Adsorption of Zwitterionic Drugs on Oxidized Cellulose from Aqueous

Oct 22, 2004 - Understanding Adsorption Phenomena: Investigation of the Dye−Cellulose Interaction. Jayne Bird, Neil Brough, Sarah Dixon, and Stephen...
0 downloads 0 Views 109KB Size
Download PDF
17812

J. Phys. Chem. B 2004, 108, 17812-17817

Adsorption of Zwitterionic Drugs on Oxidized Cellulose from Aqueous and Water/Alcohol Solutions Dmitry S. Zimnitsky,* Tatiana L. Yurkshtovich, and Pavel M. Bychkovsky Belarusian State UniVersity, Research Institute for Physical Chemical Problems, 14 Leningradskaya street, Minsk 220050, Belarus ReceiVed: June 28, 2004; In Final Form: September 8, 2004

Adsorption of zwitterionic drugs (β-lactam antibiotics and amino acids) on samples of oxidized cellulose (OC) with various carboxyl contents and structure characteristics was investigated from aqueous and water/ alcohol solutions. The process is described according to the theory of localized stoichiometric adsorption and represented by Langmuir-like isotherms. The drug uptake increases with increase of alcohol content in the solution and with growth of alcohol molecular weight. The main contribution to the increase of drug uptake with addition of alcohol to the aqueous drug solution is provided by the desolvation of zwitterion ionic groups, which increases with growth of alcohol content. The structural characteristics of OC (degree of crystallinity and carboxyls distribution) and sorbate molecule size have considerable effect on the drug adsorption. It is shown that different drug uptake occurs on the OC samples with similar exchange capacity but various structure characteristics, which can be explained by various accessibility of carboxylic groups of OC, caused by decreased swelling of a sorbent in binary water/alcohol solutions.

Introduction Substantial progress in wound treatment has been achieved recently.1 However, the development of drugs for local wound treatment and for prevention of wound infections is still of special interest because such drugs should possess several important properties; first of all, they must have local hemostatic, antibacterial, and reparative activity.2 The immobilization of several drugs on biodegradable polymer carrier is one of the effective ways to prepare wound-healing drugs with combined effects. Oxidized cellulose (OC) is a polymer carrier, which has several useful medical characteristics.3 It is one of the most widespread hemostatics used almost in all types of surgery. OC was shown to possess antitumor,4 immunostimulant,5 wound healing,6 and adhesion prevention properties.7,8 The presence of carboxyl groups in OC permits the immobilization of drugs by adsorption9 and preparation of polymer drugs with a variety of therapeutic effects. These properties, as well as complete bioabsorption,10 characterize OC as a medical material with very high potential. The development of wound-healing drugs with combined effects on the base of OC requires elucidation of regularities of drug adsorption on this polymer. Two kinds of model sorbates were chosen, β-lactam antibiotics cephalexin and ampicillin among antibacterial drugs and R-amino acids (AA) glycine, alanine, proline, and tryptophan among reparative drugs. These substances have various molecule sizes and relative hydrophobicities and exist in zwitterionic form in neutral pH range. Many recent studies have been devoted to the adsorption of zwitterions, mostly to the AA adsorption. They have dealt with separation and purification of AA,11,12 mechanism of their binding with adsorbent,13-15 effect of temperature,16 adsorbent,17 and AA nature18 on adsorption and so on. However, these studies * Author to whom correspondence should be addressed. E-mail: [email protected].

were primarily devoted to the AA adsorption on synthetic ion exchangers from aqueous solutions. The addition of alcohol to the aqueous drug solution can modify adsorption because polymer swelling and solvation of ionic groups are altered in the water/alcohol solutions. One of the key questions of drug immobilization on OC is an achievement of sufficient therapeutic concentration of drug in the OC phase, and drug adsorption from water/alcohol solution can increase drug uptake. This requires profound investigation of regularities of drug adsorption on OC from water/alcohol solutions and elucidation of factors affecting the adsorption. The aim of this study was to investigate adsorption of zwitterionic drugs on the OC samples with various carboxyl contents and degrees of crystallinity from aqueous and water/ alcohol solutionsselucidation of nature, regularities of adsorption, and factors that affect the adsorption. The effect of drug and sorbent structure and content of alcohol in the solution on drug adsorption was also of interest. It was established that drug uptake increases with growth of alcohol mole fraction in the solution. The different drug uptake by the OC samples with similar exchange capacity but various structure characteristics was explained by the various accessibility of carboxylic groups of OC, caused by the decreased swelling of a sorbent in the binary water/alcohol solutions. Experimental Section The OC samples were obtained by the oxidation of native and mercerized celluloses at 292 ( 1 K over various periods of time. Cellulose, in the form of coarse calico, was taken as a starting material. It has cellulose I structure modification and index of crystallinity (IC) 0.87, determined according to Segal.19 Solutions with different concentrations (10-40%) of N2O4 in CCl4 were used as oxidants. The ratio of cellulose mass to the solution volume was 1:10 (g/mL). The mercerized cellulose was obtained by treatment of cellulose with 20% solution of sodium hydroxide over a period of 3 h at 273 K.20 The physical form

10.1021/jp0472010 CCC: $27.50 © 2004 American Chemical Society Published on Web 10/22/2004

Adsorption of Zwitterionic Drugs

J. Phys. Chem. B, Vol. 108, No. 46, 2004 17813

TABLE 1: Preparation Conditions and Characteristics of OC oxidation sample time (h) OC-1 OC-2 OC-3 OC-4a a

5 24 24 24

concentration exchange capacity of N2O4 in (mmol/g) CCl4 (%) 40 15 40 10

1.8 1.8 3.8 1.8

IC 0.40 0.82 0.40 0.75

swelling S (g/g) (m2/g) 0.52 0.37 0.58 0.42

12.5 6.2 14.8 8.4

Prepared by oxidation of mercerized cellulose.

and appearance of cellulose were unchanged after the oxidation procedure. The oxidation conditions and properties of the OC samples are given in Table 1. The OC samples were analyzed for carboxyl content with calcium acetate.21 The swelling of OC was analyzed gravimetrically with centrifugation.22 The detailed description of preparation and characterization of the OC samples is given in the paper.23 The surface areas S (m2/g) of the OC samples were determined by nitrogen adsorption at 77 K on a NOVA 2200 device (Quantachrome Corp.). The samples were outgassed at 333 K and 1 mPa for 2 h. Because immobilization of AA occurs in water solution, an attempt was made to evaluate surface areas of OC samples swelled in water. The water replacement procedure was used,24 that is, samples of OC were swelled in water and treated three times with acetone and hexane. After this, samples were dried in vacuo at 323 ( 2 K until they reached a constant weight. FT-IR spectra of samples were registered at room temperature on Thermo Nicolet FT-IR Nexus spectrometer. Powdered samples were finely dispersed in KBr pellets and recorded with an instrumental resolution of 2 cm-1 and an average of 256 scans. Since the minimum half-width values in the FT-IR spectra of the investigated compounds are ∼10 cm-1, the spectrum distortions due to the influence of the instrument function are TABLE 2: Properties of Sorbates

insignificant. The X-ray diffraction measurements were performed using Carl Zeiss diffractometer (CuKR, Ni-filter, HZGb4A). The adsorption of AA from aqueous and binary water/alcohol solutions was studied by a batch method at 298 ( 0.5 K over a period of time required for an achievement of adsorption equilibrium. The range of initial concentration was 5‚10-4-0.05 mol/L and the ratio of sorbent mass to the solution volume was 1:200 (g/mL). Binary water/alcohol mixtures were prepared by addition of ethanol and 2-propanol to the aqueous drug solutions. The properties of sorbates are given in Table 2. The determination of adsorbed drugs (q, mmol/g) was performed by their desorption from OC phase to 0.1 M HCl solution. Preliminary experiments showed that a complete desorption occurs in these conditions. Glycine, alanine, and proline in the desorption solution were dyed using the Ninhydrin procedure.25 Their concentrations were determined with SF-26 spectrophotometer. The absorption maxima of products of ninhydrin reaction with glycine and alanine were at 560 nm, with proline at 440 nm. The concentrations of cephalexin, ampicillin, and tryptophan in desorption solutions were determined with spectrophotometer in UV region at 262 (cephalexin and ampicillin) and 287 nm (tryptophan). This procedure was repeated three times for each initial drug concentration and the amount of AA adsorbed was taken as the average of the three replicates. The confidence interval of experimental concentration was not higher than 5%. Antibiotics and AA used in the work were obtained from Diaem (Moscow, Russia). All other chemicals were analytical grade and were purchased from Five Oceans (Minsk, Belarus). Results and Discussion The swelling of cellulose and its derivatives depends on several factors;26 fraction of ordered (crystalline) region, ion

17814 J. Phys. Chem. B, Vol. 108, No. 46, 2004

Zimnitsky et al.

Figure 1. Diffraction patterns of OC-1 (1), OC-2 (2), OC-3 (3), OC-4 (4), native (5), and mercerized (6) celluloses.

Figure 2. Adsorption isotherms of glycine from aqueous (1) and binary water/ethanol solutions with ethanol mole fraction 0.2 (2), 0.4 (3), 0.5 (4).

and polar groups solvation, amount of osmotic active particles in the polymer volume, and resistance of polymer matrix to the action of solvent are among them. The change of cellulose swelling after its oxidation with solutions of N2O4 in CCl4 can be connected, on one hand, with alteration in content of crystalline regions, and, on the other hand, with introduction of polar carboxylic group, which causes growth of osmotic active ions content. The diffraction patterns of the OC samples (Figure 1) and IC values (Table 1) show that there is no substantial decrease in content of crystalline regions occurs after oxidation of native and mercerized celluloses with 10-15% solutions of N2O4 in CCl4, that is, oxidation proceeds mainly in amorphous regions and on the surface of cellulose crystallites. Compared to the dilute solutions (10-15%) of N2O4 in CCl4, a 40% solution significantly affects the degree of crystallinity, that is, oxidation proceeds not only on the surface of crystallites, but also inside them, destroying their structure. The calculated IC values and swelling change after oxidation in these conditions significantly; the OC-3 sample with higher carboxyl content than OC-1 has higher swelling, although their IC values are similar. The addition of alcohol causes considerable decrease of swelling of all OC samples with growth of alcohol mole fraction (X2) in the solution (Table 3). The swelling decrease is connected with reduced ability of solvent to form hydrogen bonds with cellulose macromolecules and decreased intensity of ion and polar group solvation with decrease of dielectric constant () of solvent. The growth of alcohol molecular weight leads to swelling decrease at fixed alcohol mole fraction. In isoelectric pH region in water solutions, zwitterionic and neutral forms of AA coexist; the equilibrium constant neutral molecule T zwitterion is 105-106. The addition of organic solvents can alter the ratio of neutral and zwitterionic form. For example, in 90% ethanol the value of this constant is 500-

1000. However, even in this case, the portion of neutral form is less than the accuracy of determination of AA concentration. Thus, it is assumed that in isoelectric pH region in aqueous and water/alcohol solutions the concentration of zwitterion is equal to the total concentration of zwitterionic drug.27,28 The adsorption isotherms of glycine on OC sample with carboxyl content 3.8 mmol/g (OC-3) from water/ethanol solutions are shown in Figure 2. The adsorption isotherms of other sorbates on all OC samples from water/ethanol and water/ 2-propanol solutions are represented by the analogous curves. As was shown earlier,29 the adsorption of several organic ions by OC is described by the equation of the stoichiometric localized adsorption30

1 1 1 1 ) ‚ + q bqm C qm where C and q are equilibrium sorbate concentrations in the solution and the sorbent phase (mmol/g), respectively; b is the adsorption equilibrium constant (g/mmol); and qm is the constant of the ultimate adsorption capacity (mmol/g). The values of 1/q and 1/C are interrelated by a linear dependence whose slope is equal to 1/b‚qm and Y-intercept is equal to 1/qm. When passing to infinitely low equilibrium concentrations, we obtain

(lim Cq )

Cf0

) Kd ) b‚qm

where Kd is the constant of sorbate interfacial distribution.30 The equation of the stoichiometric localized sorption adequately describes the sorption of zwitterionic drugs from

TABLE 3: The Swelling of Native and Mercerized Celluloses and OC Samples in Water and Water/Alcohol Solutions swelling in water/ethanol solutions

swelling in water/2-propanol solutions

X2

cellulose

mercerized cellulose

OC-1

OC-2

OC-3

OC-4

cellulose

mercerized cellulose

OC-1

OC-2

OC-3

OC-4

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

0.38 0.35 0.33 0.30 0.29 0.26 0.23 0.20 0.18 0.15

0.42 0.38 0.35 0.33 0.30 0.27 0.23 0.21 0.19 0.16

0.52 0.46 0.41 0.38 0.34 0.30 0.26 0.22 0.19 0.17

0.38 0.35 0.33 0.30 0.28 0.26 0.23 0.21 0.20 0.17

0.58 0.52 0.49 0.46 0.43 0.39 0.35 0.32 0.27 0.21

0.42 0.38 0.36 0.33 0.30 0.28 0.26 0.24 0.22 0.20

0.38 0.34 0.32 0.31 0.28 0.25 0.20 0.17 0.15 0.12 0.10

0.42 0.36 0.33 0.31 0.27 0.24 0.20 0.17 0.13 0.10 0.07

0.52 0.44 0.39 0.36 0.32 0.27 0.23 0.19 0.16 0.14 0.13

0.38 0.32 0.30 0.28 0.26 0.23 0.21 0.18 0.16 0.13 0.11

0.58 0.50 0.46 0.43 0.39 0.35 0.30 0.25 0.20 0.17 0.11

0.42 0.37 0.34 0.31 0.28 0.26 0.23 0.20 0.17 0.14 0.12

Adsorption of Zwitterionic Drugs

Figure 3. Dependencies on lgKd for cephalexin adsorption on OC-1 (1, 2) and OC-3 (3, 4) from water/ethanol (1, 3) and water/2-propanol (2, 4) solutions.

Figure 4. Difference FT-IR spectra of glycine between spectra of products of glycine adsorption on OC-3 from aqueous (1) and water/ ethanol solutions (2) and spectrum of OC-3.

aqueous solutions by all studied OC samples (the correlation coefficients for linear form of adsorption isotherms exceed 0.99 in all cases). The Kd values of drug adsoprtion increase with an increase of alcohol mole fraction in the solution and with growth of alcohol molecular weight. The dependencies of lgKd on  for cephalexin adsorption on OC-1 and OC-3 coincide for both alcohols, which evidences prevailed effect of  in drug binding with OC (Figure 3). The mechanism of AA adsorption on carboxylic ion exchangers at neutral pH in aqueous solutions has been reported elsewhere31 and can be represented by the equation

Cell-COO- H+ + +NH3-R-COO- f Cell-COO- +NH3-R-COOH The overall electrical neutrality remains constant because of the proton transfer from carboxyl group of ion exchanger to the carboxylate ion of zwitterion of adsorbed AA. The aforementioned scheme of the interaction between drugs and OC is confirmed by the equal pH values of the initial and equilibrium solutions and by the FT-IR spectroscopy data (Figure 4). A difference spectrum (Figure 4, curve 1) obtained by the subtraction of the OC-3 spectrum from the spectrum of OC-3 containing adsorbed glycine exhibits a slight increase in the intensity of the absorption band at 1420 cm-1 and a substantial rise in the absorption at 1610 cm-1, thus indicating a salt formation in the OC phase. The intensity of band at 1750 cm-1 (undissociated carboxylic group) remains unchanged. The adsorption of another drug causes similar changes in the spectra

J. Phys. Chem. B, Vol. 108, No. 46, 2004 17815 of OC. The mentioned mechanism indicates that the adsorption occurs mainly because of the electrostatic interactions. The difference FT-IR spectra after adsorption from water/ alcohol solutions (Figure 4, curve 2) have some distinguishing features comparing to the aqueous solutions. There are reduced intensity of band at 1610 cm-1, which characterize ion exchange component of adsorption, and growth of band intensity in the region of hydrogen bonds (3600-3250 cm-1) that evidences their redistribution comparing to native sorbent and products of adsorption from aqueous solutions. It can be assumed that contribution of ionic component into the energy of adsorption decreases, and component of hydrogen bonds and polar interactions increases, that is, alteration in ratio of interaction types occurs in water/alcohol solutions comparing to aqueous solutions. The increase of adsorption with growth of alcohol mole fraction can be caused by several processes: (1) influence of solvent on acidic properties of sorbent and sorbates; (2) re-solvation of ions in external solution and ionogenic groups of sorbent and sorbates in the sorbent phase; (3) alteration of external solution structure; and (4) change in the stability of ionic pairs between sorbent functional groups and sorbate. Probably, the dominant contribution in the increase of Kd value in binary mixtures makes not the ionic component of adsorption process, but extraction of zwitterions by sorbent. One of the main reasons for it is alteration in solvation conditions of exchanging ions in solution. The desolvation of ionogenic groups of zwitterions is the main component of desolvation energy, so it would prevail during extraction of drugs by OC from binary mixtures. Affinity of zwitterionic drugs to water is much higher than that to alcohol. The confirmation for it is dramatic decrease of AA solubility in water/alcohol solutions with growth of alcohol mole fraction. Thus, energetic favor of transfer of zwitterionic group from external solution to the OC phase increases steadily with the growth of alcohol content in the solution. As have been seen earlier,32 the main factor that affects the adsorption of zwitterionic drugs from aqueous solutions was carboxyl content in the OC phase. The structural characteristics of sorbent (degree of crystallinity, swelling, and surface area) had no considerable effect on drug adsorption from aqueous solutions of both small molecules of glycine and large ampicilline. We assumed that it was connected with pore structure swelled in water sorbent. Researchers24 displayed the results of investigation of swelled water cellulose pore structure. The analysis of data allows to assume that swelled in water cellulose has two maximums of the pore sizes: one in the region of micropores (at 20 A) and another in the region of macropores (broad maximum at 100200 A). It can be proposed that change in distribution of pore sizes occurs after oxidation. However, researchers33 indicated that cellulose oxidation in the concentrated solutions of N2O4 in CCl4 leads to a considerable growth of overall pore volume, but maximum of pore sizes distribution remains unchanged. The calculated sizes of sorbate molecules (maximal distance between atoms) are in the range of 4-16 A (Table 2). However, sorbate molecules in the aqueous solution exist in hydrated state. According to ref 34, the hydration numbers of AA zwitterions in water solutions are 10-20 and are preferably the hydrates responsible for binding with the OC +NH3-group. Thus, true sizes of sorbate molecules in the aqueous solutions can exceed the size of OC micropores. This causes the inaccessiblity of part of OC carboxyls even for small molecules of glycine and

17816 J. Phys. Chem. B, Vol. 108, No. 46, 2004

Zimnitsky et al.

Figure 5. Dependencies of Kd on ethanol mole fraction for adsorption of glycine (A), alanine (B), proline (C), tryptophan (D), ampicillin (E), and cephalexin (F) on OC-1 (1), OC-2 (2), OC-3 (3), and OC-4 (4).

alanine, that is, “sieve effect” occurs. The “sieve effect” can be a reason for the fact that ultimate adsorption capacity in aqueous solutions does not exceed 20% of overall exchange capacity even for tryptophan, which adsorbes mostly high. The addition of alcohol to water leads to a substantial reduction of sorbent swelling (Table 3). Researchers35 with NMR spectroscopy have shown that maximum of macropores size distribution of bleached softwood kraft pulp shifts into the region of meso- and micropores with a decrease of swelling (the maximum of pore radiuses decreases from 10 to 1 nm with decrease of moisture content from 50 to 15 wt %). They indicated that the location of maximum did not depend on the way by which certain solid content was achieved (drying or pressing). This allows us to assume that the increase of alcohol content, which causes swelling decrease, leads to shift of maximum of macropores size distribution into the region of meso- and micropores, that is, compression of cellulose structure occurs. Since the swelling decrease of OC samples is similar to that of cellulose, it can be considered that the shift of maximum of OC pores sizes into the region of micropores takes place in the water/alcohol solution with high alcohol content. Compression of cellulose structure hinders capillary transport and leads to a reduction of accessibility of OC adsorption centers for sorbate molecules. The adsorption of zwitterionic drugs on the OC samples with the same exchange capacity but various degrees of crystallinity reveals the general tendency of Kd values growth for adsorption of all sorbates with increase of alcohol content in the solution. However, as against the aqueous solutions, the numerical Kd

values in water/alcohol solutions differ substantially for the OC samples with various structure characteristics. Figure 5 shows the divergence of Kd values dependencies on alcohol mole fraction for different sorbents, which depend on size of sorbate molecule. The common feature for all sorbates is maximal Kd values on OC-4 and minimal on OC-1. The obtained dependencies we explain by the different accessibility of sorbent functional groups in the water/alcohol solutions. Considerable decrease of sorbate hydration numbers and true sizes of solvated sorbate molecules occurs in water/alcohol mixtures. The difference of true sizes of solvated molecules between glycine and cephalexin increases with growth of alcohol content in the solution. The accessibility of sorbent functional groups depends on cellulose oxidation conditions. The concentrated N2O4 solution penetrates into cellulose crystallites and destroys them; the OC-1 sample with minimal distinction of structure elements forms in this condition. The carboxylic groups are located uniformly in the volume of amorphous sample. In the dilute solution, the oxidation of native cellulose proceeds only in amorphous regions and on the surfaces of crystallites; the distribution of carboxyls in the volume of the OC-2 sample is less uniform than in OC1. The mercerization of cellulose with further washing and drying leads to reversible collapse of cellulose capillaries and violation of capillar transport. The placement of mercerized cellulose in water restores capillary structure, which is expressed in increased surface area of OC-4 comparing to OC-2 (Table 1), since the total regularity of OC-4 is lower. However, the oxidation of mercerized cellulose is carried out after drying in

Adsorption of Zwitterionic Drugs CCl4 solution, where swelling of cellulose is negligible. It can be assumed that capillar transport was hindered in collapsed mercerized cellulose immerged in the CCl4 solution, so the sites on the fiber surface were oxidized. The distribution of carboxyls obtained in these conditions in the OC-4 sample is less uniform that even in the OC-2 sample, which was obtained by oxidation of native cellulose with dilute solutions of N2O4. The different carboxyls distribution during water adsorption is leveled by the high swelling of samples in water, so the accessibility of carboxyls is almost the same. In water/alcohol solutions, the decrease of swelling and pore sizes and a subsequent violation of capillar transport led to the inaccessibility of part of the carboxyls for sorbates molecules. As a result, the lowest carboxyls accessibility at fixed alcohol mole fraction shows OC-1 sample with the most uniform carboxyls distribution and the highest OC-4 sample with the least uniform carboxyls distribution in the volume of the sample and their location on the surface of the fiber. The carboxyls accessibility at the other conditions depends on the size of the sorbate molecule. Conclusion Adsorption of zwitterionic drugs (β-lactam antibiotics and amino acids) on samples of OC with various carboxyl contents and structure characteristics from aqueous and water/alcohol solutions was investigated. The adsorption process was described according to the theory of localized stoichiometric adsorption and represented by the Langmuir-like isotherms. The constants of adsorption process were calculated. The drug uptake increases with an increase of alcohol mole fraction in the solution and transferring to the binary water/2-propanol from water/ethanol solutions. The dominant contribution to the increase of uptake makes desolvation of zwitterions ionic groups in the solution, which increases with growth of alcohol content. The addition of alcohol to the drug solution leads to alteration in the ratio of interaction types between drug and sorbent in water/alcohol solutions comparing to aqueous solutions; the contribution of ionic component into energy of adsorption decreases, and component of hydrogen bonds and polar interactions increases. The structural characteristics of OC (degree of crystallinity and carboxyls distribution) and sorbate molecule size have considerable effect on the drug adsorption. The different drug uptake by the OC samples with similar exchange capacity but various structure characteristics can be explained by the various accessibility of carboxylic groups of OC, caused by the decreased swelling of a sorbent in the binary water/alcohol solutions. References and Notes (1) Natarajan, S.; Williamson, D.; Stiltz, A.; Harding, K. G. Am. J. Clin. Dermatol. 2000, 1, 269.

J. Phys. Chem. B, Vol. 108, No. 46, 2004 17817 (2) Moon, C. H.; Crabtree, T. G. Curr. Treat. Opt. Infect. Dis. 2003, 5, 251. (3) Stillwell, R. L.; Marks, M. G.; Saferstein, L.; Wiseman, D. Drug Target. DeliVery. 1997, 7, 291. (4) Tokunaga, Y.; Naruse, T. T. Cancer. Biother. Radiopharm. 1998, 13, 437. (5) Jelinkova, M.; Briestensky, J.; Santar, I.; Ry´hova, B. Int. J. Immunopharmacol. 2002, 2, 1429. (6) Finn, M. D.; Schow, S. R.; Schneiderman, E. D. J. Oral. Maxillofac. Surg. 1992, 50, 608. (7) Sawada, T.; Nishizawa, H.; Nishio, E.; Kadowaki, M. J. Reprod. Med. 2000, 45, 387. (8) Wiseman, D. M.; Saferstein, L.; Wolf, S. U.S. Patent 6,500,777, 2002. (9) Yurkshtovich, T. L.; Alinovskaya, V. A.; Butrim, N. S. Colloid J. 2002, 64, 379. (10) Dimitrijevich, S. D.; Tatarko, M.; Gracy, R. W.; Wise, G. E.; Oakford, L. X.; Linsky, C. B.; Kamp, L. Carbohydr. Res. 1990, 198, 331. (11) Soldatov, V. S.; Kuvaeva, Z. I.; Bychkova, V. A.; Vodopyanova, L. A. React. Funct. Polym. 1998, 38, 237. (12) Dye, S. R.; De Carli, J. P.; Carta, G. Ind. Eng. Chem. Res. 1990, 29, 849. (13) Helfferich, F. React. Polym. 1990, 12, 95. (14) Melis, S.; Markos, J.; Cao, G.; Morbidelli, M. Ind. Eng. Chem. Res. 1996, 35, 1912. (15) Bianco-Peled, H.; Gryc, S. Langmuir. 2004, 20, 169. (16) Borst, C. L.; Grzegorczyk, D. S.; Strand, S. J.; Carta, G. React. Funct. Polym. 1997, 32, 25. (17) Grzegorczyk, D. S.; Carta, G. Chem. Eng. Sci. 1996, 51, 807. (18) Wang, D.; Lei, S.-B.; Wan, L.-J.; Wang, C.; Bai, C.-L. J. Phys. Chem. B 2003, 107(33), 8474. (19) Cellulose and Cellulose DeriVatiVes; Bikales, N. M., Segal, L., Eds.; Wiley-Interscience: New York, 1971. (20) Warwicker, J. O. J. Polym. Sci., Part A: Polym. Chem. 1967, 5, 2579. (21) United States Pharmacopeia (USP) 23; United States Pharmacopeial Convention, Inc.: Rockville, MD, 1995; Vol. 18, p 319. (22) Lindstrom, T. In Paper Structure and Properties; Bristow, J. A., Kolseth, P., Eds.; Marcel Dekker: New York, 1986; Vol. 8, pp 88-92. (23) Zimnitsky, D. S.; Yurkshtovich, T. L.; Bychkovsky, P. M. J. Polym. Sci. Part A: Polym. Chem. 2004, 42, 4785. (24) Klenkova, N. I. Structure and ReactiVity of Cellulose (in Russian); Nauka: Leningrad, 1976. (25) Snell, F. D.; Snell, C. T. Colorimetric methods of analysis; D. Van Nostrand: New York, 1955; Vol. 4. (26) Mantanis, G. I.; Young, R. A.; Rowell, R. M. Cellulose 1995, 2, 1. (27) Spink, H.; Auker, M. J. Phys. Chem. 1970, 74, 1742.; (28) Nozaki, Y. N.; Tanford, C. J. Biol. Chem. 1971, 216, 2211. (29) Starobinets, G. L.; Kaputskii, F. N.; Yurkshtovich, T. L.; Bychkovskii, P. M. Zh. Fiz. Khim. 2001, 75, 1684. (30) Marshell, A. Biophysical Chemistry; Wiley: New York, 1978. (31) Seno, M.; Yamabe, T. Bull. Chem. Soc. Jpn. 1961, 34, 1021. (32) Yurkshtovich, T. L.; Zimnitski, D. S.; Bychkovski, P. M. Colloid J. 2004, 66, 273. (33) Kaputsky, F. N.; Pavluchenko, G. M.; Klymchuk, V. N. Dokl. Akad. Nauk BSSR (in Russian) 1973, 17, 927. (34) Hollenberg, J. L.; Iftt, J. B. J. Phys. Chem. 1982, 86, 1938. (35) Haggkvist, M.; Li, T.-Q.; Odberg, L. Cellulose 1998, 5, 33.