Hydrophilic Matrices Geometry, Swelling and Erosion Investigations to Clarify the Release Mechanism

Rajendra Kotadiya^*,1, Vishnu Patel² and Harsha Patel¹

¹Indukaka Ipcowala College of Pharmacy, New V. V. Nagar, Anand, Gujarat

²A. R. College of Pharmacy, V. V. Nagar, Anand, Gujarat

ABSTRACT

Aim of present work is to study the effect of viscosity and geometry of tablets on swelling, erosion and drug release behavior of matrix tablets of theophylline, a model drug, using natural gums viz. Chitosan [F5], Xanthan [F3], Locust bean gum [F4] and Guar gum [F2] and hydroxypropyl methylcellulose [F1]. Matrix tablets were produced by wet granulation method. The physical characteristics of tablets including geometry of tablets, the swelling and erosion behavior of tablets were studied and the results were correlates with the in vitro drug release. Drug release was proportional to surface area/volume ratio and it was similar for similar surface area/volume ratio. The formulation F5 containing chitosan starts erosion immediately when contacted with dissolution medium and eroded within 5 minutes. Based on the degree of swelling, the formulations arranged as F4>F2>F3>F1 and as per the erosion study the formulations were arrange as F1>F3>F2>F4. These may attributes to polymer viscosities because the formulation F2 (240cp) and F4 (250cp) which showed higher degree of swelling and lower rates of erosion compare to formulation F3 (150cp) and F1 (107cp). Thus, the effect of viscosity and geometry on swelling and erosion behavior of matrix tablets was profound and thus they are significant parameters to study out for the formulation of matrix tablets.

KEYWORDS: Natural gum • swelling • erosion • geometry of tablet

INTRODUCTION

Hydrophilic polymers have attracted considerable attention in recent years as sustained and controlled release devices for the delivery of water-soluble and water-insoluble agents.¹ Drug release from hydrophilic matrix tablets can be strongly influenced by the proportion of matrix forming polymer, their swelling and the geometry of the tablets.

Drug release from hydrophilic matrices is known to be a complex interaction involving swelling, diffusion and erosion mechanisms.^2-6 Upon contact with the gastrointestinal fluid, a polymer swells, gels, and finally dissolves slowly. The gel becomes a viscous layer acting as a protective barrier to both the influx of water and the efflux of the drug in solution.⁷ The mechanism of drug release from hydrophilic polymeric matrices involves solvent penetration, hydration and swelling of the polymer, diffusion of the dissolved drug in the matrix, and erosion of the gel layer. Initially, the diffusion coefficient of drug in the dehydrated polymer matrix is low; it increases significantly as the polymer matrix imbibes more and more water and forms a gel, as time progresses.⁸ Their characteristics and their ability to hydrate and form a gel layer are well known and are essential to sustain and control drug release from matrices.⁹ The hydrated gel layer thickness determines the diffusion path of the drug molecules through the polymer mass into the dissolution medium.¹⁰ The hydration rate of the polymer matrix, and thereby the gel formation and subsequent erosion, depends significantly on polymer proportion, viscosity, and to a lesser degree on polymer particle size ¹¹.

So swelling and erosion studies were performed according to the method reported by Al-Taani and Tashtoush¹² to understand the influence of swelling and erosion behavior on drug release and also to determine the effect of polymer viscosity on swelling and erosion and subsequently on drug release. Narasimhan and Peppas¹³showed that the dissolution can be either disentanglement or diffusion controlled depending on the molecular weight and thickness of the diffusion boundary layer. The rate of polymer swelling and dissolution as well as the corresponding rate of drug release are found to increase with either higher levels of drug loading or with use of lower viscosity grades of polymers.¹⁵

Thus, the viscosity of polymers plays a vital role in achieving the desired release rate. The higher the viscosity, the more will be the resistant offered by matrix to dissolution and erosion. Thus, viscosity of a polymer gel is a rate-controlling factor in drug dissolution. A number of natural and semi synthetic polymers, such as Xanthan gum, Guar gum, Locust bean gum, Chitosan and Hypromellose (HPMC) have been shown to be useful for controlled release due to their hydrophilic properties.^16-17

Thus, the objectives of present investigation were to study the effect of geometry of tablets on drug release and effect of viscosity on swelling, erosion drug release behavior of matrix tablets of theophylline, a model drug, prepared by natural gums viz. Chitosan, Xanthan, Locust bean gum and Guar gum and hydroxypropyl methylcellulose.

MATERIALS AND METHODS:

Materials:

Theophylline: Lifeline Industries Limited, Mumbai

Guar gum: Dabur Research Foundation, New Delhi, India

Xanthan gum: Lucid colloids, Mumbai

Locust bean gum: Lucid colloids, Mumbai

Chitosan: Central Fisheries Technology, Cochi

HPMC: Loba Chemie Pvt. Ltd., Mumbai

Others: S.D. Fine-chem Ltd. Mumbai

Table 1 Formulations

Name of the component	Quantity per tablet (mg)
Name of the component	F1	F2	F3	F4	F5
Drug	150	150	150	150	150
HPMC K15	150	--	--	--	--
GG	--	150	--	--	--
XG	--	--	150	--	--
LBG	--	--	--	150	--
Chitosan	--	--	--	--	150
IPA	qs	qs	qs	qs	qs
PVP K 30	60	60	60	60	60
Magnesium stearate	5	5	5	5	5
Talc	5	5	5	5	5
MCC	qs to 500	qs to 500	qs to 500	qs to 500	qs to 500

Note: qs: quantity sufficient, HPMC K15: Hydroxypropyl methyl cellulose of K15 viscosity grade, PVP K 30: Polyvinyl pyrrolidone of K 30 viscosity grade, GG: Guar gum, XG: Xanthan gum, LBG: Locust bean gum, IPA: Iso propyl alcohol, MCC: Microcrystalline cellulose.

Viscosity Determination:

Viscosities of natural gums and HPMC in phosphate buffer pH 7.4 at 37 °C (1% wt/vol) were determined at constant ionic strength using Brookfield’s viscometer (Brookfield ENG, Labs Inc, Stoughton, MA)

Figure 1 Photographic images of swelling study (after 1h, except F5 which disintegrates within 5 min)

Chitosan (F5)

Guar gum (F2)

HPMC (F1)

Locust Bean gum (F4)

Xanthan gum (F3)

Preparation of Sustained Release Matrix Tablet:

Matrix tablets were prepared by non aqueous wet granulation method. The composition of various formulations is given in Table 1. Theophylline and polymer were mixed in a polybag, and the mixture was passed through mesh no. 60. Granulation was done using a solution of PVP K30 in sufficient isopropyl alcohol by using Micro crystalline cellulose as diluent. The wet mass was passed through mesh no. 8. The wet granules were air dried for ~2 h. The granules were then sized by mesh no. 16 and mixed with magnesium stearate and talc. Tablets were compressed at 500 mg weight on a 10-station mini rotary tableting machine (General Machinery Co, Mumbai, India) with 12-mm punches. Five different formulas, having different polymers viz. guar gum, xanthan gum, chitosan, locust bean gum and HPMC, were developed to evaluate the drug release and to study the effect of different polymer on drug release.

Figure 2 Swelling study

Characterization of Tablets:

The properties of the compressed matrix tablet, such as hardness, friability, weight variation, and content uniformity were determined using reported procedure.¹⁴ Briefly, hardness was determined by using Monsanto hardness tester. Friability was determined using Roche friability testing apparatus. Weight variation and uniformity of drug content were performed according to the IP procedures.¹⁷ Content uniformity was determined by weighing 10 tablets individually, and the drug was extracted in water.¹⁸

Geometry of Tablets

Surface area and volume of the prepared tablets were determined to study the effect of these geometrical parameters on the drug release study.

Surface area of tablets = 2Πr (r+h)

Volume of the tablets= Πr²h

Where,

r- Radius of flat faced round tablets

h- Band thickness (Edge thickness)

Swelling and Erosion Study

Measurements of hydration and erosion rates of the formulations were carried out, after the immersion of the tablets in the test medium, to correlate the observed drug release phenomena with the rates of polymer hydration. Weighed tablets were placed in the USP XXIV dissolution apparatus II (Tab-Machines, Mumbai, India) at 50 rpm containing dissolution medium of phosphate buffer pH 7.4 at 37 ± 0.5°C. After 1, 2, 3, 4, 5, and 6 h, tablets were withdrawn, blotted to remove excess water and weighed on an analytical balance (Shinko Sansui, Japan). The wet tablets were then dried in an oven at 110–120°C for 24 h, allowed to cool in a dessicator and finally weighed until constant weight was achieved (final dry weight). The experiment was performed in triplicate for each time point and fresh samples were used for each individual time point. The increase in weight due to absorbed liquid (Q) was estimated at each time point from the following equation1:

Where, Ww is the mass of the hydrated sample before drying and Wf the final weight of the same dried and partially eroded sample. The percentage erosion (E) was estimated from the following equation 2:

where, Wi is the initial dry sample weight.

Dissolution Studies:

Determination of theophylline release from different formulated tablets was performed using USP XXIV dissolution apparatus II (Tab-Machines, Mumbai, India) at 50 rpm. Dissolution was tested either in 900 mL simulated gastric fluid (without pepsin) at pH 1.2 for the first 2 h followed by dissolution in simulated intestinal fluid (without enzymes) at pH 7.4 for the remained six hours at 37 ± 0.5 °C. Drug release was monitored at 272 nm as a function of time using a diode array UV visible spectrophotometer (Hewlett-Packard, Agilent Technologies, New Delhi, India).

Figure 3 Erosion study

RESULTS AND DISCUSSION:

The viscosity study showed that LBG and Guar gum are having similar viscosities of 250 cp and 240 cp, respectively compare to Xanthan gum and HPMC of 152 cp and 107 cp, respectively.

The weight variation, friability, hardness and content uniformity were found to be within acceptable limits as per Indian Pharmacopoeia. The weight variation and friability were less than 5% and 0.5%, respectively with hardness in the range of 4-6 kg/sq. cm. Good uniformity in drug content was found among different formulations with the range of 95-110%.

The geometry of the tablet (Radius, Thickness, Volume, Surface area and Surface Area/Volume) was found to affect the drug release pattern from the matrix tablets. The geometry of the tablets was depicted in Table 1and correlate with drug release pattern.

Table 2 Geometry of matrix tablets

Formulations	Diameter (mm)	Thickness (mm)	Surface area (cm²)	Volume (cm³)	SA / Volume (cm^-1)
F1	6.060	3.15	117.59	90.80	1.29
F2	6.040	3.12	116.44	89.35	1.30
F3	6.005	3.07	114.35	86.75	1.31
F4	6.005	3.07	114.35	86.75	1.31
F5	6.025	3.10	115.49	88.19	1.30

Note: n – average of three tablets were used for each parameters

It was found that formulations with increase in surface area/volume ratio (F5<F4<F3<F2<F1) the drug release was increases and formulations with similar surface area/volume ratio (F1 and F3) shows similar kind of release pattern.

The aqueous medium on contact with hydrophilic polymer matrix gradually begins to hydrate from the periphery towards the centre, forming a gelatinous swollen mass, which controls the diffusion of drug molecules through the polymeric material into aqueous medium. The hydrated gel layer thickness determines the diffusional path length of the drug. The swelling behavior indicates the rate at which this formulation absorbs water from dissolution media and swells. The change in weight is characteristic of the water uptake and swelling which started immediately and continued for 6 h.

These formulations exhibited varied degree of swelling. It was observed that formulation (F5) containing chitosan starts disintegration immediately when contacted with aqueous medium and disintegrated within 5 minutes (Fig. 1).

Remaining formulations were observed for swelling and erosion study where visual observation of remaining formulations showed that the matrices appeared swollen almost from the beginning, and a viscous gel mass was created when they came into contact with the liquid. Based on the degree of swelling, the formulations arranged starting from highest value of degree of swelling viz. F4>F2>F3>F1 (Fig. 2).

On the other hand matrix erosion study measured the weight loss from matrix tablets immersed in dissolution media as a function of time was determined. The weight loss of the tablets was study up to 6 h, which illustrates matrix erosion profiles of the formulation and indicates their inverse relationship with water uptake. It follows that the hydrated formulation network maintains its tight integrity with drug release by erosion and dissolution of the drug accounting for most of the weight loss during the remainder of the experimental period. As per the erosion study the formulations were arrange in descending order starting from higher rate to lower one viz. F1>F3>F2>F4 (Fig. 3).

In the case of F1 and F3, a rapid erosion of the hydrated layer was observed, releasing most of the drug content after 5 h.

In correlation of these results with drug release profiles of the formulations it was found rather fast drug release from tablets containing only chitosan (F5) a matrix component owing to protonation of chitosan and then erosion of tablets. The utilization of other matrix former could sustain the drug release with formulation F4 and F2 showed higher degree of swelling and lower rate of erosion with subsequent sustained release of drug. On the other hand, formulation F3 and F1 showed lower degree of swelling and higher rate of erosion with subsequent faster release of the drug (Fig. 4).

These may attributes to polymer viscosities because the formulation containing guar gum (F2) and locust bean (F4) with viscosity of 240 cp and 250 cp, respectively which showed higher degree of swelling and lower rates of erosion compare to formulation containing xanthan gum (F3) and HPMC (F1) with viscosities of 150 cp and 107 cp, respectively which showed lower degree of swelling and higher rates of erosion. The higher viscosity will have higher and faster water absorption capacities and tend to swell more rapidly and these polymers would have more gel strength than the one formed by the lower viscosity grade because of which, the erosion would be less. For these reasons the diffusional path length increased and the diffusion coefficient of the drug through the matrix decreased as the viscosity grade was increased.

CONCLUSION:

The effect of viscosity and geometry of tablets on swelling, erosion and drug release behavior of matrix tablets of theophylline using natural gums were studied. It was found that drug release was proportional to surface area/volume ratio and it was similar for similar surface area/volume ratio. It was also found that higher viscosity shows higher degree of swelling and lower rates of erosion. Thus, the effect of viscosity and geometry on swelling and erosion behavior of matrix tablets was profound and thus they are significant parameters to study out for the formulation of matrix tablets.

Figure 4 In vitro drug release study

ACKNOWLEDGMENTS:

Authors are thankful to SICART, Vallabh Vidyanagar, India for providing necessary facilities for carried out experimental work.

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