Formulation of Fenofibrate Liquisolid Tablets Using Central Composite Design

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Formulation of Fenofibrate Liquisolid Tablets Using Central Composite Design

Tejas Patel1*, L.D. Patel2, B.N. Suhagia1, Tejal Soni and Tushar Patel1

1Faculty of Pharmacy, Dharmsinh Desai University, Nadiad-387001, Gujarat, India; 2C.U. Shah College of Pharmacy and Research, Wadhwan, Surendranagar, Gujarat, India

Abstract: Liquisolid technique has been widely used to enhance the dissolution of poorly water soluble drugs. The pre-sent investigation is on formulation of liquisolid tablets of fenofibrate, a lipid lowering agent. Liquisolid formulation was prepared by applying central composite design (CCD) to optimize various formulation parameters. Amounts of PEG 600 (X1), Avicel PH 102 (X2), and Aerosil 200 (X3) were selected as independent variables while the angle of repose, hard-ness, disintegration time, and T90% (time required to release 90% drug) of liquisolid tablets were selected as dependent variables. Optimization of formulation was done by multiple linear regression analysis. The results indicated amounts of PEG 600 and Aviel PH 102 show greater effect on dependant variables. In vitro dissolution of fenofibrate in liquisolid formulations was enhanced compared to the pure form. To conclude, Liquisolid technique is a promising strategy in im-proving dissolution of poorly water soluble fenofibrate.

Keywords: Central Composite Design, Dissolution Enhancement, Fenofibrate, Liquisolid System.

INTRODUCTION

The active ingredient in a solid dosage form must un-dergo dissolution before it is available for absorption from the gastrointestinal tract [1]. The poor dissolution rate of water-insoluble drug is a substantial problem confronting the pharmaceutical industry. The absorption rate of a poorly water-soluble drug from solid oral dosage form is poor due to the low dissolution rate of the drug. Hence, dissolution rate is the rate determining step in drug absorption.

To enhance the dissolution, various formulation tech-niques have been introduced with different degrees of suc-cess. The use of water-soluble salts and polymorphic forms, the formation of water-soluble molecule complexes, drug micronization, solid dispersion, co-precipitation, lyophiliza-tion, microencapsulation, liquisolid technique and the inclu-sion of drug solutions or liquid drugs into soft gelatin cap-sules are some of the techniques that have been reported to enhance the dissolution characteristics of water-insoluble drugs. The technique of liquisolid compacts is one of the most promising techniques [2-4].

Liquisolid powder is a free flowing and a compressible powder form of liquid medication. The term liquid medica-tion implies liquid drug and solution or suspension of water-insoluble solid drug carried in suitable non-volatile liquid vehicles. Using formulation technique, a liquid medication can be converted into a dry-looking, non-adherent, free-flowing, and readily compressible powder by blending with selected powder excipients referred to as the carrier and coat ing materials [1]. Various grades of cellulose, starch, lactose

*Address correspondence to this author at the Faculty of Pharmacy, Dharm-sinh Desai University, Nadiad-387001, Gujarat, India; Tel: +91-09924107039; E-mail: [email protected]

etc. may be used as carriers, whereas very fine-particle-size silica powder may be used as the coating (or covering) mate-rial [5]. In liquisolid compact, the drug is in a tablet or en-capsulated dosage form and it is held in a solubilized liquid state, which consequently contributes to increased drug wet-ting properties, thereby enhancing drug dissolution. Liquid lipophilic drug or water insoluble solid drug dissolved in non-volatile solvent and this liquid medication can be con-verted into a free-flowing, non adherent, dry looking, and readily compressible powder to use of carrier and coating material [6]. In liquisolid formulating as the drug is in either solubilized or molecularly dispersed state in the liquid vehi-cle, which is absorbed into or onto the carrier and coating material respectively. Hence, increased surface area of drug in powder form and enhanced dissolution of drug [7]. Low cost, simple formulation technique and capability of indus-trial production serve to be advantage of this technique [8].

Fenofibrate, Isopropyl 2-[4-(4-chlorobenzoyl) phenoxy]-2-methylpropionate, is a fibric acid derivative that reduces elevated plasma concentrations of triglycerides. It also de-creases elevated plasma concentrations of LDL and total cholesterol. The solubility of fenofibrate is 0.008mg/ml in distilled water. The log P value of fenofibrate is 5.28. Thus, solubility and dissolution enhancement is necessary to in-crease oral bioavailability of fenofibrate.

In the present study, an attempt was made to formulate a liquisolid system of fenofibrate using PEG 600, Avicel PH 102, and Aerosil 200. The central composite design was used to formulate a liquisolid system of fenofibrate. The aim of the present investigation was to optimize various formulation parameters affecting preparation of liquisolid system. Con-centrations of PEG 600, Avicel PH 102 and Aerosil 200 were selected as independent variables for preparation of

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12 Current Drug Delivery, 2014, Vol. 11, No. 1 Patel et al.

liquisolid system using response surface methodology. Op-timization was done by generating polynomial equation for study of effect of independent variables on dependant vari-ables like flow property of liquisolid powders, hardness, dis-integration time and in vitro drug release behavior of liquisolid system.

MATERIALS AND METHODS

Fenofibrate was obtained as a gift sample from Cadila pharmaceuticals limited, Ahmedabad, India. PEG 600, Avicel PH 102, Aerosil 200 was purchased from BASF Lim-ted, Mumbai, India. Tablet compression machine used was of Chronimach machineries, Ahmedabad, India. Dissolution apparatus used to be of Elecrolab Inc. USA and UV Spectro-photometer of Shimadzu 1800. All other solvents and excipi-ents were used in the analysis was of analytical grade pur-chased from Sigma Aldrich.

EXPERIMENTAL METHODS

Solubility Study

Solubility of fenofibrate was determined in different sol-vent like PEG 600, PEG 400, Tween 80, Tween 40, Tween 20, Span 80, glycerin and Brij 35 by preparing saturated drug solutions. 10mg of fenofibrate was added in 10 ml of vehicle solution and the solution was stirred on the shaker for 48 hours at 25 °C under constant stirring. Drug content was analyzed by UV-Spectrophotometric method at �max of 290 nm after filtration using Whatman filter paper.

Preparation of Liquisolid System

Fenofibrate and PEG 600 was accurately weighed in 50 ml glass beaker and then heated to 80 °C. The resulting heat dispersion was incorporated into calculating quantity of car-rier (Avicel PH 102) and coating (Aerosil 200) material. Mixing was carried out in three steps as described by Spireas et al. [9, 10]. During the first stage, the system was blended at an approximate mixing rate of one rotation per second for approximately one minute in order to distribute liquid medi-cation evenly in the powder. In the second stage, the liq-uid/powder admixture was spread as a layer on the surface of mortar and was allowed to stand for 5 minutes to allow the drug solution to be absorbed in the interior of powder mate-rial. In the third stage, powder was scraped off from the mor-tar surface by means of aluminum spatula and then blended with 5% sodium starch glycolate for 30 second giving final formulation of liquisolid system. Liquisolid powder was dried in tray dryer at 60oC for 2 hours and dried mixture was gently passed from 60#. The liquisolid powder was com-pressed by single punch tablet press machine to prepare tab-lets [11-14].

Central Composite Design for Formulation of Liquisolid System

The central composite design was used as a part of ex-perimental designs of response surface methodology. The central composite design was constructed naturally as per construction of factorial designs and it consisted of several groups of experiments as follows:

• Nf experiments of a factorial design. • 2k experiments of a "star" or axial design (2 experi-

ments on the axis associated with each factor at a value xi = ± �, with all other variables set at zero).

• N0 central points: the number chosen according to the desired properties of the design.

The central composite design was generated in 2-8 fac-tors. The number of tests required for the CCD includes the standard 2k factorial with its origin at the center, 2k points fixed axially at a distance from the center to generate the quadratic terms, and replicate tests at the center; where k is the number of variables. The axial points were chosen such that they are rotatable which ensures that the variance of the model prediction was constant at all points equidistant from the design. Test replications were at the center and were very important as they provide an independent estimate of the experimental error.

In the present study, CCD was applied using a 3 -factorial level. 3-independent factors and 4- dependent factors were used to generate CCD for preparation of liquisolid system. The design includes 23 factorial experiments, 6 axial or star experiments and 6 center point experiments. Accordingly low (-1) and high (1) level of factors was selected in factorial experiments, (-1.68) and (+1.68) level were selected as a part of the axial experiment for �- level and center point level was indicated using (0) as a code. A polynomial equation for the 3-factor CCD was shown as follows: Y= b0 + b1X1+b2X2+b3X3+b11X1

2+b22X22+b33X3

2+b12X12+b23X23+b13X13 (1)

Where, Y is response measured. b0 is intercept. b1, b2, b3 are coefficients main effect of factors X1, X2, X3

b11, b22, b33 are coefficients with second order terms indicated quadratic nature of factors. b12, b23, b13 are coefficients of interaction terms of factors.

In the present study, amount of PEG 600 (X1), amount of carrier molecule Avicel PH 102 (X2) and amount of coating material Aerosil 200 (X3) were selected as independent vari-ables. Angle of repose, disintegration time of tablets, and hardness of tablets and T90% were selected as dependent vari-ables. Experimental runs were designed as per central com-posite design were depicted in (Table 1). Composition of CCD batches L1 to L20 was depicted in (Table 2).

Evaluation of Liquisolid System

Flow Property

Flow property of liquisolid powder was accessed by measuring angle of repose, Carr’s index and Hausner’s ratio. Each study was carried out in triplicate. Angle of repose was calculated by a fixed height cone method. Bulk density measurement was carried by placing fixed weight of powder in a graduated cylinder and initial bulk density was calcu-lated from volume occupied by powder. The cylinder was then tapped at a constant velocity till a constant volume was obtained and tapped density was calculated [11-14].

Formulation of Fenofibrate Liquisolid Tablets Using Central Composite Design Current Drug Delivery, 2014, Vol. 11, No. 1 13

Table 1. Central composite design for formulation of fenofibrate liquisolid system.

Actual Values Coded Values Batch

X1 X2 X3 X1 X2 X3

L1 100 100 5 -1 -1 -1

L2 300 100 5 1 -1 -1

L3 100 200 5 -1 1 -1

L4 300 200 5 1 1 -1

L5 100 100 15 -1 -1 1

L6 300 100 15 1 -1 1

L7 100 200 15 -1 1 1

L8 300 200 15 1 1 1

L9 32 150 10 -1.68 0 0

L10 368 150 10 1.68 0 0

L11 200 66 10 0 -1.68 0

L12 200 234 10 0 1.68 0

L13 200 150 1.6 0 0 -1.68

L14 200 150 18.4 0 0 1.68

L15 200 150 10 0 0 0

L16 200 150 10 0 0 0

L17 200 150 10 0 0 0

L18 200 150 10 0 0 0

L19 200 150 10 0 0 0

L20 200 150 10 0 0 0

Independent Factors for Liquisolid System

LevelIndependent Factors

-� (-1.68) Low (-1) Center (0) High (1) +� (+1.68)

Amount of PEG 600 (mg), (X1) 32 100 200 300 368

Amount of AVICEL PH 102 (mg), (X2) 66 100 150 200 234

Amount of AEROSIL 200 (mg), (X3) 1.6 5 10 15 18.4

% Friability

Friability of the liquisolid tablet was measured using Roche friability tester at a rotation speed of 25 RPM. The drum was rotated for 4 min (100 rotations) [14-19, 26]. Any loose dust from the tablet was removed and was weighed accurately. Percentage friability was calculated from the weight of the tablet before and after the test according to the equation shown below:

% Friability =Initial Weight of Tablet � Final Weight of Tablet

Initial Weight of Tablet�100

Hardness

The hardness of the liquisolid tablet was evaluated using a Monsanto hardness tester. The tablet to be tested was placed between the spindle and the anvil. The desired pres-sure needed to hold the tablet in position was applied by moving the screw knob in a clockwise direction. The scale was moved so that the indicator was fixed at zero. The pres-sure was applied until tablet breaks. The reading was noted, indicating the pressure that was needed to break the tablet. The mean hardness of each batch was determined and ex-pressed in kg/cm2 [15-17, 19, 27].


Disintegration Time

A tablet was placed in each of the six tubes of the USP disintegration test apparatus and one disc was added to each tube. The time taken for the complete disintegration of the tablet with no palatable mass remaining in the apparatus was measured in minutes.

Content Uniformity

Content uniformity of the each liquisolid system was measured by dissolving the liquisolid tablet in the methanol. The drug content was analyzed by UV-spectroscopic at 290 nm.

In Vitro Drug Release Study

The dissolution rate of fenofibrate from liquisolid tablets was determined using USP dissolution test apparatus I (Bas-ket apparatus) containing 900 ml of 0.1 N HCl (pH 1.2) at 37±0.5°C. This was done by placing liquisolid tablet con-taining an equivalent amount of 160 mg fenofibrate. The basket was fitted with stainless steel screen of pore size 100 �m to prevent fine particles from emerging. The basket was rotated at 100 RPM. 10-ml aliquot was withdrawn from the dissolution medium at predetermined time interval. An ali-

quot was filtered through 0.45 �m Milli-pore® membrane filter and adequately diluted and analyzed by UV-spectroscopy for fenofibrate content at �max 290 nm using dissolution as blank medium (n=3).

Table 3. Solubility of fenofibrate in non-volatile liquid.

Sr. No Non-volatile Liquid Solubility (mg/ml)

1 Polyethylene glycol 400 0.3235±0.032

2 Polyethylene glycol 600 0.4062±0.012

3 Tween 80 0.2636±0.025

4 Tween 40 0.2532±0.026

5 Tween 20 0.2436±0.041

6 Span 80 0.2630±0.026

7 Glycerin 0.1532±0.010

8 Brij 35 solution 0.1089±0.012

9 Propylene glycol 0.3425±0.012

10 Distilled water 0.0080±0.012

Table 2. Composition of CCD batches L1 to L20.

Batch Fenofibrate (mg) PEG 600 (mg) Avicel pH 102 (mg) Aerosil 200 (mg)

L 1 160 100 100 5

L 2 160 300 100 5

L 3 160 100 200 5

L 4 160 300 200 5

L 5 160 100 100 15

L 6 160 300 100 15

L 7 160 100 200 15

L 8 160 300 200 15

L 9 160 32 150 10

L 10 160 368 150 10

L 11 160 200 66 10

L 12 160 200 234 10

L 13 160 200 150 1.6

L 14 160 200 150 18.4

L 15 160 200 150 10

L 16 160 200 150 10

L 17 160 200 150 10

L 18 160 200 150 10

L 19 160 200 150 10

L 20 160 200 150 10


RESULT AND DISCUSSION

Solubility Study

The results of solubility study were depicted in (Table 3). According to Indian pharmacopeia (2007) and US Pharma-copeia, fenofibrate is practically insoluble in water. The solubility of fenofibrate was found to be 0.4062 mg/ml in PEG 600 and 0.3425 mg/ml in propylene glycol. PEG 600 was selected as suitable solvent for preparing fenofibrate liquisolid system in the present study.

Evaluation of Liquisolid System

Flow Property

Flow property measurement was important for the liquisolid system because the non-volatile vehicle was used for adsorption of the drug onto the carrier and coating mate-rial. If developed formulation had no good flow behavior, then it may have sticky property due to improper absorption of the drug onto the internal and external surface of the car-rier molecule in the nonvolatile liquid vehicle. Poor Flow-ability results in variation in hardness and other tablet char-acteristics. Accordingly angle of repose greater than 40o was

described as poor flow. Hausner’s ratio and Carr’s index were measured as a function of compressibility of the liquisolid system. After the study pre-compression properties all the formulations were subjected for preparation of tablet using rotary tablet machine. The tablets were evaluated for friability, hardness, content uniformity, in vitro dissolution, disintegration time etc. and the result of liquisolid tablets was depicted in the (Table 4).

Hardness

Hardness of the formulation was found in the range of 1.56 kg/cm2 to 6.32 kg/cm2. It was observed that as the amount of Aerosil 200 was increased, the hardness was also increased. Decreased hardness might be due to the lower amount of Avicel PH 102 and increased amount of the Aerosil 200.

% Friability

From the result of friability study it was revealed that all the formulation was shown the friability below 1%. Friabil-ity below 1% was indicated good mechanical resistance of the liquisolid tablet.

Table 4. Evaluation results of fenofibrate liquisolid system.

Batch Angle of

Repose (o)Hausner’s

Ratio Carr’s Index

Hardness (Kg/Cm2)

Friability (%) Disintegration

Time (min) Content

Uniformity (%)

L1 26.75±0.021 32.41±0.021 1.44± 0.027 2.33±0.024 0.98±0.043 2.1±0.013 96.75±0.031

L2 27.41±0.036 26.59±0.020 1.30± 0.030 2.65±0.035 0.90±0.042 2.6±0.071 97.41±0.011

L3 28.56±0.058 18.61±0.010 1.26± 0.016 4.56±0.034 0.55±0.040 2.9±0.018 98.56±0.010

L4 28.60±0.060 30.65± 0.012 1.16± 0.010 4.89±0.026 0.56±0.030 3.2±0.018 98.60±0.011

L5 25.50±0.025 19.96±0.012 1.24± 0.021 5.12±0.020 0.48±0.030 3.5±0.049 95.50±0.010

L6 29.56±0.36 31.63± 0.030 1.11± 0.050 5.98±0.012 0.40±0.029 4.9±0.035 99.56±0.015

L7 26.49±0.015 20.25± 0.014 1.26± 0.049 6.12±0.015 0.41±0.034 6.5±0.098 96.49±0.040

L8 29.71±0.042 25.83± 0.025 1.35± 0.037 6.25±0.010 0.38±0.037 7.1±0.019 99.71±0.50

L9 25.97±0.035 23.28± 0.050 1.31± 0.029 4.98±0.010 0.85±0.030 4.2±0.014 95.97±0.053

L10 29.39±0.012 30.37± 0.041 1.44± 0.027 5.35±0.035 0.75±0.038 5.3±0.024 99.39±0.053

L11 25.85±0.025 24.61± 0.042 1.36± 0.043 3.89±0.045 0.89±0.050 3.6±0.026 95.85±0.046

L12 27.70±0.045 28.94± 0.050 1.32± 0.057 4.75±0.055 0.95±0.052 6.5±0.0.22 97.70±0.075

L13 29.30±0.014 30.94± 0.036 1.42±0.075 2.56±0.060 0.25±0.0.053 2.4±0.033 99.30±0.018

L14 29.11±0.024 28.00± 0.075 1.40± 0.065 6.32±0.035 0.15±0.052 7.5±0.010 99.11±0.013

L15 29.35±0.012 29.23± 0.061 1.40± 0.026 5.29±0.028 0.36±0.055 7.2±0.010 99.35±0.010

L16 29.28±0.035 29.09± 0.052 1.39± 0.081 4.75±0.075 0.75±0.044 6.5±0.013 99.28±0.030

L17 29.40±0.062 31.15± 0.035 1.44± 0.040 5.35±0.024 0.83±0.030 5.9±0.018 99.40±0.031

L18 29.32±0.070 30.62± 0.035 1.50± 0.012 5.89±0.035 0.73±0.010 6.2±0.050 99.32±0.025

L19 29.30±0.084 29.20± 0.025 1.35± 0.026 4.98±0.012 0.62±0.010 6.4±0.051 99.30±0.063

L20 29.28±0.090 29.02± 0.038 1.32±0.024 6.18±0.010 0.39±0.012 6.8±0.050 99.28±0.062


Disintegration Time

Disintegration time of liquisolid tablets was measured in distilled water. It was found that disintegration time was de-creased as friability was increased and hardness was de-creased. Disintegration time of the tablets was in the range of 1.5 min to 7.5 min.

Content Uniformity

Fenofibrate content was measured in liquisolid tablet us-ing UV-Spectroscopic analysis. The drug content was in the range of 94.25 % to 102 % of the drug. This value of drug content was laid in the content uniformity specification of the official compendia study.

In vitro Drug Release Study

The liquisolid tablet was kept in the dissolution test appa-ratus at 37o C ± 1oC; 50 RPM up to 100% drug was released. 0.1 N HCl was taken as dissolution medium. (Fig. 1) illus-trated in vitro dissolution curve for the batches. The liquisolid tablets showed almost complete dissolution of the drug within 90 minutes. Batch L12 was showed dissolution of fenofibrate in 40 minutes. In case of center point batches L15 to L20, fenofibrate was completely released in 40 min-utes. Dissolution from axial point batches L 9 and L 13 was in 60 minutes. Batches L2, L7, L9 showed the total drug release in 90, 90 and 80minutes, respectively.

Dissolution from liquisolid tablet was higher. This might be due to the drug adsorbed onto or absorbed into the carrier molecule and its solubilized form in PEG 600. The drug re-lease was increased by higher solubility and wettability after disintegration of the compact to the dissolution medium. The wettability of the tablet in the dissolution media was one of

the most proposed mechanisms for enhanced dissolution rate of liquisolid tablet. PEG 600 facilitated wetting of drug par-ticle by decreasing interfacial tension between dissolution medium and tablet surface.

Central Composite Design of Fenofibrate Liquisolid System

Responses surface curvature was examined when the three variables were investigated at three levels as design points. The design provided the following empirical second order equation (Full Model).

Results of dependent variables as per experimental runs were shown in (Table 5).

DESIGN EXPERT 8.0.2 and Microsoft Excel were used to identify non-significant terms. A coefficient was signifi-cant if P < 0.05. The refined model was used for calculation of residuals or for drawing contour plots and 3D response surface plots. The full model (FM) and refined model (RM) (P < 0.05) of the batches L1 to L20 for angle of repose, dis-integration time, hardness and T 90%, were illustrated in (Table 6).

Angle of Repose

Positive sign of coefficients indicated synergistic effect and negative sign indicated the antagonistic effect of factors on response. Regression analysis of independent factors for response angle of repose showed coefficient b1 and b2 with positive signs (1.005 & 0.5309) and b3 with a negative sign (-0.0277). This indicated that the amount of PEG 600 and an amount of Avicel PH 102 had positive effect which increase the angle of repose of liquisolid powders. A negative sign for Aerosil 200 indicated that the increase in amount of Aerosil 200 increased angle of repose and affected flow property of

Fig. (1). In vitro Dissolution Curve of Batch L1 to L20.


Table 5. Experimental runs and measured responses of fenofibrate liquisolid system.

Factors Response

Batch X1 X2 X3 Angle of Repose (o) Hardness (Kg/Cm2)

Disintegration Time (min)

T 90% (min)

L1 -1 -1 -1 26.75±0.021 2.33±0.024 2.1±0.013 52.63

L2 1 -1 -1 27.41±0.036 2.65±0.035 2.6±0.071 72.78

L3 -1 1 -1 28.56±0.058 4.56±0.034 2.9±0.018 38.48

L4 1 1 -1 28.60±0.060 4.89±0.026 3.2±0.018 29.68

L5 -1 -1 1 25.50±0.025 5.12±0.020 3.5±0.049 44.56

L6 1 -1 1 29.56±0.36 5.98±0.012 4.9±0.035 43.39

L7 -1 1 1 26.49±0.015 6.12±0.015 6.5±0.098 56.69

L8 1 1 1 29.71±0.042 6.25±0.010 7.1±0.019 24.62

L9 -1.68 0 0 25.97±0.035 4.98±0.010 4.2±0.014 56.69

L10 1.68 0 0 29.39±0.012 5.35±0.035 5.3±0.024 41.35

L11 0 -1.68 0 25.85±0.025 3.89±0.045 3.6±0.026 39.34

L12 0 1.68 0 27.70±0.045 4.75±0.055 6.5±0.022 29.96

L13 0 0 -1.68 29.30±0.014 2.56±0.060 2.4±0.033 47.36

L14 0 0 1.68 29.11±0.024 6.32±0.035 7.5±0.010 45.44

L15 0 0 0 29.35±0.012 5.29±0.028 7.2±0.010 30.69

L16 0 0 0 29.28±0.035 4.75±0.075 6.5±0.013 30.69

L17 0 0 0 29.40±0.062 5.35±0.024 5.9±0.018 30.25

L18 0 0 0 29.32±0.070 5.89±0.035 6.2±0.050 29.72

L19 0 0 0 29.30±0.084 4.98±0.012 6.4±0.051 30.59

L20 0 0 0 29.28±0.090 6.18±0.010 6.8±0.050 30.60

Table 6. Summary of results of regression analysis for batches L1 to L20.

Response b0 b1 b2 b3 b11 b22 b33 b12 b23 b13 R2

FM 29.320 1.0054 0.5309 -0.0277 -0.5755 -0.8955 -0.0364 -0.1825 -0.2325 0.8225 0.9991 Angle of Repose (o) RM 29.320 1.0054 0.5309 -0.0277 -0.5755 -0.8955 -0.0362 -0.1825 -0.2325 0.8225 0.9989

FM 5.4020 0.1656 0.5262 1.1249 -0.0554 -0.3541 -0.3117 0.0901 -0.4001 0.0425 0.9168 Hardness (kg/cm2) RM 5.3567 -0.1656 0.5262 1.1249 - -0.3486 -0.3062 - -0.4001 - 0.8991

FM 6.5262 0.3404 0.8403 1.4481 -0.7707 -0.6647 -0.7008 -0.1250 0.4750 0.1501 0.9557 DisintegrationTime (min) RM 6.5232 0.3404 0.8403 1.4481 -0.7707 -0.6647 -0.7008 - 0.4750 - 0.9509

FM 30.386 -3.4916 -5.8019 -2.0164 6.8213 1.7846 5.8954 -7.4815 6.3272 -5.5731 0.9555 T90% (min)

RM 31.846 -3.4916 -5.8013 -2.0164 6.6441 - 5.7182 -7.4815 6.3272 -5.5731 0.9205


Fig. (2). 3D Response Surface Plot showing effect of X1, X2 and X3 on Angle of Repose.


Fig. (3). 3D Response Surface Plot showing effect of X1, X2, and X3 on Hardness of Liquisolid Tablets.


Fig. (4). 3D Response Surface Plot showing effect of X1, X2 and X3 on Disintegration Time of Liquisolid Tablets.


Fig. (5). 3D Response Surface Plot showing effect of X1, X2, and X3 on T90%.


the liquisolid powder system. Interaction coefficients b12(-0.1825) and b23 (-0.2325) were found to have a negative effect on the angle of repose that might affect flow property of the liquisolid powder system. Interaction coefficient b13(0.8225) showed positive effects on flow property of the liquisolid powder system. It was found that the amount of Avicel pH 102 and Aerosil 200 had a positive effect on the angle of repose. Higher level of X2 and X3 were found in acceptable flow of the liquisolid powder system (Fig. 2) pre-sented 3D response surface plots showing the effect of inde-pendent variables X1, X2 and X3 on angle of repose.

Hardness of Liquisolid Tablets

It was found that the coefficients of the main effect of X1,X2, and X3 had positive magnitude 0.1656, 0.5262 and 1.1249 respectively. Refined model (RM) indicated that the interaction of X13 was found to ha significant effect on hard-ness of liquisolid tablet (Fig. 3) indicated the effect of X1,X2, and X3 on hardness of liquisolid compacts. It was found that at higher level of X2 and X3, the hardness of the tablet was increased. Fenofibrate content in PEG 600 was not sig-nificantly affected hardness of liquisolid tablets. As there was a change in the amount of Avicel PH 102 and Aerosil 200, there was a change in hardness of liquisolid compacts. Hence, conclusions should not be drawn by considering mathematical signs of the main effects. All the batches showed acceptable range of hardness. The final selection of batch was done by considering other requirements of liquisolid system. i.e. angle of repose, T90%, and disintegra-tion time.

Disintegration Time of Liquisolid Tablets

It was found that the coefficients of the main effect of X1,X2, and X3 had positive magnitude 0.3404, 0.8403 and 1.4481 respectively. Refined model (RM) indicated that the interaction of X1, X2 and X3 have no significant effect on disintegration time of liquisolid tablet (Fig. 4) indicated the effect of X1, X2, and X3 on disintegration time of liquisolid tablet. It was found that at higher level of X2 and X3 disinte-gration time of the tablet was increased. It was might be due to disintegrating effect of Avicel PH 102 and Aerosil 200. Fenofibrate content in PEG 600 was not significantly af-fected the disintegration time of liquisolid tablet. As there was a change in the amount of Avicel PH 102 and Aerosil 200, there was a change in disintegration time of liquisolid tablet. Hence, conclusions should not be drawn by consider-ing mathematical signs of the main effects. All the batches showed acceptable range of disintegration time. The final selection of batch was done by considering other require-ments of liquisolid tablet i.e. T90%.T90%

Positive sign of coefficient indicated synergistic effect and negative sign indicated the antagonistic effect of factors on response. Regression analysis of independent factors for response T90% showed coefficient b1, b2 and b3 with negative signs (-3.4916, -5.8019 & -2.0164, respectively). It indicated that independent factors namely the percentage of fenofibrate in PEG 600 and an amount of Avicel PH 102 had antagonistic effect on T90%. Regression coefficients of X11, X22 and X33

were found to have a positive magnitude of the coefficients which indicated synergistic effect on T90%. Interaction coef-ficients of X12, X12 and X23 were found to have a positive effect on T90%. It indicated that higher levels of X1 and X2were found to have more effect on the T90%. This might be due to more to drug adsorbed onto the surface of the carrier material and coating material (Fig. 5) illustrated the effect of X1, X2 and X3 on T90%.

CONCLUSIONS

The dissolution of the drug can be enhanced by solid dispersion, inclusion complex, micronization, co-grinding, etc. Liquisolid technique is gaining importance for sparingly water soluble drug. The present investigation was aimed to formulate liquisolid tablets of fenofibrate to enhance its solubility and dissolution. The central composite experimen-tal design was applied to optimize the formulation variables for liquisolid system. The factor X2 and X3 were found to have a major effect on the angle of repose, hardness, disinte-gration time and T90% of liquisolid system. Batch L12 was the best formulation among the 20 batches of CCD in terms of optimum disintegration, superior dissolution profile and acceptable tablet property. Incorporation of PEG 600 in-creases the wetting property and surface area of drug parti-cle. Hence, solubility and dissolution enhancement was achieved using a liquisolid system for fenofibrate.

CONFLICT OF INTEREST

The authors confirm that this article content has no con-flicts of interest.

ACKNOWLEDGEMENTS

Declared none.

PATIENT CONSENT

Declared none.

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Received: March 08, 2013 Revised: April 29, 2013 Accepted: June 12, 2013

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Formulation of Fenofibrate Liquisolid Tablets Using Central Composite Design