water soluble polymers || water solubility characteristics of poly(vinyl alcohol) and gels prepared...

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WATER SOLUBILITY CHARACTERISTICS OF POLY(VINYL ALCOHOL) AND GELS PREPARED BY FREEZING/THAWING PROCESSES

Christie M. Hassan, Patrina Trakampan, and Nicholas A. Peppas

Polymer Science and Engineering Laboratories School of Chemical Engineering Purdue University West Lafayette, Indiana 47907-1283

1. ABSTRACT

Poly(vinyl alcohol) (PVA) is a water soluble polymer whose water solubility de-pends on its degree of hydrolysis, molecular weight, and tendency to hydrogen bond in aqueous solutions. PVA exhibits both upper and lower critical solubility temperatures and can be readily solubilized in water. For long-term dimensional stability, a new method in-volving freezing and thawing of aqueous PVA solutions was used to prepare insoluble PVA gels held together by physical crosslinks formed predominantly by crystallites. Solu-tions containing 15% PVA were frozen at -20 °C for ,1, 8, and 18 hours and thawed at room temperature for 30 minutes to 6 hours. These cycles were repeated for up to 10 times. The ensuing gels were analyzed by equilibrium swelling studies. Each cycle led to further crystallization of PVA leading to stable gels. Differential scanning calorimetry was used to analyze the gel morphology. Degrees of crystallinity varied from 4 to 16% on a swollen basis. Upon exposure to swelling temperatures of up to 37 °C, the crystallites of these gels remained remarkably stable for a period of several weeks. However at 60 °C relatively fast crystal melting occurred. The dissolution process was followed using com-plexation with boric acid.

2. INTRODUCTION

Poly(vinyl alcohol), henceforth designated as PVA, is a widely used hydrophilic polymer that can dissolve in water over a wide range of temperatures. Its solubility has been well characterized by Finch1 and Peppas.2 Typically PVA solubility is a function of

Water Soluble Polymers, edited by Amjad Plenum Press, New York, 1998 31

32 C. M. Hassan et al.

the PVA molecular weight and the degree of hydrolysis of the samples. As PVA is pro-duced by methanolysis of poly(vinyl acetate), a small amount of acetate groups is always present. The characteristic Flory interaction parameter for the PVA-water system has been determined by Peppas and Merrill3 as a function of temperature and concentration.

Aqueous PVA solutions exhibit two critical temperatures, an upper and a lower one,4

according to well known thermodynamic characteristics. Long term stability of PVA solu-tions is rather difficult because of aging, “retrogradation

“

,4,5 or hydrogen bonding. Long-term stability can be obtained by treatment of aqueous PVA solutions in the absence of any additives, in order to produce temporary (or sometimes permanent) gel structures by crys-tallization. These physical hydrogels have a wide range of applications. For example, PVA hydrogels have many characteristics which make them desirable for a wide range of appli-cations. Some of these characteristics include swelling to a high degree in water, high me-chanical strength, and high elasticity. For biomedical applications, PVA gels are commonly crosslinked with formaldehyde or glutaraldehyde to yield insoluble networks.2

Often, unreacted residue from the crosslinking agent may be eluted slowly over time re-sulting in the release of toxic agents. This toxicity is undesirable for pharmaceutical appli-cations because the activity of the drug or agent being released could be destroyed. For biomedical applications, the direct release of toxic agents into the body would result in obvious undesirable effects.

A method of solidification by freezing and thawing aqueous solutions of PVA has been developed. This method involves casting dilute, aqueous solutions then cooling to -20 °C and thawing back to room temperature several times. This results in the formation of a stable three-dimensional network held together by crystallites. The stability of the structure is rein-forced by an increasing number of freezing/thawing cycles.6

3. HEAT-TREATED POLY(VINYL ALCOHOL) GELS

The stabilization of aqueous PVA solutions and the preparation of ultrapure PVA hy-drogels using freezing and thawing techniques was first reported by Peppas7 in 1975. In this work, aqueous solutions of 2.5 to 15 wt% PVA were frozen at -20 °C and thawed back to room temperature. Turbidimetric studies were performed in which the transmittance of visible light was examined as a function of thawing time. Crystallite formation was found to be a function of time of freezing, time of thawing, and PVA solution concentration. In particular, it was determined that crystallinity increased with increasing freezing time and increasing PVA solution concentration. It was also found that during thawing, the size of crystalline structures initially increased and then decreased due to the breaking down of regions that were not very dense (smaller crystallites).

Nambu8 reported a process for the preparation of a freeze-dried PVA hydrogel. The process consisted of preparing a 2.5 to 25 wt% aqueous PVA solution. The average degree of polymerization of the PVA was at least 800. A water-soluble polyhydric alcohol such as ethylene glycol, propylene glycol, or glycerin was added to the PVA solution which was then cooled to -3 °C or lower and then dehydrated. This procedure resulted in the forma-tion of a hydrogel that could be used as a cooling medium.

Ohkura et al.9 reported interesting features of PVA gels formed from solutions with the addition of organic solvents. A mixture of dimethyl sulfoxide (DMSO) and water was chosen as an appropriate solvent for PVA because it would not freeze until very low tem-peratures. From their work, it was found that gels obtained below 0 °C were transparent and exhibited high elasticity. It was also shown that higher gelation rates were observed

Water Solubility Characteristics of Poly(Vinyl Alcohol) 33

when compared to aqueous solutions consisting only of PVA and water. The properties were dependent on the DMSO to water ratio. Gelation from the mixture occurred without phase separation at temperatures below 20 °C. However, above this temperature, phase separation played a significant part in the gelation process. Their work also increased in-terest in the use of wide- and small-angle neutron scattering in order to understand the structure of the gels from a microscopic perspective.

Stauffer and Peppas6 investigated PVA gels prepared by freezing and thawing tech-niques. In this work, hydrogels were prepared by existing aqueous solutions of 10–15 wt % PVA to freezing at -20 °C for 1–24 hours and thawing at 23 °C for up to 24 hours for 5 cycles. It was found that higher PVA concentrations produced strong thermoreversible gels with mechanical integrity. This was specifically observed for gels that were frozen for 24 hours for 5 cycles but thawed for any period of time. Swelling experiments as a function of thawing time and freezing cycles indicated that denser structures were observed after 5 cycles. These results showed that the crystallinity increased with increasing number of freezing/thawing cycles.

Ficek and Peppas10 investigated PVA microparticles that were prepared by freezing and thawing processes. An aqueous solution of PVA was dispersed in corn oil with 1.25 wt% sodium sulfate as the surfactant. The suspended droplets of PVA solution were solidified by freezing and thawing cycles to produce microparticles with diameter ranging from 150 to 1400 mm. Some of the important parameters in this work were found to be the oil to PVA ratio, and the amount of surfactant added. The microparticles were capable of releasing bovine serum albumin for up to 7 days. In the work of Hickey and Peppas,11

PVA membranes were prepared by freezing and thawing aqueous PVA solutions for up to 10 cycles. The crystalline PVA fraction was determined to be a function of the number of cycles and the duration of each cycle. The volume-based crystalline fraction of PVA on a wet basis varied from 0.052 to 0.116. The equilibrium volume swelling ratios were found to increase from 4.48 to 9.58 as a function of decreasing degree of crystallinity. Diffusion studies with theophylline and FITC-dextran indicated that the transport of solutes was a function of the crystalline PVA fraction and mesh size. Peppas and Mongia12 examined the bioadhesive behavior of PVA gels prepared by freezing and thawing methods. Adhesion studies showed that the work of fracture, or detachment, decreased with increasing number of freezing/thawing cycles due to the increase in the degree of crystallinity. It was also found from oxprenolol and theophylline delivery studies that the number of freezing and thawing cycles affected drug release behavior. Their results showed that the mucoad-hesive characteristics and release behavior could be optimized by controlling the freez-ing/thawing conditions.

In the present work, we examined the preparation of PVA hydrogels using freezing and thawing techniques. The stability of the gels was examined for different freezing and thawing conditions. In particular, the swelling behavior in water and the dissolution be-havior of PVA chains were examined as a function of time for gels that were exposed to varying numbers of freezing and thawing cycles.

4. EXPERIMENTAL

4.1. Synthesis of Poly(Vinyl Alcohol) Hydrogels

Aqueous solutions of 15 wt% PVA were prepared by dissolving PVA (Elvanol®90–50, E.I. duPont de Nemours, Wilmington, DE, Mn = 35,740, polydispersity index =


2.15, degree of hydrolysis = 99.0%) in deionized water for 6 h at 90 °C. The solutions were cast between glass microscope slides with 0.7 mm thick spacers. The samples were then exposed to 3 to 12 cycles of freezing for up to 8 hours at -20 °C and thawing for up to 6 hours at 25 °C.

4.2. Swelling Studies

Equilibrium swelling studies were conducted in deionized water at 37 °C. The PVA films prepared by repeated cycles of freezing and thawing were cut into thin disks of 12 mm diameter using a cork borer. Each disk was initially weighed in air and heptane and then placed in a jar containing 50 ml of deionized water. At specific times during swelling, the samples were blotted and weighed in air and heptane and 5 ml samples were removed from the swelling media.

4.3. Dissolution Studies

The swelling media samples were analyzed for PVA dissolution by complexing each 5 ml sample of aqueous PVA with 2.5 ml of a 0.65M boric acid solution and 0.3 ml of a 0.05M I2 / 0.15M KI solution and then diluting to 10 ml with deionized water at 25 °C. The absorbance of visible light at 67 1 nm was then measured with a UV/Vis Spectrometer (Lambda 10 model, Perkin Elmer, Norwalk, CT) to determine the concentration of com-plexed PVA in solution.

5. RESULTS AND DISCUSSION

5.1. Equilibrium Swelling and Stability

In order to investigate the stability of the PVA solutions after the freezing/thawing process, a series of experimental studies was undertaken whereby 15 wt% PVA solutions were frozen for 8 hours at -20 °C and thawed for 4 hours at 25 °C. Figure 1 shows the vol-ume swelling ratio, Q, as a function of thawing time for samples prepared with 3, 5 and 7 cycles. It can be seen that in all cases the swelling ratio increases with time and passes through a maximum at about 10 to 30 hours. This maximum is followed by a re-equilibra-tion to a lower value. Figure 2 shows the water uptake in the first 50 hours, clearly indicat-ing the nature of that “overshoot”. Eventually, all gels attained a constant volume swelling ratio. The samples treated for 3 cycles showed a much more swollen structure than those treated for 5 or 7 cycles. Evidently, the freezingg/thawing process leads to crystal forma-tion. The ensuing physical network seems to be relatively stable. However, the “over-shoot” in the volume swelling ratio is a strong indication of some loss of initial crystallinity or, most probably, chain dissolution.

Indeed, using the boric acid technique, we were able to determine that a certain amount of amorphous PVA was dissolved at 37 °C in water over the same period of time (Figure 3). By taking this into consideration, it was possible to calculate the true volume swelling ratio represented in the swelling results (Figures 1 and 2). These results clearly indicate that after an initial loss of PVA chains that were not incorporated in the physical network structure, the gels remained relatively stable as a function of time over a period of approximately 2 months. This stability is not necessarily true for longer periods of time as we will discuss in a future publication from our laboratory.


Figure 1. Equilibrium swelling at 37 °C of PVA hydrogels with 3 ( •), 5 and 7 cycles of 8 hour freezing and 4 hour thawing.

5.2. Crystalline Structure of Stable Gels

To further investigate the nature of the crystalline structure, we conducted differen-tial scanning calorimetry experiments on PVA samples. Figure 4 shows a typical thermo-gram for a PVA sample prepared by freezing for 6 hours followed for thawing for 4 hours, this cycle being repeated 6 times. The first broad peak observed corresponds to water

Figure 2. Initial swelling “overshoot” at 37 °C of PVA hydrogels with 3 (•), 5 and 7 cycles of 8 hour(freezing and 4 hour thawing.

•


Figure 3. Fractional dissolution in water at 37 °C of PVA samples with 3 ( ), 5 ( ), and 7( ) cycles of 8 hour freezing and 4 hour thawing.

evaporation, roughly starting at 85.1 °C. The melting peak of PVA starts at 196.8 °C and exhibits a maximum melting point of 2 11.6 °C. Based on these studies, the PVA degree of crystallinity on a dry basis was calculated as 32.9%. Taking the equilibrium swelling ratio of this sample into consideration, this degree of crystallinity corresponded to 6.7% on a swollen basis. Similar analysis for all other samples tested indicated that the degrees of

Figure 4. DSC thermogram for a PVA sample exposed to 6 cycles of 6 hour freezing and 4 hour thawing.


Figure 5. Equilibrium swelling at 37 °C of PVA samples with 6 cycles of 1 hour freezing and 45 minute thawing.

crystallinity on a swollen basis varied from 4 to 16%. Clearly this amount of crystallites was sufficient for the formation of a stable, three-dimensional network of physical crosslinks.

5.3. Gel Stability under Rapid Cycling Conditions

An important consideration in the development of stable PVA gels is the time re-quired for the freezing/thawing cycles. Previous studies have shown that optimal freezing times for the attainment of a significant degree of crystallinity were 4 to 6 hours.

To investigate the possibility of utilizing rapid freeze/thaw cycles, we conducted a six-cycle study shown in Figure 5. These gels were frozen for 1 hour at -20 °C followed by thawing for 45 minutes at 25 °C for six cycles. At the end of the final thawing process, the samples were immersed in water at 37 °C and allowed to swell to equilibrium. The weight uptake of water during this swelling process is expressed as a function of time where the abscissa indicates the weight of water incorporated in the system per weight of the original polymer solution. These results indicate that after a small overshoot associated with the leaching out of any PVA chains that were not incorporated in the crystalline struc-ture, the remaining gel achieved a constant weight after a period of about 20 hours.

Figure 6 shows the swelling behavior of a PVA sample prepared with 10 cycles con-sisting of freezing for 1 hour followed my thawing for 30 minutes. Again, stable gels were obtained after about 20 hours, although the increased amount of water in the gel was an indication of a less crystalline (therefore, less stable) structure. Further reduction of the freezing time lead to a series of interesting samples. For example, Figure 7 shows the swelling behavior of a PVA sample prepared with 10 cycles of freezing for only 30 min-utes and thawing for 45 minutes. Again, the dimensional stability seemed to have been at-tained after about 15 hours, although the variation in the data is larger than that of samples with longer freezing and thawing times.


Figure 6. Equilibrium swelling at 37 °C of PVA samples with 10 cycles of 1 hour freezing and 30 minute thawing.

Although shorter-term freezing and thawing processes are possible, one inherent dif-ficulty in these techniques is the very weak mechanical stability of the gels produced. Thus, although mechanical and dimensional stability of PVA solutions can be easily achieved by a rapid freezing process, the ensuing gels are only of theoretical interest. In our own studies, we were able to produce more stable gels with freezing/thawing tech-

Figure 7. Equilibrium swelling at 37 °C of PVA samples with 10 cycles of 30 minute freezing and 45 minute thawing.


Figure 8. Equilibrium swelling at 37 °C of PVA samples with 7 cycles of 1 hour freezing and 1 hour thawing.

niques using freezing and thawing times of 1 hour each. Figures 8 and 9 show the swelling behavior of two such gels prepared after 7 and 12 cycles, respectively, and then swollen at 37 °C for up to 7 days. These gels have a higher degree of crystallinity (therefore a lower equilibrium swelling) than those previously discussed and seem to attain their equilibrium swelling after about 2 days. Obviously, further experimental studies are needed in order to ascertain the long-term stability of these gels.

Figure 9. Equilibrium swelling at 37 °C of PVA samples with 12 cycles of 1 hour freezing and 1 hour thawing.


ACKNOWLEDGMENT

This work was supported in part by a grant from the Showalter Trust.

REFERENCES

1. Finch CA, Polyvinyl Alcohol Properties and Applications, Wiley, NY, 1973. 2. Peppas NA, Hydrogels in Medicine and Pharmacy, Vol 2, Polymers, CRC Press, Boca Raton, FL, 1987. 3. Peppas NA and Merrill EW, “Determination of interaction parameter c1 for PVA and water in gels

crosslinked from solutions”, J. Polym. Sci.,. 1976;14:459. 4. Klenina OV, Klenin VI, and Frenkel S Ya, “Formation and breakdown of supermolecular order in aqueous

PVA solutions”, Polym Sci USSR, 1970;12:1448. 5. Peppas NA, Merrill EW, “PVA Hydrogels: Reinforcement of radiation-crosslinked networks by crystal-

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Polymer, 1992;33:3932. 7. Peppas NA, “Turbidimetric studies of aqueous PVA solutions”, Makromol. Chem. 1975; 176:3433. 8. Nambu M, “Freeze-dried poly(vinyl alcohol) gel”,US Patent No. 4,472,542. 1984. 9. Ohkura M, Kanaya T, Kaji K, “Gels of poly(vinyl alcohol) from dimethyl sulphoxide/water solutions,”

Polymer, 1992;33:3686. 10. Ficek BJ, Peppas NA, “Novel Preparation of poly(vinyl alcohol) microparticles without crosslinking agent

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