Non-solvent Ratio Research Articles

Insights into the preparation of zein nanoparticles by continuous membrane nanoprecipitation

Nanoparticles (NPs) preparation is limited to an exclusive use in batch processes and small-scale formulations. The use of membranes as high-performance micromixers is expected to open new scenarios to overcome limitations of conventional nanoprecipitation system such as stirred tank (ST) nanoprecipitation. The ability of the porous membrane to add uniformly one phase to another and govern their mixing at the membrane interface seems to be an important parameter for obtaining uniform NPs. Inorganic membranes (pore size of 1 μm) were used to carry out membrane nanoprecipitation (MN) to form Zein nanoparticles (ZNPs) at pores level by non-solvent induced phase separation. A systematic study of the preparation of ZNPs in the ST and MN systems was carried out to establish the Ouzo diagram. The influence of zein concentration and solvent to non-solvent ratio on the size and size distribution of ZNPs was also investigated. A wider stable Ouzo zone was obtained with MN than with the ST process. ZNPs size increased from 100 nm up to 700 nm, while maintaining low polydispersity index (PDI < 0.2). The results demonstrate the suitability of MN for the continuous production of ZNPs and open the possibility of scaling up the nanoprecipitation process.

Porosity Tunable Poly(Lactic Acid)-Based Composite Gel Polymer Electrolyte with High Electrolyte Uptake for Quasi-Solid-State Supercapacitors.

The growing popularity of quasi-solid-state supercapacitors inevitably leads to the unrestricted consumption of commonly used petroleum-derived polymer electrolytes, causing excessive carbon emissions and resulting in global warming. Also, the porosity and liquid electrolyte uptake of existing polymer membranes are insufficient for well-performed supercapacitors under high current and long cycles. To address these issues, poly(lactic acid) (PLA), a widely applied polymers in biodegradable plastics is employed to fabricate a renewable biocomposite membrane with tunable pores with the help of non-solvent phase inversion method, and a small amount of poly (vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) is introduced as a modifier to interconnect with PLA skeleton for stabilizing the porous structure and optimizing the aperture of the membrane. Owing to easy film-forming and tunable non-solvent ratio, the porous membrane possesses high porosity (ca. 71%), liquid electrolyte uptake (366%), and preferable flexibility endowing the GPE with satisfactory electrochemical stability in coin and flexible supercapacitors after long cycles. This work effectively relieves the environmental stress resulted from undegradable polymers and reveals the promising potential and prospects of the environmentally friendly membrane in the application of wearable devices.

Novel triptorelin acetate-loaded microspheres prepared by a liquid/oil/oil method with high encapsulation efficiency and low initial burst release

Low encapsulation efficiency (EE) and high initial burst release are key issues for the development of microspheres loading highly water-soluble peptide drugs. In this study, novel triptorelin acetate-loaded microspheres with high EE and low initial burst release were prepared by a liquid/oil/oil (L/O/O) phase separation method using poly(lactic-co-glycolic acid) (PLGA) as the sustained-release carrier. The formulation of the microspheres and the preparation process were optimized in terms of particle size, surface morphology, EE, and in vitro drug release. Importantly, PLGA concentration, solvent and non-solvent ratio, solidification solvent volume, and solidification speed were found to significantly affect the properties of the obtained microspheres. The optimal microspheres present 50–100 μm spherical-shaped particles with remarkably high drug loading and EE. The in vitro drug release of these microspheres exhibit a delayed-release manner, starting to release drug at the third week and displaying approximately 20% drug release at day 28. Fourier transform infrared spectroscopy and differential scanning calorimetry results show that triptorelin acetate slightly interacted with PLGA, indicating that the drug was successfully encapsulated into PLGA microspheres. The drug content in the microspheres had no significant change after the 12-month storage at 4 °C, suggesting their excellent long-term stability. In conclusion, novel triptorelin acetate-loaded PLGA microspheres have been achieved via the L/O/O phase separation method to effectively improve the EE and reduce the initial burst release.

A focus of the nanoprecipitation by solvent displacement: example of poly(MAOTIB) intended to in vivo applications

Through this study, we propose to specifically focus on a particular stage of the fabrication of polymeric nanoparticles intended to be used as contrast agent for biomedical X-ray imaging. These nanoparticles, made from nanoprecipitation of preformed polymer, poly(MAOTIB) (poly(2-methacryloyloxyethyl(2,3,5-triiodobenzoate))) follow a solvent displacement process. This method, widely used in literature, is sensitive to the formulation and process parameters such as nature and concentrations of surfactant and polymer, solvent / non-solvent ratio, rate of addition of one phase in the other one, respective volumes of the phase, and homogenization shearing rate. On the other hand, in function of the aimed administration route, the final suspension should obey to specific constraints on final product, e.g. size range and polydispersity, final particle concentration (i.e. iodine concentration) and surfactant concentration. In the present work, we report a specific investigation on the nanoprecipiation of poly(MAOTIB) in tetrahydrofuran, dropped in water or ethanol (as non-solvent) and stabilized by nonionic surfactant. The objective is to show and explain the potentials and limitations of such the process, but also to provide a guidance on the way to optimize it.

Physicochemical, Pharmacodynamic and Pharmacokinetic Characterization of Soluplus Stabilized Nanosuspension of Tacrolimus.

Tacrolimus, an immunosuppressive drug has a variable pharmacokinetic and poor oral bioavailability due to poor solubility. The aim of the present study was enhancing the solubility and oral bioavailability of this drug. Tacrolimus nanoparticles were prepared by precipitation anti-solvent evaporation method. The effect of different parameters including: surfactant type, solvent to nonsolvent ratio and drug to surfactant ratio were studied on the particle size, saturated solubility and dissolution rate of the drug. The solid state characterization was done by fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and scanning electron microscopy. The untreated drug (5 mg.kg-1day-1), nanoparticles or physical mixture of the drug and the stabilizers were administered to rats and blood levels of tacrolimus were assessed by electrochemiluminence method. The oral drug administration was done for 10 days then the changes in white blood cells (WBC) and percent lymphocyte count were determined before drug administration, 5 and 10 days after drug administration. FTIR spectroscopy showed no interaction between the drug and stabilizers. XRPD and DSC studies indicated the amorphous state of the drug in nanosuspensions. The solvent to nonsolvent ratio of 1:20 and drug to surfactant ratio of 1:3 enhanced 185 fold the saturated solubility and 17 fold dissolution rate of the drug. In vivo studies also showed tacrolimus nanoparticles significantly reduced the lymphocyte and WBC, enhanced 66 and 34 fold the AUC0-24 and Cmax of the drug, respectively. The precipitation anti-solvent evaporation is a nano-crystalization technique which showed to be an effective approach for enhancing water solubility and bioavailability of tacrolimus.

Preparation and characterization of acetylated starch nanoparticles as drug carrier: Ciprofloxacin as a model

The objective of this study was to characterize in-vitro the potential of acetylated corn starch (ACS) particles as a matrix for the delivery of ciprofloxacin (CFx). ACS was successfully synthesized and optimized by the reaction of native corn starch using acetic anhydride and acetic acid with low and high degrees of substitution (DS). The nanoprecipitation method was applied for the formation of the ACS-based nanoparticles, by the dropwise addition of water to acetone solution of ACS under stirring. The effects of acetylation and nanoprecipitation on the morphology and granular structure of ACS samples were examined by the FT-IR, XRD, DSL and SEM techniques. The efficiency of CFx loading was also evaluated via encapsulation efficiency (EE) in ACS nanoparticles. The average degree of acetyl substitution per glucose residue of corn starch was 0.33, 2.00, and 2.66. The nanoparticles size of the ACS and ACS-loaded with CFx were measured and analyzed relative to the solvent:non-solvent ratio. Based on the results, ACS nanoparticles with DS of 2.00 and water:acetone of 3:1 had 312nm diameter. Increasing DS in starch acetate led to increase in the EE from 67.7 to 89.1% and with increasing ratio of water/acetone from 1:1 to 3:1, the EE raised from 48.5 to 89.1%. X-ray diffraction indicated that A-type pattern of native starch was completely transformed into the V-type pattern of acetylated starch. The scanning electron microscopy showed that the different sizes of pores formed on the acetylated starch granules were utterly converted into the uniform-sized spherical nanoparticles after the nanoprecipitation.

Ultrasound-Assisted Rapid Extraction of Bacterial Intracellular Medium-Chain-Length Poly(3-Hydroxyalkanoates) (mcl-PHAs) in Medium Mixture of Solvent/Marginal Non-solvent

Intracellular medium-chain-length poly(3- hydroxyalkanoates) (PHAs) produced by Pseudomonasputida Bet001 were extracted in an ultrasound-assisted process. A mixture of acetone (solvent) and heptane (marginal non-solvent) was used as the extraction medium. The effects of volumetric energy dissipation, extraction medium ratio and irradiation time on the extraction process were investigated. Sonication frequency of 37 kHz and heptane as marginal non-solvent facilitated the process. Following optimization, high PHA extraction rate of \({74 \times 10^{-3}{\rm g}}\) PHA \({{\rm g}^{-1}}\) dried biomass \({{\rm min}^{-1}}\) was observed at ultrasonic energy output of \({1151 \pm 3 {\rm J ml}^{-1}}\) with 50:50 solvent/marginal non-solvent ratio for irradiation time of 5 min. PHA showed good stability under the rapid extraction process.

Taguchi approach-assisted optimization of spraying in non-solvent process for preparation of potassium perchlorate nanoparticles

In this study, Taguchi robust design as a statistical route was utilized to optimize the variables of spraying in non-solvent process in order to achieve KClO4 nanoparticles. The experimental factors of the spraying in non-solvent technique, which may be effective in KClO4 particle size, were optimized efficiently via Taguchi method. The procedure operating conditions, i.e., KClO4 concentration, solvent ratio, non-solvent identity, and spray steps, were considered at triple levels. The role of these operating conditions on the size of resulted KClO4 particles was evaluated quantitatively by analysis of variance (ANOVA). It was found that the particle size of KClO4 prepared by spraying in non-solvent technique might be adjusted efficiently by tuning the main parameters at the corresponding optimum level. Moreover, the optimal conditions for the preparing of KClO4 nanoparticles via the studied method were proposed. The ANOVA exhibited that 3 % (w/v) as KClO4 concentration, CHCl3 as type of non-solvent, solvent to non-solvent ratio of 1:6, and single-step spraying are optimal conditions for the production of KClO4 nanoparticles by spraying in non-solvent. Experimental data revealed that at optimum conditions of the process, the average particle size of produced KClO4 is about 41 nm. Meantime, KClO4 nanoparticles were prepared by supercritical carbon dioxide anti-solvent process for comparison. It was found that the size of the produced KClO4 particles is about 55 nm.

Surface characterization of flat and rough films of perfluoromethacrylate-methylmethacrylate statistical copolymers synthesized in CO2-expanded monomers

Statistical copolymers of perfluoroalkyl ethyl methacrylate (Zonyl-TM) and methylmethacrylate were synthesized in CO2-expanded monomer mixture at a low pressure of 10–13 MPa for the first time. M w of the copolymers was found to decrease with the increase of Zonyl-TM content. Flat films of these copolymers were obtained by dip coating from their chloroform solutions and were characterized using contact angle measurements, optical microscopy, and 3D profilometry. The increase in the Zonyl-TM content of the copolymers resulted in a decrease of the total surface free energy. Superhydrophobic and oleophobic rough copolymer films were also prepared by applying a phase-separation process where THF was used as the solvent and ethanol as the non-solvent. Surface roughness increased with the increase in the nonsolvent ratio resulting in an increase in the water contact angle from 103° to 151° and hexadecane contact angle from 49° to 73°.

Superparamagnetic iron oxide – Loaded poly (lactic acid)- d-α-tocopherol polyethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agent

We developed a strategy to formulate supraparamagnetic iron oxides (SPIOs) in nanoparticles (NPs) of biodegradable copolymer made up of poly(lactic acid) (PLA) and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) for medical imaging by magnetic resonance imaging (MRI) of high contrast and low side effects. The IOs-loaded PLA–TPGS NPs (IOs-PNPs) were prepared by the single emulsion method and the nanoprecipitation method. Effects of the process parameters such as the emulsifier concentration, IOs loading in the nanoparticles, and the solvent to non-solvent ratio on the IOs distribution within the polymeric matrix were investigated and the formulation was then optimized. The transmission electron microscopy (TEM) showed direct visual evidence for the well dispersed distribution of the IOs within the NPs. We further investigated the biocompatibility and cellular uptake of the IOs-PNPs in vitro with MCF-7 breast cancer cells and NIH-3T3 mouse fibroblast in close comparison with the commercial IOs imaging agent Resovist ®. MRI imaging was further carried out to investigate the biodistribution of the IOs formulated in the IOs-PNPs, especially in the liver to understand the liver clearance process, which was also made in close comparison with Resovist ®. We found that the PLA–TPGS NPs formulation at the clinically approved dose of 0.8 mg Fe/kg could be cleared within 24 h in comparison with several weeks for Resovist ®. Xenograft tumor model MRI confirmed the advantages of the IOs-PNPs formulation versus Resovist ® through the enhanced permeation and retention (EPR) effect of the tumor vasculature.

Taste masking of diclofenac sodium using microencapsulation

This study addresses how to mask the undesirable taste of diclofenac sodium (DS) without interfering with an adequate rate of drug release. DS microcapsules were successfully prepared using a system of ethylcellulose (EC)- toluene - petroleum ether. The system was optimized by the construction of the phase diagram and determination of the amount of EC precipitated under different solvent:non-solvent ratios to determine the most appropriate conditions for preparing good microcapsules. Microcrystalline cellulose (Avicel) and lactose were mixed with DS powder and converted into spherical cores by the wet agglomeration technique which facilitated coacervation and formation of thin and uniform microcapsule walls. Diethylphthalate (DEP) and Polyethyleneglycol 600 (PEG) in different concentrations (20 or 40% w/w) were used as plasticizers to impart better elasticity to the microcapsules. The microcapsules were evaluated for DS released against crushed commercial DS enteric coated tablet (Voltaren). The prepared microcapsules were taste evaluated by a taste panel of 10 volunteers. The results revealed that the optimum solvent:non-solvent ratio required for microcapsule formation was 1:2. Microcapsules containing PEG 20% or DEP 40% showed a faster rate of DS release compared to that obtained from other microcapsules and crushed commercial enteric coated tablets (Voltaren). The palatability and the taste of DS were significantly improved by microencapsulation. The extent of taste masking was influenced by the microcapsule core:wall ratio, the presence of additives within the core, the type and concentration of plasticizer and initial core size.

Submicron-size particles of ultrahigh molecular weight polyethylene produced via nonsolvent and temperature-induced crystallization.

Submicrometer size particles of ultrahigh molecular weight polyethylene (UHMWPE) were produced by crystallization from dilute (0.1-1.0 wt % of UHMWPE) solvent/nonsolvent emulsions. The procedure consisted of mixing a hot solution of UHMWPE in decalin or decane with a nonsolvent (tetraglyme) at approximately 160 degrees C, followed by rapid cooling of the mixture to zero or subzero temperatures. The rapid cooling causes microphase separation between the two liquids, resulting in the formation of an emulsion, which consists of microdroplets of the supercooled UHMWPE solution dispersed in tetraglyme. The consequent crystallization of the polymer in the microdroplets produces a suspension of fine crystals of UHMWPE, which can easily be isolated. The particles were characterized using scanning electron microscopy, differential scanning calorimetry, and Raman spectroscopy. Their degree of crystallinity is between that of GUR 1050 original (powder) and processed (molded) polymer. By changing the polymer concentration, solvent to nonsolvent ratio, and temperature, the size (from 0.1-1.0 microm) and shape (spheroids or rods) of the particles can be controlled. These particles may be used for immunochemical investigations and the study of the influence of UHMWPE wear debris on cell response.

Novel methods for the characterization of water-soluble polymers

The liquid chromatography of four water-soluble polymers [pullulan, polyacrylamide, poly(ethylene glycol), and poly(ethylene oxide)] have been investigated and used to categorize separation processes which couple enthalpic and entropic mechanisms. Experiments were carried out with a binary mobile phase which combined a thermodynamically good solvent (water or aqueous 0.02M Na2SO4) and nonsolvent (methanol). The polymer solute was injected in a good solvent. By varying the solvent–nonsolvent ratio in the eluent, conditions could be obtained where the free energies of exclusion and solvation were balanced. This has been given the nomenclature “liquid chromatography under limiting conditions of solubility” (LC-LCS) since the polymer elutes just in front of the system peak at the “limit” of its solubility. Conditions can also be identified where exclusion is balanced with adsorption (“liquid chromatography under limiting conditions of adsorption,” or LC-LCA). To our knowledge, these are the first experimental reports of LC-LCS for any polymer and the first LC-LCA observation on water-soluble macromolecules. All measurements were carried out over a poly(hydroxymethylacrylate) sorbent. Cloud point curves were found to generally distinguish the regions where LC-LCA or LC-LCS dominate. The data illustrate the need to consider the polymer when analyzing LC-LCA. Conversely, polymer adsorption may play an important role in LC-LCS. © 1998 John Wiley & Sons, Inc. J Appl Polym Sci 69: 2549–2557, 1998

Microencapsulation of ketorolac tromethamine by means of a coacervation-phase separation technique induced by the addition of non-solvent

Ketorolac tromethamine (KT) is a non-steroidal drug with potent analgesic and anti-inflammatory activity and is absorbed rapidly (Tmax < 1.0h) with an efficiency >87% following oral and intramuscular administration. The plasma half-life of ketorolac ranges from 1.1 to 6.0 h. Its oral bioavailability is estimated to be 80%. Ketorolac has been found 36 times more potent than phenylbuta-zone, approximately twice as potent as indomethacin, and three times more potent than naproxen in suppressing carrageenan-induced paw oedema in rat. In this study, microcapsules of KT were prepared by means of coacervation-phase separation technique induced by the addition of non-solvent, and release rates from microcapsules were studied. Eudragit S100 was used as the coating material. Coacervation was achieved by the addition of cyclohexane at 2 ml/min at 25 °C and 1:4 solvent:non-solvent ratio was used. The microcapsules were washed with cyclohexane to harden the wall and dried at room temperature. Microcapsules with core:wall ratio of 1:l and 1:2 were prepared and the particles obtained by sieving with an average diameter of 177–500 pm were used. The yield was calculated and the release properties of KT were investigated by USP XXII paddle method and using UV spectrophotometry at 318 and 323 nm.

Influence of Process Parameters on the Precipitation of Organic Nanoparticles by Drowning-Out

Ethylcellulose (the organic substance), ethanol (the solvent) and water (the nonsolvent) are chosen as a model system for the production of uniform nanoparticles by drowning-out. Experiments carried out under various operating conditions show that many process parameters, such as the type of stirrer and the stirring speed, the temperature and the solvent–nonsolvent ratio, have practically no influence on the formation of ethylcellulose particles. On the other hand, the ethylcellulose concentration in the initial alcoholic solution seems to be the most important parameter controlling the particle size distribution. A comparison is made between experimental results and predictions of classical nucleation theories or aggregative growth models.

Microwave dielectric and mechanical behavior of foams from polystyrene and poly(methyl methacrylate) blends

AbstractFoams have been generated from blends of polystyrene and poly(methyl methacrylate) under identical conditions of solvent–nonsolvent ratio, impregnation time, and heating period. Scanning electron micrographs of copper‐coated fractured surfaces of the samples reveal a distinct transition in their structures from a more or less homogeneous cell‐size distribution with prominent grain boundaries to complete lack of foaming and cellularity through random dispersions of spherical poly(methyl methacrylate) inclusions in polystyrene‐foam matrix. Dielectric measurements have been made on test specimens at 9.375 GHz X‐band microwave frequency by the method of Smith and Hippel modified by Dakin and Works. Percent porosity is the least at 20 wt% of polystyrene while foam density linearly decreases with percent porosity. Dielectric constant is linear in foam density on direct and semilog scales (passing through unity and zero, respectively), in blend composition and also in percent porosity. Dielectric constant increases with increase of foam density or weight percent of polymethyl‐methacrylate and decreases with increase of percent porosity. The dielectric constant is, however, nonlinear in volume fraction of polystyrene on both direct and semilog scales, obeying Weiner's inequalities. The logarithmic law of Lichtenecker and Rother with an empirical factor 0.8276 in the index fits the data best. Specific polarization is minimal at 60 wt% of polymethyl methacrylate. The calculated Bottcher‐Bruggleman plot based on the interacting spherical particle model is found to be of limited applicability. This is explained on the basis of long‐range intra‐ and intermolecular dipole–dipole interactions. The pattern of the change of dielectric loss tangent (tan δ), lying in the range 0.150–0.045 and attaining a minimum at 20 wt% polystyrene, has similarly been explained in terms of α and β relaxations due to conformational rearrangements and steric hindrances of rotations. The compressive strength measured as a function of composition shows that the reinforcement depends on an optimization between the degree of cellularity and packing.

The preparation and characterization of ethylcellulose-walled theophylline microcapsules.

The use of sustained-release preparations of theophylline has become routine in the treatment of bronchial asthma. Microencapsulation provides a possible means of producing such a product. The present paper examines, by means of triangular diagrams, the phases present in the system ethylcellulose-petroleum ether-toluene. The separated cellulose was used to coat the drug theophylline. The effects of temperature, petroleum ether fraction, solvent:non-solvent ratio and rate of non-solvent addition on the size and size distribution of the microcapsules was studied.

Precise molecular weight distributions of high polymers by semiautomatic solvent extraction

AbstractIt has been found practical to fractionate relatively monodisperse polystyrenes of molecular weights up to 4 × 106 by using a semiautomatic solvent extraction procedure. The fractionators consist of flow‐through mixing chambers provided with settling regions for the removal of finely suspended solid material. Provision is made for accurate control of both temperature and solvent–nonsolvent ratio. Two such apparatus, operated in tandem, were used in the present work; in principle, several more stages could be employed if desired for most polymer systems. Results on polystyrenes prepared in well defined ways appear to be in good agreement with predicted distributions. Applicability to other polymer systems is discussed.