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Nanostructures of Cellulose Acetate Phthalate Obtained by Electrospinning from 2Methoxyethanol-Containing Solvent Systems: Morphological Aspects, Thermal Behavior, and Antimicrobial Activity
Niculae Olaru,*, Liliana Olaru, Nita Tudorachi, Simona Dunca, and Manuela Pintilie

Petru Poni Institute of Macromolecular Chemistry, Aleea Gr. Ghica-Voda 41 A, Iasi 700487, Romania Al. I. Cuza University, Bd. Carol I 11, Iasi 700506, Romania ABSTRACT: Cellulose acetate phthalate (CAP) is well-known and largely used as a pharmaceutical excipient for enteric coating of tablets and capsules. Recent literature has proved that this polymer exhibits antimicrobial and antiviral properties when it is used as a micronized powder. Nanostructures of CAP are also prepared, and their potential for antimicrobial and technological applications is recently reported. In the present work, we are focused on synthesis and characterization of CAP nanobers and powders by electrospinning/electrospraying from solutions in solvent mixtures containing 2-methoxyethanol. The morphologies of the obtained nanostructures are investigated by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses and discussed in comparison with those previously reported for products obtained in 2-methoxyethanol alone. Thermal properties of CAP nanostructured as powders and bers are studied in comparison with those of CAP lms using thermogravimetric (TG), Fourier transform infrared (FTIR), and mass spectrometry. TG analysis reveals that CAP nanoproducts exhibit an apparent lower stability than CAP lms. Further investigations of both residual polymer and the evolved degradation gas products evidence the presence of phthalic anhydride as a main degradation product in the initial stage of the process. In the case of nanostructures of CAP, due to their high porosity and very high specic surface areas, this degradation product is easier and continuously eliminated during the thermal treatment. This behavior explains their apparent lower thermal stability as compared with that of the lms where the diusion of phthalic anhydride proceeds slowly and therefore the weight loss of the sample is delayed. The paper also reports preliminary results of antimicrobial activities of the investigated products against Escherichia coli and Staphylococcus aureus. and bers of CAP with sizes in the submicrometer range and dierent morphologies can be easily obtained using a simple electrospinning laboratory setup. It has also been observed that the morphology of the electrospun CAP changes as a function of the solution characteristics like viscosity, surface tension, and conductivity. When using only 2-methoxyethanol as the electrospinning solvent, polymer concentrations higher than 25% (w/v) were necessary to obtain smooth laments without beads, whereas at a polymer concentration as low as 12.5% (w/ v), only micro/nanoparticles that look like void hemispheres have been obtained. When a ternary system 2-methoxyethanolacetonewater 50/42.5/7.5 (v/v/v) was used as the electrospinning solvent system for CAP, smooth laments without beads and ber diameters of about 600 nm could be produced at concentrations of 25% (w/v). The potential use of electrospun CAP bers as a tool to prevent HIV transmission has been very recently discussed by Huang et al.24 By taking into account the observation that the electrospinnability of CAP from 2-methoxyethanol-containing solvents was better than that from acetonewater mixtures,23 in
Received: Revised: Accepted: Published:
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1. INTRODUCTION Cellulosic polymers have gathered great interest in recent years in the eld of nanoproducts useful for high-value applications. The biodegradability, biocompatibility, and versatility of these natural polymers are the reasons for those approaches regarding the possibilities to transform them in nanostructured materials with large applications especially in biomedicine, for tissue engineering scaolds, wound dressing, controlled release, and technology purposes such as ltration, catalysis, sensors, anity membranes, etc.115 One of the most interesting cellulose derivative from this point of view is cellulose acetate phthalate (CAP), a mixed ester with acetic and o-phthalic acids. CAP has been known for several decades as a pharmaceutical excipient used for enteric coating of tablets and capsules. Recently, it has been shown that CAP formulated as a micronized powder exhibits activity against the human immunodeciency virus type I (HIV-I), several herpes viruses (herpes simplex viruses I and II), and many nonviral sexually transmitted disease pathogens.1622 In a previous paper,23 we have studied the possibility to obtain micro/nanostructured CAP with high specic surface areas via the electrospinning procedure. Several solvent systems (2-methoxyethanol, acetonewater mixture 85/15 (v/v), and 2-methoxyethanolacetonewater mixture 50/42.5/7.5 (v/v/ v)) were investigated, and it has been found that by variation of the solvent system and the polymer concentration, powders
2012 American Chemical Society

May 17, 2012 December 12, 2012 December 12, 2012 December 12, 2012
dx.doi.org/10.1021/ie301299d | Ind. Eng. Chem. Res. 2013, 52, 696705

Industrial & Engineering Chemistry Research the present paper we further investigate the electrospinning of CAP from 2-methoxyethanol and 2-methoxyethanolwater systems with dierent compositions. A detailed characterization of CAP has been reported by Roxin et al.25 including data about its thermal behavior when treated in oxygen and inert atmospheres. Glass transition temperatures of CAP samples were also determined. Earlier26 we demonstrated that by treating CAP lms at temperatures between 120 and 220 C for various times of exposure, one of the principal degradation products is the phthalic anhydride, which is partially evolved during the process. Having in mind the possibility to change drastically the polymer properties by transforming it into nanostructured materials and also taking into account the importance of the thermal behavior of these materials from an applicative point of view, in the present paper we are concerned with a study on thermal properties of micro/nanopowders and bers of CAP in comparison with those of the usual lms obtained from the same polymer. TG-DTG analysis, FTIR, ATR, and mass spectrometry were used to investigate thermal stability of nanostructured CAP. On the basis of literature reports, we expect that the obtained nanostructures of CAP could enhance its potential as antimicrobial agent. Therefore, in this paper, preliminary tests on the antimicrobial activity of the electrospun CAP products are also reported in relation to their morphology.

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2. MATERIALS AND METHODS 2.1. Materials. The chemicals were of reagent grade and were used as received, without further purication. 2.2. Synthesis and Characterization of CAP. Cellulose acetate phthalate investigated in this work had a degree of phthaloylation of 0.70 and a degree of acetylation of 1.73 and was synthesized by phthaloylation of cellulose acetate (CA) with degree of acetylation of 1.77 and degree of polymerization of 185. Both cellulose derivatives were prepared in our laboratory, as described in our previous papers.23,27 Characterization of CAP and CA with respect to their degrees of modication was performed by means of the known methods: refs 28 and 29, respectively. 2.3. Electrospinning and Electrospraying Experiments. The experiments for obtaining of both bers and powders of CAP were carried out using the same typical laboratory setup, consisting of a high voltage source, a pump and a syringe for polymer solution and a rotary collector disk. Solutions of CAP were prepared in 2-methoxyethanol and mixtures of 2-methoxyethanolwater of three compositions: 95/5 (v/v), 90/10 (v/v), and 85/15 (v/v). On the basis of previous results,23 the concentration of polymer solutions was chosen to be 10% and 30% (w/v) so as to obtain powders and bers, respectively, with sizes in the submicrometer range. The same parameters were chosen for both electrospinning and electrospraying experiments, as follows: voltage potential, 1520 kV; tip-to- collector distance, about 15 cm; ow rate of the solution through the syringe, 1.5 mL h1. The processes were carried out in air at room temperature. 2.4. Characterization of CAP Micro/nanoproducts. The morphology of CAP ultrane bers and powders was characterized by scanning electron microscopy (SEM; VEGA II SBH TESCAN) and transmission electron microscopy (TEM; TESLA BS 513A).
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The particle size distribution curves for CAP powders were obtained by means of a system Mastersizer 2000 version 5.31, Malvern Instruments. The electrical conductivity of polymer solutions was measured using a CDM 210 (Radiometer, Copenhagen) Conductometer. Viscosity of CAP solutions was determined by means of a Brookeld SYNCHRO-LECTRIC Viscometer, model LVF. 2.5. Thermal Treatment. Thermal analysis was performed by simultaneous TG, MS, and FTIR determinations using the following equipment: TG-DSC model STA 449F1 Jupiter (NetzschGermania), QMS 403C Aeo los (NetzschGermania), and FTIR spectrophotometer model Vertex-70 (Bruker) with an accessory for ATR (attenuated total reectance) type Golden Gate. The experiments were carried out in the following conditions: heating rate 10 K min1; gas purge He; reference material Al2O3; temperature range 30600 C. 2.6. Antimicrobial Tests. The in vitro antimicrobial activity was assessed using the disk-diusion method KirbyBauer30 on two strains of bacteria: Staphylococcus aureus ATCC 25923 (S. aureus) and Escherichia coli ATCC 25922 (E. coli). CAP samples obtained from solutions in 2-methoxyethanol and 2-methoxyethanolwater 85/15 (v/v) at 10% (w/v) polymer concentration were used for these tests. The bacterial inoculum obtained from bacterial cultures preincubated for 18 h at 37 C was standardized according to McFarland scale and a number of 107108 CFU/mL was obtained. The culture medium (LB-Lysogeny broth) was seeded with the inoculum thus obtained and then microdisks of 1 cm diameter impregnated with CAP powders (0.01 g/ microdisk) were placed on the surface of the medium. Three determinations were carried out for each sample, and the average values obtained for the diameters of the inhibition zones are shown in Table 1. Table 1. Antimicrobial Activity Expressed by the Diameter of the Inhibition Zone (mm) of CAP Nanopowders Obtained from Solution in 2-Methoxyethanol for P1 and Solution in 2MethoxyethanolWater 85/15 (v/v) for P2 at 10% (w/v) Polymer Concentration
microorganism test sample P1 P2 Staphylococcus aureus ATCC 25923 12 16 Escherichia coli ATCC 25922 11 14

Samples of CAP nanobers were placed directly on the surface of the culture medium. The plates were then incubated at 37 C for 24 h, and the antibacterial activity was evidenced by the occurrence of an inhibition zone around the sample area.

3. RESULTS AND DISCUSSION 3.1. Morphological Aspects of Nanostructured CAPs. 3.1.1. Ultrane CAP Powders. The morphology of CAP micro/ nanoparticles obtained from 2-methoxyethanolwater systems, as revealed by SEM images for 10% (w/v) polymer concentration in the electrospun solution (Figure 1), does not dier from that reported for similar products obtained from 2-methoxyethanol solvent. The shape of void hemispheres for CAP micro/nanoparticles is preserved when water is present in the electrospinning solvent.
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Figure 1. SEM micrographs of CAP micro/nanoparticles obtained from 2-methoxyethanol (a) and 2-methoxyethanolwater 85/15 (v/v) (b) at 10% (w/v) polymer concentration.

Figure 2. TEM images of CAP micro/nanoparticles obtained from 2-methoxyethanol (a) and 2-methoxyethanolwater mixtures 95/5 (v/v) (b), 90/10 (v/v) (c), and 85/15 (v/v) (d) at 10% (w/v) polymer concentration.

As in the case of the particles obtained at 12.5% (w/v) polymer concentration,23 most of the particles obtained in the present work appear to have the same orientation, with the bowl directed to the positive electrode, probably as a consequence of the orientation in the electric eld of the solvated polymer molecules. However, TEM images suggest a slight deformation of the spherical part of the bowl (that part oriented to the collector plate) when adding water and increasing the proportion of water in the solvent (Figure 2a d). This may be due to the increased polarity of the solvent
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system containing water, which can inuence the polarity of the solvated polymer molecules, but the lower viscosity of the system may be also involved. As compared with particles obtained from 2-methoxyethanol at 12.5% (w/v) polymer concentration,23 those obtained from the same solvent at 10% (w/v) polymer concentration as well as those obtained from 2-methoxyethanolwater mixture 85/ 15 (v/v) at 10% (w/v) polymer concentration seem to have lower width of their walls (Figure 1) and also lower diameters as revealed by the particle size distribution data. Thus,
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Figure 3. Particle size distribution of CAP micro/nanoparticles obtained from 2-methoxyethanol (a) and 2-methoxyethanolwater mixture 85/15 (v/v) (b) at 10% (w/v) polymer concentration.

Figure 4. SEM micrographs of CAP nanober mats obtained from 2-methoxyethanol (a) and 2-methoxyethanolwater mixture 85/15 (v/v) (b) at 30% (w/v) polymer concentration.

distribution curves in Figure 3 clearly show that 10% polymer concentration in the electrospun solutions for both solvent systems investigated in this paper gave 50% of the obtained particles with diameters lower than 5 m as compared with 10 m previously reported for higher polymer concentrations.23 At the same time, the polymer solution in the solvent mixture 2699

methoxyethanolwater 85/15 (v/v) gave smaller particles with specic surface area higher than of those produced from 2methoxyethanol solution (Figure 3). The presence of water in the electrospinning solution may be responsible for such eect, due to the higher electrical conductivity of the polymer solution containing water (19.0 S/cm as compared with 4.82 S/cm
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Figure 5. TEM images of CAP nanobers obtained from 2-methoxyethanol (a) and 2-methoxyethanolwater mixture 85/15 (v/v) (b) at 30% (w/ v) polymer concentration.

for the solution free of water), on one hand. On the other hand, the presence of water may contribute to the disruption of some macromolecular associations linked together by strong hydrogen bonding between the carboxyl groups of the polymer. One consequence of this eect is the lower viscosity of the polymer solution containing water which also favors formation of smaller particles. Thus, solvent systems based on 2-methoxyethanol containing small proportions of water (until 15% (v/ v) and low polymer concentration (10%, w/v) can be more ecient for obtaining membranes with higher porosity and higher specic surface areas. The electrospinning of cellulose acetate phthalate from 2methoxyethanolwater mixtures proceeded without interruption and the polymer jet was as uniform as in the case of 2methoxyethanol alone, previously described.23 No variation was observed from the electrospinnability point of view depending on the polymer concentration and on the proportion of water in the mixture. 3.1.2. Ultrane CAP Fibers. As it has been already shown for 2-methoxyethanol solutions,23 higher polymer concentrations (up to 35%, w/v) provided smooth nanober mats and the morphology of the nanosized material gradually changed from particles to beaded nanober and nally to nanober mats. The same behavior was observed in the case of electrospinning of CAP from 2-methoxyethanolwater mixtures. SEM micrographs in Figure 4 reveal that nanober mats obtained from 2methoxyethanolwater mixture 85/15 (v/v) at 30% (w/v) polymer concentration appear more uniform in terms of entanglement and bers diameters. Besides, TEM images (Figure 5) suggest that bers diameters produced from solvent mixture could be lower than those obtained from 2-methoxyethanol solvent. This fact is expected because of the presence of water which determines higher conductivity for the solution in this mixture (19.66 S/cm) as compared with the solution in 2-methoxyethanol (5.52 S/ cm), as well as lower viscosity for water-containing solution: 17 800 cP comparatively with 28 000 cP in the absence of water. 3.2. Thermal Behavior of Nanostructured CAPs. During preliminary experiments, we have observed that the composition of the solvent used for electrospinning experiments did not produce signicant dierences between the obtained CAP nanoproducts from the point of view of their thermal behavior. For this reason, in this section we discuss the results obtained during thermal treatment of CAP nanobers and powders obtained from polymer solutions in 2-methox700

yethanolwater mixture 85/15 (v/v) in comparison with the behavior of CAP lm. It is established that, irrespective of the solvent used for electrospinning process, the two CAP nanostructures obtained in this work have specic surface areas of the same size order and much higher than those of CAP lms which have a thickness of about 10 m. This can be an important parameter for the behavior of these dierent CAP morphologies when they are subjected to thermal treatment in dynamic conditions. Thermograms of nanobers and powder of CAP are quite similar (Figure 6), and it can be seen that both nanostructures are apparently less stable to thermal treatment up to 600 C as compared with the lm.

Figure 6. TG and DTG curves obtained at 10 C/min for CAP: (*) lm; () bers; () powder.

Three degradation stages could be detected on TG-DTG curves for all the samples (Figure 6), but the amount of the solid residue after the thermal treatment represents 16.45 wt % from the initial sample for the lm while it is reduced to only 8.00 and 7.50 wt % in the case of the bers and powder, respectively. Dierences between the nanostructured products and the lm with respect to the rate of weight loss are more pronounced in the initial stages of the process: 10 wt % of the lm sample is removed at 201 C while the corresponding temperature is considerably lower for the bers (164 C) and the powder (170 C). This is no more the case at higher temperatures of exposure when 50 wt % of the initial sample is
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Figure 7. 3D FTIR spectra of gaseous products evolved during thermal degradation of CAP lm (a), bers (b), and powder (c).

degraded at about the same temperature (about 325 C) for all the three materials. In order to nd an explanation for this thermal behavior we have further examined the information provided by FTIR and mass spectrometry analyses. Thus, Figure 7 emphasizes 3D FTIR spectra of gaseous products evolved during the degradation process of the three investigated products for all the studied temperature range. For a more detailed examination, in Figure 8 are presented FTIR spectra recorded for the gaseous product evolved at temperatures corresponding to maxima on DTG curves and in Figure 9 are presented FTIR spectra for the solid residue at 175 C as both transmission (Figure 9a) and ATR (Figure 9b). In our previous paper on thermal stability of CAP,26 we found out that when treating lms of CAP at temperatures between 120 and 220 C one of the main degradation products as detected by HPLC is the phthalic anhydride which is partially evolved during the process. Thus, new bands of absorption specic to the anhydride groups could be detected on IR spectra in the vicinity of 18601780 cm1 (usually assigned to the carbonyl stretching vibration), at 910 cm1 (assigned to the anhydride cycle) and 715 cm1.26 Figure 8 in this paper shows evidence of the presence of all these anhydride peaks in the gases evolved during thermal degradation of the three samples at various temperatures. Besides, another strong IR band specic to cyclic anhydrides at about 1260 cm1 appears in the spectrum of gaseous products, but it cannot be identied on the solid residue spectrum (Figure 9) because of the superposition over the acetyl band in this region.
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A comparative analysis of FTIR spectra of the lm on one hand and of the powder and bers on the other hand clearly evidence some peculiarities of nanostructured CAPs with respect to the thermal behavior. In Figure 8, the bands characteristic to the anhydride groups as detected in gaseous products evolved at 172 C are clearly more pronounced for bers and powders of CAP than for the lm because the highly porous micro/nanostructures present a much higher specic surface than in the case of the more compact product (the lm), and this feature allows a much easier diusion of the degradation product. At higher temperatures, the amount of the gases evolved from the lm is considerably increased and the bands specic to anhydride also increase. The initial characteristic gas phase CO2 peak at 2360 cm1 is attributable to air ow uctuation found within the air vent inside the IR beam chamber (due to the presence of CO2 content in the laboratory atmosphere), but it is possible that this CO2 could be adsorbed for a while on the very high surface of nanoparticles and nanobers and subsequently evolved gradually when owing the helium inside the chamber. This could explain the decrease of this peak with increasing the temperature and time of exposure just for nanopowder and nanobers, not in the case of the lm (see Figure 8b and c comparatively with a). The wide absorption band at 3200 cm1 is characteristic to the MCT detector of the TGA-IR external module, but this could be overlapped with the absorption band of acetic acid. The spectral characteristics of gaseous products as discussed above for anhydride groups region are conrmed by FTIR
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Figure 8. FTIR spectra of gaseous products evolved during thermal degradation of CAP lm (a), bers (b), and powder (c) at temperatures corresponding to maxima on DTG curves.

analysis (transmission spectra) of the solid residue at 175 C (Figure 9a) where the most pronounced band specic to anhydride groups at 1870 cm1 appears in the case of the lm. It should be further noted that ATR spectra do not emphasize any trace of anhydride on the surface of any of the three investigated products (Figure 9b) which is also consistent with the above explanation. Mass spectrometry used to identify the degradation products proved that one of the main gaseous products evolved was phthalic anhydride as we have shown previously using HPLC method.26 Figure 10 presents the amounts of phthalic
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anhydride evolved during degradation of CAP bers (a), powder (b), and lm (c) as a function of temperature. It is observed that phthalic anhydride can be detected in degradation products at lower temperatures in the case of the bers and powder (about 170 C) than for the lm (above 200 C). This behavior is due to the higher specic surface of nanostructured CAP products as it is also conrmed by FTIR analysis discussed above. MS spectra also evidence the presence of other compounds like acetic acid, formic acid, phthalic acid, water, and carbon dioxide beside phthalic anhydride.
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Figure 9. FTIR spectra for the solid residue of CAP at 175 C as (a) transmission and (b) ATR. Figure 10. MS analysis of phthalic anhydride produced by thermal degradation of CAP bers (a), powder (b), and lm (c) as a function of temperature.

3.3. Antimicrobial Activity of Nanostructured CAPs. The antimicrobial tests show evidence of the susceptibility of the two investigated microorganisms over the nanober samples and nanopowders of CAP as it is illustrated in Figures 11 and 12 by the occurrence of an inhibition zone around the sample. For CAP powders, in Table 1 the antimicrobial activity is expressed by the diameter of the inhibition zone, as in the case of CAP lms previously reported.31 Both nanopowders of CAP exhibit antibacterial activity, but this is slightly more pronounced in the case of powder obtained from solution in 2-methoxyethanolwater mixture 85/15 (v/v) (P2 sample),
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probably because of the lower particle size resulted in these conditions. In the case of CAP nanobers, the samples were soaked on the surface of the culture medium and the inhibition zone in this case may be associated with the area occupied by the sample and around it. The dark color of the sample area and the halo around it suggest the inhibition of microorganism growth within these areas.
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Figure 11. Antimicrobial tests for CAP nanopowders obtained from solutions in 2-methoxyethanol (P1) and in 2-methoxyethanolwater mixture 85/15 (v/v) (P2) at 10% (w/v) polymer concentration, against S. aureus (a) and E. coli (b).

Figure 12. Antimicrobial tests for CAP nanobers obtained from solutions in 2-methoxyethanol (F1) and in 2-methoxyethanolwater mixture 85/15 (v/v) (F2) at 10% (w/v) polymer concentration, against S. aureus (a) and E. coli (b).

CONCLUSIONS Cellulose acetate phthalate (CAP) micro/nanoparticles obtained from 2-methoxyethanol at 10% (w/v) polymer concentration and those obtained from 2-methoxyethanol water mixture 85/15 (v/v) at 10% (w/v) polymer concentration exhibit lower width of their walls and lower diameters than particles obtained from 2-methoxyethanol at 12.5% (w/v) polymer concentration previously reported. Also, polymer solution in the solvent mixture 2-methoxyethanolwater 85/ 15 (v/v) gives smaller particles with specic surface area higher than of those produced from 2-methoxyethanol solution. CAP nanober mats obtained from 2-methoxyethanolwater mixture 85/15 (v/v) at 30% (w/v) polymer concentration appear more uniform and bers diameters produced from solvent mixture are lower than those obtained from 2methoxyethanol solvent. TG analysis reveals that CAP nanoproducts exhibit an apparent lower stability than CAP lms. Although TG/DTG curves show a lower temperature of weight loss for the rst stage of degradation for nanostructured products as compared with the lm, FTIR investigations of the residual polymer and the evolved degradation gas products as well as mass spectrometry evidence the presence of phthalic anhydride as a main degradation product for all CAP samples. The higher porosity and specic surface areas of nanostructured CAPs allow a better diusion of this degradation product which is easier and continuously eliminated from these samples during the thermal treatment.
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Nanostructured CAPs exhibit antimicrobial activity on both Staphylococcus aureus and Escherichia coli.

AUTHOR INFORMATION

Corresponding Author

*E-mail: nolaru@icmpp.ro.
Notes

The authors declare no competing nancial interest.

REFERENCES

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dx.doi.org/10.1021/ie301299d | Ind. Eng. Chem. Res. 2013, 52, 696705