Production of Naproxen Nanoparticle Colloidal Suspensions for Inkjet

Jan 24, 2014 - A simple technique for producing and processing naproxen nanoparticle colloids for use in inkjet printing is presented in this report. ...
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Production of Naproxen Nanoparticle Colloidal Suspensions for Inkjet Printing Applications Jonathan T. Essel,* Andrew C. Ihnen, and Joshua D. Carter Naval Air Warfare Center Weapons Division, China Lake, California 93555, United States ABSTRACT: Nanoparticulate drugs show promise for a variety of reasons, including novel targeted delivery mechanisms, enhanced in vitro diagnostics, and increased bioavailability. However, there are often practical limitations to using nanoparticles, such as nanoparticle agglomeration and processing. Inkjet printing provides a viable method to produce nanocomposites from nanoparticles. A simple technique for producing and processing naproxen nanoparticle colloids for use in inkjet printing is presented in this report. Naproxen nanoparticles predominantly 50 nm in diameter and coated in polyvinylpyrrolidone were produced using a supercritical solution-based method, the rapid expansion of a supercritical solution into a liquid solvent (RESOLV) process. The viscosity and surface tension of the RESOLV suspensions were then modified to 10.6 cSt and 34.2 mN/ m, respectively, to demonstrate the feasibility of turning the RESOLV suspension into a printable ink. The results suggest that combining the RESOLV and inkjet platforms can overcome the processing and agglomeration issues often associated with producing true nanocomposites. deposited onto edible substrates using a syringe pump.10 One advantage of applying inkjet technology would be the controlled deposition of nanoparticle drugs, where practical concerns often prevent their use. To be effective, sufficiently small, dispersed colloids need to be formed in a solution that can be manipulated as needed to become a printable ink, with sufficient solids loading, surface tension, volatility, and viscosity among other key variables of concern. This will allow true nanoparticulate drugs to be used and their potential effects to be realized. A promising method of producing naproxen nanoparticles is through supercritical fluid precipitation. Supercritical fluids have proven to be very useful in the precipitation of fine powders. One particularly useful process is the rapid expansion of a supercritical solution (RESS) process, which mechanically expands a supercritical solution through an orifice or nozzle.11 While the RESS process has been shown to be useful in producing submicrometer particles, an even more effective method of producing nanoparticles is the rapid expansion of a supercritical solution into a liquid solvent (RESOLV) process, in which a supercritical solution is mechanically expanded into a liquid and dispersant solution.12 The dispersants in the liquid solution stabilize the newly formed particles and help prevent their aggregation as well as arrest their growth from the coagulation of particles during the supercritical fluid expansion process. The result is often the formation of well-dispersed nanoparticles in a colloidal suspension. Previously, polymer particles under 100 nm have been formed with the RESOLV process,13,14 and ibuprofen nanoparticles as small as 30 nm have been created with the process using the polymers PVP and polyethylene glycol (PEG) as a dispersant.15 In addition,

1. INTRODUCTION Growing evidence indicates that nanoparticles are superior to their micrometer-sized counterparts in their ability to provide effective drug delivery to certain parts of the body. One drug that has the promise to make use of these benefits is the nonsteroidal anti-inflammatory drug (NSAID) naproxen, which is commonly used to alleviate pain and reduce inflammation.1 Generally, naproxen is formed from the consolidation of micrometer-sized particles into a single tablet. Most tablets of naproxen consist of 250−500 mg of naproxen with small amounts of inactive ingredients, such as cellulose, magnesium stearate, iron oxides, and polyvinylpyrrolidone (PVP) as a binder.2 Relative to those used in tablets, naproxen nanoparticles with higher surface areas increase the rate of introduction to the bloodstream and can be used in novel delivery methods.3 Naproxen nanoparticles can also enhance intracellular uptake in comparison to micrometer-sized particles.4 In addition, studies have shown that nanoparticles of naproxen are absorbed at 4 times the amount of micrometersized particles and showed decreased gastric irritation.5 While naproxen nanoparticles have many benefits, they can be difficult to process. Nanoparticles agglomerate easily in air and thus can potentially leave voids when the material is pressed into tablets. An alternative method to manufacturing the nanoparticles would be ideal. Novel additive manufacturing processes of NSAID drugs could provide a novel means to produce the drug in a more convenient and efficient way with higher bioavailability. Direct-write material processing platforms, particularly inkjet printing, have revolutionized how materials are made by allowing for increasingly complex geometries over a variety of length scales.6−8 The unique capabilities of the technology is evident in the variety of materials that have been printed, including pharmaceutical compounds.9 The technology can be used to accurately deposit nanoparticles onto a substrate. Edible substrates are of interest, and in related work, naproxen−PVP solutions were processed using a droplet printing technique, where the solutions were This article not subject to U.S. Copyright. Published 2014 by the American Chemical Society

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November 13, 2013 January 22, 2014 January 24, 2014 January 24, 2014 dx.doi.org/10.1021/ie4038517 | Ind. Eng. Chem. Res. 2014, 53, 2726−2731

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temperature at all times, an extraction vessel, and an expansion vessel. All of these components were manufactured or supplied by Waters. For this investigation, soda-grade carbon dioxide (Praxair, Danbury, CT) was used. The solvent cylinder was equipped with a siphon tube to ensure that only liquid carbon dioxide was delivered to the solvent pump. The naproxen solute was placed in the extraction vessel as it was received and a mechanical fluid agitator was turned on to decrease the dissolution time. The expansion vessel was filled with a liquid water and PVP-360 solution, consisting of 25 mg of PVP-360 in 400 mL of deionized water. The expansion nozzle was located at the bottom of the expansion vessel. For producing a batch of the colloidal suspension, the naproxen solute was dissolved in supercritical carbon dioxide for about 1 h and then the supercritical solution was expanded through the nozzle for about 20 min. The process was repeated until enough naproxen particles were produced. A pre-expansion pressure of P0 = 275 bar and a pre-expansion temperature of T0 = 75 °C was used. On average, about 400 mg was produced in 400 mL of aqueous PVP-360 solution. After formation, the properties of the particles in the colloidal suspension were characterized for their size, shape, ζpotential, and chemical integrity. Dynamic light scattering (DLS) measurements were taken with a Zetasizer Nano ZS (Malvern Instruments, Worcestershire, England). For a comparison to the DLS measurements, field emission scanning electron microscope (FE-SEM) images were taken of the produced particles with a SUPRA55 FE-SEM (Carl Zeiss AG, Jena, Germany). For the FE-SEM images, a few drops of the produced colloidal suspension were placed on an aluminum pan, which was located directly on an aluminum stub used with microscope imaging. The stub was allowed to dry for 24 h and was later iridium-coated for better imaging purposes. In addition to images, the ζ-potential of the particles was measured with the Zetasizer Nano ZS. About 1 mL of suspension was placed into a cuvette and the ζ-potential of the particles was measured by electrophoresis. Finally, Fourier transform infrared (FTIR) analysis was performed on naproxen, PVP, and the RESOLV-produced particles to see if the chemical integrity of the particles changed after being formed with the RESOLV process. FTIR was carried out using a Nicolet iS10 FTIR (Thermo Fisher Scientific, Waltham, MA). FTIR spectra were taken at an average of 32 scans, at 2 cm−1 resolution, and were baseline and background corrected. The fluid properties of the RESOLV-produced suspension were characterized as produced and after ingredient modifications to determine the feasibility of using this colloidal suspension as an ink. As the suspension was aqueous-based, its boiling point was sufficiently high for typical printing requirements, and therefore, only the viscosity and surface tension were investigated. Viscosity measurements were taken using either a 75 (range 1.6−8 cSt) or 150 (range 7−35 cSt) size U-tube Cannon-Fenske routine viscometer (Cannon Instrument Co., State College, PA). It should be noted that the measured value was the kinematic viscosity (cSt), and the viscosities of inks for printing are often described using absolute or dynamic viscosity (cP). For the purposes of this study, the values are considered equivalent, as the suspension in this investigation is aqueous-based with a density of around 1 g/ cm3.21 Surface tension measurements were taken with a Nima Langmuir−Blodgett trough (Coventry, England) configured to measure the surface tension of potential ink formulations using the Wilhelmy method. The surface tension measurements were

particles produced with the RESOLV process have been shown to be more stable against aggregation,16 which is a common problem with nanoparticles. For naproxen, researchers have shown that naproxen particles produced through the RESOLV process are submicrometer in diameter.17 The RESOLV process also has an additional advantage in forming biodegradable polymer-coated naproxen particles in situ, as the polymer coating can increase a drug’s therapeutic range.18,19 A big advantage of the RESOLV process is that the colloidal suspensions produced in the process occupy the length scale ideal for inkjet printing, which are particles less than 200 nm in diameter.20 Another advantage is that the RESOLV-produced suspensions can be made into printable inks by incorporating easy to obtain additives to adjust the bulk fluid properties, such as viscosity and surface tension. For this study, the RESOLV process was used to produce naproxen nanoparticles, initially suspended in water with PVP as the main dispersant. The PVP-coated particles were analyzed and their colloidal properties were investigated for inkjet printing purposes. After the initial colloidal suspensions were formed and characterized, additives were introduced to make the suspension’s bulk fluid properties typical of inks suitable for drop-on-demand inkjet printing.

2. EXPERIMENTAL SECTION For this investigation, PVP was used as the dispersant and naproxen as the substance to be printed. The naproxen was obtained from Aldrich (St. Louis, MO). The PVP was obtained from Aldrich and had a molecular weight of 360 000 (PVP360). It was anticipated that higher molecular weight PVP would produce smaller particles that are more effectively dispersed in the RESOLV process.15 In addition to acting as a dispersant, PVP can also increase the viscosity of aqueous solutions. This increase in viscosity is advantageous for turning the RESOLV-produced aqueous solution into an ink for inkjet printing applications. Polysorbate 20, which was purchased from Aldrich, was used in this investigation to reduce the surface tension of the aqueous solution to levels that are suitable for inkjet printing. Molecular structures for the naproxen, PVP, and polysorbate 20 are depicted in Figure 1.

Figure 1. (a) Naproxen, (b) PVP, and (c) polysorbate 20 molecules.

For this investigation, the RESOLV process was used to form the fine naproxen particles in a water and PVP-360 solution. As previously mentioned, the RESOLV process has the advantage of producing and dispersing ultrafine naproxen particles in one step. A process flow diagram of the RESOLV system is shown in Figure 2. The system is a modified version of a prefabricated RESS system (Waters Corp., Milford, MA). The system consists of a solvent supply cylinder, a chiller to ensure that the solvent remained a liquid while being pumped, a pump, multiple heaters to ensure that the fluid was above its critical 2727

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Figure 2. Flow diagram of the RESOLV system.

calibrated against deionized water, which has a well-known value. After the fluid properties of the produced colloid were altered for printing purposes, jettability studies were conducted with a Dimatix DMP-2800 series materials printer (Fujifilm Dimatix Corp., Santa Clara, CA) in which the feasibility of printing the colloidal suspension was determined. In addition, deposition studies of the final ink were performed with the inks so that the final nanocomposite could be investigated.

3. RESULTS AND DISCUSSION FE-SEM and DLS analysis indicates that the RESOLV method predominantly produced naproxen nanoparticles. An example of the as-received naproxen powder is illustrated in Figure 3a. As can be seen, the particles are flakelike in appearance with a wide size distribution, ranging from about 3 to 10 μm. To be readily suitable for our target inkjet printing platform, the naproxen should be reduced to a maximum of about 200 nm in size,20 ideally with a more uniform, less flakelike shape. Otherwise, clogging of the print head nozzle will ensue as the print head nozzles are only micrometers in diameter. FE-SEM images of the RESOLV-produced naproxen particles can be seen in Figure 3b. The particles are clearly more spherical in shape and, at 50 nm in size, orders of magnitude smaller than the as-received material. The discrete nanoparticles observed in Figure 3c suggest there was minimal nanoparticle agglomeration. DLS analysis (Figure 4) showed a bimodal distribution with a large peak 50 nm in size and a smaller peak centered around a micrometer in size. This confirmed that the RESOLV-produced suspension was primarily a colloidal suspension of nanoparticles. The RESOLV-produced particles are an ideal size and shape for inkjet printing, as most of the particles were below the 200 nm threshold size. The larger micrometer-size particles were filtered out of the ink with a 0.20 μm filter prior to loading the ink cartridge for printing. After determining that the RESOLV-produced particles were the desired size, they were subjected to ζ-potential and FTIR characterization. The ζ-potential of the as-received naproxen was measured to be −51 mV, while the RESOLV-produced naproxen had a value of −5 mV. The reason for the reduction

Figure 3. FE-SEM image of (a) as-received naproxen powder and (b and c) RESOLV-produced naproxen nanoparticles at two different magnifications.

to an almost zero absolute value is that the adsorbed PVP shields the native charge of the naproxen particle. Previous research has shown that nonionic polymers such as PVP reduce the native charge of the particle to a value of zero, if the molecular weight is large enough.22 The reduction in the absolute value of the RESOLV-produced particle’s ζ-potential 2728

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Oh =

suggests that the particles were well-coated with PVP. FTIR spectra of naproxen, PVP, and PVP-coated naproxen produced through the RESOLV process are shown in Figure 5. From the

Figure 5. FTIR spectra of naproxen, PVP, and PVP-coated naproxen produced through the RESOLV process.

Figure 6. Ink viscosity as a function of PVP-360 polymer weight percent. About 3.5 wt % PVP-360 is needed to achieve the desired ink viscosity.

figure, it is clear that the produced particles are naproxen, but the particles also have characteristics of PVP in their spectra as well. This finding confirms that the chemical integrity of the sample does not change in the RESOLV process and also suggests that the particles were coated with PVP, and thus agrees with the recorded ζ-potential measurements. Fluid properties were characterized following confirmation that naproxen nanoparticles were not agglomerated and were well-coated with PVP in the aqueous solution produced using the RESOLV process to determine the feasibility of formulating an ink for printing. The Weber (We) and Ohnesorge (Oh) numbers, defined below, are two dimensionless parameters often used to characterize the general “printability” of a fluid

v 2ρ a γ

(2)

where v is the velocity; a is the characteristic length; and ρ, η, and γ are the density, dynamic viscosity, and surface tension of the fluid, respectively. Comparing the We and Oh values provides a framework to predict ink printability and behavior on a substrate. For example, the Ohnesorge number of printable fluids typically falls within the range of 1 < 1/Oh < 10 and is ejected without satellite droplets. The We and Oh numbers will also indicate how a droplet will behave when impacting a target substrate.23 In most situations, controlling the viscosity and surface tension of an ink to be within a certain range will make it a printable ink. The ideal ranges for fluid viscosity and surface tension are 10−12 cP and 28−33 mN/m, respectively, for the Dimatix DMP-2800 printer.20 The viscosity was investigated prior to surface tension. The measured viscosity of the as-produced RESOLV suspension was 0.91 cSt. Therefore, increasing the viscosity of the as-produced suspension was important. PVP360 was added in various increments to the RESOLV suspension in the range of 0.05−5 wt % PVP-360. The results of the study are shown in Figure 6 and suggest that using about 3.5 wt % PVP-360 would produce a viscosity of about 11 cSt, which is in the desired range.

Figure 4. DLS size results for RESOLV-produced naproxen showing a 50 nm peak and a 1 μm peak.

We =

η (γρa)1/2

Surface tension measurements were performed after determining that using 3.5 wt % PVP-360 would produce the desired viscosity. The RESOLV suspension with 3.5 wt % PVP360 had a measured surface tension of 68 mN/m. While slightly less than pure water (∼72 mN/m), the surface tension value was still significantly higher than the desired range. The surface tension was modified by adding a small amount of polysorbate 20 surfactant, which is a surfactant commonly used in the pharmaceutical industry.24 The surfactant was added in the range of 0.02−1.0 wt %, and the results of the surface tension study are shown in Figure 7. It is clear that adding more than 0.5 wt % polysorbate 20 will not have a significant impact on the surface tension. At 0.5 wt % the surface tension was measured to be 34.2 mN/m, which is around the desired range

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Figure 7. Ink surface tension as a function of the weight percent of polysorbate 20 in the 3.5 wt % PVP-360 inks.

of the target inkjet platform. The measured reduction in surface tension is consistent with what has been reported in the literature.25 The results show that naproxen nanoparticle inks can be stabilized and formulated with optimal printing properties using chemicals that are commonly used in the pharmaceutical industry. An attempt was made to print the naproxen nanoparticle−3.5 wt % PVP-360−0.5 wt % polysorbate 20 preliminary ink; however, ink droplets could not be ejected from the print nozzles. This particular PVP likely resulted in an ink with relatively high fluid elasticity and high elongational viscosity during droplet ejection.9,26 The ink was therefore reformulated using a 10 000 molecular weight PVP (PVP-10) to increase the viscosity of the RESOLV-produced suspension stabilized with a small amount of PVP-360 as a direct comparison. The reformulated ink had a measured viscosity of 10.6 cSt, and it should be noted that to achieve this value about 30 wt % of the low molecular weight PVP was required. The reformulated ink was printable with ejected droplets illustrated in Figure 8. These images were captured from a CCD camera, which is built into the printer. Note that the image is inverted with the print head located in the bottom of each image. The initial jetting behavior of the ink is shown in Figure 8a. Here, long tails are visible as the droplet is ejected, and there is evidence of ink splattering around the nozzles on the print head. Periodic satellite droplets were also seen. Through adjustments of printing parameters the long tails and occasional satellite droplets were eliminated as shown in Figure 8b. Ink was also prevented from splattering around the nozzles further. This was accomplished primarily through changes in jetting voltage amplitude and modifications to the slew rate and duration of waveform segments. As a final qualitative analysis, a drop of ink was prepared on a carbon tape substrate and was allowed to dry, leaving behind an optically transparent nanocomposite film. FE-SEM images of the film are shown in Figure 9, with Figure 9a showing that a relatively uniform PVP film was deposited on the substrate as the droplet evaporated. Under higher magnification, Figure 9b, it was possible to see some of the naproxen nanoparticles that were embedded into the film. Due to the relatively low solids

Figure 8. CCD images of ejected droplets leaving the print head: (a) initial droplet jetting behavior of ink and (b) droplet jetting after adjusting printing parameters.

Figure 9. FE-SEM images of produced PVP−polysorbate 20− naproxen film. Particle loading was low (1 mg of PVP/mL of suspension), but naproxen nanoparticles can be seen in the film: (a) low magnification view of the produced nanocomposite film with (b) embedded naproxen nanoparticles clearly visible under higher magnification.

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(7) Ihnen, A. C.; Petrock, A. M.; Chou, T.; Samuels, P. J.; Fuchs, B. E.; Lee, W. Y. Crystal Morphology Variation in Inkjet-Printed Organic Materials. Appl. Surf. Sci. 2011, 258, 827−833. (8) Calvert, P. Inkjet Printing for Materials and Devices. Chem. Mater. 2001, 13, 3299. (9) de Gans, B.-J.; Duineveld, P. C.; Schubert, U. S. Inkjet Printing of Polymers: State of the Art and Future Developments. Adv. Mater. 2004, 16, 203−213. (10) Hsu, H. Y.; Toth, S. J.; Simpson, G. J.; Taylor, L. S.; Harris, M. T. Effect of Substrates on Naproxen−Polyvinylpyrrolidone Solid Dispersions Formed via the Drop Printing Technique. J. Pharm. Sci. 2013, 102, 638−648. (11) Teipel, U.; Kröber, H.; Krause, H. H. Formation of Energetic Materials using Supercritical Fluids. Propellants, Explos., Pyrotech. 2001, 26, 168−173. (12) Meziani, M. J.; Pathak, P.; Hurezeanu, R.; Thies, M. C.; Enick, R. M.; Sun, Y. P. Supercritical-Fluid Processing Technique for Nanoscale Polymer Particles. Angew. Chem.-Int. Ed. 2004, 43 (6), 704−707. (13) Meziani, M. J.; Pathak, P.; Desai, T.; Sun, Y. P. Supercritical Fluid Processing of Nanoscale Particles from Biodegradable and Biocompatible Polymers. Ind. Eng. Chem. Res. 2006, 45, 3420−3424. (14) Essel, J. T.; Cortopassi, A. C.; Kuo, K. K.; Leh, C. G.; Adair, J. H. Formation and Characterization of Nano-Sized RDX Particles Produced Using the RESS-AS Process. Propellants, Explos., Pyrotech. 2012, 37, 699−706. (15) Pathak, P.; Meziani, M. J.; Desai, T.; Sun, Y. P. Formation and Stabilization of Ibuprofen Nanoparticles in Supercritical Fluid Processing. J. Supercrit. Fluids 2006, 37, 279−286. (16) Essel, J. T.; Kuo, K. K.; Adair, J. H.; Merritt, A. R.; Carter, J. Benefits of the RESOLV Process in Forming Polymer-Coated, Ultrafine RDX Particles. Int. J. Energ. Mater. Chem. Propul. 2011, 10, 455−468. (17) Türk, M.; Bolten, D. Formation of Submicron Poorly WaterSoluble Drugs by Rapid Expansion of Supercritical Solution (RESS): Results for Naproxen. J. Supercrit. Fluids 2010, 55, 778−785. (18) Kim, J. H.; Paxton, T. E.; Tomasko, D. L. Microencapsulation of Naproxen Using Raid Expansion of Supercritical Solutions. Biotechnol. Prog. 1996, 12, 650−661. (19) Javadzadeh, Y.; Ahadi, F.; Davaran, S.; Mohammadi, G.; Sabzevari, A.; Adibkia, K. Perparation and Physiochemical Characterization of Naproxen−PLGA Nanoparticles. Colloid Surf. B 2010, 81, 498−502. (20) Ink Fluid Formulation Guidelines; Fujifilm Dimatix: Santa Clara, CA, 2013. (21) Munson, B. R.; Young, D. F.; Okiishi, T. H. Fundamental of Fluid Mechanics, 4th ed.; Wiley: New York, 2002. (22) Keck, C. M. Cyclosporine Nanosuspensions: Optimized Size Characterization & Oral Formulations. Chapter 7, Zeta Potential of Nanosuspensions. Ph.D Dissertation, Free University of Berlin, 2006, pp 221−232. (23) Derby, B. Inkjet Printing of Functional and Structural Materials: Fluid Property Requirements, Feature Stability, and Resolution. Annu. Rev. Mater. Res. 2010, 40, 395−414. (24) Joint FAO/WHO Expert Committee on Food Additives. Toxicological Evaluation of Some Food Additives Including Anticaking Agents, Antimicrobials, Antioxidants, Emulsifiers and Thickening Agents; WHO Food Additives Series No. 5.; World Health Organization: Zurich, 1974. (25) Patist, A.; Bhagwat, S. S.; Penfield, K. W.; Aikens, P.; Shah, D. O. On the Measurement of Critical Micelle Concentrations of Pure and Technical-Grade Nonionic Surfactants. J. Surf. Deterg. 2000, 3, 53−58. (26) Shore, H. J.; Harrison, G. M. The Effect of Added Polymers on the Formation of Drops Ejected from a Nozzle. Phys. Fluids 2005, 17, 033104-1−033104-7.

loading of the RESOLV-produced suspensions (1 mg naproxen/1 mL suspension), the particle loading in the composites shown here is not high. However, in future efforts this can easily be fixed by concentrating the suspensions.

4. CONCLUSIONS Nanoscale drug particles dissolve significantly faster than micrometer-sized particles, drastically increasing their bioavailability. The RESOLV process provides a unique way to produce true nanoparticles that are suitable for ink formulation. Concurrently, inkjet printing of nanoscale drug particles provides an alternative processing method, potentially enabling novel delivery techniques or devices. The RESOLV process was used to produce naproxen particles 50 nm in diameter. The initial colloidal suspensions were then modified with additional PVP-10 to about 30 wt % and polysorbate 20 surfactant to 0.5 wt % to increase the viscosity and lower the surface tension of the colloidal suspensions, respectively. The resulting bulk fluid characteristics, with a viscosity and surface tension of 10.6 cSt and 34.2 mN/m, respectively, were around the range typical of printable fluids, and the ability to print the ink was demonstrated. Combining the RESOLV and inkjet platforms provides a straightforward method for producing and processing nanoparticulate drugs.

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +1-760-939-7272. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the Naval Air Systems Command (NAVAIR) In-House Laboratory Independent Research (ILIR) program, managed at the Office of Naval Research by the N*Star Program, for funding this research. Without their contributions this work would not be possible. We would also like to thank Dr. Joseph Roberts at the Naval Air Warfare Center Weapons Division for his assistance with surface tension measurements.

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REFERENCES

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