Analysis of Burst Release of Proxyphylline From Poly(Vinyl Alcohol)

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Analysis of burst release of proxyphylline from poly(vinyl alcohol)hydrogelsXiao Huanga; Christopher S. Brazela

a Department of Chemical Engineering, University of Alabama, Tuscaloosa, Alabama, USA

Online publication date: 09 September 2010

To cite this Article Huang, Xiao and Brazel, Christopher S.(2003) 'Analysis of burst release of proxyphylline frompoly(vinyl alcohol) hydrogels', Chemical Engineering Communications, 190: 4, 519 — 532To link to this Article: DOI: 10.1080/00986440302081URL: http://dx.doi.org/10.1080/00986440302081

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ANALYSISOFBURSTRELEASEOFPROXYPHYLLINEFROMPOLY(VINYL ALCOHOL)HYDROGELS

XIAOHUANGCHRISTOPHERS. BRAZEL

Department of Chemical Engineering,University of Alabama,Tuscaloosa,Alabama, USA

The initial high-rate drug release observed at the beginning of many

controlled-release processes can be caused by a number of mechanisms, in-

cluding surface desorption, pore diffusion, or the lack of a diffusion front

barrier to regulate the diffusive process. This initial nonsteady-state period is

usually referred to as ‘‘burst release.’’ A small molecular size drug, proxy-

phylline, was used as a model solute to study the burst release of a drug from

swellable hydrogels based on cross-linked poly(vinyl alcohol) (PVA). The

influences of several factors, including drug loading concentration, initial

cross-linking ratio of the polymer, initial swollen state of the hydrogel sam-

ples, pore diffusion of the drug versus swelling of the hydrogel at the beginning

of the release, and osmotic pressure, were investigated to understand the burst

behavior. Results show that high drug loading and low cross-linking ratio of

the polymer led to more pronounced bursts. Compared to release experiments

starting with relaxed samples, samples in dry states had magnified burst

effects, but prolonged the release process. Pore diffusion of the drug at the

initial stage and the osmotic pressure were shown not to be effective factors

leading to burst release within the range of the experimental conditions of this

study.

Keywords: Controlled release; Burst release; Hydrogel; Poly(vinyl alcohol);

Proxyphylline

Received 28 December 2000; in final form 16 December 2001.

Address correspondence to Xiao Huang, Department of Chemical Engineering,

University of Alabama, Tuscaloosa, AL 35487, USA.

Chem. Eng. Comm.,190: 519�532, 2003

Copyright# 2003 Taylor & Francis

0098-6445/03 $12.00+ .00

DOI: 10.1080/00986440390192555

519

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INTRODUCTION

In recent years, the study of the controlled release of drugs and otherbioactive agents from polymeric devices has attracted many researchersfrom around the world. While zero-order sustained release is needed inmany controlled drug delivery applications, an initial large bolus of drugreleased before the release rate reaches a stable profile makes the processunpredictable and difficult to control. The initial fast release of a drug,common in both reservoir and monolithic systems, is typically referred toas ‘‘burst release.’’

Normally short in duration, burst release is worth thorough study dueto the high release rates that can be reached in the initial stages after acti-vation. Although favorable in certain drug administration strategies(Setterstrom et al., 1984) and for flavor release in food development, burstrelease has negative effects inmost situations because the initial high releaserates may lead to toxicity or tissue irritation in the human body (Lu andAnseth, 1998; Jeong et al., 2000; Shively et al., 1995). Although lackingspecific investigation inmost published results, burst phenomenahave beenobserved in many controlled-release publications. For further details, thereader is referred to a review of burst release observations, mechanisms,and suggested ways to prevent it (Huang and Brazel, 2001).

Since much interest has been expressed in the application of hydrogelmatrices for controlled drug delivery (Colombo, 1993), burst release inthese devices has also been observed or investigated. Mallapragada et al.(1997) observed and attempted to minimize burst but gave no advancedanalysis in a study of metronidazole release from PVA systems; Patil et al.(1996) tried to interpret burst from the heterogeneous nature ofpoly(sucrose acrylate) hydrogels and sought to reduce burst by adjustinghydrogel synthesis conditions to change the structure of the network.Computational studies have also been done to explore the influence ofinitial drug distribution (Lu and Anseth, 1998; Lee, 1984) and nonuni-form drug diffusivity (Lu and Anseth, 1998) on release profiles in order toachieve zero-order release. Suggested causes of burst release in mono-lithic hydrogel systems include:

(1) release or desorption of the drugs trapped on the surface duringformulation (Pekarek et al., 1994);

(2) nonuniform distribution of drugs during formation, drying,or storage (Mallapragada et al., 1997; Kishida et al., 1998);

(3) heterogeneous nature of polymer matrices (Patil et al., 1996); and(4) percolation-limited diffusion of the drugs (Tzafriri, 2000).

This study focuses on the burst behavior of proxyphylline fromcross-linked PVA hydrogels. Proxyphylline, a low molecular weight drug,

520 X. HUANG AND C. S. BRAZEL


was chosen because solutes of small size are more likely to release in aburst. PVA is a hydrophilic, nontoxic, and biocompatible polymer(Mallapragada et al., 1997) that has been widely used in controlled-release devices (Mallapragada et al., 1997; Morimoto et al., 1989; Moritaet al., 2000; Brazel and Peppas, 1999). We investigate the effects of severalphysical factors on burst release to obtain a better understanding of themechanisms of burst, so that in future work reasonable models can beestablished to predict and control burst more precisely.

EXPERIMENTAL SECTION

Materials

Methanol and poly(vinyl alcohol), PVA, with an average molecularweight of 88,000, and 88% hydrolyzed acetate groups, were obtainedfrom Acros Organics (Fairlawn, N.J.). Glutaraldehyde (25wt% solu-tion), acetic acid, and sulfuric acid were purchased from Aldrich(Milwaukee, Wisc.). Proxyphylline was purchased from Sigma (St. Louis,Mo.). Pro-Sil1, a siliconizing agent, was obtained from the StephensonGroup Limited (U.K.). All chemicals were used as received.

Hydrogel Sample Preparation

Dry PVA was dissolved in deionized water at a concentration of 10wt%by heating at 90�C for approximately 6 h to form an aqueous polymersolution. After the solution was cooled to room temperature, a knownamount of drug (at 5 to 30wt% of the dry PVA) was added. The solutionwas stirred to allow the drug to dissolve completely. Glutaraldehyde wasemployed as a cross-linking agent, in ratios of 1 to 2mol% of total vinylalcohol repeating units. Based on the amount of glutaraldehyde, a 2:1:2:3volume ratio of the following solution was sequentially added to the PVAsolution according to the desired cross-linking ratio and mixed by stirring(Korsmeyer and Peppas, 1981):

(1) 50 vol% methanol (solvent)(2) 10 vol% acetic acid (buffering agent)(3) 25wt% glutaraldehyde (cross-linking agent)(4) 10 vol% sulfuric acid (catalyst).

After thorough mixing, PVA solutions were cast between two glassplates that had been previously treated with Pro-Sil to prevent thepolymer from adhering to the glass. Teflon1 spacers were placed betweenthe plates to control the thickness of the resulting gels. Because the drugwas added prior to the cross-linking step, reaction temperatures were

ANALYSIS OF BURST RELEASE OF PROXYPHYLLINE FROM PVA 521


kept at 37�C for 24 h. After the reaction, disk-shaped samples were cutfrom the membrane and placed under vacuum to dry to constant weight.The dry samples had average dimensions of 0.09 cm thickness and 1.5 cmdiameter, and weighed between 0.15 and 0.20 g each.

Swelling Experiments

Swelling experiments were conducted because drug release behavior isdependent upon the polymer morphology during the swelling process.In these experiments, PVA samples were placed in deionized water(37�C) to allow swelling. Sample weights were recorded as a function oftime after blotting the wet gel with absorbent tissue to remove surfacewater.

InV|tro Release Experiments

Release experiments were conducted in USP type II dissolution cells(Distek, Model 2100C, North Brunswick, N.J.). The release mediawere kept at 37�C with 900mL of solution stirred at 250 rpm duringthe experiments. This volume ensured that the perfect sink conditionassumption could be used, especially in the region of the burstrelease. Samples of the release solutions were circulated continuouslyto quartz flow through cuvettes with proxyphylline concentrationmonitored by a UV/Vis spectrophotometer (Shimadzu, UV-2401PC,Norcross, Ga.).

RESULTSANDDISCUSSION

Swelling Behavior of PVA Samples

Hydrogels are swelling controlled-release devices, for which absorptionof solvent (water) leads to polymer expansion, which directly affects thediffusivity of imbedded drugs and greatly influences release kinetics(Baker, 1987). The release rate is determined by the ability of solutemolecules to move through the gel networks, which change morphologyduring swelling due to diffusion of fluid in the polymer and its macro-molecular relaxation (Colombo et al., 1990). Figure 1 shows the effect ofcross-linking ratios on the swelling profiles of PVA hydrogel samples(with no drug loaded) under different cross-linking ratios. Both the rateand the extent of swelling decreased as the cross-linking ratio increased.This result is attributed to more bonds between the polymer chains inhighly cross-linked samples, which provides greater resistance to the gelswelling. Brazel and Peppas (1999) also demonstrated that the increase ofthe cross-linking ratio in PVA samples decreased the water uptake and



hence the swelling rate because of the large degree of restriction in thehydrogel network.

Release Experiments

Because our research is concerned primarily with burst release, onlythe results in the early stage of release are shown. Release rateswere determined using a forward divided difference technique foreach point. The release rates were normalized by the surface area(SA) of the dry disk-shaped hydrogel samples to account for smallvariations in sample dimensions. Five conditions theorized to beimportant factors in burst release from monolithic systems wereinvestigated:

(1) Cross-linking ratio of the hydrogels: 1, 1.5, and 2mol%.(2) Drug loading concentration: 5, 10, 15, 20, 25, and 30wt%.(3) Sample states: relaxed and dry.(4) Pore diffusion of the drugs: water and isopropanol as release media.(5) Osmotic pressure: water and 0.1M KCl as release media.

Figure 1. Swelling behavior of PVA as a function of time for cross-linking ratios of 1mol%

(*), 1.5mol% (j), and 2mol% (m). Error bars represent standard deviations for experi-

ments conducted in triplicate.



Cross-linking Ratio. As shown in Figure 1, the cross-linking ratio of hy-drogels has a big influence on swelling behavior. Due to the strong cor-relation between swelling and release kinetics, the investigation of thecross-linking effects on the release profile is also very important. Goheland Amin (1999) showed that drug release rates are dependent on thedegree of cross-linking and consequently the mesh space available fordrug diffusion (Mallapragada et al., 1997). However, initial burst was notmentioned in this study. Brazel and Peppas (1999) found that vitamin B12

release rates decreased with smaller hydrogel mesh sizes and slowerswelling kinetics in cross-linked PVA systems. Although the burst effectwas observed in this study, it was ignored in the discussion, and eveninitial release rates were calculated using the first few data points afterinitial burst effect. The results of our experiments with proxyphylline areshown in Figure 2 as a function of the cross-linking ratio. Higher cross-linking ratios reduced burst (the initial normalized release rate had a 40%drop as the cross-linking ratio was increased from 1 to 2mol%), but italso reduced the steady-state release rate following burst, which is due tothe increase of the links between polymer chains and subsequent decreaseof space inside the gel, which hindered drug diffusion. These experimentsalso suggest that even with the same amount of drug loaded in the PVA

Figure 2. Effect of cross-linking ratio on the release rate of proxyphylline from PVA hydro-

gels loaded with 20wt% proxyphylline. Cross-linking ratios were 1% (�), 1.5% (&), and

2% (m). Error bars represent standard deviations of three or four experiments.



hydrogel, the morphology of the hydrogel network will affect the releaseprofile, including the initial burst. Since the drug loading concentrationwas the same in the three experiments, the difference in initial release ratesuggests that burst cannot be caused solely by surface desorption, or thethree sets of samples would have the same burst rate.

Drug Loading Concentration. Burst release of proxyphylline was ob-served for loading concentrations ranging from 5 to 30wt% of drypolymer, with more pronounced burst for the higher drug loading con-centrations. To develop economically viable pharmaceutical products,controlled-release devices must contain relatively large amounts of thedrug to enable a long-term release with less frequent drug dose admin-istration. Unfortunately, the severe burst phenomenon in cases of higherdrug loading becomes a barrier to safe and effective use, and methods ofovercoming it present a big challenge. Experimental results suggest thatthe fraction of drug released during the burst stage does not changeappreciably with the drug loading concentration. In the experiments withproxyphylline, a very significant portion (15�25%) of the total loadingmay be lost in the burst. It is also shown in Figure 3 that the initial burst

Figure 3. Effect of drug loading concentration on the proxyphylline release rate from PVA

hydrogels with 1mol% cross-linking ratio. Proxyphylline was loaded at 5 (�), 10 (&), 15

(m), 20 (!), and 30 (^) wt%. Error bars represent standard deviations of three or four

experiments.



rate is largely proportional to drug loading concentration within therange of this study, and this proportional trend still roughly holds for thesteady-state release after burst. This observation suggests that as long asthe polymer network properties are fixed, the burst release rate isquantitatively dependent upon the amount of drug loaded.

Sample State. Solute migration during the drying process of the drug-loaded hydrogels has been suggested to contribute to the burst effect(Mallapragada et al., 1997; Kishida et al., 1998). It is assumed that thediffusion and migration of drugs might occur during the drying step byconvection of the drug molecules with the evaporating water, leaving anuneven drug distribution across the gel, with higher concentrations at thesurface. However, burst was also found in Patil et al.’s research (1996)with poly(sucrose acrylate) hydrogels used in their prepared state withoutdrying, so the drying process was exempted from the potential causes ofburst in this case. In a similarly designed set of experiments, proxy-phylline release rate profiles were monitored for both dried samples andsamples left in their prepared (relaxed) state (Figure 4). Except for thefirst data point, which for some reason has a slightly lower value,

Figure 4. The effect of the initial state of hydrogel samples on the release rate of proxyphyl-

line from PVA hydrogels with a 1.5% cross-linking ratio and 20wt% proxyphylline loaded.

Samples were either dried (*) or left in their relaxed (*) states. Error bars represent stan-

dard deviations of three or four experiments.



the relaxed samples showed a release rate profile continuously dimin-ishing with time due to the absence of polymer relaxation and swellingcontributions to convection. Since dimensions of the relaxed samples donot change significantly during the release process, the release processinvolves only two steps: dissolution of the drug and its subsequent dif-fusion through the hydrogel mesh. This leads to release behavior in ac-cordance with the characteristics of a diffusion-controlled monolithicsystem as defined by Fick’s Law (Baker, 1987; Langer, 1980).

Two reasonably simple equations have been used to approximaterelease during early and late time periods of release in nonswellablemonolithic devices. For a slab containing a total amount of drug M0, theamount of drug released at any given time, Mt, can be approximated by(Baker, 1987; Langer, 1980):

Mt

M0¼ 4

Dt

pl 2

� �1=2

ð1Þ

for 0 � Mt

M0� 0:6, and the late-time approximation:

Mt

M0¼ 1� 8

p2exp

�p2Dt

l 2

� �ð2Þ

for 0:4 � Mt

M0� 1. In these equations, D is the diffusion coefficient of drug

in polymer, and l is the half-thickness of the slab. Equations (1) and (2)were used to fit the release data of the relaxed samples, giving the valuesof diffusion coefficient of 9.34� 1077 and 10.20� 1077 cm2/s, respec-tively. Regardless of the slight deviation of the experimental data at veryinitial time, both the early- and late- stage approximations fit the datavery well and generate similar diffusion coefficient values, indicating thatFick’s Law accurately describes the release process. In contrast, the driedPVA samples had an obvious burst release followed by a period ofsteady-state release, and Equations (1) and (2) do not fit the release dataas well, suggesting that the release kinetic of the system is not diffusioncontrolled. The equations estimate early- and late-time diffusivities of3.23� 1078 and 5.89� 1078 cm2/s, respectively, for release from theswellable system. The difference in the two curves in Figure 4 is attributedto the difference in release mechanisms. It can be concluded from theresults that although the drying process magnifies the burst effect,the swelling process leads to a period of zero-order release, extending theeffective release time. The burst effect observed when proxyphylline wasreleased from dry samples could be partly due to the migration of drugstowards the sample surface with water convection during the drying and



storage process, which results in higher drug concentration near thesurface of the hydrogel, as has been suggested (Mallapragada et al., 1997;Kishida et al., 1998). The higher burst could also be the nature ofswelling-controlled systems.

A few publications (Harland et al., 1988; Colombo, 1993; Conte et al.,1988; Baveja et al., 1987; Colombo et al., 1996) have investigated the gellayer that is formed when a solvent is transported into swellable hydro-gels during the release process. This gel layer thickness, which acts as agrowing diffusion barrier, is theorized to control the release rate.Although there is some inconsistency in the definition of this release-controlled gel layer among the published studies, it is common that uponcontact with a solvent, the gel layer starts to develop, and during the timeneeded for the development of the gel layer, the release rate is high, evenif the drug is uniformly distributed. Because the polymer system inves-tigated here is similar in properties to those observed in the above studies,the release-controlling gel layer theory may also contribute to the causesof the initial burst. However, since drug concentration distributionsacross the gel were not examined in this study, no substantial conclusioncan be drawn. Both drug redistribution during drying and the develop-ment of the release-controlling gel layer are considered as factors thatcontribute to the initial burst.

Pore Diffusion. Proxyphylline is a small-molecular-size solute, having amolecular weight of 238.2 and an effective radius of 3.47 A, as estimatedaccording to van der Waals volumes, as detailed by Bondi (1964).Therefore, it is possible that proxyphylline is able to diffuse from thepolymer network as soon as the device is put into an appropriate releasemedium, even before the hydrogel begins to swell. To test the possibilityof this assumption, release experiments were carried out in water andisopropanol, respectively. PVA is insoluble in isopropanol, and thereforedoes not swell during these experiments, restricting the diffusion ofproxyphylline, which is soluble in isopropanol, to the void volume in thepolymer networks. The results (Figure 5) show that initial release inisopropanol was much lower than that in water, and the release rate keptdecreasing without reaching a zero-order stage. Therefore pore diffusionof the drug at the very beginning of the release was shown to make onlyminor contribution to the initial burst in swellable systems.

Osmotic Pressure. Osmotic pressure is often an additional driving forcefor release. The osmotic pressure occurring during the release process inswelling controlled-release systems is related to the high drugconcentration inside the network (Brazel and Peppas, 1999). However,the osmotic gradient is not always significant relative to that gradient



induced by the polymer network (Brown et al., 1994). The influence ofosmotic pressure on burst release in PVA hydrogel systems was in-vestigated by using two release media: water and 0.1M KCl (Figure 6).There was no observable difference in release profiles, and therefore itwas concluded that osmotic pressure, at least up to the concentration ofKCl used, has little effect on burst and the whole release process.

CONCLUSIONS

Cross-linked PVA samples loaded with the small molecular weight drugproxyphylline were prepared, and release experiments were carried out tostudy the initial burst release. Burst was more pronounced when the drugwas loaded at higher concentrations, which challenges the goal of manypharmaceutical studies of increasing the drug content in controlled-release devices. The initial drug release rate was found to be approxi-mately proportional to drug loading concentration in the experiments.The change in morphology of the polymer network, which was broughtby the change of cross-linking ratio, also contributed to varied extent ofburst. Higher cross-linking ratios effectively reduced initial burst, and

Figure 5. The contribution of pore diffusion to the overall release process for proxyphylline

release from PVA hydrogels, with 1mol% cross-linking ratios and 30wt% proxyphylline

loaded. Release experiments were carried out in isopropanol (*) and water (*). Error bars

represent standard deviations of three or four experiments.



the release rate in the subsequent stage as well, suggesting that there mustbe an additional mechanism besides surface desorption of the drug toaccount for the observed burst behavior. By drying the PVA gels burstrelease was magnified, and the whole release process was extended as therelease mechanism switched from diffusion controlled to swellingcontrolled. The pore diffusion of proxyphylline at the very beginning ofthe release had little contribution to the burst, and, within the rangeof this study, osmotic pressure during the release did not show anynoticeable effect. Burst release is still a therapeutically and economicallyimportant phenomenon for the development of pharmaceutical treatmentstrategies, and further studies must be conducted to fully understand themodes of and mechanisms causing the burst effect.

ACKNOWLEDGMENTS

The authors acknowledge the support of Department of ChemicalEngineering of The University of Alabama for funding the research.

Figure 6. The effect of release media salt concentration on proxyphylline release from PVA

hydrogels with 1.5mol% cross-linking ratio and 15wt% proxyphylline loaded. Release

experiments were carried out in water (�) and 0.1M KCl solution (*). Error bars represent

standard deviations of three or four experiments.



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Analysis of Burst Release of Proxyphylline From Poly(Vinyl Alcohol)

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