Semicontinuous Heterophase Polymerization Research Articles

Semi-Continuous Heterophase Polymerization to Synthesize Poly(methacrylic acid)-Based Nanocomposites for Drug Delivery

The design of nanocomposites with the potential for drug delivery is a topic of great interest. In this work, the synthesis of nanocomposites of poly(methacrylic acid) (PMAA) grafted onto carbon nanotubes (CNTs) functionalized with poly(amidoamine) (PAMAM) dendrimer by semicontinuous heterophase polymerization SHP, at three different methacrylic acid (MAA) dosing rates, is reported. SHP is a polymerization technique poorly used to prepare nanocomposites containing CNTs and has the potential to produce more ordered alkyl methacrylic polymer chains, which could favor the obtaining of a homogenous nanocomposite. For the nanocomposites synthesized, a lowest addition rate monomer-starved condition was reached. Analysis by X-ray photoelectron spectroscopy (XPS), and thermogravimetric analysis (TGA) demonstrate that functionalized CNTs are grafted onto the PMAA matrix. The ability of prepared nanocomposites to deliver hydrocortisone was evaluated by ultraviolet-visible spectroscopy (UV-Vis). The hydrocortisone release profiles of pure PMAA and of their nanocomposites prepared at the lowest monomer fed rate were fitted with Higuchi and Korsmeyer–Peppas models, successfully. Functionalized CNTs have a crucial role to induce an effective release of hydrocortisone from the prepared nanocomposites.

Synthesis of sulfonated poly(styrene‐co‐methyl methacrylate) by semicontinuous heterophase polymerization for filtration membranes

AbstractIn this study, styrene (St) and methyl methacrylate (MMA) were copolymerized in semicontinuous heterophase using Hitenol‐BC10 (HBC10) as polymerizable surfactant and ammonium persulfate as initiator to obtain copolymers of poly(St‐co‐MMA). The effects of St/MMA weight ratio and surfactant concentration on kinetics, and colloidal properties of latexes were studied. Copolymers and latexes were characterized by scanning electron microscopy, thermogravimetric analysis (TGA), gel permeation chromatography (GPC), Fourier transform infrared (FTIR) spectroscopy, and X‐ray diffraction analysis. Fast reaction rates under monomer starved conditions and high conversions (>85%) were observed in all cases, with a weight‐average molecular weight in the range of 2.10 × 106 to 0.96 × 106 g mol−1, decreasing with the HBC10 concentration due to an effect of chain transference to surfactant. Stable latexes with spherical particles with average diameter in the interval of 65–41 nm and Z‐potential in the interval of −68.24 to −38.44 mV were obtained. Copolymers were sulfonated using acetyl sulfate as sulfonating agents and subsequently used for filtration membrane fabrication through the phase inversion method. Membranes were tested in simulated seawater filtration (3.5% NaCl) under constant pressure. At a pressure of 20 psia, permeated flux (J) of pure water and salt rejection (R) varied from 13.8 to 20.5 L m−2 h−1 and 37.8%–50.7%, respectively. It was concluded that membrane's performance is dependent on copolymer composition, the crystallinity of copolymers, and the ionic exchange capacity of membranes, being the best membrane composed of 90/10 of St‐to‐MMA weight ratio and using a monomer‐to‐surfactant weight ratio of 29.9.

Study on the properties of a polymer system based on poly (ethylene glycol), n-isopropyl acrylamide and chitosan for controlled drug delivery

Structured hydrogels with thermo-sensitivity properties to be used as a novel carrier for controlled drug delivery were prepared here. These hydrogels were formed by core-shell particles, where the core is a semi-interpenetrated polymer network (semi-IPN) made of n-isopropylacrylamide (NIPAAm) and poly (ethylene glycol) (PEG), and a chitosan shell. All polymers were synthesized by using semi-continuous heterophase polymerization at different dosing rates to study their effect on particle size, system stability and drug deliver efficiency. Structural (FTIR, particle size, SEM) and functional analysis were performed (stability and drug delivery). FTIR confirmed the polymerization by showing the development of interactions between the characteristic functional groups from the polymers. SEM micrographs from hydrogels revealed a porous structure, which is affected by the dosing rate during the polymerization process as well as the particle size which affect the stability of the obtained latex. Drug release analysis of the hydrogels was performed into distilled water and in a buffer at different temperatures. Results shown that most of the characteristics of this polymer system can be controlled, and so tuning the controlled release behaviour, these findings made these hydrogels an important contender for controlled drug delivery.

A simple model for the semicontinuous heterophase polymerization: Ethyl methacrylate as a case example

A simple but comprehensive model considering homogeneous and micellar nucleation, coagulation, entry of radicals to particles and to micelles and radicals' exit from particles, is presented. The model is validated, in a starved semicontinuous heterophase polymerization of ethyl methacrylate, at three monomer addition rates. The model accurately describes the overall and instantaneous conversion, the average particle density and diameter, and the number and weight average molar masses evolutions over time. It is found that even though the average number of radicals is much smaller than 0.5, the system is not 0‐1. An empirical function was used to describe the gel effect. The homogeneous nucleation was the prevailing mechanism for particle formation and large exit rates of radicals were observed. POLYM. ENG. SCI., 60: 223–232, 2019. © 2019 Society of Plastics Engineers

Ultrafine Nanoparticles of Poly(Methyl Methacrylate-co-Methacrylic Acid) Loaded with Aspirin

Nanoparticles of the poly(methyl methacrylate-co-methacrylic acid) or copolymer of P(MMA-co-MAA), were prepared by semicontinuous heterophase polymerization; they show a mean diameter of 12 nm and a 1.75 MMA/MAA molar ratio determined by carbon-13 nuclear magnetic resonance. The content of MAA, greater than that of Eudragit S100, copolymer of P(MMA-co-MAA) accepted by the FDA for the preparation of tablets, ensures its biocompatibility and its metabolism without toxic effects. Loaded with up to 22 wt. % aspirin, that is, acetylsalicylic acid (ASA), these nanoparticles increase slightly their size, according to transmission electron microscopy; however, the presence of ASA on the nanoparticle surface decreases their stability, which leads to a certain aggregation of the particles in the dispersion. Fourier transform infrared spectrometry was used for demonstrating the loading of ASA in the nanoparticles.

Tunable mechanical properties of core‐shell polymers of poly(hexyl methacrylate) and poly(methyl methacrylate) by semicontinuous heterophase polymerization

The synthesis of core/shell polymers with tunable mechanical properties made of poly(hexyl methacrylate) (PHeMA) and poly(methyl methacrylate) (PMMA) by a two‐stage semicontinuous heterophase polymerization, is presented here. This polymerization technique is characterized by employing low surfactant concentrations to produce large polymer‐to‐surfactant ratios. In this process, monomer is added in a continuous low rate to achieve monomer starved conditions, allowing to control particle size (usually smaller than 50 nm). To modulate the mechanical properties, the weight ratio of core/shell polymers are varied from 10/90 to 90/10 for direct and reverse compositions, respectively. Conversion was followed gravimetrically; nanoparticles were characterized with quasi‐elastic light scattering, IR spectroscopy, differential scanning calorimetry, transmission electron microscopy, and mechanical tests (tensile and hardness). Highly stable latex formed of nanoparticles, with high conversions are obtained. Tensile tests show that the mechanical properties can be tuned according to core/shell composition, mainly in the system formed by PMMA/PHeMA. These results are explained in terms of core‐and‐shell polymers location, composition and hardness. As expected, an increment in concentration of PMMA produces a more rigid material independently of its position. POLYM. ENG. SCI., 59:365–371, 2019. © 2018 Society of Plastics Engineers

Ibuprofen Release from Poly(ethyl cyanoacrylate) Nanoparticles Prepared by Semicontinuous Heterophase Polymerization

Ibuprofen-loaded poly(ethyl cyanoacrylate) nanoparticles were prepared by semicontinuous heterophase polymerization of ethyl cyanoacrylate in the presence of ibuprofen; different surfactant concentration, pH, and temperature were used. Particle size was measured by quasi-light scattering and transmission electron microscopy, while the amount of drug released was determined by UV spectroscopy. Nanoparticles with diameters between 10 and 58 nm, loaded with ibuprofen, were obtained. The smallest particles and the higher drug loading were obtained at the highest pH tested. The analysis of the release data showed that the drug release profiles correspond to the Weibull model. Moreover, it was found that most of the ibuprofen is released within the first 80–120 min; initially the release rate is slow, but then it increases to finally decrease. This behavior contrasts with the reported burst of drug concentration in the plasma after oral administration of IB.

Synthesis, Characterization, and Drug Delivery from pH- and Thermoresponsive Poly(N-Isopropylacrylamide)/Chitosan Core/Shell Nanocomposites Made by Semicontinuous Heterophase Polymerization

Temperature- and pH-responsive core/shell nanoparticles were prepared by semicontinuous heterophase polymerization of N-isopropylacrylamide (NIPA) in the presence of chitosan micelles for drug delivery purposes. Micelles of chitosan, formed in an acetic acid aqueous solution at 70°C containing potassium persulfate, were fed with N-isopropylacrylamide (NIPA) at a controlled rate, to produce PNIPA/chitosan core/shell nanoparticles of about 350 nm. Then, the crosslinking agent, glutaraldehyde, was added to crosslink the nanoparticles. These nanocomposites were temperature- and pH-responsive, which make them suitable as controlled drug releasing agents. The nanoparticles exhibit thermoreversibility to heating-and-cooling cycles and show different responses depending on the releasing medium’s pH. Drug delivery tests were performed, employing as a model drug, doxycycline hyclate.

Preparation of ultrafine poly(methyl methacrylate-co-methacrylic acid) biodegradable nanoparticles loaded with ibuprofen

Ibuprofen-loaded polymeric particles with around 9.2 nm in mean diameter, as determined by electron microscopy, dispersed in an aqueous media containing up to 12.8% solids were prepared by semicontinuous heterophase polymerization. The polymeric material is a (2/1 mol/mol) methyl methacrylate-co-methacrylic acid copolymer similar to Eudragit S100, deemed safe for human consumption and used in the manufacturing of drug-loaded pills as well as micro- and nanoparticles. The loading efficiency was 100%, attaining around 10–12% in drug content. Release studies showed that the drug is released from the nanoparticles at a slower rate than that in the case of free IB. Given their size as well as the pH values required for their dissolution, it is believed that this type of particles could be used as a basis for preparing nanosystems loaded with a variety of drugs.

Biocompatible and Biodegradable Ultrafine Nanoparticles of Poly(Methyl Methacrylate-co-Methacrylic Acid) Prepared via Semicontinuous Heterophase Polymerization: Kinetics and Product Characterization

Ultrafine nanoparticles, less than 10 nm in mean diameter, of the FDA approved copolymer methyl methacrylate- (MMA-)co-methacrylic acid (MAA), 2/1 (mol/mol), were prepared. The method used for the preparation of these particles stabilized in a latex containing around 11% solids includes the dosing of the monomers mixture on a micellar solution preserving monomer starved conditions. It is thought that the operation at these conditions combined with the hydrophilicity of MMA and MAA units favors the formation of ultrafine particles; the propagation reaction carried out within so small compartments renders copolymer chains rich in syndiotactic units very likely as consequence of the restricted movements of the end propagation of the chains. Because of their biocompatibility and biodegradability as well as their extremely small size these nanoparticles could be used as vehicles for improved drug delivery in the treatment of chronic-degenerative diseases.

Preparation and Loading with Rifampicin of Sub-50 nm Poly(ethyl cyanoacrylate) Nanoparticles by Semicontinuous Heterophase Polymerization

We report the preparation of poly(ethyl cyanoacrylate) (PECA) nanoparticles by semicontinuous heterophase polymerization carried out at monomer starved conditions at three monomer addition rates. Particles in the nanometer range were obtained, the size of which diminishes with decreasing monomer addition rate as shown by the fact that particles with mean diameters of ca. 42 and 30 nm were obtained at the faster and intermediate dosing rates, respectively, whereas two populations of particles, one of 15.5 and the other of 36 nm in mean diameters, were produced at the slower dosing rate. The obtained molecular weights were from 2,200 to 3,500 g/mol, depending on the addition rate, which are typical of the anionic polymerizations of cyanoacrylates in aqueous dispersions at low pHs. The rifampicin (RIF) loading into the nanoparticles was successful since the entire drug added was incorporated. The drug release study carried out at pH of 7.2 indicated a faster release from the free RIF at intermediate and larger release times as expected since, in the nanoparticles, first the drug has to diffuse through the nanoparticle structure. The comparison of several drug release models indicates that the RIF release from PECA nanoparticles follows that of Higuchi.

Semi-Continuous Heterophase Polymerization to Synthesize Nanocomposites of Poly(acrylic acid)-Functionalized Carbon Nanotubes

Two materials, pure poly(acrylic acid) (PAA) and nanocomposites with a matrix of PAA and carbon nanotubes (CNTs) as reinforcing agent were synthesized by semi-continuous heterophase polymerization (SHP). CNTs were prepared by a chemical vapor deposition technique and purified by steam. CNTs were characterized by a high resolution scanning electron microscopy (HRSEM) and Raman and Fourier transform infrared spectroscopies. Nanocomposites were prepared with: (i) purified CNTs (CNTsp) or (ii) purified and functionalized CNTs possessing an acyl chloride moiety (CNTsOCl). In both cases, the nanocomposites synthesis was carried out by in situ polymerization of acrylic acid (AA) by SHP. When CNTsOCl were used previously to the polymerization of AA, a series of specific amounts of CNTsOCl and AA were mixed to induce a chemical reaction between the carboxyl group of AA and the acyl chloride group of the CNTsOCl. The product, acrylic acid grafted to CNTsOCl (CNTsOCl-AA), was used to prepare the PAA-CNTsOCl nanocomposites. The PAA-CNTsOCl nanocomposites were characterized by HRSEM, Raman, FTIR and CPMAS 13C-NMR spectroscopies and also by thermogravimetric analysis (TGA). The results reveal that PAA-CNTsOCl nanocomposites were formed by PAA macromolecules grafted to CNTsOCl. The kinetic behavior observed for the synthesis of pure PAA or PAA-CNTsOCl nanocomposites by SHP was similar. Latexes of PAA-CNTsOCl nanocomposites were stable without formation of a precipitate of CNTsOCl for over 1.5 years, while latex prepared with CNTsp and PAA, was unstable and formation of a precipitate of CNTsp was observed immediately after its preparation. PAA-CNTsp nanocomposites were characterized only by TGA. Moreover, latex of the PAA-CNTsp nanocomposite that did not precipitate immediately after its preparation, turned into a gel; this gelation never occurred with the PAA-CNTsOCl nanocomposite latex.

On the Modeling of the Semicontinuous Heterophase Polymerization of Alkyl Methacrylates With Different Water Solubilities

A generalized model is presented here for the semicontinuous heterophase polymerization of methyl and hexyl methacrylate, which have very different water solubility. In this polymerization technique, neat monomer is fed at a controlled rate over a monomer‐free aqueous solution of surfactant and initiator, to produce nanometer size particles with controlled molar masses, and high polymer/surfactant ratios similar to those used in conventional emulsion polymerization. For the two monomers studied at three different addition rates, model predictions accurately reproduce conversion‐versus‐time curves, the evolution of particle size, and the number density of particles. The model reveals that the controlling nucleation mechanism shifts from micellar to homogeneous nucleation as the monomer solubility in water increases.

Effect of pH and Monomer Dosing Rate in the Anionic Polymerization of Ethyl Cyanoacrylate in Semicontinuous Operation

Nanoparticles of poly(ethyl cyanoacrylate) with more than 10% solids content were prepared by semicontinuous heterophase polymerization at monomer-starved conditions varying the initial pH in the interval of 1–1.75 and at two monomer dosing rates. Measurements by scanning-transmission electron microscopy allowed us to identify an inverse dependence of particle size on pH. Furthermore, all the polymerizations conducted at the slower monomer dosing rate rendered two particle populations, with the larger one formed from the aggregation of a fraction of the smaller particles. It was believed that the so slow addition of the monomer caused the formation of very small but instable particles, thereby a fraction of which aggregated to reduce the total interface particles-aqueous phase, increasing the latex stability. An increase in the monomer dosing rate led to larger and more stable particles in such way that only one population of nanoparticles with around 40 nm in average diameter was obtained.

Effect of Monomer Dosing Rate in the Preparation of Mesoporous Polystyrene Nanoparticles by Semicontinuous Heterophase Polymerization

The semicontinuous heterophase polymerization of styrene in the presence of cross-linking and porogen agents was carried out. Latexes with close to 20% solid content, which contained mesoporous nanoparticles with 28 nm in average diameters, up to 0.5 cm3/g in porosity and 6–8 nm in pore diameters were obtained. By varying the monomer dosing rate over the micellar solution, an unexpected direct dependence of instantaneous conversion on the monomer dosing rate was found. This was ascribed to the higher average number of radicals per particle attained in the polymerization at the higher dosing rate, which in turn would arise from the higher gel percentage in the polymer. It is believed that the cross-linked chains prevent encounters between radicals, delaying the bimolecular termination reactions and allowing the existence of more than one radical inside the particles, which in turn increases the propagation rate.

Ultrasound-assisted polymerization of methyl methacrylate using the reactive surfactant Hitenol BC10 in a semicontinuous heterophase process

Semicontinuous heterophase polymerization was used to polymerize methyl methacrylate (MMA) with the reactive surfactant Hitenol BC10 (polyoxyethylene(10)alkylphenyl ether ammonium sulfate, HBC10) in the presence of ultrasound at 50 °C. The effects of HBC10 concentrations and the monomer addition rate (R a) on kinetics, colloidal behavior, and molar masses were studied. Latexes with polymer content between 20 and 24 % were obtained. Particle size distributions (PSD) of latexes without HBC10 were bimodal, whereas those obtained in the presence of HBC10 were mono-modal in all cases. The average particle diameters (D p) were in the range of 39–63 nm decreasing with the HBC10 concentration and increasing with R a. Polymerization rates (R p) were decreased, by increasing the HBC10 concentration, which was ascribed to chain transfer events to HBC10. It was also observed that R p increased with R a; however, monomer-starved conditions were favored at lower R a values. Very high-average molecular weights were observed (1.63 × 106 ≤ M w ≤ 2.34 × 106 g/mol) which decreased when HBC10 concentration increased, and increased with R a. The corresponding polydispersity indexes (M w/M n) were in the range of 1.55–2.30, showing relatively wide molar masses distributions. It was observed from differential scanning calorimetry that polymers with HBC10 presented two T g (123 and 178 °C) which was ascribed to HBC10 incorporated to PMMA chain, corroborated by 1H NMR.

SEMICONTINUOUS HETEROPHASE POLYMERIZATION AS A TOOL FOR PREPARING ULTRAFINE NANOPARTICLES OF IBUPROFEN-POLY(METHYL METHACRYLATE)

Ibuprofen-loaded poly(methyl methacrylate) nanoparticles with mean diameters smaller than 20 nm were prepared by a novel method. This consists in carrying out a semicontinuous heterophase polymerization, in which a solution of drug-monomer is added on a micellar solution at an appropriate dosing rate. Scanning transmission electron microscopy (STEM) measurements showed number-average diameters in the range 16–19 nm with 1.14–1.15 in polydispersity, determined as the ratio of weight-average to number-average diameter. Drug contents in nanoparticles close to 24% were determined by UV-Vis spectrophotometry, confirming the results obtained from a procedure that combines latex filtration and quasielastic light scattering (QLS) measurements. Differential scanning calorimetry (CDSC) determinations suggest that at the ibuprofen contents attained in this study, crystals and dispersed molecules of the drug coexist inside the nanoparticles. Based on the relative simplicity of the process it is expected that its use will be adopted to prepare ultrafine nanoparticles composed of different hydrophobic polymers and water insoluble drugs.

Swelling Behavior of Poly(N-isopropylacrylamide) Nanogels with Narrow Size Distribution Made by Semi-continuous Inverse Heterophase Polymerization

The synthesis of poly(N-isopropylacrylamide) nanogels by semi-continuous inverse heterophase polymerization (SIHP) under monomer starved conditions is reported here. This process consists in adding a N-isopropylacrylamide (NIPA) aqueous solution at a controlled rate over a monomer-free oleic solution containing surfactant and initiator. The nanogels became smaller with narrower size distributions as the addition rate was decreased. Moreover, nanogel sizes, the size distributions and more importantly, the polymer/surfactant ratios were smaller than those of PNIPA nanogels synthesized by batch inverse microemulsion polymerization (BIMP). The swelling behavior of these nanogels in water as a function of temperature is reported. As expected, all nanogels have a volume phase transition temperature at ca. 33–34°C.

Synthesis of polypyrrole nanoparticles by batch and semicontinuous heterophase polymerizations

Nanoparticles of semiconducting polypyrrole (PPy) were synthesized by batch heterophase (BHP) and semicontinuous heterophase polymerization (SHP) using ferric chloride (FeCl3), potassium persulfate (KPS), or ammonium persulfate (APS) as the oxidizing agent, sodium dodecyl sulfate (SDS) as surfactant, and ethanol (EtOH) or iso-pentyl alcohol (iC5OH) as co-surfactants. In all cases, the molar ratios of monomer/oxidizing agent were 1/1. Pyrrol polymerization by BHP and SHP allowed using much lower percentages of surfactant than those employed in microemulsion polymerization of this monomer. The effects of temperature, oxidizing agent, and co-surfactant on conductivity were studied. The polymers were analyzed by transmission electron microscopy (TEM), UV/Visible and Fourier transform infrared (FTIR) spectroscopies, and cyclic voltammetry. Higher PPy conductivities were obtained by polymerizing at 0 °C with FeCl3 as the oxidizing agent, in the presence of iC5OH as co-surfactant. When the reaction was carried out by SHP with low reaction times, smaller particles with similar conductivities were obtained compared to those obtained by BHP; the conductivity of PPy decreases with increasing polymerization time, which can be explained by PPy overoxidation.

Semicontinuous Heterophase Polymerization of Methyl and Hexyl Methacrylates to Produce Latexes with High Nanoparticles Content

The semi-continuous heterophase polymerization (SHP) under monomer-starved conditions of methyl methacrylate and hexyl methacrylate is reported, at various monomer addition rates to elucidate the effect of monomer solubility on the mechanism of particle nucleation and growth. Polymer particles in the nanometer range from both monomers were obtained, which decreased in size as monomer addition rate was decreased. Molar masses of both polymers also diminished as monomer addition rate was slowed down. The propagation rate constant dictates how fast the starved condition is achieved rather than the monomer solubility in the aqueous phase. A slow particle rate of growth helps to obtain a narrower PSD.