Supercritical Phase Inversion To Form Drug-Loaded Poly (vinylidene

Feb 4, 2010 - as drug delivery devices, such as phase inversion, gas foaming/particulate leaching, and solvent evaporation. Supercritical CO2 (SC-CO2)...
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Ind. Eng. Chem. Res. 2010, 49, 2783–2789

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Supercritical Phase Inversion To Form Drug-Loaded Poly(vinylidene fluoride-co-hexafluoropropylene) Membranes Stefano Cardea,† Margherita Sessa,† and Ernesto Reverchon*,†,‡ Department of Chemical and Food Engineering, UniVersity of Salerno, and NANO_MATES, Research Centre for Nanomaterials and Nanotechnology at the UniVersity of Salerno, Via Ponte Don Melillo, 84084 Fisciano, Italy

Membranes loaded with an active principle are one of the alternatives proposed to obtain controlled release pharmaceutical formulations. Until now, several methods have been proposed for the fabrication of membranes as drug delivery devices, such as phase inversion, gas foaming/particulate leaching, and solvent evaporation. Supercritical CO2 (SC-CO2) phase inversion offers an alternative process to obtain solvent-free membranes with short processing times, avoiding the collapse of the structure. We prepared poly(vinylidene fluorideco-hexafluoropropylene) (PVDF-HFP) loaded membranes by SC-CO2 phase inversion, performing experiments at pressures ranging between 150 and 250 bar and at temperatures ranging between 35 and 55 °C. We selected as the base case the PVDF-HFP-acetone solution at 15% w/w polymer and modified the drug (amoxicillin) concentration from 20 to 50% w/w with respect to PVDF-HFP. Different membranes morphologies, ranging from nanometric gel-like networks (mean pores diameter of about 150 nm) to micrometric cellular structures (mean cells diameter ranging between 5 and 12 µm), and different drug distributions were obtained, depending on the process conditions. Drug-controlled release experiments were also performed to study the kinetics and duration of the release process. 1. Introduction Poly(vinylidenefluoride) (PVDF) is a polymer with industrial relevance because of its electrical properties, durability, and biocompatibility.1 These properties, coupled with its intrinsic hydrophobicity, make it an outstanding membrane material, particularly for soft tissue applications and as suture material,2,3 organic/water separation,4,5 gas absorption and stripping,6 membrane distillation,7,8 and ultrafiltration;9 PVDF membranes can also be autoclaved for sterile applications. The most interesting applications are related to the pharmaceutical and biomedical fields, for example, tissue engineering and controlled delivery of drugs. Membranes loaded with an active principle are one of the alternatives to obtain controlled release formulations. The goal of an ideal drug delivery system is to deliver the drug to a specific site, in a specific time and release pattern. The traditional medical forms (tablets, injection solutions, etc.) provide drug delivery with hemeatic concentration peaks. The constant drug level in blood or sustained drug release to avoid multiple doses are the main challenges for controlled delivery systems.10,11 The release of a drug from a controlled release device can depend on different mass-transfer mechanisms controlled by swelling, erosion, or diffusion or by more than one of the abovementioned mechanisms. In the case of nonswelling and nondegradable membranes, as for PVDF membranes, the release process is diffusion-controlled. The transport of the drug across the membrane depends on drug diffusivity through the membrane, according to Fick’s law. The membrane can be porous or nonporous and can find application in the fabrication of pills, implants, and patches. The design of a particular membrane system requires an accurate * To whom correspondence should be addressed. Telephone/fax: 0039-089-964116. E-mail: [email protected]. † Department of Chemical and Food Engineering, University of Salerno. ‡ Research Centre for Nanomaterials and Nanotechnology at the University of Salerno.

screening to select the specific polymer/drug pair, which will satisfy the therapeutic criteria. Until now, many methods have been proposed for the fabrication of loaded membranes as drug delivery devices, such as phase inversion,12,13 gas foaming/particulate leaching,14 and solvent evaporation.15 All the techniques proposed in the literature present various limitations; the most common are as follows: (a) separation of the suspended materials from the polymer solution during the membrane formation process, due to the long processing times (several hours) that allow the stratification of the suspension (the obtained membrane shows reduced efficiency due to the nonuniform load distribution); (b) high levels of organic solvent may remain in the structures produced; (c) a long drying process (12-48 h) has to be performed, which can lead to the collapse of the porous structure. Supercritical CO2 (SC-CO2) phase inversion offers an alternative process to obtain solvent-free membranes with short processing times and no collapse of the structure. The substitution of the liquid nonsolvent with SC-CO2 has several advantages: SC-CO2 can form the membrane rapidly without the collapse of the structure due to the absence of a liquid-liquid interface. Performing the process at different pressures allows modulation of membrane morphology and cell size by simply changing the operative conditions; the process does not require additional post-treatments and the organic solvent is easy to recover. In the last 7 years, several works on membrane generation have been proposed in the literature in which the potential advantages of the SC-CO2 technique have been exploited.16-31 The results obtained have been sometimes explained through a modification of the classical solvent-nonsolvent-polymer ternary diagrams, analyzing the different membrane formation paths. For example, Matsuyama et al.16,17 used a SC-CO2assisted phase inversion process to analyze the effect of several process parameters (temperature, pressure, and polymer concentration) on the pore size of polystyrene membranes16 and the influence of the kind of solvent used in the formation of

10.1021/ie901616n  2010 American Chemical Society Published on Web 02/04/2010

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cellulose acetate membranes.17 Reverchon et al.22,23 and Xu et al.24,25 proposed the formation of membranes using biodegradable polymers like poly-L-lactide acid (PLLA) and polyvinyl alcohol (PVA), demonstrating that these polymers can successfully interact with SC-CO2. At the typical supercritical processing conditions (80-250 bar, 35-70 °C), SC-CO2 and water show a very reduced affinity that hinders the application of the supercritical phase inversion technique to water-soluble polymers. However, Reverchon et al.27 showed that this process limitation can be overcome using pressurized CO2-ethanol mixtures whose behavior can be very similar to that of a supercritical nonsolvent. The possibility of producing poly(vinylidene fluoride-cohexafluoropropylene) (PVDF-HFP) membranes28 and aerogels29 has also been tested; the copolymer PVDF-HFP presents the same interesting peculiarities of PVDF and, also, high stability and plasticity as a result of the crystalline properties of the vinylidene fluoride (VdF) unit and the amorphous nature of the hexafluoropropylene (HFP) unit, respectively; moreover, it is acid-resistant and inert. The effect of the process parameters such as polymer concentration, temperature, pressure, and liquid solvent on membranes and gels morphology and cell/pore size has been studied.28,29 The overall result of these studies is that, by proper selection of the process parameters, it is possible to modulate cell and pore size of membranes and to obtain different morphologies using the same liquid solvent: cellular structure, bicontinuous structure, and microparticles. In some cases it is also possible to modulate all membrane characteristics simply by changing the nonsolvent power of SC-CO2. However, supercritical-assisted phase inversion to produce loaded membranes has been until now used only in a few cases. Reverchon et al.32 loaded poly(methyl methacrylate) (PMMA) membranes with suspended or cosolubilized amoxicillin and performed the experiments varying some process parameters. The drug was efficiently encapsulated inside the membrane (i.e., no burst effect was observed and an uniform drug distribution was obtained) and the control of the rate of dissolution was obtained, depending on the kind of drug loading performed (suspended or solubilized) and on the membranes morphology obtained. Temtem et al.33 prepared PMMA membranes loaded with hydroxypropyl-β-cyclodextrins (HP-β-CDs) and demonstrated the possibility of tuning the release of a drug (i.e., ibuprofen) subsequently impregnated in the loaded membrane. Duarte et al.34 successfully generated PLLA + dexamethasone loaded membranes for tissue engineering applications. Therefore, the aim of this work is to use the supercritical CO2 phase inversion to produce new PVDF-HFP membranes loaded with a test antibiotic, amoxicillin, as an oral delivery system (i.e., tablets), analyzing the efficiency of the encapsulation at different process conditions. The interactions between the suspended drug and the polymer structure will also be studied. Drug controlled release experiments will also be proposed to evaluate the kinetic and duration of the release process. 2. Materials and Methods 2.1. Materials. PVDF copolymer VF2-HFP with high molecular weight (SOLEF 21216, number average 199 × 103, weight average 353 × 103, polydispersity 1.8, density 1.78 g cm-3, Tg ) -30 °C, Tm ) 135 °C) was kindly supplied by Solvay S.A. (Ixelles, Belgium); amoxicillin (purity 99.6%) and acetone (purity 99.8%) were bought from Sigma-Aldrich; CO2 (purity 99%) was purchased from SON (Societa` Ossigeno Napoli, Italy). All materials were processed as-received.

2.2. Membrane Preparation. Porous PVDF-HFP membranes were prepared in a laboratory apparatus equipped with a 316 stainless steel high-pressure vessel with an internal volume of 80 mL in which SC-CO2 contacts the polymer solution in a single pass. The casting process is similar to the traditional procedure. PVDF-HFP was dissolved in the solvent (i.e., acetone); drug was loaded into the PVDF-HFP solutions at various polymer/drug weights ratio. The suspension obtained was placed in a membrane formation cell (steel caps with a diameter of 25 mm and heights of 300-500 µm), spreading it with a glass stick to control the thickness of the film at room temperature. The cell was rapidly (ca. 30 s) put inside the preparation vessel to avoid the evaporation of the solvent. Then the vessel was closed and filled from the bottom with SC-CO2, up to the desired pressure using a high-pressure pump (Milton RoysMilroyal B, France). In the first part of the process, we operated in batch mode for 20 min; after this period of time, a micrometric valve was opened and the operation was performed in continuous mode; i.e., with a constant CO2 flow rate of 1.5 kg/h. Pressure and temperature were held constant and the phaseseparated membrane was dried for 10 min. Then the vessel was slowly depressurized for 10 min. 2.3. Scanning Electron Microscopy. PVDF-HFP porous structures were examined by cryofracturing them with a microtome (Bio-optica S.p.A, Italy, model Microm HM 550 OMVP) by sputter coating the sample with gold and viewing it with a scanning electron microscope (SEM) (model LEO 420, Assing, Italy) to determine cells size, morphology, and drug distribution. Sigma Scan Pro 5.0 software (Jandel Scientific, San Rafael, Canada) and Origin 6 software (Microcal, Northampton, USA) were used to determine the average diameter of the cells and pores. 2.4. Energy-Dispersive X-ray Analyzer. Amoxicillin dispersion in the membranes was measured using an energydispersive X-ray analyzer (EDX model INCA Energy 350, Oxford Instruments, Witney, UK), using the signal of sulfur atoms to characterize amoxicillin crystals. Before the evaluation of the elemental composition, the samples were coated with chromium (layer thickness 150 Å) using a turbo sputter coater (model K575X, EmiTech Ashford, Kent, UK). 2.5. Differential Scanning Calorimetry. Differential scanning calorimetry (DSC) traces of loaded PVDF-HFP structures were obtained using a Mettler (model TC11, USA) differential scanning calorimeter at a heating rate of 10 °C/min under a nitrogen atmosphere. DSC trace for the two pure compounds was performed beforehand. 2.6. In Vitro Drug Release. In vitro release rate assays were performed to determine the kinetics of drug release from the porous structures. The drug-loaded membrane was immersed in a glass bottle containing a physiological saline solution (pH 7.2) as a drug-releasing medium (1000 mL). The sealed bottle was placed in an oven at 37 °C and shaken at 200 rpm. At predetermined time intervals, the concentration of drug was assayed using a UV spectrophotometer (Varian, model Cary 50 Scan, Palo Alto, CA, USA). 3. Results and Discussions In the first part of the work, we focused our attention on the feasibility of the loading process and on the effect of the process parameters on the PVDF-HFP membranes. In particular, we modified process pressure and temperature and verified the membranes structural modifications by SEM and EDX analysis. Then we studied the release of a model drug (amoxicillin) from

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Figure 1. PVDF-HFP + amoxicillin membrane section obtained at 250 bar and 35 °C: (a) whole membrane section; (b) enlargement showing membrane microstructure and amoxicillin crystals.

the loaded membranes to verify the effectiveness of the encapsulation process. 3.1. Effect of SC-CO2 Density. In a previous work,28 the formation of PVDF-HFP membranes by supercritical CO2 phase inversion has been studied. The results indicated that SCCO2 solvent power influences the morphology of these membranes. In particular, with an increase of the SC-CO2 solvent power (i.e., increasing pressure and/or decreasing the temperature), the membranes structure changed from cellular to gellike (i.e., a nanoporous network was formed). Starting from these results, we performed experiments on the PVDF-HFP/amoxicillin system operating at pressures ranging between 150 and 250 bar and temperature ranging between 35 and 55 °C. We focused the attention on limit experiments performed at 250 bar and 35 °C, which corresponds to the case of highest SC-CO2 solvent power (i.e., high SC-CO2 density, 890 kg/m3), and at 150 bar and 55 °C, which corresponds to the case of lowest SC-CO2 solvent power (i.e., low SC-CO2 density, 652 kg/m3). We selected as the base case the PVDF-HFP-acetone solution at 15% w/w polymer. A drug can be loaded in a membrane using two different techniques: dissolving it in the organic solvent used to solubilize the polymer or forming a suspension of the drug in the organic solution formed by polymer and solvent. These two strategies can give different results in terms of membrane formation, characteristics, and drug release kinetics.32 In this case, the experiments were performed forming an amoxicillin suspension in the starting solution; the amount of amoxicillin was 20% w/w with respect to PVDF-HFP. In Figure 1, SEM images of a PVDF-HFP loaded membrane produced at 250 bar and 35 °C are reported. It is possible to

Figure 2. PVDF-HFP + amoxicillin-loaded membrane obtained at 150 bar and 55 °C: (a,b) section at different enlargement; (c) higher enlargement showing amoxicillin crystals entrapped in the polymeric structure.

observe that the structure is homogeneous along the whole membrane section and it is characterized by a nanometric network (i.e., a gel-like structure) with a mean pore diameter of about 150 nm; this result confirms the structure observed in the case of PVDF-HFP unloaded membranes.28 In Figure 1b, taken at a higher magnification, the presence of amoxicillin crystals inside the nanometric network is also evidenced. When the experiments are performed at 150 bar and 55 °C, the membranes morphology considerably changes. Indeed, in SEM images reported in Figure 2, a double structure along the membrane section can be observed. In the upper part of the membrane, a nanometric network with a mean pore diameter of about 120 nm is obtained, whereas in the lower part a cellular structure with a mean cell diameter of about 12 µm is formed. Also in this case, it is possible to observe the amoxicillin crystals

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Figure 3. EDX analysis of loaded membranes obtained at (a) 250 bar and 35 °C and (b) 150 bar and 55 °C. Sulfur atom used as a reference of amoxicillin presence is evidenced in green and shows the position of drug crystals inside the structure.

inside the nanometric network (Figure 2c). It is possible to make a qualitative consideration: the amoxicillin crystals seem to “migrate” in the upper part of the membrane and a larger concentration of drug in the upper part is visible. To confirm these results, EDX analysis was performed in these two cases and the results are reported in Figure 3a,b. The amoxicillin crystals are clearly visible (green color) in both membranes; however, a quantitative analysis is required to obtain information about the drug distribution across the membranes. Therefore, in Figure 4 is reported the % w/w of amoxicillin detected by EDX along the thickness of the membranes for the two kinds of morphologies obtained. Membranes obtained at 150 bar and 55 °C (nanometric network + cellular structure) present an accumulation of the drug in the upper part of the section that constitutes about 25% of the total thickness, with an abrupt variation of concentration in the region in which the transition between the two structures is observed. Then a practically uniform distribution along the cellular zone is shown. Membranes obtained at 250 bar and 35 °C, which are characterized by the nanometric network, present a homogeneous distribution of drug along the whole membrane thickness that is practically equal to the loading of amoxicillin in the starting polymeric solution; this also means that practically all the loaded drug is entrapped in the solid structure. This

Figure 4. Amoxcillin content vs normalized membrane thickness (0 ) bottom surface; 1) top surface).

interesting result was not obvious; indeed, the traditional loaded membranes formation techniques tend to generate structures characterized by a nonuniform drug distribution (part of the drug migrates toward the membrane surface, producing burst effect phenomena on drug dissolution) and by a partial drug loss during the loading procedure. To explain the results obtained, we consider a qualitative ternary diagram reported in Figure 5, which is related to the final process pressure. However, pressurization of the vessel is very fast; therefore, it is possible to assume that massive CO2

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Figure 5. Qualitative ternary phase diagram for PVDF-HFP/acetone/SCCO2 system.

dissolution in the liquid phase is obtained only at pressures near the final process value. Starting from the solution at point A, the pathway moves inside the ternary diagram due to SC-CO2 diffusion and passes the solid-liquid (S-L) demixing line. The position of this line, next to the solvent apex, has already been studied and reported in previous works.28,29 In this way, the gel-like structure is formed (point B). Depending on the process conditions, the pathway can stop at point B, or as in the case of the lower solvent power conditions, can proceed until it overcomes the liquid-liquid (L-L) demixing line generating the cellular structure (C). In particular, in the case of the doublemorphology membranes, the cellular structure is formed only in the lower part of the membrane obtained at 150 bar and 55 °C, probably because the upper part is more rapidly formed by CO2 diffusion. In the lower part of the membranes, SC-CO2 diffuses later and induces an L-L demixing (C). This interpretation justifies the membranes morphology obtained: when SC-CO2 solvent power is high, the phase separation is rapid and S-L demixing is only obtained, leading to a gel-like structure; when SC-CO2 solvent power is lower, the process is slower and in the upper part of the membrane a gel-like structure is formed, whereas, in the lower part, the pathway moves toward the L-L demixing gap, leading to a cellular structure (L-L demixing). Drug distribution depends on the morphologies obtained. To justify these results, it is important to point out that amoxicillin is initially in suspension inside the polymeric solution. We also verified that during the preparation of the suspension, once the stirring of the solution is stopped, the drug slowly tends to migrate toward the upper part of the solution because the drug density (about 0.45 g/mL) is lower than the solution density (it is about 0.94 g/mL, for 15% w/w PVDF-HFP at room temperature). For this reason, when the SC-CO2 solvent power is high (250 bar and 35 °C), the phase inversion process is very rapid and the drug has no time to migrate inside the solution, whereas when the SC-CO2 solvent power is low (150 bar and 55 °C), the phase inversion process is longer and part of the drug can migrate toward the membrane top skin, causing an increase of drug concentration as observed in Figure 4. 3.2. Effect of Drug Concentration. We performed some experiments, keeping constant the process parameters such as pressure (200 bar), temperature (45 °C), and polymer concentration (15% w/w), and modified the drug concentration from 20 to 50% w/w with respect to PVDF-HFP. In Figure 6, SEM images of membranes obtained with 30% w/w amoxicillin are reported. Comparing these images with those of the membranes containing 20% w/w amoxicillin, it is possible to observe that the drug concentration does not influence the membranes morphology, whereas a mean cell diameter of

Figure 6. PVDF-HFP loaded membranes obtained at 200 bar, 45 °C and with 30% w/w amoxicillin: (a,b) section; (c) upper part of section; (d) lower part of section.

about 5 µm was obtained. This result has been observed for all drug concentrations and process conditions tested. Interesting information has been obtained by performing DSC analysis on the membranes containing different drug concentra-

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Figure 7. DSC analysis of PVDF-HFP (a) and PVDF-HFP loaded membranes with amoxicillin: (b) 20% w/w, (c) 30% w/w, (d) 50% w/w, and (e) amoxicillin.

Figure 8. Release curves of untreated amoxicillin (9), PVDF-HFP loaded membranes obtained at 150 bar and 55 °C (0), and PVDF-HFP loaded membranes obtained at 250 bar and 35 °C (O).

tions. Figure 7 reports the thermograms of PVDF-HFP membranes containing 50, 30, and 20% w/w of amoxicillin. DSC of pure amoxicillin and polymer are also reported for comparison. Traces “a” and “e” in Figure 7 show the characteristic fusion peaks of the polymer and of pure amoxicillin, respectively. These same peaks (though they are smaller) can be observed in the membranes containing the 20% of suspended amoxicillin (trace “b”); however, the fusion peak of the polymer is shifted to a lower temperature. When the percentage of drug in the membrane is increased, the fusion peak of the polymer disappears progressively (traces “c” and “d”) since it merges with the drug fusion peak. These results confirm the presence of the drug in the membrane as shown by SEM and EDX analysis and its influence on the overall behavior of the formed composite structure. 3.3. Drug Release Analysis. We performed these experiments using the two limit membranes morphology previously discussed. Figure 8 reports the release rate curves of untreated amoxicillin (9) and of PVDF-HFP membranes obtained operating at 150 bar and 55 °C (nanometric network + cellular structure, 0) and at 250 bar and 35 °C (nanometric network, O) containing 20% w/w of suspended drug. Untreated amoxicillin dissolves completely in about 10 min, confirming that a modulation of its release is necessary for a practical application. An amoxicillin prolonged release of about 50 and 100 h can be estimated from the diagram for the double-structure and singlestructure membrane, respectively. Therefore, gel-like structure shows, as expected, a slower drug release. It depends on the fact that the nanometric network structure, with a mean pore diameter of about 150 nm, allows a slower diffusion of the physiological solution and the release time is longer; indeed, it is clear that mass transfer of a liquid inside a nanometric structure is more difficult, due both to the low diffusivity and to the surface tension. In contrast, in the case of the double-

structure membrane, the cellular part, formed by micrometric cells, is characterized by a faster diffusion of the physiological solution. It is interesting to note that, in the first 24 h of processing, a quasi-first-order release kinetics is observed for both membranes; i.e., a quasi-constant concentration of amoxicillin is obtained in the dissolving medium that is the ideal performance for a controlled release medium. In particular, the double-structure membrane releases, during the first day, about 85% of the drug, whereas the nanometric network releases ca. 75% of the drug. Moreover, no burst effect has been observed; i.e., no initial fast release of the drug has been evidenced for both membranes. These two characteristics are the ones required for controlled 24 h somministration of an antibiotic like amoxicillin, and therefore, the release systems produced in this study could represent a formulation suitable for an oral delivery system. It can ensure a constant blood concentration of the drug, avoiding hemeatic concentration peaks and limiting the number of somministrations to one a day. Another advantage of this formulation is related to the physical-chemical characteristics of the polymer used. The polymeric structure neither swells nor collapses (it is biocompatible but not biodegradable) during the drug release, preserving its original geometry and being eliminated by the patient by physiological means. If we perform a comparison of the membranes produced in this work with the PMMA-amoxicillin membranes analyzed in a previous work,30 it is possible to put in evidence that, in the case of PVDF-HFP loaded membranes, the drug release is slower. Indeed, in the cited study, the loaded drug was dissolved completely in 3 hours. Moreover, an initial burst release was observed, indicating that, probably, part of the drug particles were exposed on the surface of the polymeric membrane. An explanation of these different behaviors is related to the structure and characteristics of the two kinds of membranes: PMMA is less hydrophobic than PVDF-HFP and presents a cellular structure along the entire section. These two factors produce a faster diffusion of the physiological solution and consequently a higher drug release rate. 4. Conclusions We showed the possibility of producing novel polymeric membranes, loaded with an antibiotic. The supercritical-assisted phase inversion method confirmed its flexibility: it is possible to obtain different membranes morphologies and drug distributions, depending on the process conditions. A quasi-first-order release kinetics was observed; that is the most important characteristic required for controlled 24 h somministration of an antibiotic. Literature Cited (1) Urban, E.; King, M. W.; Guidon, R. Why make monofilament sutures out of polyvinylidene fluoride? ASAIO J. 1994, 40, 145. (2) Laroche, G.; Marois, Y.; Guidoin, R.; King, M. W.; Martin, L.; How, T.; Douville, Y. Polyvinylidene fluoride (PVDF) as a biomaterial: from polymeric raw material to monofilament vascular suture. J. Biomed. Mater. Res. 1995, 29, 1525. (3) Mary, C.; Marois, Y.; King, M. W.; Laroche, G.; Douville, Y.; Martin, L.; Guidoin, R. Comparison of the in vivo behavior of polyvinylidene fluoride and polypropylene sutures used in vascular surgery. ASAIO J. 1998, 44, 199. (4) Jian, K.; Pintauro, P. N.; Ponangi, J. Separation of dilute organic/ water mixtures with asymmetric poly(vinylidene fluoride) membranes. J. Membr. Sci. 1996, 117, 117. (5) Jian, K.; Pintauro, P. N. Asymmetric PVDF hollow-fiber membranes for organic/water pervaporation separations. J. Membr. Sci. 1997, 135, 41.

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ReceiVed for reView October 16, 2009 ReVised manuscript receiVed January 15, 2010 Accepted January 22, 2010 IE901616N