Article pubs.acs.org/Langmuir
Continuous Polymer Nanocoating on Silica Nanoparticles Dengyue Chen, Dhananjay Singh, and Kamalesh K. Sirkar* Otto York Department of Chemical, Biological and Pharmaceutical Engineering, New Jersey Institute of Technology, University Heights, Newark, New Jersey 07102, United States
Jiangtao Zhu School for Engineering of Matter, Transport and Energy and LeRoy Eyring Center for Solid State Science, Arizona State University, Tempe, Arizona 85287, United States
Robert Pfeffer School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, Arizona 85287, United States ABSTRACT: Continuous polymer coating of nanoparticles is of interest in many industries such as pharmaceuticals, cosmetics, food, and electronics. Here we introduce a polymer coating/precipitation technique to achieve a uniform and controllable nanosize polymer coating on nanoparticles in a continuous manner. The utility of this technique is demonstrated by coating Aerosil silica nanoparticles (SNPs) of diameter 12 nm with the polymer Eudragit RL 100. Both hydrophilic and hydrophobic SNPs were successfully coated. After determining the cloud point of an acetone solution of the polymer containing a controlled amount of the nonsolvent water, the solid hollow fiber cooling crystallization (SHFCC) technique was employed to continuously coat SNPs with the polymer. A suspension of the SNPs in an acetone−water solution of the polymer containing a surfactant was pumped through the lumen of solid polypropylene hollow fibers in a SHFCC device; cold liquid was circulated on the shell side. Because of rapid cooling-induced supersaturation and heterogeneous nucleation, precipitated polymers will coat the nanoparticles. The thickness and morphology of the nanocoating and the particle size distribution of the coated SNPs were analyzed by scanning transmission electron microscopy (STEM) with electron energy loss spectroscopy (EELS), thermogravimetric analysis (TGA), and dynamic light scattering (DLS). Results indicate that uniformly polymer-coated SNPs can be obtained from the SHFCC device after suitable post-treatments. The technique is also easily scalable by increasing the number of hollow fibers in the SHFCC device.
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INTRODUCTION
Silica nanoparticles can often be used as a model or surrogate for drug nanoparticles. In fact, silica nanoparticle-based drug delivery systems have also attracted considerable attention for a variety of reasons (see ref 12). A facile method of continuously coating or encapsulating SNPs with a desired polymer would be quite useful for a variety of applications. Wang et al.13 have summarized dry or wet methods currently utilized to encapsulate nanoparticles: sol-gel processes, emulsification, and solvent evaporation techniques are examples of wet methods; physical vapor deposition, plasma treatment, chemical vapor deposition, atomic layer deposition, and pyrolysis of polymeric organic materials are examples of dry methods. In addition, supercritical fluid-based processes such as rapid expansion of supercritical solutions (RESS), supercritical antisolvent (SAS), and gas antisolvent (GAS) processes have
Nanoparticles are being increasingly utilized for a variety of novel applications including circulation diagnostics,1 therapies,2 drug delivery systems,3 developing surfaces having antifungal, antibacterial, and antiviral properties,4 and enzyme stabilization.5 Drug delivery systems are of particular interest especially in controlled release of drugs,6,7 as nonviral gene delivery vehicles,8 and in delivery of anticancer drugs and imaging agents to tumors,9 among others. In many drug delivery applications, drug nanoparticles have to be coated with a polymer to protect fragile drugs such as proteins against, for example, stomach acids. In other applications, a dense poly(ethylene glycol) coating improved penetration of polymeric nanoparticles within brain tissue in cases where the blood−brain barrier is compromised;10 such a coating also allowed nanosized drug particles to overcome a mucus barrier, resulting in sustained drug delivery to specific cells in the body at mucosal surfaces.11 © 2014 American Chemical Society
Received: March 2, 2014 Revised: May 6, 2014 Published: June 5, 2014 7804
dx.doi.org/10.1021/la500834p | Langmuir 2014, 30, 7804−7810
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Herein we describe the results of using such a device to continuously coat 12 nm SNPs with Eudragit, a polymer frequently used to coat drug particles. The thickness and morphology of the nanosized polymeric coating and the silica nanoparticle size distribution were analyzed using the following techniques: scanning transmission electron microscopy (STEM) with electron energy loss spectroscopy (EELS), thermogravimetric analysis (TGA), and dynamic light scattering (DLS).
been successfully used to coat nanoparticles. Among these batch processes,13−17 those utilizing supercritical CO216 require very high operating pressures, ∼190 MPa; SAS processes require a pressure ∼10 MPa, which is still quite high.13 Very low polymer solubility in supercritical CO2 at lower temperatures ( 80% as clear. A small amount of the polymer solution in acetone containing the nanoparticles along with a few drops of water was decanted to a cuvette in the UV spectrophotometer under continuous stirring; the solution in the cuvette was first heated up to 50 °C for 30 min then slowly cooled down in steps of 1 °C/min to 5 °C. The temperature at which the transmissivity was reduced sharply was regarded as the cloud-point temperature for the solution concentration level used. A scanning transmission electron microscope (ARM 200F, JEOL, Peabody, MA) was used to capture the image of polymer-coated SNPs and to visualize the thickness and the morphology of the coating. Elemental mapping was done using electron energy loss spectroscopy (EELS) to analyze the surface coating structure by locking onto carbon, which is the main element of the coating. A small amount of dry-coated particles was first dispersed in deionized water and sonicated to break up soft agglomerates. Then a single drop of water containing coated nanoparticles was placed on the pin stub for STEM analysis after drying. A thermogravimetric analyzer (Pyris 1, PerkinElmer, Waltham, MA) was also used to determine the amount of coating on the nanoparticles. The coating thickness was calculated from the weight loss during heating. A nanoparticle size analyzer (N4 Plus, Beckman Coulter, Brea, CA) based on photon correlation spectroscopy was used to determine particle size distribution (PSD) and the degree of agglomeration of the uncoated and coated nanoparticles.
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RESULTS AND DISCUSSION Different concentrations of Eudragit RL100/acetone solutions were added to a set of cuvettes to determine the absorbance change as the solution concentration was varied at room temperature (25 °C). From such data, we find that there is a sharp change of absorbance at a concentration of 0.16 g/mL; the absorbance rises to 0.28 from 0.14 as the solution concentration is increased to 0.18 g/mL. The turning point of ∼0.16 g/mL was therefore chosen as the cloud point at room temperature. This solution has a high viscosity; it cannot be easily passed through the lumen of the hollow fibers in the module. Furthermore, this Eudragit−acetone solution is insensitive to temperature change. Therefore, the cloud point for a ternary system of polymer/solvent/water was studied by using the transmissivity test under visible wavelength. For example, without any nonsolvent addition, even with a rapid reduction in the temperature of the solution from 20 to 9 °C, the transmissivity of a 10 wt % Eudragit/acetone solution still remained above 90%, which indicated that this solution was 7806
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temperature rise, leading to a weight loss of the sample. Figure 4 shows the observed weight loss results for uncoated and
almost clear without any polymer precipitation. This observation was also consistent with visual observation. After adding a limited amount of deionized (DI) water as a nonsolvent, a small amount of Aerosil 200 was added to the polymer solution. When the temperature was reduced from 40 to 10 °C, the transmissivity deceased rapidly as the temperature was decreased. Polymer precipitated in the solution during this process, and visually the solution tuned from clear to cloudy. It was relatively easy to adjust the cloud-point temperature by varying the ratio of the solvent to water. The higher the amount of nonsolvent added to the solution, the higher the observed value of the cloud point temperature. A temperature of 15 °C was chosen as the cloud point in this experiment. Figure 3 shows the variation in the cloud-point temperature with the amount of water added to the acetone solution in vol %.
Figure 4. TGA micrographs for uncoated SNPs and Eudragit-coated SNPs after post-treatments (filtration, sonication, and drying).
coated SNPs. The dotted line indicates that pure Aerosil 200 SNPs underwent hardly any weight loss during heating. However, both solid lines for the coated SNPs show considerable weight loss due to the decomposition of the polymer coating. The mass losses of coated particles from the large and smaller modules are estimated to be 60% and 55%, respectively; these values are quite close to each other. This result suggests that scale-up of the coating device and process may be easily implemented by maintaining the same residence time in SHFCC modules of different sizes having different numbers of hollow fibers. If we assume that the polymer coating is evenly spread over all SNPs and the nanoparticles are spherical, the relation between the coating thickness h of the polymer and the silica nanoparticle of radius r is given by eq 1 where mSilica and mPolymer are the mass of a nanoparticle and its polymer coating, respectively:
Figure 3. Cloud-point temperature versus the percentage of water added to Eudragit RL100 solutions containing SNPs.
The amount of SNPs plays an important role in polymer coating using the SHFCC method. The amount of polymer that will precipitate depends on the temperature, pressure, and concentrations of solvent and antisolvent. However, the rate of precipitation is quite slow in the absence of nanoparticles for the residence times employed. When present, the nanoparticles act as nuclei for heterogeneous precipitation. The more nanoparticles present (greater surface area) for a fixed amount of polymer precipitation, the thinner is the coating on each individual nanoparticle. The coated SNP samples obtained after post-treatment steps of filtration, sonication, and vacuum drying were analyzed by TGA to determine the relationship between the average coating thickness on a SNP and the amount of silica added in the feed solution−suspension. It is useful to specify first the conditions used to obtain the coated SNPs that were subjected to TGA studies. We used both the larger and the smaller SHFCC modules to produce coated particles and compared their effective coating thicknesses. For both modules, we kept the operating conditions the same: 0.1 g SNPs, 20 mL acetone, 0.025g SDS, 2.4 g Eudragit RL 100, and 4 mL DI water. The only difference between the two modules is the number of hollow fibers. To maintain the same residence time for precipitation in both modules, a feed flow rate of 4 mL/min was maintained in the large module, which was twice that in the small module (2 mL/min). Details of the results from TGA are provided below. A small amount of sample was placed in a hangdown pan inside the TGA analyzer; then the temperature was increased to 550 from 25 °C at a rate of 10 °C/min. The polymer coating around the silica nanoparticles decomposed during this
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ρSilica 3 πr 3 mSilica = 4 mPolymer ρPolymer 3 π {(r + h)3 − r 3}
(1)
The coating thickness h can then be calculated from eq 1 as h = r(1 + (ρSilica mPolymer /ρPolymer mSilica ))1/3 − r
(2)
The radius r of a silica nanoparticle is 6 nm. The densities of the host particles and the polymer are ρSliica (2.65 g/mL) and ρPolymer (1.1 g/mL), respectively. Using the results of TGA experiments for different amount of SNPs added, we can estimate the average nanocoating thickness on the SNPs from eq 2. For example, 0.05 g of SNPs added to the original feed solution resulted in a thickness of 4.3 nm whereas 0.10 g of SNPs yielded a thickness of 3.9 nm. With a further increase in SNP addition to 0.15 g, the coating thickness decreased to 3.6 nm. The amount of SNPs plays an important role in polymer coating using the SHFCC method because the precipitated polymer will coat every SNP due to heterogeneous nucleation. The higher the amount of silica added, the lower is the amount of polymer that will be precipitated on a given particle (resulting in a thinner coating) due to the much higher density of nucleation sites with increasing number of SNPs. All of these experiments were carried out in the larger SHFCC module. 7807
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the polymer coating and silica nanoparticles appear as red and purple zones. This figure shows that all silica nanoparticles were uniformly coated by Eudragit RL 100 in both the small and the large module. We do not observe any significant difference in coating thickness between the two modules. Parts a and b of Figure 6 show that the coating thicknesses in the small and large modules are 3.6 and 4.0 nm, respectively. The very limited difference in coating thickness from one module to another indicates that, as long as the residence time is the same, scaling up by simply increasing the number of fibers is feasible. STEM analysis is a good way to characterize the film coating thickness, surface morphology, element distribution, particle size, and degree of agglomeration. In our case, a 1D line scan and 2D mapping provided by EELS add-on are used to analyze the samples. The blue straight line in Figure 7a shows that the detector moves along the direction of the arrow so that it first contacts the left side of the polymer coating boundary, passes through the interior of the SNP, and then moves across the right polymer coating boundary. Two peaks at the edge of the particle showing the carbon profile in Figure 7b illustrate the polymer coating around the outer surface area of the nanoparticle. EELS spectrum (not shown here) confirmed that the nanoparticle is silica as it contains three elements, silicon, oxygen, and carbon, which comes from the coating. Figure 7c is the silicon intensity profile across the particles following the same arrow in Figure 7a, which also shows that the material inside consists of only silica. STEM 2D mapping (Figure 8) can directly visualize different element distributions to reveal the coating morphology. Figure 8b shows that the polymer coating is evenly distributed over the entire SNP surface area and the thickness is quite uniform. The actual coating thickness can also be estimated by using the scale bar on the bottom left of Figure 8a. In this case the thickness is estimated to be 4 nm. We have also investigated whether the SHFCC technique can be employed to coat host nanoparticles having different surface properties such as hydrophilicity or hydrophobicity. For all of the results presented above, Aerosil 200, which is hydrophilic, was used as the host particles. However, Aerosil R974, a hydrophobic silica particle having a primary particle size of 12 nm, was also successfully coated with Eudragit RL100 by applying the SHFCC technique (see Figure 9). The green area in this figure suggests that the polymer was evenly coated
The coating thickness can also be determined directly by measuring the coating thickness from the STEM micrographs of coated SNPs based on the scale bar at the bottom left side of the images (see Figure 8). Figure 5 shows that the measured
Figure 5. Results of coating thickness versus silica addition (larger module) obtained by two methods: STEM and TGA.
coating thickness decreases as the amount of SNPs is increased. Figure 5 also shows the coating thicknesses obtained from the TGA studies described above. The results from STEM measurements appear to be in reasonable accord with those from TGA measurements. For every sample tested, we have 2 or 3 other images (not shown here). The average values have been reported. STEM micrographs shown in Figure 6 are 2D mapping images obtained by EELS in which the green cover represents
Figure 6. EELS 2D elemental maps for coated SNPs, carbon K-edge in green, silicon L3,2-edge in red or purple from (a) the small module and (b) the large module.
Figure 7. . (a) STEM images of coated nanoparticles; (b) carbon intensity profile and (c) silicon intensity profile along the arrow in panel (a). 7808
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Figure 8. EELS 2D elemental map of (a) carbon K-edge, (b) silicon L3,2-edge, and (c) colorized map, with carbon in green and silicon in red. Figure 10. Particle size distribution by number for uncoated SNPs and those coated by two methods; mean particle size and the extent of agglomeration of the particles are provided for the three cases in the inset at the top of the figure.
particle size of a single SNP (12 nm). Before coating it appears that on average ∼4 primary nanoparticles are sintered together and aggregated with an estimated size of 50 nm. After coating with Eudragit in the presence of a higher surfactant concentration based on the measured mean size (103 nm), ∼9 coated nanoparticles stick together to form agglomerates. It is important to note that because the silica nanoparticles were produced in a high-temperature furnace, sintering of the primary SNPs as well as attractive van der Waals force caused uncoated SNPs of 12 nm diameter (blue line) to show a certain level of aggregation. The PSD of the coated nanoparticles by the standard procedure using a lower level of surfactant is much wider than that of the uncoated particles because of the fact that polymer coating will also cause the particles to stick to one another and form solid bridges between particles upon drying, even in the presence of a surfactant and sonication posttreatment. However, as seen in Figure 10, a higher surfactant concentration and reducing post-treatment processing delays considerably reduced the level of observed agglomeration. It would be worthwhile to investigate nanocoating of a single SNP if the primary SNPs have not undergone any sintering and van der Waals force may be counteracted. Nance et al.10 have shown that, with the right coating, larger nanoparticles can diffuse throughout the extracellular space in rat and human brains, which is especially useful for diseases in the case of a compromised blood−brain barrier. However, recent literature evidence suggests that monodisperse NPs of size
