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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access  Full Text Article                                                                        Research Article

Formulation and Evaluation of Gastroretentive Floating Tablets of Quetiapine Fumarate

Patel Keyur S.¹*, Rao Akshar N.¹, Patel Deepa R.¹, Patel Dhaval M.², Patel Advaita B.²

¹  Kalol Institute of Pharmacy, Kalol, Gandhinagar, Gujarat, India

²  SAL Institute of Pharmacy, Ahmedabad, Gujarat, India

INTRODUCTION

Gastroretentive drug delivery systems (GRDDS) are designed to be retained in the stomach for a prolonged time and release their active ingredients and thereby enable sustained and prolonged input of the drug to the upper part of the gastrointestinal tract.^{1, 2} GRDDS provide extended residence time in the stomach is of specific interest for drugs having an absorption window in the stomach or in the upper portion of small intestine; acting locally in the stomach; those having low solubility at high pH values; or those unstable in the colonic or intestinal environments.^{1, 3}  Floating drug delivery systems(FDDS) is one of the great approaches of GRDDS to prolong gastric residence time  and to obtain sufficient drug bioavailability. ^{4, 5} FDDS have a bulk density less than stomach fluids and so remain float in the stomach for a prolong period of time. While the system is floating in the stomach, the drug is liberated slowly at the desired rate from the system.^6-8 The controlled, slow delivery of drug in the stomach provides sufficient local therapeutic levels for long time and limits the systemic exposure to the drug. ^5,9

Quetiapine fumarate (QF) is a psychotropic drug used to cure schizophrenia, bipolar disorder, sudden episodes of mania or depression associated with bipolar disorder. It is an anti-psychotic agent showing serotonin/dopamine binding ratio, dopamine D2-receptor and 5-HT2-receptor blocking effects and resulting minimal extrapyramidal side effects.^10,11 QF has mean elimination half life of 6 h and hence there is a need for twice or thrice daily administration. Quetiapine fumarate shows pH depended solubility. Quetiapine fumarate is highly soluble in acidic pH and slightly soluble in basic pH.  It would be more helpful to retain the drug in stomach for prolonged period so as to achieve maximum absorption and bioavailability.¹² So, gastroretentive floating tablet is desirable approach to prolong the residence time of the dosage form in the stomach or upper gastrointestinal tract until the drug is completely released from the system. The aim of this study was to prepare gastroretentive floating tablets of quetiapine fumarate by using natrosol 250 HHX (hydroxyethyl cellulose 250 HHX) as a sustained release hydrophilic polymer and sodium bicarbonate (NaHCO₃) as a gas forming agent.

MATERIALS AND METHODS

Materials

Quetiapine fumarate was obtained gift sample from Torrent Research Center, Ahmedabad. Natrosol 250 HHX, Avicel PH102 and polyvinylpyrrolidone (PVP K-30) were purchased from Yarrow chem Product, Mumbai.  Sodium bicarbonate, citric acid, magnesium stearate and talc were purchased from Chemdyes Corporation, Rajkot, Gujarat.

Drug and excipient compatibility study by FTIR  

FTIR study carried out to identify the drug sample and to establish drug polymer compatibility in physical mixture of drug and polymers. The FTIR spectra were obtained by using an FTIR spectrometer (FTIR- 8400S, Shimadzu, Japan). The samples were mixed thoroughly with potassium bromide, an infrared transparent matrix, at 1:1 (sample: KBr) ratio, respectively. FTIR study was accomplished in the range of 400-4000cm^-1

Preparation of floating Tablet

Direct compression technique was used to prepare floating tablets of QF. All ingredients were accurately weighed and passed through sieve # 40 and mixed thoroughly for 10 min. The blend was lubricated with talc and magnesium stearate for 2 min. The lubricated blend was compressed using single rotary tablet compression machine (Karnavati Engineering, Mehsana).

Experimental Design:

In this design, two factors were evaluated each at three levels and experimental trials were performed using all possible nine combination. In this present study, concentration of natrosol 250 HHX (X₁) and concentration of sodium bicarbonate (X₂) were selected as independent variables. The % in-vitro drug liberate at 1 h (% CDR at 1 h) (Y₁), in-vitro drug liberate at 8 h (% CDR at 8 h) (Y₂) and floating lag time (FLT) (Y₃) were elected as depended responses. A statistical design, incorporating interactive and polynomial terms was applied to check the response. ¹³

Dependent variables: Y₁: in vitro drug release at 1 h (% CDR at 1), Y₂: in vitro drug release 8 h (% CDR at 8 h), Y₃: floating lag time (FLT) (sec),

Table 2 Formulation of factorial batches

* 58 mg of Quetiapine fumarate is equivalent to 50 mg of Quetiapine

Evaluation of floating tablets

Weight variation

Twenty (20) tablets from each batch were individually weighed in grams on a digital analytical balance. The average weight and standard deviation were calculated, individual weight of each tablet was also calculated using the same and compared with average weight.

Tablets Thickness:

The thickness of the tables was determined by using digital vernier calipers. Randomly five tablets from each batch were taken and average values were calculated.

Hardness

Five tablets will select at random and the hardness of each tablet will measure with Monsanto hardness tester. The hardness is usually measured in terms of kg/cm². ¹³

Friability

The friability test will carried out in Roche friabilator. Ten tablets weighed (W _initial) at the start and kept in a rotating drum of friability apparatus for 100 revolutions. After ending of 100 revolutions, the tablets again weighed (W _final). The percent loss in weight or friability (f) determined by the formula given below. ¹³

Drug Content

10 QF floating tablets were taken, powdered. The powder equivalent to 58 mg QF was shifted to a 100 ml volumetric flask and 0.1N HCl was added upto the mark. The solution was filtered and diluted suitably and drug content in the samples was estimated using UV-spectrophotometer at 248 nm.¹⁴

In-vitro buoyancy studies

Tablets were kept in a 100 ml beaker containing 0.1 N HCl (pH 1.2). The duration required for the QF floating tablet to increase to the surface and float was determined as floating lag time (FLT). The total duration of QF floating tablet continuously present on the surface was carried out as the total floating time. ^{15, 16}

In-vitro drug release

It was conducted for a period of 12 h using USP XXIV type-II (Paddle) dissolution apparatus at 37±0.5^oC at 50 rpm utilizing 900 ml of 0.1N HCl as dissolution medium. At predetermined interval of time, ten ml of sample was taken from the dissolution medium and replaced with 0.1 N HCl to maintain the constant volume. After sample solution was filtered and diluted sufficiently, it was analyzed at 248 nm by UV-Visible spectrophotometer. ¹⁷

In-vitro release kinetic study

The drug release data of floating tablets was fitted to kinetics models, that is, zero order, first order, higuchi and Korsemeyer-Peppas to find out drug release pattern and mechanism. ¹⁸

RESULTS AND DISCUSSIONS

Drug –excipients compatibility study by FTIR:

Figure 1: IR Spectra of Quetiapine Fumarate

Figure 2: IR spectra of Physical mixture

 Figure 3: In vitro drug release data of F1-F9 batches

From the IR studies (Figure 1and 2), important function group IR bands of QF and physical mixture were identified. Characteristic IR bands of  QF includes the peaks at 3750 cm^-1 (O-H stretching), 2880 cm^-1 (C-H stretching), 2380 cm^-1 (aromatic C=C stretching), 1600 cm^-1 (C-N stretching), 1340 cm^-1 (C-H bending) and 1030 cm^-1  (C-O-C stretching) which remained unaltered in IR spectrum of  physical mixture of QF and polymers. IR analysis showed that there was not any interaction between QF and polymers.

Factorial design batches tablet evaluation parameters

Prepared all batches QF tablets were assessed for weight variation, thickness, hardness, % friability and % of drug content. (Table 3).

Table 3: Results of factorial design batches tablet evaluation

             * n=20, # n=5, $= 10 (mean±SD)

The prepared tablets were smooth and white to off white color. Hardness of the QF floating tablets was in the range of 5.1-6.3 kg/cm². Weight variation in all above batches of QF tablets was within ±2.5% of theoretical tablet weight and within the acceptance criteria. The prepared tablets showed in range thickness of 4.45-4.53 mm. % drug content of QF floating tablets was found between 98.32% to 99.85%.  Friability of QF tablets was less than 1% in all factorial batches.

In-vitro buoyancy studies (Table 4)

The floating lag time was found between 25 ± 2 sec to 178 ± 3 sec. QF tablets were prepared by effervescent technique using NaHCO₃ as a gas forming agent. NaHCO₃ produced CO₂ liberation in presence of acid. The liberated gas is protected within the gel. Then polymer is hydrated and reducing the tablet density. As the tablet density falls below 1 g/ ml, the tablet becomes buoyant.^{1, 19-20} The effect NaHCO₃ on tablets buoyancy was evaluated by using it at three different levels 25, 35 and 45 mg per tablet. Lowest FLT was found in batch F3 which contain 45 mg NaHCO₃ and 60 mg natrosol 250 HHX. Highest FLT was found in batch F7 which contain 25 mg NaHCO₃ and 90mg natrosol 250 HHX. All QF floating tablets of factorial batches maintained their matrix integrity for more than 9 h. So from the result it was concluded that FLT decreases with increasing amount of NaHCO₃. It was due to increased amount of carbon dioxide as the concentration of NaHCO₃ was increased, being entrapped in the formed gel to give rapid buoyancy. ¹

Table 4: floating lag time and floating time of F1-F9 batches

* n=5 (mean±SD)

% In-vitro drug release

It was showed that the drug release was higher in case of F1, F2 and F3 batch while drug release was lower in case of F7, F8 and F9 batch. Batch F1 and F7 showed the 95.82 % and 69.67% at 8 h respectively. It indicates that as the amount of natrosol 250 HHX increase in formulation, the drug release decrease. It may be due to formation of more viscous gel layer around the tablet at high concentration of polymer.

• Factorial design analysis

Analysis of factorial batches data was done using Design Expert DoE software. The data compiled for the selected responses and data analysis was done. Table 5 was used for data analysis.

Table 5: 3² factorial design layout

Regression analysis for the effect of X₁ and X₂   on Y₁

Table 6: ANOVA table for response Y₁

Y₁  = +28.39-4.43* X₁+2.91* X₂-1.20 * X₁ ²-0.64* X₂² -0.32* X₁X₂                     (1)                                                                   

Where, X₁=Natrosol 250 HHX,  X₂=Sodium Bicarbonate

From the equation (1), it was concluded that X₁ had negative & X₂ had positive effect on Y₁. So it was concluded that % drug release at 1 h decreased with an increase the amount of natrosol 250 HHX and decrease the amount of sodium bicarbonate.

Regression analysis for the effect of X₁ and X₂   on Y₂

Table 7: ANOVA table for response Y₂

Y₂ = +80.53-12.92* X₁+1.90* X₂+3.79* X₁ ²+0.031* X₂² +0.15*X₁X₂            (2)                                                                        

From the equation (2), it was concluded that X₁ had negative & X₂ had positive effect on Y₂. So it was concluded that % drug release at 8 h decreased with an increase the amount of natrosol 250 HHX and decrease the amount of sodium bicarbonate

Regression analysis for the effect of X₁ and X₂   on Y₃

Table 8: ANOVA table for response Y₃

Y₃ = +48.34+11.67* X₁-63.83* X₂ -0.21* X₁ ²+53.29* X₂²-0.50* X₁X₂              (3)

From the equation (3), it was concluded that X₁ had positive & X₂ had negative effect on Y₃. So it was concluded that floating lag time decreased with decrease the amount of natrosol 250 HHX and increase the amount of sodium bicarbonate.

Check point batch analysis (Validation of design)

To assess the validity of prediction, a checkpoint batch C1 and C2 was prepared and evaluated under the same conditions as outlined for the other batches. The response data was compared with that of required data. The obtained response variables of check point batch compared with target response parameters. The bias for predicted versus observed responses was acceptable. The Check point batch C1 and C2were prepared and results of check point batches are shown in Table 9.

Figure 4:   Surface plot for Y₁

Figure 5:  Surface plot for Y₂

Figure 6:  Surface plot for Y₃

Figure 7: Overlay plot of check point batches

Figure 8: Overlay plot of optimized batch

Table 9: Results of check point batches

Observed value of C1 and C2 batch was measured and compared with the predicted value of check point batch. % error was found to be less than 5 of all the responses. Hence, this model was valid and optimized batch can be selected from the overlay plot of this model.

Optimized batch

Table 10: Results of optimized batch O1

Here in Figure 8 shows the yellow area was the optimized area and batch O1was fall in the yellow region. The optimized batch O1 was prepared and results of optimized batch are shown in Table 10.The tablets have uniform drug distribution hence drug content was found satisfactory. Weight variation also found well within acceptable range. Thickness was found uniform. In vitro buoyancy studies properties also found satisfactory. % CDR was found 27.82± 2.92, 80.24± 1.74 and 99.54± 0.81 at 1h, 8h and 12 h respectively.

In vitro release kinetic studies

Table 11:  In vitro release kinetic studies of optimized batch

The in vitro release profile of drug from all the formulations could be best expressed by Korsmeyer-Peppas model, as the plot shows high linearity (R² = 0.9976). The “n” value was found to be 0.5182 in Korsmeyer- Peppas model, so it follows non-fickian diffusion or anomalous diffusion mechanism [Table 11].

CONCLUSIONS

Quetiapine fumarate floating tablets successfully prepared by using natrosol 250 HHX as a sustained release polymer and sodium bicarbonate as a gas forming agent. Concentration of Natrosol 250 HHX had significant effect on % in-vitro drug release and FLT. It was found that increase the concentration of polymer resulted that increased FLT and reduced the release rate. In-vitro release kinetics revealed Korsmeyer-Peppas model is followed and drug release is by anomalous diffusion. From the study it  can be conclude that floating tablets of quetiapine fumarate an innovative and promising perspective for the delivery of quetiapine fumarate as extended drug release over 12 h which is better formulation in the schizophrenia therapy with minimizing the adverse effects and improves patient compliance.

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