Drug Development and Industrial Pharmacy

ISSN: 0363-9045 (Print) 1520-5762 (Online) Journal homepage: https://www.tandfonline.com/loi/iddi20

Investigation of the mucoadhesivity, swelling and

drug release mechanisms of indomethacin buccal
tablets: effect of formulation variables

Ozgur Esim, Ayhan Savaser, Cansel Kose Ozkan, Cetin Tas & Yalcın Ozkan

To cite this article: Ozgur Esim, Ayhan Savaser, Cansel Kose Ozkan, Cetin Tas & Yalcın
Ozkan (2020): Investigation of the mucoadhesivity, swelling and drug release mechanisms of
indomethacin buccal tablets: effect of formulation variables, Drug Development and Industrial
Pharmacy, DOI: 10.1080/03639045.2020.1831526

To link to this article: https://doi.org/10.1080/03639045.2020.1831526

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Investigation of the mucoadhesivity, swelling and drug release
mechanisms of indomethacin buccal tablets: effect of formulation
variables

Ozgur Esima, Ayhan Savasera*, Cansel Kose Ozkana, Cetin Tasb, Yalcın
Ozkana

a
University of Health Sciences, Gulhane Faculty of Pharmacy, Department of
Pharmaceutical Technology, Ankara, 06010, TURKEY

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b
Yeditepe University, Faculty of Pharmacy, Department of Pharmaceutical Technology,

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Istanbul, 34755, TURKEY

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Corresponding author: Ayhan Savaser* Mailing address: University of Health Sciences,
Gulhane Faculty of Pharmacy, Department of Pharmaceutical Technology, Ankara,
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06010, TURKEY, Tel.: +90-312-3046073; Fax: +90-312-3046091, E-mail:
ayhan.savaser@sbu.edu.tr
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Investigation of the mucoadhesivity, swelling and drug release
mechanisms of indomethacin buccal tablets: effect of formulation
variables

The purpose of this study was to investigate the effect of formulation variables on
properties related to critical functionality for their use in indomethacin buccal
tablets. Chitosan (CH), carbopol (PAA) and hydroxypropyl methyl cellulose
(HPMC) concentration and filler type were evaluated as parameters for
describing tablet hardness, swelling index, indomethacin release and
mucoadhesion in controlled release buccal tablets. Moreover, a 32 full factorial
design was employed to study the effect of each polymer ratios in CH and PAA

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combination, which significantly influenced characteristics. A slower
indomethacin release and a considerably larger degree of swelling were found for

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different concentrations of PAA or CH (P<0.05). The buccal tablets formed a
continuous gel layer while in contact with the aqueous medium undergoing a

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combination of swelling and erosion. In vitro drug release in simulated saliva (pH
6.75) appears to occur both by diffusion and a swelling-controlled mechanism,
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exhibiting anomalous, Case II type transport or Super Case II type transport. The
diluent present in all study samples, mannitol (MAN), spray dried lactose (SDL)
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and microcrystalline cellulose (MC) were believed to contribute minimally to

hydrogel formation and drug release regulation. The dissolution values for the
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three co-excipients were a decreasing order mannitol, spray dried lactose and
microcrystalline cellulose. In conclusion, the type and concentration of all
polymers seem to change the functionality of buccal tablets and it seems
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important to understand and characterize these excipients to fully predict the drug
release, mucoadhesion and swelling of buccal tablets.
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Keywords: buccal tablet; swelling; dissolution; mucoadhesion

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1. Introduction
The systemic administration of some drugs via oral route is not a preferred approach

due to gastrointestinal side effects since gastrointestinal ulceration and bleeding are

frequently observed in some patient populations [1]. Administration of drugs to the oral

mucous membrane can be an alternative approach to avoid these side effects [2, 3].

Buccal drug delivery has gained popularity in recent years with its unique

advantages, such as availability for controlled release, high patient acceptance,

improved bioavailability due to avoidance of enzymatic degradation in the

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gastrointestinal tract and hepatic first pass metabolism [4]. However, permeability

barrier and cytotoxicity of the buccal mucosa remain as a major limitation to delivery of

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drugs via this route [5].

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Different dosage forms can be applied to the buccal cavity. In this study, matrix
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tablet formulations are used because of their low cost and easy manufacturing steps.

The matrix system also appears to be a very attractive approach from process
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development and scale up points of view [6].

To understand the performance of a buccal tablet, the influence of the excipients

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must be explained and correlated to in vitro performance of the tablets [7, 8]. Hence, in
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this study, the effect of water-soluble carbopol (PAA) and insoluble polymers chitosan
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(CH) at given pH (6.75), hydroxypropyl methyl cellulose (HPMC) and fillers were

characterized and the effects were correlated with the tablet hardness, drug release,
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swelling and mucoadhesion of indomethacin buccal matrix tablets.

Indomethacin 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic

acid, is a nonsteroidal drug with anti-inflammatory (NSAID), and one of the

prostaglandin synthesis inhibitors which is used to reduce the inflammatory cell

infiltrate and to suppress bone resorption in periodontitis [9]. Indomethacin is known to

be a Class II drug that shows poor solubility and high permeability [10].
 In this study, it was investigated that the contribution of several formulation

variables on the drug release rate and mucoadhesive properties of buccal tablets using

poorly water soluble indomethacin as a model drug. To achieve this objective, just one

type or a mixture of mucoadhesive polymers (PAA and CH) was used as the matrix

base of the mucoadhesive tablets. These two polymers are widely used as a

pharmaceutical additive because they have low irritant properties [11]. Furthermore,

HPMC was used to control the release of indomethacin. For swelling-controlled

systems, the coupling of diffusion and macromolecular relaxation control the

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mechanism of drug release, providing conditions of zero-order release [12]. As for

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tablet fillers, water-soluble and water insoluble excipients were used. The effect of

fillers on characteristics of buccal tablets and the physical properties of the

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mucoadhesive matrix tablets containing various polymers were investigated.
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Furthermore, the effect of formulation variables on drug release were studied.
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2. Materials and methods

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2.1. Materials

Indomethacin (IND) was a gift from Deva Pharm. Co. (Turkey) and mannitol (MAN)
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was a gift from Eczacıbaşı Baxter (Turkey). The following materials were used as
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received: Carbopol 941 (B.F.Goodrich Chemical Company, USA), cellulose membrane

(Travenol Lab. Inc., USA), chitosan (medium molecular weight) and HPMC (Viscosity
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of 4% solution 25°C; 4000 cps) (Sigma-Aldirch, USA), microcrystalline cellulose (MC)

(90 M , Penwest Pharm. Co.,USA), spray dried lactose (SDL) (FlowLac 100) (Meggle

Pharma Excipients & Technology, Germany), colloidal silicon dioxide (CSD) (Aerosil

200) (Evonik, Germany), sucralose (SUC) (Kimetsan, Turkey). All other chemicals

were of analytical grade.

2.2. Preparation of the Tablets
Direct compression method was used to prepare buccal tablets. In all formulations,

indomethacin concentration was kept constant at 25% (w/w). The remaining part of the

formulation consisted of MAN, adhesive polymer, CSD and SUC. The detail of all

formulations was given in Table 1. Moreover the effect of fillers on the different

properties of buccal tablets were evaluated by comparing buccal tablets with three

different fillers at same concentration (mannitol, spray dried lactose (SDL)

microcrystalline cellulose (MC)).

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Prior to compression, each sample of granules was screened using 300 µm sieve

and then thoroughly blended in mortar with pestle. A single punch tablet machine

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(Erweka EP-1, Germany), equipped with flat faced punches with a die diameter of 8

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mm was employed to prepare tablets with an average weight of 100 mg.
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2.3. Hardness of the Tablets
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A hardness tester (Pharma Test Type PTB301, Germany) was used to measure the

crushing strength of tablets. Ten tablets from each lot were analysed. The mean
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hardness was calculated and expressed in Newton (N±S.D.).

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2.4. Swelling Studies of Buccal Tablets

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Buccal tablets were weighed individually; initial weight was recorded (W1) and placed

separately in Petri dishes containing 15 ml of artificial saliva fluid (1.491 g KCl, 0.015 g
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MgCl2·6H2O, 0.06 g CaCl2·2H2O, 0.005 g NaF, 0.108 g NaH2PO4, 0.124 g Na2HPO4

and 1.157 g NaCl per liter of distilled water, pH adjusted to 6.75 with phosphoric acid)

[13]. At regular intervals (1, 2, 3, 4, 5, 6, 7 and 8 h), the buccal tablets were removed

from the petri dishes using cover slips and excess surface water was removed carefully

using the Whatman filter paper. Then, the swollen tablets were reweighed (W2). This
experiment was performed in triplicate. The swelling index (water uptake) was

calculated according to the following equation [14]:

Swelling Index = (W2 -W1)/W1 (1)

2.5. In Vitro Drug Release of Buccal Tablets

The USP rotating paddle (Apparatus II) (Caleva 7, UK) method was used to study the

drug release from the buccal tablets. The dissolution medium consisted of 900 ml of

artificial saliva. The experiment was performed at 37±0.2°C, with a rotation speed of 50

t
rpm. Tablet was placed at the bottom of the dissolution vessel (n=6). Samples (2 ml)

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were withdrawn at predetermined time intervals and equivalent amount was replaced

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with fresh medium. The samples were filtered through Whatman filter paper (0.2 μm)

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and analysed after appropriate dilution by UV spectrophotometer at 260 nm.
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2.6. Modelling of Drug Release
Mathematical modelling of dissolution profiles was performed using DD Solver™
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software (China) [15]. The Korsmeyer - Peppas model, which is a widely used model
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for the kinetic analysis of diffusion-controlled release systems was used to evaluate the

drug release characterization of the prepared matrix buccal tablets [16]. Relationship
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between drug diffusion from the matrix tablet and dissolution time was analysed
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through the following equation:

Mt /M∞ =k·t n (2)

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Where Mt /M∞ is the fraction of drug release, k release rate constant, n the

diffusional release exponent indicative of drug release mechanism, and t the dissolution

time. Dissolution data of the study (Mt/M∞≤0.6) was correlated linearly.

2.7. Mucoadhesion Studies
Mucoadhesion studies of designed formulations (n=6) were carried out using modified

texture analyser (Tinius Olsen, USA). Freshly excised bovine buccal mucosa was

obtained from the local slaughterhouse. The tissue was placed in Krebs buffer solution

and stored at 4 °C till further usage. The thawed mucosal tissue was held using clips on

a holder immersed in simulated salivary fluid maintained at 37 °C. Thus the fluid is just

in contact with the surface of the mucosal tissue. The buccal tablet was attached to the

probe using cyanoacrylate adhesive. The probe was lowered until the tablet contacted

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mucosal tissue. A constant force was applied for 30 s, after which the probe was

withdrawn at a speed of 50 mm/min and resulting peak detachment force was noticed.

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2.8. Experimental Design
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Statistical software, Design Expert Version 7.0.0, was used to perform the 32 factorial
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design analysis. Quadratic regression modelling with backward elimination (i.e.,
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successive removal of model terms until all remaining terms in the final model have F

values above a set target F value), 2FI and linear modelling were employed for
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calculating the main effects and significant interactions for the two independent

variables. The target F value for model significance was 4 which is equivalent to a
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probability P value of 0.05 used in at test (+ Table 1-2) [17].

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2.9. Statistical Analysis

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All data was expressed as the mean value ± S.D. Mean values were compared for

statistical significance at the 5% level using Student’s t-test and ANOVA.

3. Results and discussion

3.1. Effect of CH
The hardness of indomethacin admixed with different ratios of CH is shown in Fig. 1A.

The experimental data described in Fig. 1A allow the perception of different hardness in

indomethacin admixtures containing different proportions of CH. The hardness of

buccal tablets increased with the increasing proportions of CH (p<0.05). This can be

described by a difference in hardness between MAN and CH in given ratios [18].

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Fig. 1B shows the direct correlation between increased ratios of CH within the

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buccal tablet and the effect on maximum swelling index. Formulation without CH (0 %

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CH) exhibited the nearly no swelling (0.008 ± 0.001 at 1h). Increasing CH ratio within

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the buccal tablet increased the swelling index as it was seen in the case of formulations

(7.5 % CH) and (15 % CH) with maximum swelling index at 2.40 ± 0.22 (3 h) and 4.43
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± 0.79 (8 h), respectively. This could be related to the presence of a higher amount of
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CH within the network structure with a major number of pendant groups. These groups

ionize, and time dependent increased ionization can cause enhanced electrostatic
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repulsions [19]. However, the ionization of CH is low in given pH (pH 6.75) which

explains the low swelling index when compared with PAA (P<0.05).
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In ionic cross-linked hydrogels, erosion of the network structure is prevented by

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ionic interactions, which exist between polymer chains [20]. These labile bonds can be
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broken in simulated saliva as a result of electrostatic repulsions. The erosion profile of

the hydrogel was taken as the time point after the highest swelling index was observed.

At lower CH concentrations, the greater rate of erosion was observed.

In Fig. 1C is shown the indomethacin release from buccal tablets with different

ratios of CH. All formulations present an initial burst release effect which may be

attributed to the diffusion of the drug caused by rapid gel swelling and erosion, also the
release of drug adsorbed towards the surface of the gel matrix [21]. The rate of

indomethacin dissolution from the CH buccal tablets was slower than the tablet without

CH tested at pH 6.75 (Fig. 1C). In addition, the rate of drug dissolution from the CH

matrix tablet in simulated saliva at low concentration was faster than the highest CH

concentration. This might be due to the gel forming ability of CH, which retards the rate

of drug release from the tablet. It was reported that the rapid rate of drug dissolution

from the CH tablet was due to the low gel formation ability and fast disintegration

characteristics of CH at neutral pH [22, 23].

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In Table 2 is shown that indomethacin buccal tablets contain various ratios of

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CH presented an anomalous (non-Fickian) release with n values between 0.65–0.91.

The kinetic parameters obtained here may suggest that release of indomethacin from

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CH matrix was controlled by a combination of diffusion and erosion of the polyionic
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complex [24].

The peak detachment force results obtained with various CH concentrations

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support previous findings about its weak and short lasting bioadhesion [25]. CH is a
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cationic polymer and its mucoadhesion is primarily driven by ionic interactions with

anionic mucus layer substructures [26]. Tablets containing different concentrations of

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CH underwent minimal swelling in simulated saliva (pH 6.75) and detached from the
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mucosa without a significant change (P>0.05) (Fig. 1D).

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3.2. Effect of PAA

It was shown that PAA forms tablets with higher hardness than the other excipients

(CH, HPMC and fillers) used in buccal tablet formulations. As can be observed in Fig.

2A, increasing proportions of PAA produce buccal tablets with an increasing tablet

hardness (P<0.05). This significant increase in hardness can be attributed to the high

binding capacity of PAA [18].

 The swelling index obtained for PAA with different ratios indicated high

swelling property of this polymer both at 5 % and 10 % ratios in artificial saliva (Fig.

2B). After 8 h of experiments, the swelling index values of indomethacin buccal tablets

ranged from about 3.85 ± 0.05 (5 % PAA) to 7.67 ± 0.21 (10 % PAA) and significantly

lower values were obtained for buccal tablets without PAA (0.008 ± 0.001) (P<0.05).

Higher values of swelling index for higher PAA containing indomethacin buccal tablets

in contact with simulated saliva were determined. The swelling of PAA is related to the

uncharged –COOH group which get hydrated by forming hydrogen bonds with the

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imbibing water thus extending the polymer chain [27]. Buccal tablets without PAA

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exhibited a lower swelling and higher erosion, because PAA is a highly cross-linked

polymer and when contacted with water, it would swell and hold water inside its gel

network structure [28].

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PAA, compared with other excipients in buccal tablets, showed a drug release of

39.01 % ± 2.30 (5 % PAA) and 27.51 % ± 5.05 (10 % PAA) at the end of 12 h, which
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exhibited clearly the most retarded effect on the in vitro dissolution of indomethacin
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buccal tablets (Fig. 1C). This can be related with noticeably slow release rate linked

with the required induction time of PAA before dissolution [29]. It has been reported
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that increase in the percentage of PAA results to a reduction in the drug release rate
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[30]. The increase in the ratio of polymer causes a higher cross-linking of the polymer

side chains, which reduces the viscosity and improves the gel forming, which prevents
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the diffusion of the drug through the gel [31]. Furthermore, the slow drug release from

buccal tablets may be due to the slow erosion of the outer gel layer of PAA-containing

matrices, which subsequently improved the diffusional path length for the indomethacin

with time, thus reducing the dissolution [32].

 Increasing the amount of PAA in the formulations resulted in a decrease in the

drug release rate and a linearization of the release curve, leading to a shift from

anomalous type of release towards a swelling and erosion controlled, case II transport

mechanism (Table 3). This might be owed to a decrease in regions of low micro

viscosity and the closing of micropores in the swollen buccal tablets [30].

As is shown in Fig. 2D the ex vivo peak detachment force was increased linearly

with increasing concentration of PAA after contact with bovine buccal mucosa. The

peak detachment force of buccal tablets with different PAA concentrations varied from

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0.04 ± 0.01 N (0 % PAA) to 0.17 ± 0.04 N (5 % PAA) and 0.33 ± 0.04 N (10 % PAA)

(Fig. 2D) and had a good correlation coefficient (r2 = 0.9964). The high mucoadhesive

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strength can be owing to the strong gel formation which penetrates deeply into the

mucin molecules [33].

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3.3. Effect of CH and PAA mixture
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The greater hardness of PAA over that of CH observed in Figure 1 and 2 is maintained

after combination of the two polymers, although the difference in combination is lesser.
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This can be observed in Supplementary Fig. 1. As can be seen in the figure, the effect of

the polymer ratio on the buccal tablet hardness of indomethacin tablets can be described
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with a quadratic relationship (Supplementary Table 2). Buccal tablets containing 10 %

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CH exhibit a tablet hardness of 81 ± 21 N, 100 ± 27 N and 91 ± 17 N at a PAA

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proportion of 5%, 10% and 15%, respectively (Supplementary Table 1). The hardness

of buccal tablets decreases when ratio of CH increased. Conversely, indomethacin

buccal tablets containing both PAA and CH displayed an increase in hardness with the

increase in the percentage of the PAA. Similar results were obtained by Aguilar-Lopez

et al [18]. The equation obtained from the mathematical fitting was:

Hardness (N) = 75.00 - 3.06 * CH + 8.76 * PAA - 0.36 * PAA2 (3)

 The maximum swelling index was greatly increased by the increasing ratios of

PAA (Supplementary Fig. 2). However, increased CH ratios showed distinct swelling

index changes at different PAA concentrations. The presence of a PAA (polymer with a

high molecular weight) in the matrix tablet could assist in facilitating the initial

hydrogel hydration by creating an osmotic gradient. And the existence of PAA within

the buccal tablets could assist the protonation of amine groups from CH producing an

electrostatic repulsion between polymeric chains [20]. The equation obtained from the

mathematical fitting was:

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Swelling Index =2.14889 + 0.17667 * CH +0.60050 * PAA - 0.013900 * CH * PAA

cr
(4)

The rate of indomethacin release from the buccal tablets decreased as the ratio of

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PAA increased (dissolution curves not shown) (Supplementary Fig. 3). For all buccal
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tablet formulations, where the ratio of hydrophilic PAA varied between 5 and 15% of

the overall buccal tablet weight, the release of indomethacin was linearly decreased with
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the increase of PAA percentages. When PAA took 15 % of the buccal tablet weight,
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drug dissolution was significantly reduced from 21.70 % ± 1.46, 33.00 % ± 2.28 and

30.42 % ± 2.82 to 16.28 % ± 1.44 , 13.00 % ± 1.89 and 28.21 % ± 2.41 at 12 h,

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respectively. Thus indicating a slower water penetration into the buccal tablet matrix as
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well as a longer indomethacin diffusion from the resultant exterior hydrogel layer

(Supplementary Table 1) [34]. For tablets containing CH and PAA polymer mixture, in
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which the ratio of non-swellable CH varied, changes in CH ratio increased the drug

dissolution (Supplementary Table 2). This might have been attributed to the presence of

an erodible excipient that contributed conversely to the formation of hydrogel layer by

PAA hydration [20]. The equation obtained from the mathematical fitting was:

Drug Release at 12 h (%) = 15.31389 + 1.10500 * CH - 0.92100 * PAA (5)

 However, for total polymer ratios higher than 20 %, it has been shown that

differences in the PAA and CH concentrations do not cause vital variations in the

release of the indomethacin, which highlights the importance of the total polymer ratio

as shown in different studies [31].

Supplementary Fig. 4 shows the diffusional release exponent “n” parameter

according to Korsmeyer-Peppas equation which indicates the drug dissolution

mechanism. The diffusional release exponent of buccal tablets were well correlated with

the changes in ratio of PAA present in the buccal tablet. Hydrophilic polymer produced

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a hydrogel layer upon in contact with water; drug dissolution observed a combination of

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diffusion and dissolution, with predominant in drug diffusion [34]. For buccal tablet

formulations containing various ratios of PAA in PAA and CH polymer mixture, the

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diffusional release exponent followed a quadratic pattern between 5 and 15 % of PAA.
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However, increased percentage of CH would result in more matrix erosion than polymer

hydration, subsequently facilitating higher the diffusional release exponents and

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dissolution. According to Korsmeyer-Peppas equation, the value of diffusional release

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exponent n dictates drug dissolution mechanism. Drug release in super case II transport,

case II transport and anomalous (non-Fickian) diffusion is represented by n>1, n=1 and
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0.5 <n< 1, respectively. The n values from the test formulations ranged 0.66–1.31,
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indicating that all of these diffusion mechanisms were observed in prepared buccal

tablet formulations. For buccal tablets containing low CH (10 and 15 %) and PAA (5
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%) concentrations, where n was between 0.5 and 1.0, the release mechanism was

categorized by anomalous (non-Fickian) transport where both diffusion and erosion

were taking place. For (10 % CH and 10 % PAA), (10 % CH and 15 % PAA) and (15 %

CH and 10 % PAA) formulations, where n was close to 1.0, the release mechanism was

characterized by case II transport, indicating that drug release was controlled by

erosion. For the other buccal tablet formulations, indomethacin release was controlled

by super case II transport (erosion), with n> 1.0. The higher n value shows a greater role

of tablet erosion in matrices [24]. The equation obtained from the mathematical fitting

was:

n value = - 0.62833 + 0.045000 * CH + 0.21867 * PAA - 0.010533 * PAA2 (6)

The drug can be released from a swellable hydrogel through diffusion,

degradation or both depending on the level of swelling and the solubility of the drug.

The degradation will be a primary mechanism for the release of water-insoluble drugs

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[35]. One another possible explanation of the high diffusional release exponent values

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which indicates that the drug release from the formulations are mainly driven by erosion

of the matrices (case II and super case II transport) may be the result of our model drug

indomethacin is insoluble in water.

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Supplementary Fig. 5 shows that the ex vivo peak detachment force was

increased with increasing concentration of PAA and CH after contact with bovine
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buccal mucosa. The increase in mucoadhesivity may be due to the formation of a strong
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gel that penetrates deeply into the mucin molecules [33]. The ex vivo mucoadhesive

strength after contact with bovine buccal mucosa varied from 0.14 ± 0.01 N (10 % CH
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and 5 % PAA) to 0.79 ± 0.03 N (20 % CH and 15 % PAA) (Supplementary Table 1).
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The results also indicate that the effect of PAA was more significant than the effect of

CH. The equation obtained from the mathematical fitting was:

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Peak Detachment Force (N) = 0.081111 + 0.039667 * CH - 0.070333 * PAA +0.0004 *

CH * PAA – 0.00126667 * CH2 + 0.00593333 * PAA2 (7)

3.4. Effect of HPMC

Fig. 3A and 3B show the effect of HPMC on hardness of CH/PAA containing tablets

and buccal tablets without polymer. While buccal tablets without a polymer content
display a significant increase in hardness (from 22 ± 6 N to 55 ± 12 N), after inclusion

of 20 % HPMC (P<0.05) (Fig. 3B), tablets with a total polymer content of 25 % do not

display an increase in hardness after inclusion of 10 % and 20 % HPMC (p>0.05) (Fig.

3A). The addition of PAA and CH admixture increased indomethacin buccal tablet

hardness in the same way as does the HPMC, although less hardness increase per unit of

percentage of added polymer mixture may be the reason of the non-significant change

[18].

HPMC is the most commonly used excipient as a drug release retardant in

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hydrophilic matrices [31]. Rate of swelling was calculated from swelling index of the

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polymer system. Fig. 3E shows that maximum swelling index of 0.01 ± 0.001 was

found for 20 % HPMC addition while a value of 0.008 ± 0.001 was found for buccal

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tablets without a polymer (P>0.05). Furthermore, for tablets with a total polymer
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content of 25 %, the swelling index of 10 % and 20 % HPMC addition did not differ

significantly (9.69 ± 0.38 and 9.88 ± 0.14, respectively) when 0 % HPMC has shown a
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value of 9.93 ± 0.31 at 8 h (P>0.05). It is proven that the rate of hydration and erosion
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of tablet was dependent on the polymer combination used and in the case of the

manufacture of hydrophilic matrices by direct compression, it is important to take into

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account the high compression rates of HPMC tablets afford matrices that have less
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resistance to breakage that leads the improve porosity of tablet [31].

Some researchers have shown that either HPMC or HPMC/polymer

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combinations affords zero-order, or at least time-independent, release kinetics. Based on

this, we have performed studies comparing the effect of HPMC on buccal tablets either

with or without another polymers as excipients, observing differences in the release of

the indomethacin assayed (Fig 3F and Fig. 3G). The presence of PAA/CH combination

appears to decrease the overall indomethacin release rate from the HPMC buccal tablets
(Fig. 3F). However, the difference in drug release is not significant among different

concentrations of HPMC (10% and 20 %). When HPMC is used with another polymer

which is used to modify the release such as PAA, the interactions established between

the HPMC and PAA and more ionized insoluble polymer complex forms and this delay

the release of drug from buccal tablet [31].

The release profile obtained for only HPMC containing buccal tablet is faster

than polymer mixture, the former Fickian or diffusion kinetics and the latter zero order

and super case II transport kinetics (Table 4) [36]. The differences observed for the two

t
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buccal tablet types in the release profiles can be explained in terms of the hydration

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properties: PAA hydrates faster than HPMC [31]. When the effect of HPMC

concentration on buccal tablets with 25 % polymer mixture was investigated, it is found

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that the values of n ranged 0.96 to 1.19 can be called as case II transport type release
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(n=1) and super case II transport type release (n>1). This indicates that the predominant

mode of drug release was erosion through the swollen polymer matrix and partially
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diffusion based.
ed

Buccal tablets with only HPMC showed comparatively poor mucoadhesion

(0.04 ± 0.01 N) and the effect of HPMC on mucoadhesion of buccal tablet was not
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significant (P>0.05) (Fig. 3D). However, when it was used in combination with PAA,
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its overall mucoadhesion was increased (Fig. 3C). The presence of HPMC in the

polymer complex in buccal tablets has shown high peak detachment force (0.72 ± 0.04
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N and 0.56 ± 0.13 N). Peak detachment force was varied with the increasing HPMC

concentrations (P<0.05). The maximum peak detachment force was considered to be

dependent on the formation of hydrogen bonds between the functional groups of the

HPMC/PAA polymer system and the mucus [36].

3.5. Effect of filler type
In the formulation of buccal tablets it is necessary to have excipients that increase the

flow and compressibility properties of the final blend formed by the drug and the

polymer. The physicochemical characteristics of the fillers present in the buccal tablets

can modify the drug release rate and mechanisms [31]. In order to show the effect of

fillers on buccal tablet formulation, MAN, MC and SDL was compared.

The hardness of buccal tablets described in Fig. 4A shows an average for MAN

containing buccal tablets of 78 ± 11 N. This value can be taken as reference for the

t
ip
binding ability of the polymer. This ability is about lower that exhibited by MC

admixtures (49 ± 8 N) (P<0.05). However, the use of MAN or SDL did not change the

cr
hardness of buccal tablets (78 ± 11 N and 74 ± 11 N, respectively) (P>0.05). Similar

us
studies have shown that lactose based mixtures were smaller from mannitol based
an
mixtures, the compacted ribbons shows similar solid fractions and tensile strength [17].

In Fig. 4B is shown the swelling index of buccal tablets in 8 h. The studies

M

showed that all the formulations contain the same proportion of polymers displayed

similar swelling behaviour. Furthermore, an increasingly linear swelling behaviour was

ed

exhibited in case of formulations with MAN. This behaviour is due to the fact that
pt

polymers are the ones who predominate the swelling of the buccal tablets [30].
ce

As shown in Fig. 4C the buccal tablets containing MC, as filler, exhibited faster

release rates at extended dissolution time periods (12 h), as compared to the same type
Ac

of formulations with respective drug-to-polymer ratios but without MC, as well as those

contain MAN and SDL. The faster drug release (Fig. 4C) observed with MC is because

of its inherent disintegrant properties, immediate disintegration of the tablets in the

dissolution medium, and quick release of the indomethacin from the buccal tablets [30].

These results are in agreement with those observed by some other investigators where
rapid release rates of water-insoluble drugs, from the formulations containing MC as

filler were observed [37].

For buccal tablets formulated with the same polymer compositions, studies have

been conducted to assess the impact of fillers at approximately 50%. For all buccal

tablet formulations, dissolution of indomethacin followed drug release (Table 5) is

represented by n = 1.01, 0.99, and 1.02, respectively. The n values from the tablet

formulations indicating a case II transport release mechanism.

The effect of diluent type on mucoadhesion was also evaluated. It was found that

t
ip
the buccal tablets containing MAN (0.33 ± 0.09 N), MC (0.31 ± 0.16 N) and SDL (0.31

cr
± 0.12 N) demonstrated no significant effect on the bioadhesiveness (P>0.05) (Fig. 4D).

4. Conclusion

us
When in contact with water, hydrophilic PAA polymer allow gradual hydration of the
an
buccal tablet matrix, leading to modified dissolution and diffusion of the water insoluble

indomethacin from within the swelling matrix. CH is insoluble in simulated saliva at

M

given pH (6.75). When these two polymers incorporated in the buccal tablet, they do not
ed

only affect the important tableting properties, but also help in controlling the drug

release. Especially, when PAA took 15 % of the buccal tablet weight, drug dissolution
pt

was significantly reduced from 21.70 % ± 1.46, 33.00 % ± 2.28 and 30.42 % ± 2.82 to
ce

16.28 % ± 1.44 , 13.00 % ± 1.89 and 28.21 % ± 2.41 at 12 h, respectively. Combined

use of PAA and CH in this study enabled the preparation of modified release matrix
Ac

buccal tablets with satisfactory swelling, drug release and bioadhesion properties and

direct compressibility of the mixtures. Furthermore, addition or changing the ratio of the

HPMC affected the tablet characteristics. However, for tablets with a total polymer

content of 25 %, the swelling index of 10 % and 20 % HPMC addition did not differ

significantly (9.69 ± 0.38 and 9.88 ± 0.14, respectively) when 0 % HPMC has shown a
value of 9.93 ± 0.31 at 8 h (P>0.05). Among the prepared formulations tested in the

study, PAA ranged between 5 and 15 % of the total tablet weight while CH was

incorporated between 10 and 20 % of the total buccal tablet weight. The diluent present

in all study samples, MAN, SDL and MC, were believed to contribute minimally to

hydrogel formation and drug release regulation. They were used primarily as tablet

fillers to achieve required identical tablet weight.

Declaration of interest

The authors report no conflicts of interest. The authors are only responsible for the

t
ip
content and writing of this article.

cr
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us
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Figure 1. Effect of CH ratio on (A) hardness, (B) swelling index, (C) indomethacin
release and (D) peak detachment force of buccal tablets (mean ± SD), (*formulation
versus 0% CH (P<0.05)).

t
ip
cr
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Figure 2. Effect of PAA ratio on (A) hardness, (B) swelling index, (C) indomethacin
an
release and (D) peak detachment force of buccal tablets (mean ± SD), (*formulation
M

versus other formulations (P<0.05)).

ed
pt
ce
Ac
Figure 3. Effect of HPMC ratio on (A) hardness (with PAA and CH), (B) hardness

(without PAA and CH, (C) peak detachment force (with PAA and CH), (D) peak

detachment force (without PAA and CH), (E) swelling index, (F) indomethacin release

of buccal tablets (with PAA and CH) and (G) indomethacin release of buccal tablets

(without PAA and CH) (mean ± SD), (*formulation versus other formulations

(P<0.05)).

t
ip
cr
us
an
M
ed
pt
ce
Ac
Figure 4. Effect of filler type on (A) hardness, (B) swelling index, (C) indomethacin

release and (D) peak detachment force of buccal tablets (mean ± SD), (*formulation

versus MAN (P<0.05)).

t
ip
cr
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ed
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Table 1. Contents of indomethacin buccal tablet batches (amounts of all components are
given in percentages) (-1, 0 and +1 show the low, mid and high levels of the factors)
Formulation Code IND CH PAA HPMC MAN MC SDL SUC CSD
Tablets containing CH
% 0 CH 25 0 0 0 73.6 0 0 0.4 1
% 7.5 CH 25 7.5 0 0 66.1 0 0 0.4 1
% 15 CH 25 15 0 0 58.6 0 0 0.4 1
Tablets containing PAA
% 0 PAA 25 0 0 0 73.6 0 0 0.4 1
% 5 PAA 25 0 5 0 68.6 0 0 0.4 1

t
% 10 PAA 25 0 10 0 63.6 0 0 0.4 1

ip
Tablets containing PAA and CH mixture

cr
-1, -1 25 10 5 20 38.6 0 0 0.4 1
-1, 0 25 10 10 20 33.6 0 0 0.4 1
-1, +1
0, -1
25
25
10
15
15
5
20
20 us
28.6
33.6
0
0
0
0
0.4
0.4
1
1
an
0, 0 25 15 10 20 28.6 0 0 0.4 1
0, +1 25 15 15 20 23.6 0 0 0.4 1
M

+1, -1 25 20 5 20 28.6 0 0 0.4 1

+1, 0 25 20 10 20 23.6 0 0 0.4 1
ed

+1, +1 25 20 15 20 18.6 0 0 0.4 1

Tablets containing HPMC (without PAA and CH)
pt

% 0 HPMC 25 0 0 0 73.6 0 0 0.4 1

% 20 HPMC 25 0 0 20 53.6 0 0 0.4 1
ce

Tablets containing HPMC (with PAA and CH)

% 0 HPMC 25 15 10 0 48.6 0 0 0.4 1
Ac

% 10 HPMC 25 15 10 10 38.6 0 0 0.4 1

% 20 HPMC 25 15 10 20 28.6 0 0 0.4 1
Tablets containing Different Fillers
MAN 25 15 10 0 48.6 0 0 0.4 1
MC 25 15 10 0 0 48.6 0 0.4 1
SDL 25 15 10 0 0 0 48.6 0.4 1
IND: Indomethacin, SUC: Sucralose, CSD: Colloidal Silicon Dioxide
Table 2. Effect of CH ratio on Drug Release Kinetic of Buccal Tablets (k: release rate
constant, n: the diffusional release exponent indicative of drug release mechanism and
r2: the coefficient of determination)
k n r2 Mechanism
0 % CH 7.23 0.65 0.97 Anomalous
7.5 % CH 1.04 0.76 0.98 Anomalous
15 % CH 2.48 0.91 0.94 Anomalous

t
Table 3. Effect of PAA ratio on Drug Release Kinetic of Buccal Tablets (k: release rate

ip
constant, n: the diffusional release exponent indicative of drug release mechanism and

cr
r2: the coefficient of determination)
k n r2 Mechanism
0 % PAA
5 % PAA
7.23
0.08
0.65
0.95
0.97
0.97 us
Anomalous
Case II Transport
an
10 % PAA 0.04 0.94 0.97 Case II Transport
M
ed

Table 4. Effect of HPMC ratio on Drug Release Kinetic of Buccal Tablets (k: release
rate constant, n: the diffusional release exponent indicative of drug release mechanism
and r2: the coefficient of determination)
pt

k n r2 Mechanism
ce

Effect of HPMC (without PAA and CH)

0 % HPMC 7.23 0.65 0.97 Anomalous
Ac

20 % HPMC 3.40 0.49 0.97 Fickian Diffusion

Effect of HPMC (with PAA and CH)
0 % HPMC 0.00 1.01 0.95 Case II Transport
10 % HPMC 0.03 0.96 1.00 Case II Transport
20 % HPMC 0.05 1.19 0.97 Super Case II Transport