Liquid and Supercritical Carbon Dioxide-Assisted Implantation of

Ind. Eng. Chem. Res. 2010, 49, 7281–7286

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Liquid and Supercritical Carbon Dioxide-Assisted Implantation of Ketoprofen into Biodegradable Sutures Randy D. Weinstein,* Kenneth R. Muske, Sherrie-Ann Martin, and Danielle D. Schaeber Department of Chemical Engineering, VillanoVa UniVersity, VillanoVa, PennsylVania 19085

In this study we explored the use of liquid and supercritical carbon dioxide for the creation of a sustained release drug delivery device. An anti-inflammatory (ketoprofen) was dissolved into carbon dioxide at various temperatures (25-55 °C) and pressures (65-300 bar) and then exposed to biodegradable braided sutures made of poly(lactide-co-glycolide) copolymers. The effect of temperature, pressure (and hence density), and exposure time were explored on the ability of the sutures to absorb ketoprofen. The diffusion of the drug into the suture was modeled, and diffusion coefficients were calculated. The amount of ketoprofen loaded into the suture increased with pressure and density and decreased with temperature; however, increasing temperature tended to speed up the absorption process. Introduction Compressed carbon dioxide is becoming a common solvent for the processing of both pharmaceutical products1 as well as polymer systems2 used for biomedical applications. Carbon dioxide has the advantages of being environmentally friendly, basically inert, nonflammable, inexpensive, and easy to recycle in a closed-loop process. In addition, this unique solvent has some additional properties which makes it ideal for processing many polymers and generating polymer-based sustained delivery devices. Carbon dioxide tends to swell most polymers, opening up space for drug molecules to enter. It also lowers the glass transition temperature of most polymers. In this study, we explore the use of compressed carbon dioxide to swell a poly(lactide-co-glycolide) (PLGA) suture and load ketoprofen into it. Many polymers, including PLGA,3 have been processed in liquid and supercritical carbon dioxide. Liu and Tomasko4 recently quantitatively explored the ability of carbon dioxide to swell PLGA. They studied copolymers that were 100%, 75%, or 50% lactide in carbon dioxide between 30 and 60 °C and at pressures up to approximately 100 bar. They were able to swell all their blends significantly (even below the glass transition temperature) and increased the polymer volume by over 30% in some cases while loading up to almost 25 wt % carbon dioxide into them. Lower temperatures and higher pressures (higher densities of carbon dioxide) tended to load the largest amount of carbon dioxide into the polymer and swell the polymer the most. The different blends behaved very similarly in carbon dioxide. The PLGA braided sutures (Polysorb) we used in this study were approximately 10% lactide.5 We expect the swelling of our sutures to behave similarly; however, we will have lower carbon dioxide loading because of the more crystalline nature of our copolymer2a compared to those used by Liu and Tomasko.4 Besides swelling the polymer, carbon dioxide will also need to solubilize ketoprofen and transport it into the suture. Our group6 along with two others7,8 have previously explored ketoprofen solubility in compressed carbon dioxide. Over the temperature and pressure ranges used in this study, ketoprofen was found to have a solubility on the order of 10-5-10-4 mole * To whom correspondence should be addressed. E-mail: [email protected]. Tel.: (610) 519-4954. Fax: (610) 5197354.

fraction. The solubility tended to increase with increasing pressure as well as temperature, although there was a crossover point at higher pressures. Like most pharmaceutical products in carbon dioxide,9 ketoprofen had a low solubility, but it was high enough to be practical for loading into a polymeric device with compressed carbon dioxide as was done by Manna et al.10 with ketoprofen into poly(vinylpyrrolidone) beads. Experimental Section Materials. Carbon dioxide (grade 5) was supplied by BOC Gases. Wash ethanol (95%) and 5 M aqueous sodium hydroxide were purchased from Fisher Scientific. Polysorb 6.0 sutures (0.3 mm diameter braided) were purchased from Covidien Syneture. These sutures were PLGA random copolymers consisting of approximately 10% lactide.5 Ketoprofen (>99% purity) was supplied by Sigma-Aldrich. All materials were used as received. Ketoprofen Solubility in Carbon Dioxide. Although there were some previous studies of ketoprofen solubility in carbon dioxide,6–8 we wanted to cover the complete range of temperatures (25-55 °C) and pressures (65-300 bar) used in our drug loading studies so we collected data on ketoprofen solubility using a variable volume view-cell by the cloud point technique. This procedure is described in several of our earlier publications.6,11,12 Suture Breaking Strength. Breaking experiments were performed using a Unitek Micropull I model 6-092 wire bond pull tester with Ametek Accuforce force gauge. Each set of conditions was tested three times, and an average breaking force was reported. Since the Micropull was not designed for the thin sutures, the sutures were not clamped to the load cell and driving mechanism directly. Instead, two metal bars were attached to the unit and each of these bars had a 1/16 in. hole (polished smooth) drilled in them so the suture could be attached to each bar. The suture was wrapped twice through each hole and held to the bar with a small clamp. Once activated, the unit recorded the maximum force achieved before breaking of the suture. These breaking experiments were performed to verify that exposure to carbon dioxide did not significantly alter the mechanical integrity of the suture. Suture Loading with Ketoprofen. A 10 mL Thar Technologies finger tight vessel was used for the suture loading experiments. In the bottom of the vessel was placed 0.2 g of ketoprofen, a large quantity which ensured that carbon dioxide

10.1021/ie901913x  2010 American Chemical Society Published on Web 07/08/2010

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was saturated with ketoprofen for the duration of the experiment. At the top of the vessel was placed a frit filter over which 10 cm of the suture was hung. The suture was loosely wrapped as to always hang at least 1 in. from the bottom of the vessel where the solid excess ketoprofen was present. The vertically oriented vessel was placed in a water bath to achieve the desired temperature while low pressure CO2 (∼2 bar) was flushed through the vessel for several minutes. Carbon dioxide was fed into the vessel from the top and exited through the bottom. The water bath and vessel were rocked slightly to assist in mixing. The rocking was achieved by a homemade device which tilted the vessel and water bath 60 times a minute between 40° to the right and 40° to the left. This rocking continued throughout the entire adsorption experiment. This method was found sufficient to quickly (less than 2 min) obtain the maximum solubility of ketoprofen in carbon dioxide without causing undissolved ketoprofen to come in contact with the suture. The solubility of ketopfen was determined using a 6-way Valco high pressure value with a 0.25 mL sample loop. The procedures for properly collecting the sample from the sample loop are described elsewhere.13 If rocking was increased or mechanical stirring used (by using a magnetic stir bar inside the vessel which rested on a magnetic stir plate) we found sufficient solid ketoprofen being suspended in the carbon dioxide. This was verified by samples containing a higher amount of ketoprofen than would be allowed from the solubility limit, and hence solid ketoprofen would stick to the surface of the suture. Also, with more vigorous mixing the sample loop would often get clogged with ketoprofen. After the flushing procedure, an Isco 260D syringe pump was then used to pressurize the vessel with carbon dioxide over several minutes. The pump was set in constant-pressure mode and left running during the entire exposure time so that as carbon dioxide and ketoprofen dissolved into the polymer, the pressure in the vessel remained constant. The inlet to the vessel contained about 10 feet of capillary tubing which was also in the water bath to provide preheating of the carbon dioxide if needed. After the fixed exposure time, the pump was turned off and isolated from the vessel. Pressurized helium was then immediately delivered via another syringe pump to displace the carbon dioxide out the bottom of the vessel and hence prevent the suture from being exposed to the phase change process during depressurization. Once all the carbon dioxide was displaced, the helium was slowly vented, the vessel was opened, and the suture was removed for analysis. After an experiment, the vessel was cleaned with acetone and ethanol, and it was air-dried in an oven at roughly 75 °C. Sample Analysis. Once exposed, sutures with embedded ketoprofen were dissolved into 25 mL of solvent consisting of 10 mL of wash ethanol and 15 mL of 5 M NaOH solution. This mixture was rigorously mixed on a magnetic stir plate using a stir bar. The dissolution process took about 30 min. UV spectroscopy was used to measure the concentration of ketoprofen in the solution at 256 nm. A calibration curve was made using known concentrations of ketoprofen in the same solvent with the 10 cm of suture dissolved in it. Once the concentration was known, the amount of ketoprofen in the suture could easily be calculated. A few “quick dip” tests were done to verify that the ketoprofen was embedded in the suture and not just coating its surface. After exposure, the suture was dipped into the solution for 20 s and removed, and the solution was analyzed by UV spectroscopy. In all cases, less than 4% of the ketoprofen was recovered verifying that the ketoprofen was embedded in the suture and not resting on the surface. Details of a time release

Figure 1. Solubility of ketoprofen in liquid and supercritical carbon dioxide as a function of pressure.

Figure 2. Solubility of ketoprofen in liquid and supercritical carbon dioxide as a function of carbon dioxide density.

of ketoprofen study will be given in the Results and Discussion section where the mass of ketoprofen released into the solvent as a function of time is presented. Results and Discussion Ketoprofen Solubility. The solubility of ketoprofen in liquid and supercritical carbon dioxide is presented in Figure 1 as a function of pressure and in Figure 2 as a function of system density. Carbon dioxide density was obtained at a particular pressure and temperature using a NIST database.14 As with most solid material solubilities in compressed carbon dioxide, an increase in pressure or system density tends to increase the solubility. As the density of carbon dioxide increases its solvating power increases as it becomes more liquidlike in its packing and molecular interactions. At high pressures, an increase in temperature decreased ketoprofen solubility. However the opposite trend is observed at lower pressures. A crossover point is observed in Figure 1. Although pressure is the property controlled during the solubility experiments, density has been shown to be the more dominant property which should be used to correlate solubility data with temperature. Hence, by examining Figure 2, an increase in temperature at fixed density will increase ketoprofen solubility in carbon dioxide. This increase in solubility can be attributed to increasing the sublimation pressure of ketoprofen which is a dominant factor in the fugacity relationship used to describe the factors influencing solubility.15 Although solubilities were on the order of 10-5-10-4 mole fraction, high loading of low solubility compounds can still be expected to be achieved in carbon dioxide.10,16


Figure 3. Breaking strength of sutures exposed to carbon dioxide at 103 bar and 25 °C.

Figure 4. Breaking strength of sutures exposed to carbon dioxide at 103 bar for 24 h (() or just exposed to temperature for 24 h but no carbon dioxide (9).

Suture Strength. The exposure of the sutures to carbon dioxide cannot change their mechanical properties as doctors require specific suture strengths for stitching and for holding wounds closed. The sutures must also have the same life span in the body and cannot dissolve at a different rate after carbon dioxide exposure. We first tested suture strength after exposure to carbon dioxide and after exposure to higher temperatures. Figure 3 shows the breaking strength of sutures exposed to carbon dioxide at 103 bar and 25 °C. On this plot is also a data point without exposure to carbon dioxide (time ) 0). Carbon dioxide exposure has a slight negative effect on the suture strength, dropping it on average of about 3%, regardless of how long the suture is exposed (above some minimum not shown). The effect of temperature on suture strength is shown in Figure 4. Sutures were exposed at temperature for 24 h in carbon dioxide at 103 bar or in ambient air. Without exposure to carbon dioxide an increase in temperature decreased the strength of the suture slightly; however, even up to 80 °C the suture still maintained over 95% of its original strength. With added carbon dioxide the effect of temperature exposure was larger. Up to 60 °C, the sutures with carbon dioxide exposure behaved very similarly to those without having been exposed to carbon dioxide. However, above this temperature, the sutures with carbon dioxide exposure had a drop in their mechanical strength with increasing temperature. As temperature increased from 60 to 80 °C, the suture breaking strength decreased by 23%. Interestingly, 60 °C is just slightly above the glass transition temperature of the PLGA copolymers.4 On the basis of the data

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Figure 5. Breaking strength of sutures exposed to carbon dioxide at 24 h at 60 °C.

shown in Figure 4, we choose to keep our suture exposures below 60 °C in order to maintain their strength after exposure. The effect of exposure pressure on the suture strength is shown in Figure 5 where all experiments were done for 24 h at 60 °C. As pressure is increased the breaking strength of the suture decreases, but only slightly. An increase of almost 207 bar above the 103 bar exposure decreased the suture strength by less than 5%. Therefore, it does not appear that the specific exposure pressure selected will have much effect on the suture strength. We will therefore keep all exposure experiments below 60 °C and we will explore the effect of temperature, pressure, and exposure time on the ability of carbon dioxide to transfer ketoprofen into the suture. Before performing the implantation experiments we also wanted to check that the exposure to carbon dioxide did not change the dissolution time of the suture. We took several exposed sutures and dissolved them in 25 mL of solvent consisting of 10 mL of wash ethanol and 15 mL of 5 M NaOH solution and found the times to dissolve (as visually determined such that no solid suture could be observed in solution) were the same as those when the sutures were not exposed to carbon dioxide. Since these dissolutions times were short (less than 30 min) we also diluted our solvent by using 20 mL of the wash ethanol and 5 mL of the 5 M NaOH solution to increase the dissolutions times and found that exposed sutures dissolved within 2% of the time of the unexposed sutures. Therefore, it was concluded that carbon dioxide exposure did not effect the suture dissolution time. We also wanted to verify that exposure to ketoprofen did not alter the mechanical properties of the suture nor the dissolution time. We took four sutures and exposed each separately to carbon dioxide at 103 bar and 60 °C for 24 h with and without ketoprofen in the vessel. After removal two sutures were broken (one with ketoprofen exposure and one without) and the other two were dissolved in our diluted solvent (again one with ketoprofen exposure and one without). The suture breaking strength and dissolution time after exposure with carbon dioxide and ketoprofen were practically identical to the data obtained when the suture was just exposed to carbon dioxide alone. Ketoprofen Loading. Since the sutures were found to have enough integrity after exposure to pressure and temperature, ketoprofen was loaded into the sutures at three different temperatures (25, 40, and 55 °C) at various pressures. The pressures were selected to keep the density of the carbon dioxide fixed at one of three values, 0.65, 0.74, or 0.87 g/cm3. The room

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Figure 6. Mass of ketoprofen loaded per mass of suture as a function of carbon dioxide exposure time at 25 °C.

Figure 7. Mass of ketofprofen loaded per mass of suture as a function of carbon dioxide exposure time at 40 °C.

temperature loadings are shown in Figure 6. As exposure time is increased the amount of ketoprofen absorbed into the suture increased until it reached a maximum loading value. This maximum value was higher for the higher pressure (and hence density) exposure. As the pressure was increased the time to reach the maximum loading decreased, so it appears that at a fixed temperature of 25 °C it would be more beneficial to increase the system pressure to increase the loading of ketoprofen into the suture at a faster rate. Ketoprofen loadings at 40 and 55 °C are shown in Figures 7 and 8, respectively. These higher temperature loadings followed similar trends to the room temperature loadings. As pressure is increased the maximum amount loaded into the suture increased. The time to reach maximum loading varied again with pressure. As temperature was increased above room temperature the maximum loading into the suture decreased. The maximum loading decrease was larger between 25 and 40 °C then between 40 and 55 °C as shown in Figure 9. To maximize the loading of ketoprofen into the suture (which almost reached 60 wt % at 25 °C and 0.87 g/cm3) it should be exposed to the lowest temperature and highest pressure possible. As mentioned previously, we believed ketoprofen to be embedded in the suture and not absorbed on the surface as a “quick dip” test revealed that less than 4% of the loaded ketoprofen was released into the solvent after 20 s of exposure.

Figure 8. Mass of ketoprofen loaded per mass of suture as a function of carbon dioxide exposure time at 55 °C.

Figure 9. Maximum loading of ketoprofen as a function of carbon dioxide exposure density.

To provide further evidence that the ketoprofen was embedded, sutures, after being exposed to ketoprofen at 25 °C and 103 bar for 24 h in carbon dioxide, were dissolved in 25 mL of the solvent consisting of 10 mL of wash ethanol and 15 mL of 5 M NaOH solution. Samples were taken of the solvent as a function of dissolution time and analyzed to track the amount of ketoprofen released. If the ketoprofen was mainly on the suture surface, it would be released quickly. If it was embedded throughout the suture, it would be released during the entire time it took the suture to dissolve (∼30 min). Figure 10 supports our conclusion that the ketoprofen was embedded throughout the suture. To explore the time required to load the ketoprofen into the suture, we modeled the absorption. First we assumed that the bulk concentration of ketoprofen in carbon dioxide remained constant. This assumption is supported by the fact that we placed excess ketoprofen in the bottom of the vessel to ensure we were always at the solubility limit. Having a bulk concentration being constant would also ensure that we have a constant surface concentration which is required for the model we selected. We also assumed the suture was an infinite cylinder, which was supported by the fact that the ratio of the suture diameter to its length that was used in our experiments was 3 × 10-3. Finally we assumed the diffusion coefficient of ketoprofen into the


Figure 10. Dissolution profile of ketoprofen from a suture (exposed to carbon dioxide saturated with ketoprofen for 24 h at 103 bar and 25 °C) into 25 mL of solvent consisting of 10 mL of wash ethanol and 15 mL of 5 M NaOH solution.

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Figure 11. Diffusion coefficient of ketoprofen into the suture as a function of carbon dioxide density.

suture was constant for a particular temperature and pressure condition and did not vary with the amount of ketoprofen absorbed into the suture. Using these assumptions, unsteady state Fickian diffusion into a infinite cylinder can be modeled so that the mass of ketoprofen in the suture (M) at a given exposure time (t) can be found:17 M )1M∞

∞

∑ r R4

2

2

n)1

exp(-DRn2t)

(1)

n

where M∞ is the maximum mass of ketoprofen loaded in the suture at equilibrium, r is the radius of the suture, D is the diffusion coefficient of ketoprofen into the suture, and Rn are the positive roots of Jo(rRn) with Jo(x) being the Bessel function of the first kind. For short times, eq 1 can be simplified to17

( )

M 4 Dt ) 1/2 2 M∞ π r

1/2

-

( )

Dt 1 Dt 2 r 3π1/2 r2

3/2

+ ...

(2)

Figure 12. Measured (points) and predicted (line) uptake curves for the first 100 min of exposure in carbon dioxide at 25 °C.

which allows us to plot M/M∞ versus t1/2 and fit the short time data with a third order polynomial so that M ) At1/2 + Bt + Ct3/2 M∞ 4D1/2 π1/2r -D1/2 B) r2 -D3/2 C) 3π1/2r3 A)

(3)

A linear least-squares fit on the three constants, A, B, and C, allowed for the calculation of the diffusion coefficient of ketoprofen into the suture at a given temperature and pressure (and hence carbon dioxide density) and these diffusion coefficients are shown in Figure 11. Exposure times of less than 100 min were used. Figures 12-14 show the measured uptake curves for the first 100 min exposure along with the fitted model predictions which capture the loading reasonably well. The diffusion coefficient increased slightly with increasing carbon dioxide density at a fixed temperature. The diffusion coefficient increased more rapidly with increasing temperature.


Since Fickian diffusion is proportional to the diffusion coefficient as well as the concentration gradient driving force, one would want to optimize both of these factors to obtain the fastest and largest loading. Higher temperatures provide for a larger diffusion coefficient, but maximum loading decreases (the

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concentration driving force) with increasing temperature as shown in Figure 9. Therefore, there is a trade off with temperature. Higher density always provided for a larger diffusion coefficient as well as for increased maximum loading and therefore Fickian diffusion would increase with an increase in density. Summary Ketoprofen was implanted into a biodegradable suture using liquid and supercritical carbon dioxide. Loadings up to almost 60 wt % were achieved, and the suture mechanical strength and dissolution time remained intact after processing in carbon dioxide. The Fickian diffusion process was able to be modeled as unsteady state diffusion into an infinite cylinder which produced experimental diffusion coefficients. The diffusion coefficient of ketoprofen into the suture increased with increasing density as well as with increasing temperature. Lower temperatures were able to increase the quantity absorbed into the suture while higher densities did the same. Carbon dioxide’s ability to swell PLGA while still being an inert molecule with minimal surface tension, small molecular size, and low quadropole moment makes it an excellent solvent for creating polymeric drug delivery devices. Literature Cited (1) (a) Vamsi, K. M.; Gowri, S. D. Role of Supercritical Fluids in the Pharmaceutical Research-A Review. Indian J. Pharm. Educ. Res. 2007, 41, 10. (b) Foster, N.; Mammucari, R.; Dehghani, F.; Barrett, A.; Bezanehtak, K.; Coen, E.; Combes, G.; Meure, L.; Ng, A.; Regtop, H. L.; Tandya, A. Processing Pharmaceutical Compounds Using Dense Gas Technology. Ind. Eng. Chem. Res. 2003, 42, 6476. (c) Subramaniam, B.; Rajewski, R. A.; Snavely, K. Pharmaceutical Processing with Supercritical Carbon Dioxide. J. Pharm. Sci. 1997, 86, 885. (2) (a) Davies, O. R.; Lewis, A. L.; Whitaker, M. J.; Tau, H.; Shakeshedd, K. M.; Howdle, S. M. Applications of Supercritical CO2 in

the Fabrication of Polymer Systems for Drug Delivery and Tissue Engineering. AdV. Drug. DeliVery ReV. 2008, 60, 373. (b) Yeo, S. D.; Kirana, E. Formation of Polymer Particles with Supercritical Fluids: A Review. J. Supercrit. Fluids 2005, 34, 287. (c) Tomasko, D. L.; Li, H.; Liu, D.; Han, X.; Wingert, M. J.; Lee, L. J.; Koelling, K. W. A Review of CO2 Applications in the Processing of Polymers. Ind Chem. Eng. Res. 2003, 42, 6431. (d) Kompella, U. B.; Koushik, K. Preparation of Drug Delivery Systems Using Supercritical Fluid Technology. Crit. ReV. Ther. Drug Carrier Syst. 2001, 18, 173. (3) (a) Koushik, K.; Kompella, U. B. Preparation of Large Porous Deslorelin-PLGA Microparticles with Reduced Residual Solvent and Cellular Uptake using a Supercritical Carbon Dioxide Process. Pharm. Res. 2004, 21, 524. (b) Conway, S. E.; Byun, H. S.; McHugh, M. A.; Wang, J. D.; Mandel, F. S. Poly(lactide-co-glycolide) Solution Behavior in Supercritical CO2, CHF3, and CHClF2. J. Appl. Polym. Sci. 2001, 80, 1155. (c) Hile, D. D.; Amirpour, M. L.; Akgerman, A.; Pishko, M. V. Active Growth Factor Delivery from Poly(DL-lactide-co-glycolide) Foams Prepared in Supercritical CO2. J. Controlled Release 2000, 66, 177. (4) Liu, D.; Tomasko, D. L. Carbon Dioxide Sorption and Dilation of Poly(lactide-co-glycolide). J. Supercrit. Fluids 2007, 39, 416. (5) Ratner, B. D., Hoffman, A. S., Schoen, F. J., Lemons, J. E., Eds. Biomaterials Science, 2nd ed.; Elsevier Academic Press: San Diego, CA, 2004. (6) Weinstein, R. D.; Muske, K. R.; Moriarty, J.; Schmidt, E. K. The Solubility of Benzoicaine, Lidocaine, and Procane in Liquid and Supercritical Carbon Dioxide. J. Chem. Eng. Data 2004, 49, 547. (7) Stassi, A.; Bettini, R.; Gazzaniga, A.; Giordano, F.; Schiraldi, A. Assessment of Solubility of Ketoprofen and Vanillic Acid in Supercritical CO2 under Dynamic Conditions. J. Chem. Eng. Data 2000, 45, 161. (8) Macnaughton, Stuart J.; Kikic, Ireneo; Foster, Neil R.; Alessi, Paolo; Cortesi, Angelo; Colombo, Italo. Solubility of Anti-inflammatory Drugs in Supercritical Carbon Dioxide. J. Chem. Eng. Data 1996, 41, 1083. (9) (a) Supercritical Fluid Technology for Drug Product DeVelopment; York, P.; Kompella, U. B.; Shekunov, B. Y., Eds., Marcel Dekker: New York, 2004. (b) Subramaniam, B.; Rajewski, R. A.; Snavely, K. Pharmaceutical Processing with Supercritical Carbon Dioxide. J. Pharm. Sci. 1997, 86, 885. (10) Manna, L.; Banchero, M.; Sola, D.; Ferri, A.; Ronchetti, S.; Sicardi, S. Impregnation of PVP Microparticles with Ketoprofen in the Presence of Supercritical CO2. J. Supercrit. Fluids 2007, 42, 378. (11) Weinstein, R. D.; Gribbin, J. J.; Muske, K. R. The Solubility and Salting Behavior of Several β-Adrenergic Blocking Agents in Liquid and Supercritical Carbon Dioxide. J. Chem. Eng. Data 2005, 50, 226. (12) Weinstein, R. D.; Hanlon, W. H.; Donohue, J. P.; Simeone, M.; Rozich, A.; Muske, K. R. Solubility of Felodipine and Nitrendipine in Liquid and Supercritical Carbon Dioxide by Cloud Point and UV Spectroscopy. J. Chem. Eng. Data 2007, 52, 256. (13) Weinstein, R. D. Organic Synthesis in Supercritical Carbon Dioxide, Chapter 3. Ph.D. Thesis, Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 1998. (14) Lemmon, E. W.; Peskin, A. P.; McLinden, M. O.; Friend, D. G. NIST Thermodynamic and Transport Properties of Pure FluidssNIST Pure Fluids, version 5.0; U.S. Secretary of Commerce: Washington, DC, 2000. (15) Poling, B. E.; Prausnitz, J. M.; O’Connell, J. P. The Properties of Gases and Liquids, 5th ed.; McGraw-Hill: New York, 2000. (16) Kazarian, S. G., Supercritical Fluid Impregnation of Polymer for Drug Delivery. In Supercritical Fluid Technology for Drug Product DeVelopment; York, P., Ed.; Marcel Dekker: New York, 2004. (17) Crank, J. The Mathematics of Diffusion, 2nd ed.; Clarendon Press: Oxford, 1975.

ReceiVed for reView December 3, 2009 ReVised manuscript receiVed June 7, 2010 Accepted June 18, 2010 IE901913X

Liquid and Supercritical Carbon Dioxide-Assisted Implantation of

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