Among the different hydrophilic polymers, cellulose ether polymers are the first choice, especially hydroxypropylmethylcellulose (HPMC), which has been extensively investigated for this purpose^6,7. The drug release for extended duration, particularly for highly water-soluble drugs, using a hydrophilic matrix system is restricted because of rapid diffusion of the dissolved drug through the hydrophilic gel network⁸.

For such drugs with high water solubility, hydrophobic polymers are suitable, along with a hydrophilic matrix for developing sustained-release dosage forms. Hydrophobic polymers provide several advantages, ranging from good stability at varying pH values and moisture levels to well establish safe applications^{9, 10}. Therefore, in this study, the hydrophobic polymers like ethyl cellulose (EC), was used. Ethylcellulose (EC) has been widely used as a barrier membrane or binder, to prepare pharmaceutical oral modified release dosage forms. An aqueous ethyl cellulose dispersion as a release retardant binder for the manufacture of inert matrices has been reported.

Main objective of study is to formulate hydrophilic and hydrophobic matrix systems by polymer material to investigate the effect of both.

Ibuprofen a phenylpropionic acid derivative is established as first-line NSAID for rheumatoid arthritis and chronic arthropathies¹¹. The mechanism of action of ibuprofen involves not only inhibition of prostaglandin synthesis but also decreased production of pro-inflammatory cytokines such as interleukin 1β and tumour necrosis factor α; inhibition of leucocyte leucotriene B4 and nitric oxide; and possibly a positive effect on the production of oxyradicals and signaling transduction via the NFκB pathway ¹². In therapeutic use, ibuprofen proved to have a favourable risk: benefit ratio and predictable adverse effects ¹³. To reduce the administered dose and to improve patient convenience and compliance, a sustained release matrix tablet formulation of Ibuprofen is desirable¹⁴.Thus for patient compliance, improve bioavailability, minimize total drug quantity, minimize accumulation on chronic use and reduce fluctuation in drug level sustained release of ibuprofen is desirable.

The objective of the present study was to develop hydrophilic polymer (HPMC K4M) and hydrophobic polymer (Ethyl cellulose) based ibuprofen matrix sustained release tablets and to examine the effects of alone and in combination and find out the effects of both hydrophilic and hydrophobic polymers on in-vitro kinetics drug release study. The kinetics of the dissolution process were studied by the application of four kinetic equations to the dissolution data–namely, the zero order, the first-order, the Highuchi-square root and Korsmeyer- Peppas equations.

MATERIALS AND METHODS:

Materials:

Ibuprofen was received as gift sample from Alkem laboratories, Mumbai, India. Hydroxylpropylmethyl cellulose (Methosil®) K4M and ethyl cellulose (EC) were also obtained from Alkem laboratories, Mumbai, India. Other materials were purchased from commercial source; Magnesium stearate, and lactose. All other chemicals used in the study were of analytical grade.

Preparation of tablets:

For preparing hydrophilic and hydrophobic matrix tablets, ibuprofen (100mg), and various concentrations of HPMC and EC along with lactose (see Table 1) were first sieved and blended thoroughly for 5 minute. The powder blend was granulated with small amount of ethanolic PVP solution (1.5%w/v in alcohol) and the wet mass was sieved through mesh No. 16 and dried at 40°C±2°C for 2 hours in an oven. The dried granules were passed through sieve No.22 and the fractions of the granules retained on the sieve were discarded. The granules passed through on sieve No: 22 were evaluated for bulk density, tapped density; angle of repose, compressibility index and Hausners ratio (see Table 2). Then the granules were mixed with magnesium stearate, talc and finally compressed into tablets were compressed using a 10 station punch tableting machine (Cadmach® Machinery Co. Pvt. Ltd., Mumbai) equipped with 6.5 mm circular, flat and plain punches. The batch size of each formulation was 100 tablets.

Evaluation of blend:

Angle of Repose:

Angle of Repose of granules was determined by the funnel method. Accurately weight powder blend were taken in the funnel. Height of the funnel was adjusted in such a way the tip of the funnel just touched the apex of the powder blend. Powder blend was allowed to flow through the funnel freely on to the surface. Diameter of the powder cone was measured and angle of repose was calculated using the following equation.¹⁴

tan α = h/r

Density:

a) Bulk density (BD): Weigh accurately 25 g of granules, which was previously passed through 22# sieve and transferred in 100 ml graduated cylinder. Carefully level the powder without compacting, and read the unsettled apparent volume. Calculate the apparent bulk density in gm/ml by the following formula.¹⁴

Bulk density = Weigh of powder/ Bulk volume

b) Tapped density (TD): Weigh accurately 25 g of granules, which was previously passed through 22# sieve and transferred in 100 ml graduated cylinder of tap density tester which was operated for fixed number of taps until the powder bed volume has reached a minimum, thus was calculated by formula.¹⁴

Tapped density = Weigh of powder / Tapped volume

Carr’s Index:

Compressibility index of the powder blend was determined by Carr’s compressibility index. It is a simple test to evaluate the BD and TD of a powder and the rate at which it packed down (15). The formula for Carr’s index is as below:

Carr's index= (Tapped density‐Bulk density) / Tapped density × 100

Hausner’s Ratio:

Hausner’s Ratio is a number that is correlated to the flow ability of a powder.¹⁵

Husner’s Ratio = Tapped density / Bulk density

Evaluation of Tablets:

Thickness:

Thickness of the tablets was determined using a vernier caliper (For-bro engineers, Mumbai, India).

Weight Variation Test:

20 tablets of each formulation were weighed using an electronic balance and the average weight was calculated and compared with the weight of each tablet. The tolerance in weight variation was allowed according to USP XXVI.¹⁶

Hardness:

The tablets to be tested are held between a fixed and a moving jaw of hardness test apparatus (Monsanto) and reading of the indicator is adjusted to zero. The screw knob was moved forward until the tablet breaks and the force required breaking the tablet was noted .¹⁷

Friability:

Ten tablets were weighed and placed in the Roche fribilator test apparatus (Electrolab, Mumbai). The tablets were exposed to rolling and repeated shocks, resulting from free falls within the apparatus. After 100 revolutions, the tablets were reweighed. The friability was determined using following formula .¹⁸

% friability = [1‐weight of the tablet after test /weight of the tablet before test] ×100

Drug content (Assay):

Ten tablets were finely powdered and an amount equivalent to 100 mg ibuprofen was accurately weighed and transferred to a 100 ml volumetric flask and extracted with 0.1N sodium hydroxide. The mixture was then filtered to remove the un-dissolve particle and 1 ml of the filtrate was suitably diluted and analyzed for ibuprofen content at 257 nm using double beam UV/Visible spectrophotometer (UV-1800-Shimadzu, Japan). This method was validated for linearity, precision and accuracy.

In-Vitro drug release Study:

Release of ibuprofen was determined using USP (XXI) six stage dissolution rate test apparatus I (Electrolab, Mumbai) at 100 rpm. The dissolution rate was studied using 900 ml of phosphate buffer (pH 6.8) for the remaining hours. The temperature was maintained at 37± 0.2°C. Samples of 5 ml each were withdrawn at different time intervals i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 12 hrs, filtered through Whatman filter paper and replaced with an equal amount of fresh dissolution medium. Samples were suitably diluted and analyzed for ibuprofen content using double beam UV/Visible spectrophotometer (UV-1800 Shimadzu, Japan) at 257 nm.

Analysis of release profiles:

The rate and mechanism of release of ibuprofen from the prepared matrix tablets were analyzed by fitting the dissolution data into the zero-order equation. In order to describe the kinetics of the release process of drug in the different formulations, zero- order (Q_t = Q₀ + K₀t), first- order (ln Q_t = ln Q₀ + K₁t), Higuchi (Q_t =K_Ht_1/2) and Korsmeyer- Peppas (Q_t/Q_∞= Ktⁿ) models were fitted to the dissolution data of Formulations (F1-F9) using linear regression analysis. Where n = diffusional exponent, Q_t = amount of drug released at time t, Q_∞ = amount of drug released at time ∞, K is the kinetic constant.

Thus Q_t / Q_∞ is the fraction of drug release at time t, a measure of the primary mechanism of the drug release and n characterizes the mechanism of drug release from the formulations during dissolution process (See table 4). A value of n = 0.5 indicates case I (Fickian) diffusion or square root of time kinetics, 0.5<n<1 anomalous (non- Fickian) diffusion, n=1 Case –II transport and n>1 Super Case II transport.

Table 1: Composition of Sustain Release Matrix Tablets of Ibuprofen (100 mg)

Formulation	Ingredients (mg/tablet)
Formulation	Ibuprofen (mg)	Lactose (mg)	PVP (1.5%w/v)	HPMC (mg)	Ethyl Cellulose (mg)	Mg Sterate (mg)	Talc (mg)	Alcohol
F1	100	70	1.5	50	-	5	2.5	q.s
F2	100	70	1.5	100	-	5	2.5	q.s
F3	100	70	1.5	150	-	5	2.5	q.s
F4	100	70	1.5	-	50	5	2.5	q.s
F5	100	70	1.5	-	100	5	2.5	q.s
F6	100	70	1.5	-	150	5	2.5	q.s
F7	100	70	1.5	25	25	5	2.5	q.s
F8	100	70	1.5	50	50	5	2.5	q.s
F9	100	70	1.5	75	75	5	2.5	q.s

qs indicate quantity sufficient. N=3

Table 2: Evaluation of Ibuprofen Granules

Formulations	Parameters
Formulations	Angle of Repose ±SD	Bulk density ±SD (gm/cm³)	Tapped density ±SD (gm/cm³)	%Carr’s Index ±SD	Hausner’s Ratio ±SD
F1	27.47 ±0.25	0.495±0.015	0.522±0.008	13.55±1.04	1.14±0.15
F2	30.17 ±0.15	0.421±0.011	0.528±0.012	10.12±0.23	1.01±0.08
F3	28.13 ±0.21	0.515±0.005	0.456±0.017	16.23±0.65	1.21±0.31
F4	27.61 ±0.11	0.428±0.015	0.489±0.005	11.88±0.45	1.15±0.43
F5	28.47 ±0.15	0.385±0.023	0.519±0.021	11.20±0.26	1.04±0.25
F6	28.32 ±0.14	0.426±0.065	0.497±0.009	12.66±0.96	1.08±0.31
F7	29.51 ±0.23	0.512±0.022	0.527±0.015	18.09±1.02	1.12±0.10
F8	30.27 ±0.13	0.396±0.012	0.531±0.012	12.42±0.23	1.09±0.08
F9	29.63 ±0.15	0..411±0.013	0.485±0.009	13.12±0.52	1.11±0.13

N=3

Table 3: Evaluation properties of the Ibuprofen matrix Tablets:

Formulations	Parameters
Formulations	Average Thickness of Tablet ±SD (mm)	Hardness ±SD(kg/cm²)	(%)Friability ±SD	Average Weight of Tablets (mg) ±SD	% Drug Content ±SD
F1	4.0±0.05	5.4 ±0.15	0.47 ±0.05	228±0.14	98.99 ±0.25
F2	4.3±0.01	5.0 ±0.09	0.35 ±0.11	278±0.19	99.65 ±0.43
F3	4.5±0.02	5.3 ±0.12	0.28 ±0.07	328±0.20	98.34 ±0.55
F4	4.0±0.08	5.5 ±0.14	0.29 ±0.05	228±0.17	99.11 ±0.23
F5	4.3±0.01	6.1 ±0.09	0.32 ±0.04	277±0.21	98.56 ±0.41
F6	4.5±0.05	5.1 ±0.10	0.58 ±0.12	328±0.15	97.88 ±0.37
F7	4.3±0.06	5.5 ±0.17	0.29 ±0.02	228±0.17	98.36 ±0.21
F8	4.5±0.11	5.4 ±0.21	0.56 ±0.06	278±0.15	99.21 ±0.32
F9	4.6±0.08	5.5 ±0.16	0.34 ±0.07	327±0.21	99.75 ±0.25

N=3

Table 4: Kinetics of Drug Release from Ibuprofen Matrix Tablets

Formulations	Zero Order plot’s Regression Coefficient(R²)	First Order Plot’s Regression Coefficient (R²)	Higuchi Plot’s Regression Coefficient (R²)	Korsemeyer Peppas plot’s slope(n)	Korsemeyer Peppas Plot’s Regression Coefficient (R²⁾
F1	0.969	0.977	0.968	0.51	0.991
F2	0.988	0.989	0.991	0.56	0.998
F3	0.977	0.991	0.978	0.51	0.978
F4	0.981	0.996	0.994	0.54	0.983
F5	0.979	0.987	0.988	0.51	0.965
F6	0.957	0.988	0.993	0.53	0.991
F7	0.987	0.991	0.991	0.55	0.996
F8	0.991	0.998	0.998	0.51	0.992
F9	0.984	0.989	0.978	0.55	0.987

N=3

Batches F7, F8, F9 were prepared with the blend of HPMC (K4M) and Ethylcellulose respectively in the ratio of 1:1, 1:2 and 2:1. Batches F7 and F8 showed cumulative drug release of 91.52±1.32 % and 87.12±2.07 % at the end of 12 hrs. While in batch F9 cumulative drug releases was about 89.75±1.37% at the end of 12 hrs. (see figure 3).

Figure 3: Cumulative percentage Drug release from formulation F7 to F9

This may occur due to presence of both hydrophilic and hydrophobic polymer which allows little swelling but did not allow rapid diffusion of the drug from the matrix. About 20 to 60% of the Ibuprofen was released within the first hour of dissolution study. This phenomenon may be attributed to surface erosion and initial disaggregation of the matrix tablet which occurs due to the formation of the gel layer around the tablet core.⁶ In case of formulations F4, F5 and F6, only 20 to 26% drug was released due to the hydrophobic nature of the ethyl cellulose polymer. However in case of formulation F7 where hydrophilic and hydrophobic polymer combination was present no burst release was observed (only 21% drug release in 1 hour). It is reported that if more than 30% drug is release in first hour of dissolution may indicate the chance of dose dumping.⁶ So the formulations prepared without ethyl cellulose may have the probability of dose dumping. Therefore the formulations formulated using the combination of HPMC and EC did not show any burst release which indicated the reduced possibility of dose dumping. The release kinetic data for all the formulations is shown in Table 4.

When the data were plotted according to zero order, the formulations showed a high linearity, with regression coefficient values (R²) between 0.957-0.991. Diffusion is related to transport of drug from the dosage matrix into the in vitro study fluid depending on the concentration. This is explained by Higuchi’s model. The release profiles of drug from all the formulations could be best expressed by Higuchi’s equations, as the plot showed high linearity with regression co-efficient values (R²) between 0.968-0.9998. The kinetic data of all the formulation showed good fit in Korsmeyer equation which indicated the combined effect of diffusion and erosion mechanism for controlled drug release. By using korsmeyer model, if n = less than 0.45 it is Fickian diffusion, if n = 0.45-0.89 it is non-Fickian transport. The value of release exponent ‘n’ was ranged from 0.55 to 0.83 which indicates non-Fickian mechanism of drug release and also follows the mechanism of both diffusion and erosion (see Table-4).

CONCLUSION:

Hydrophilic matrix of HPMC alone could not control the ibuprofen release effectively for 12 hours. It is evident from the results that a matrix tablet prepared with hydrophilic polymer and hydrophobic polymer is a better system for once-daily sustained release of a ibuprofen. The mechanism of drug release was observed the combined effect of diffusion and erosion for controlled drug release. So, combination of both hydrophilic and hydrophobic polymer was suitable to produce the matrix tablet rather than the using a single type of polymer.

ACKNOWLEDGEMENTS:

Authors are sincerely thankful to Mahatma Gandhi College of Pharmaceutical sciences Jaipur for providing necessary facilities for work.

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Received on 23.04.2011

Accepted on 10.06.2011

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(4): July-Aug. 2011, 142-147