodium towards tailored solid dispersions

The supercritical antisolvent technology is used to precipitate polyvinylpyrrolidone (PVP) particles and crystallise ibuprofen sodium (IS) crystals separately and in the form of solid dispersion together. Supercritical carbon dioxide (scCO₂) is used as antisolvent. For PVP particle generation, ethanol, acetone and mixtures of ethanol and acetone are used as solvents. The initial concentration of PVP in the solution was varied between 0.5 wt% and 1.5 wt%, the operation pressure between 10 MPa and 30 MPa and the composition of ethanol/acetone solvent mixtures between 100 wt% and 0 wt% of ethanol at a constant temperature of 313 K. Furthermore, the mean molecular weight of the polymer was varied between 40 kg mol⁻¹, 360 kg mol⁻¹ and 1300 kg mol⁻¹. An increase of the content of the poor solvent acetone in the initial solvent mixture as well as the usage of PVP with a higher molecular weight, leads to a significant decrease in mean particle size. At all the investigated parameters always fully amorphous PVP powder precipitates. For IS, only ethanol was used as the solvent, the initial IS concentration in the solution was varied between 1 wt% and 3 wt% and the operation pressure between 10 MPa and 16 MPa. A variation of these parameters leads to a manipulation of the size and the morphology of the crystallised IS crystals. Irrespective of the parameters used, always the same polymorphic form of ibuprofen sodium is produced. The solid dispersions were generated at different compositions of PVP to IS and with two different molecular weights of PVP at otherwise constant conditions. Fully amorphous solid dispersions consisting of IS and PVP together were generated at different ratios of PVP to IS.The mechanisms that control the final particle properties are discussed taking into account two different models for “ideal” and “non-ideal” solutes. Furthermore, the study of the “unconventional” SAS parameters, molecular weight and solvation power of the solvent shows that these parameters qualify to tailor polymer particle properties via SAS processing. Next to the investigation into the behaviour of both solutes separately, fully amorphous solid dispersions consisting of IS and PVP together were generated. While X-ray diffraction was used to analyze the crystalline structure of the particles, respectively, solid dispersions, their morphology was analysed using scanning electron microscopy (SEM).