use of chitosan in compressed tablets of diclofenac sodium: inhibition of drug release in an acidic...

Pharmaceutical Development and Technology, 2(3), 243-255 (1997)

RESEARCH ARTICLE

Use of Chitosan in Compressed Tablets of Diclofenac Sodium: Inhibition of Drug Release in an Acidic Environment

Shobhan Sabnis, Pankaj Rege, and Lawrence H. Block Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania

Received July 1, 1996; Accepted February 13, 1997

ABSTRACT

The purpose of this study was to evaluate the potential utility of chitosan (I) in inhibiting diclofenac sodium (11) release in the gastric environment from a directly compressible tablet formulation. I , subjected to depolymerization to improve its microcrystallinity and subsequent compressibility, was then used to prepare tablets of II. A fullfactorial design was employed to evaluate the effects of degree of N-deacetylation of I, and the p H and ionic strengths, p, of the dissolution media on drug release. Directly compressible tablets were prepared from admixtures of 25 mg of II, 1 74 mg of I of various degrees of N-deacetylation (74, 87, and 92%), and 1 mg of magnesium stearate. The in vitro dissolution studies were peflormed using aqueous buffers (pHs 1.2, 3.8, and 6.8, and p of approximately 1.0 and 0.1). The slopes of logarithmically transformed cumulative percent released-time curves from t = 0 to t = 5 hr) were compared. Analyses of variance pelLformed using SAS indicated that the degree of N-deacetylation of chitosan significantly afsected drug release at pHs 1.2 and 6.8 ( p < O.ooo1). An increase in the pH of the dissolution medium resulted in an increase in drug release ( p < O.ooO1). The ionic strength of the dissolution medium did not sig- n@cantly affect drug release at any of the pHs studied ( p > 0.198). Besides the poor aqueous solubility of 11, the two factors possibly affecting the drug release in the acidic environment were (a) the formation of a rate-limiting chitosan gel barrier; and (b) the ionic interaction of I1 with ionized amino groups of I. KEY WORDS: Biodegradable polymer, Chitosan, pH-dependent release, Polyelectrolyte, Polyionic complex.

Address correspondence to Lawrence H. Block, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282.

243

Copyright 01997 by Marcel Dekker, Inc.

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244

INTRODUCTION

Sabnis, Rege, and Block

MATERIALS AND METHODS

Diclofenac sodium, a phenylacetic acid derivative, is a nonsteroidal anti-inflammatory drug that is available commercially for peroral administration. The gastric side-effects of perorally administered diclofenac sodium may be alleviated, to some extent, by inhibiting its release in the gastric region (1,2). Chitosan has free amino groups that ionize in an acidic environment, thereby helping to solubilize the polymer. Chitosan, when used in a matrix-type tablet formulation, is likely to form a gel barrier of solubilized polymer in an acidic environment that can modulate or constrain drug release (3.4). In this way, diclofenac release in the gastric region may be minimized.

Although chirosan has been extensively evaluated as a directly compressible tablet excipient (3-7), virtually all of the formulations developed necessitated additional ingredients to facilitate direct compression. This is a re- tlection of the fact that commercially available chitosan is fibrous in nature and lacks good flow properties and compressibility.

Modifications of chitosan and chitin achieved in the past have included the preparation of depolymerized chitosans. Austin et al. (8) have reported a method of preparation of depolymerized chitin (MW = 33 kDa) by acid hydrolysis of chitin using phosphoric acid. Dunn et al. (9) have reported a similarly processed material using hydrochloric acid to yield a stable thixotropic dis- persion in water. Low molecular weight chitosan has been used to enhance the dissolution rates of several drugs (10, l l ) . Depolymerized chitosan offers several advantages over commercially available chitosan. In the latter products, the parent macromolecule exists in the form of random coils (12) with relatively inaccessible amino groups. Upon depolymerization, more amino groups on the polymer backbone tend to become acces- sible to and reactive with the bulk phase environment. Furthermore, with depolymerization, the decrease in molecular weight is accompanied by an increase in microcrystallinity and subsequent compressibility, thus improving the potential for development of solid drug delivery systems such as tablets (13). In this study, we depolymerized commercially available chitosan and evaluated its use as the sole excipient in a directly compressible tablet formulation of diclofenac sodium. Fur- thermore, the potential inhibition of diclofenac release hy depolymerized chitosan was evaluated as a function of pH.

Commercially available chitosans were purchased from Sigma Chemical Co., St. Louis, MO (batch # OOOl), or kindly donated by MMP, Inc., Mountainside, NJ (batch # 8009) and Austin Chemical Co., Holmdel, NJ (batch # 0002). Diclofenac sodium, donated by Ciba-Geigy Corp., was used as supplied. Magnesium stearate was supplied by Nuodex Inc. Reagent grades of glacial acetic acid, hydrochloric acid, methanol, potassium chloride, sodium acetate, and sodium chloride were used as supplied by Fisher Scientific, Fairlawn, NJ.

Depolymerization of Chitosans

Commercially available chitosans (10 g each) were refluxed with 400 ml of 1.7 N hydrochloric acid in a three-necked flask under a nitrogen blanket at 100°C for ihr. The resultant mixture was cooled to room tempera-. ture and its pH increased to 7.5-8 by the addition of freshly prepared sodium hydroxide solution (4 N). Pre- cipitated polymer was filtered and repeatedly washed until the pH of the washings was neutral. The resultant wet polymer mass was weighed and a slurry containing 10% wlw polymer was prepared with pure water. This slurry was subjected to high shear using a Lightnin"' mixer, model Labmaster TS2010 (Mixing Equipment C o p , Inc.) with a propeller impeller (1800 rpm for 6 min). The resultant slurry was dried in a hot air convec- tion oven at 60°C for 72 hr. The product was then milled using a Waring blender, model FCI 15 (Waring Products Corp., NY) and sieved. The fraction retained on the 120 mesh sieve was selected.

Determination of the Degree of Deacetylation of Chitosan

Approximately 25 mg of dried chitosan was triturated with 100 mg of potassium bromide powder and passed through a 120 mesh sieve. About 40 mg of the mixture was then used to prepare a pellet. The degree of deacetylation was determined by an IR spectroscopic method (14) using a Perkin-Elmer FTIR spectrometer, model 1605.

Determination of the Molecular Weight of Depolymerized Chitosan

To determine the viscosity average molecular weight. (M,) of depolymerized chitosan, polymer solutions, a1

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Chitosan in Diclofenac Sodium Tablets 245

known concentrations, were prepared in a solvent system consisting of 0.5 M acetic acid and 0.25 M sodium chloride in deionized water. The solutions were filtered through a 5-pm nylon filter (US Medical, Inc., NC) prior to the viscosity measurements. The viscosity measurements were made, in triplicate, by recording the efflux time of the filtered solution in a Ubbelohde vis- cometer at 25°C (+O. 1 "C) in a constant-temperature bath. M , was calculated from the classical Mark- Houwink relationship,

[11= Km(Mv)" (1)

where Km = 2.14 x trinsic viscosity.

a = 0.657, and q is the in-

Scanning Electron Microscopy (SEM) of Chitosan

Chitosan morphology was studied by SEM using a JEOL microscope, model 35 (JEOL Ltd., Tokyo, Ja- pan) at 20 kV. Chitosan samples (60-120 mesh) were dried under vacuum for 24 hr, mounted on graphite stubs using acetone as the dispersing medium and coated with gold, using an SEM sputter coater, model E5000 (Polaron Instruments, Inc., PA), to a thickness of 200- 500 A. Powder X-ray Diffraction Studies

Powder x-ray diffraction studies of chitosan were performed using an X'PERT System (Philips, Almelmo, Holland) with Cu K a radiation in the range of 5-70'20. Using the scans obtained for the parent chitosans as reference standards, the increase in crystallinity of chitosans was determined by the Percent Crystallinity Program@ (version 1, Philips Electronics Instruments). In calculating percent crystallinity, this program utilizes the crystalline ( C ) and amorphous (A) intensity portions of the sample by numerically integrating them over a specified 28 range. The resulting formula used in calculating percent crystallinity (% C) of the sample is as follows:

where, I , and ZA are the areas of the crystalline and amorphous regions of the scan, respectively. The ratio (C/A) is the intensity or peak height ratio, which rep- resents the relative structural scattering of the crystalline

and amorphous portions. The scan obtained for the parent chitosan (not subjected to depolymerization) was utilized as the reference material while the scan obtained for the depolymerized chitosan comprised the test material.

The powder x-ray diffraction studies of various chitosans involved the placement of about 0.6-0.8 g of the chitosan powder on a glass slide. The slide was subsequently mounted in place in the diffractometer after the powder surface was leveled appropriately.

Development of a Method of Analysis for Diclofenac Sodium

The pH 1.2 buffer medium was prepared containing 0.01 M hydrochloric acid and 0.99 M potassium chloride in methano1:water (1:4, p = 1.0). The pH 3.8 and pH 6.8 buffer media employed acetic acid and sodium acetate (0.85 M and 0.15 M, respectively, for the pH 3.8 buffer; 0.009 M and 0.991 M, respectively, for the pH 6.8 buffer) in methano1:water (1:4, p = 1.0). Methanol was incorporated in these buffered dissolution media to compensate for the low solubility of diclofenac sodium in aqueous solution. These buffers were diluted tenfold to prepare buffer media with p = 0.1. The pH of these diluted buffer solutions was readjusted by the appropriate addition of concentrated hydrochloric acid, glacial acetic acid, or 4 N solutions of sodium or potassium hydroxide.

Standard solutions of diclofenac were prepared at ionic strengths (p) of 0.1 and 1.0, for each of the pHs employed in the study. No significant differences in UV absorbance were detected for these solutions. The cali- bration curves for the subsequent UV analysis of diclofenac were then generated in the buffer media (p = 1) at pHs of 1.2, 3.8, and 6.8. The analyses were carried out at wavelengths (hmax) of 273.1, 275.1, and 277.2 nm, respectively, using a Perkin-Elmer UVlVIS spectrophotometer, model S-4A.

Evaluation of Saturation Solubility of Diclofenac Sodium

Excess diclofenac sodium (5 g) was added to 10 ml aliquots of each of the buffer solutions in 20 ml glass vials equipped with small magnetic stir-bars. The vials were sealed, placed in a 37°C constant-temperature bath, and the contents stirred continuously thereafter. Samples (approx. 0.2 ml) were drawn periodically, filtered through a 0.45-pm filter and analyzed by UV

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246 Sabnis, Rege, and Block

spectroscopy. Sampling was continued until equilibrium was attained.

Evaluation of Intrinsic Dissolution Rate of Diclofenac Sodium

The intrinsic dissolution rates of diclofenac sodium in different dissolution media (pH = 1.2, 3.8, 6.8) were determined as follows: diclofenac sodium (300 mg) was compressed into disks using a Carver press at 5000 lb for 30 sec. Each disk was secured in a die cavity, fol- lowing the approach of Block and Pate1 (15), so that only one surface of the disk was exposed to the dissolution medium (200 ml). The dissolution was carried out using USP type I1 dissolution apparatus (model 6010 VanKei Industries Inc., NJ) at 37°C and a stirring speed of 50 rpm. Samples were withdrawn every 15 min over a 90-min period and analyzed spectrophotometrically.

Preparation of Diclofenac Sodium-Chitosan Tablets

Diclofenac tablets were prepared by directly com- pressing blends of diclofenac sodium (120 mesh), 25 mgitablet; chitosan (60-120 mesh), 174 mgitablet; and magnesium stearate (120 mesh), 1 mgitablet. The tablets were compressed on a Carver press at a compaction force of 5000 lb using 3/8-in. flat-faced punches and corresponding dies. The total tablet compaction time entailed 33-35 sec, of which pressure was applied in- creasingly for the first 3-4 sec and then maintained at 5000 psi for the duration.

Determination of the Physical Characteristics of the Tablets

The diameter, thickness, and hardness of five tablets from each batch were determined using a Pharma Test'" tablet tester, model PTB 31 1 (Scientific Instruments and Technology Corp., NJ). The friability of 10 tablets from each batch was determined using an Erweka friability tester, model TA3 (Erweka Appurtebau, West Germany).

Study of In Vitro Drug Release

All in vitro dissolution tests were performed using a USP type I1 dissolution apparatus. The dissolution media contained 20% v/v methanol in aqueous buffers at pHs of 1.2, 3.8, and 6.8, and ionic strengths of approximately 1 .O and 0.1. Dissolution was evaluated at 37°C and a stirring speed of 50 rpm, from 0 to 5 hr. Three replicates from each batch were tested. Samples of the dissolution medium were withdrawn at 0.25, 0.5, 1.0, 2.0, 3.5, and 5.0 hr and filtered through 0.45 pm fil- ters. The aliquots were then analyzed by UV spectro- photometry and the slopes of the logarithmic (i.e., log- log) transformations of percent drug released-time profiles ( t = 0-5 hr) were compared.

Data Analysis

A three-way interactions analysis of variance (ANOVA) model was tested using S A P (version 6.07, SAS Institute, Inc., Cary, NC). The independent vari- ables were as follows:

Degree of deacetylation of chitosans: 92%, 87%, 74 % pH of the dissolution media: 1.2, 3.8, 6.8 Ionic strength of the dissolution media: 1.0 and 0.1

The dependent variable was the slope of the logarithmically transformed percent drug released-time profile. The effect of the degree of deacetylation of chitosan on drug release was studied at individual pHs by two-way analyses of variance.

RESULTS AND DISCUSSION

Depolymerized Chitosan Properties

Degrees of deacetylation and viscosity average mo-. lecular weights of the depolymerized chitosans used in this study are listed in Table 1.

Scanning Electron Microscopy of Chitosan Evaluation of Disintegration Time of the Tablets

Disintegration time of the tablets was measured in 0.1 N hydrochloric acid at 37°C (USP XXIII method, without disks) using a Vanderkamp disintegration tester (VanKel Industries Inc., NJ) with a Precision water bath, model 183.

Figure 1 shows the SEMs of chitosans (a-c) and their depolymerized products (d-f), respectively. All the micrographs were taken at 600 x magnification, except for the chitosan supplied by MMP, Inc. (Fig. lb), for which 1 2 0 0 ~ was used. It is evident that the chitosari particles undergo a change in appearance from a rough

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Figure 1. Scanning electron micrographs of chitosan batches 0001 (a), 8009 (b), and 0002 (c), and their corresponding depolymerized products, batches 3037 (d), 3102 (e), 3085 (f).

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Table 1

Degrees of Deacetyhrion and Molecular Weights of Chitosans and meir Corresponding Depolymerized Products

Percent Degree Chitosan Molecular Chitosan Batch # of Deacetylation Weight, kDa

O0Ola 87 400 8009a 97 350 0002a nla nla 3037b 86.9 f 1.67 24.1 3102h 91.8 f 0.77 17.6 3085b 74.1 f 0.32 19.8

%Suppliers' data. bSample size = 3 n/a: not available

to a smooth texture as a consequence of the depolymerization treatment.

Powder X-ray Diffraction Studies

Fig. 2 shows x-ray diffraction patterns for chitosans (lots 0001, 8009, 0002) and their depolymerized products (lots 3037, 3102, 3085) over 5-35 "28 range. The patterns beyond 35 "28 were diffuse and are not shown. A characteristic chitosan peak was observed at 20 "28 in these chitosan samples (11, 16, 17). This peak was much narrower for the depolymerized samples than for the parent polymers. The x-ray diffraction data were indicative of an increase in crystallinity of 20.8, 30.6, and 23.6%, respectively. Interestingly, at 29 "28, chitosan lot OOO1 showed a small peak consistent with the d-spacing of a mixture of sodium and potassium chlorides (1 8) and indicative of a lot-specific impurity that may be the result of incomplete washing of the chitosan during its manufacture.

Solubility Characteristics of Diclofenac Sodium

The intrinsic dissolution rates of diclofenac sodium were directly related to the pH of the dissolution media. The saturation solubility estimates, as reported in Table 2, were determined at 72 hr. The solubility of diclofenac was dependent on the pH of the medium. Diclofenac, with a pK, of 3.8, exists mainly in the unionized form in an acidic environment: it was sparingly soluble at pH 1.2, whereas, at pH 6.8 it mainly exists in the ionized

form and was substantially more soluble. These obser-. vations are consistent with the extensive data reported by Fini et al. (19). Diclofenac has been reported to undergo cyclization readily at pH 3.8 into an indolinone derivative (20). Thus, the low solubility of diclofenac at this pH may possibly be attributed to its decreased sta- bility.

Physical Characteristics of Diclofenac Sodium- Chitosan Tablets

All tablets were prepared with depolymerized chitosan since it was impossible to compress tablets formulated with the unmodified polymer. The physical characteristics of the tablets are listed in Table 3. Al- though the friability was marginally higher than gener- ally accepted limits (21), it may be possible to improve this property by altering the drying conditions during the depolymerization of chitosan: during slow drying, chitosan tends to form a horny and tenacious mass that does not readily undergo deformation nor facilitate par - ticulate flow. Austin and Brine (3) contend that the physical properties of depolymerized chitosan can be altered by accelerating the drying process (e.g., spray- drying). The results reported herein for tablets made with depolymerized chitosan suggest that this excipient has potential for directly compressible tablet formulations.

Evaluation of Disintegration Time of the Tablets

Preliminary disintegration testing of the tablets in deionized water yielded mean disintegration times of

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COUNT

500

COUNT,

0.01 5 10 35 20 ?5 30 I'281 35

Figure 2. X-ray diffractograms of chitosan batches 0001 (A), 8009 (B), and 0002 (C), and their corresponding depolymerized products, batches 3037 (D), 3102 (E), 3085 (F).

21.3 (+ 6.8) min. Subsequent evaluations of the disintegration times of the tablets in 0.1 N hydrochloric acid, which are more relevant to the release in the gastric environment, are reported in Table 3. Disintegration

times of the tablets were not significantly different from one another ( p > 0.158) nor were they influenced by either degree of deacetlyation or molecular weight of the chitosan.

In Vitro Diclofenac Release from the Tablets

The amount of drug dissolved was influenced consid- erably by the solubility characteristics of the drug at each pH (Figs. 3-5). The logarithmic transformations of these data yielded linear relationships, the slopes of which were then utilized in a subsequent ANOVA treatment (a representative log-log plot of the data is shown in Fig. 6). The slopes of the logarithmically transformed cumulative percent released-time plots (Table 4) were subjected to a three-way ANOVA of the slopes, which indicated that pH of the dissolution medium significantly affected the release of diclofenac (Table 5). Although the overall effect of the degree of deacetylation of chitosan was not significant, as indicated by the three- way ANOVA, two-way analyses performed at individual pHs indicated that a change in the degree of deacetylation of chitosan was associated with a significant change in drug release at neutral and acidic pHs. At pH 1.2, where chitosan exists primarily in an ionized state, the smallest amount of diclofenac was released from those tablets that contained highly deacetylated chitosan ( p < 0.0001) (i.e., 92% deacetylation). The same effect was observed at both ionic strengths of the dissolution media (Fig. 7), although at a pH of 6.8, where chitosan exists predominantly in an unionized state, the effect was reversed (p < O.OOOl), i.e., maxi- mum drug release was observed from the tablets containing highly deacetylated chitosan (Fig. 8).

These observations are consistent with those made by Hariharan and Peppas (22) who studied solute release from an initially glassy cationic polymeric network exposed to aqueous electrolyte solutions. They noted a significant change in the solvent diffusion coefficient upon the transition of the polymer from the glassy to the rubbery state. The rate of solution uptake in the polymer matrix increased with an increase in concentration of ionic groups on the polymer. If one assumes that the chitosan tablet matrices prepared in this study are analo- gous to the initially glassy cationic gels described by Hariharan and Peppas (22), at low pHs, diclofenac release would be slowest in the case of tablets containing chitosan having the highest degree of deacetylation and vice versa. The probable processes involved in such release behavior at pH 1.2 are presented in Schemel.

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Table 2

Solubility Characteristics of Diclofetiac Sodium at 37°C

Intrinsic Dissolution Saturation Solubility at t = 72 hr PH Rate (mg/(min cm2}) (mg/ml) [Mean +_ SD]

1 .z 0.004 1.37 F 0.071 3 8 6.8 0.188 2.26 f- 0.095

0.025 0.069 k 0.007 (1.132 k 0.127 at t = 6 hr)

.-___

Table 3

Phj,sical Characteristics of Diclofenac Sodium-Chitosan Tablets ___.I_ ..___I___ ____-

Crushing Disintegration Pcrcenr Diameterd Thicknessa Strengthd Weighta Friabilityh Timec Deasrr! lation ( mm ) (mm) (Kp) (mg) (% wlw) (min)

- _ I ~

92 8.74 (0.025) 2.64 (0.051) 1.91 (0.54j 199.3 (0.54) 0.81 49.5 (1s.:') 87 8.77 (0.051) 2.64 (0.076) 1.61 (0.16j 199.4 (0.46) 0.95 35.7 (9.4)

198.0 (0.74) 1.18 43.8 (9.1) 74 8.73 (0.025) 2.62 (0.076) I .48 (0.12)

aMean and SD of five tablets oSmple size = 10 tablets 'Mean and SD of six tablets

120 I

L

-0- pH 1.2;p= 0.1 -W- pH 3.8; p = 1.0 -0- pH 3.8; p= 0.1 -f pH 6.8; p= 1.0 + pH 6.8; p= 0.1

40 -9" 2o 1Ii

0 1 2 3 4 5 6 Time (Hours)

Figure 3. (p ionic srrength).

Effect of pH of the dissolution medium on diclofenac release from tablets prepared with 92% deacetylated chitosan

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Chitosan in Diclofenac Sodium Tablets

lZO 2 100

ao ; h. - - 60 E i2 aJ

40

20

0

-f pH 3.8; p= 1.0 U pH 3.8; v = 0.1 + pH 6.8; p= 1.0

25 1

0 1 2 3 4 5 6 Time (Hours)

Figure 4. (p = ionic strength).


100

80

60 M B d B 1 40

-

20

0

43- pH 1.2;p= 0.1 + pH 3.8; p= 1.0 U pH 3.8;p= 0.1 + pH 6.8; p= 1.0

pH 6.8; p= 0.1

0 1 2 3 4 5 6

Time (Hours)

figure 5. (p = ionic strength).


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1 .o

- W

f 0.5 d - ” Y E .-, - 6

0.0

-0.5

0 0

87% DD, y = O 382(x) + 0 523 [?= 0 9821 74% DD, y = 0 468(x) + 0 654 [? = 0 9981

-2.0 -1.5 -1.0 -0.5 0.0 0.5 2 .O

log Time (Hours)

Figure 6. Representative plot of logarithmic transformations of in vitro drug release at pH 1.2 (p = 1.0).

Table 4

In Vitro Drug Release from Diclofenac Sodium-Chitosan Tabletsa

pH of the Dissolution medium

1.2 3.8 6.8

DD*/Ionic Strength 1 .o 0.1 1 .o 0.1 1 .o 0.1 ___ 92 0.339 0.375 0.600 0.513 1.051 1.050 87 0.382 0.428 0.618 0.559 1.023 1.040 I4 0.468 0.452 0.616 0.569 1.017 1.015

*DD: degree of deacetylaction of chitosan %Slopes of the logarithmically transformed percent release-time profiles are used as the dependent variable.

Table 5

Three-Wq Interactions ANOVA of In Vitro Drug Release Profiles: Effect of Degree of Deaceglation of Chitosan (DD), pH, and Ionic Strength (p) of the

Dissolution Medium

Source DF Sum of Squares F Value Probability

DD 2 0.0037 6.15 0.0603 P 1 0.0007 2.37 0.1983

DD-p 2 0.0004 0.75 0.5291 DD-pH 4 0.0067 8.12 0.0335 P-PH 2 0.0063 10.47 0.0257

PH 2 1.2524 2095.20 0.0001

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10

8

6

4

2

0 0 I 2 3 4 5 6

Time (Hours)

Figure 7. Effect of percent deacetylation of chitosan on diclofenac release at pH 1.2 (p = ionic strength).

120

100

80

60

40

20

I I I I I

0 1 2 3 4 5 6

Time (Hours)

Figure 8. Effect of percent deacetylation of chitosan on diclofenac release at pH 6.8 (p = ionic strength).

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B

Scheme 1. of deacetylation. (B, chitosan of low degree of deacetylation

Procerse3 in\oived in the inhibition of drug release from chitosan matrix tablets at pH 1 2, (A) chitosan of high degree

As a result, the dependence of drug release from tablets on the extent of amino substitution in the polymer indicates that the inhibition of release from the tablet matrix occurs possibly due to either (a) diffusion rate- limiting gel formation by chitosan in an acid medium, wherein a more extensive higher-energy structure is formed by the polymer having more amino groups; and/ or (h) formation of an ionic complex between diclofenac sodium and the cationic polymer due to solvent perme- ation of the tablet matrix.

The three-way ANOVA (Table 5) indicated that gen- erally, the ionic strength of the dissolution media did not qignificantly affect drug release at the pHs studied ( p > 0.198), nor was the interaction between ionic strength and degree of deacetylation significant ( p > 0.529). However, all the interactions involving pH of the dissolution medium were significant (i.e., pH and degree of deacetylation of chitosan [ p < 0.0341; pH and ionic strength of the medium 1 p < 0.026)). These results

indicate that the extent of ionization of chitosan plays an important role in modulating the drug release. Depoly- merized chitosan selectively inhibited the release of diclofenac from a directly compressible tablet formulation in an acidic environment (e.g., pH 1.2). Based on these results, highly deacetylated chitosan might be ef- fectively utilized as a direct compression material in the preparation of peroral formulations that could minimize anionic drug release at acidic pHs in the gastrointestinal tract, thereby limiting gastrointestinal distress. The fact that the highly deacetylated material had the most rapid drug release at pH 6.8 is also significant for such an application.

CONCLUSIONS

Compression properties of chitosan may be improved by depolymerization of the commercially available poly-

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mer. Directly compressible tablet formulations utilizing depolymerized chitosan may selectively inhibit the release of anionic drugs such as diclofenac from an acidic environment (e.g., pH 1.2).

ACKNOWLEDGMENTS

The authors wish to thank M M P , Inc. and Austin Chemical Co. for their generous donations of chitosans. They also thank Dr. C. M. Adeyeye of Duquesne Uni- versity for allowing the use of diclofenac sodium donated to her by Ciba-Geigy COT. They are grateful to Dr. J. R. Blachere, Dr. Pradeep PhulC, and Ms. Yimin Liu of the Department of Materials Science and Engi- neering at the University of Pittsburgh for their facili- tation of the x-ray diffraction and SEM studies.

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use of chitosan in compressed tablets of diclofenac sodium: inhibition of drug release in an acidic...

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