The present investigation was to develop and characterize mouth dissolving tablets of Cetirizine by using superdisintegrants. A novel approach has been made to develop Cetirizine mouth dissolving tablets by including clove oil as flavor and local anesthetic on taste buds. The drug and excipients were characterized using Differential Scanning Calorimetry and Fourier Transform Infrared techniques. The blend was examined for angle of repose, bulk density, tapped density, compressibility index and Hausner's ratio. The prepared tablets were evaluated for general appearance, content uniformity, hardness, friability, mouth feel, wetting time, in vitro disintegration time, in vivo disintegration time and in vitro dissolution studies. Formulation (F-4) showed quick disintegrating time of 22±8.26 s, which is very characteristic of mouth dissolving tablets. Further optimized formulations (F-4 and F-5) were subjected to accelerated stability studies for 3 months at temperature 40±5°C/75±5%RH. Optimized tablets have shown no appreciable changes with respect to taste, disintegration, and dissolution profiles. In conclusion, the results of this work suggest the inclusion of Clove oil (which has both flavoring and local anesthetic actions), which reduces the processing charges and use of costlier taste masking agents.
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Keywords: Mouth dissolving tablet, Cetirizine, Clove oil, superdisintegrants.
Allergic disorders are most common worldwide. Cetirizine is an active non-sedative antihistamine. Mouth dissolving tablets undergo disaggregating in the mouth when in contact with the saliva in less than 60 s forming a suspension which is easy to swallow. Patients, particularly pediatric and geriatric patients, have difficulty in swallowing solid dosage forms. These patients are unwilling to take these solid preparations due to a fear of choking. In order to assist these patients, several mouth dissolving drug delivery systems has been developed. Mouth dissolving tablets dissolve rapidly in the saliva without the need for water, releasing the drug. Some drugs are absorbed from the oral cavity as the saliva passes down into the stomach. In such cases, bioavailability of drug is significantly greater than those observed from conventional tablet dosage form. The purpose of the present study is to formulate Cetirizine mouth dissolving tablets using superdisintegrants, sweeteners and local anesthetic flavour in different proportions, to achieve patient compliance in allergic disorders1-3.
MATERIALS AND METHODS
Cetirizine was a gift sample from Waksman Selman Pharmaceuticals, Anantapur, India. Stevia leaf powder was obtained from the medicinal garden of Sri Krishnadevaraya University, Anantapur, India and authenticated by the Botany department of Sri Krishnadevaraya University, Anantapur, India. Mannitol, Clove oil, talc, micro crystalline cellulose, Cross carmellose sodium, Cross Povidone, magnesium stearate and talc were purchased from S.D. Fine Chemicals, Mumbai, India. All other chemicals, solvents and reagents were used of either pharmacopoeial or analytical grade.
Preparation of Mouth Dispersible Tablets4-6
All the ingredients were passed through sieve # 60. Cetirizine, mannitol, Micro Crystalline Cellulose and stevia leaf powder were triturated in a glass mortar. Micro crystalline cellulose, Cross carmellose sodium, Cross Povidone were incorporated in the powder mixture and finally magnesium stearate and talc were added. The mixed blend was then compressed with 10mm flat face surface punches using hydraulic press single tablet punching machine.
The compatibility of drug and polymers under experimental condition was conducted using FTIR studies. In the present study, the potassium bromide disc (pellet) method was employed.
Flow properties of the blend7, 8
Angle of repose
Angle of repose was determined by funnel method. The blend was poured through a funnel that can be raised vertically until a maximum cone height (h) was obtained. Radius of the heap (r) was measured and the angle of repose was calculated. It is the angle produced between the heap of the pile and base. The Angle of repose can be mathematically calculated by the following equation.
tan (θ) = h / r
θ = Angle of repose, h = Height of heap and r = Radius of pile.
Loose Bulk density
It was determined by pouring the blend into a graduated cylinder. The bulk volume (Vb) and weight of the powder (M) was determined. Mathematically loose bulk density can be calculated by the following equation.
LBD = M / Vb
Always on Time
Marked to Standard
M = Weight of powder and Vb = Bulk volume
Tapped Bulk density
The measuring cylinder containing a known mass of blend was tapped for a fixed time. The minimum volume (Vt) occupied in the cylinder and the weight (M) of the blend was measured. Mathematically tapped bulk density can be calculated by the following equation.
TBD = M / Vt
M = Weight of powder and Vt = Volume after tapping
The simplest way of measurement of free flow of powder is compressibility. The indication of the ease with which a material can be induced to flow is given by compressibility index. Mathematically compressibility index can be calculated by the following equation.
I = [(Vb - Vt) / Vb] x 100
Vb = Bulk volume and Vt = Tapped volume
Hausner ratio is an indirect index of ease of powder flow. Mathematically loose bulk density can be calculated by the following equation.
Hausner ratio = TBD / LBD
TBD = Tapped bulk density and LBD = Loose bulk density
Preparation Tablets9, 10
Tablets were made from blends by direct compression method. All the ingredients (shown in Table No.1) were passed through mesh # 60. All the ingredients were ground in a pestle motor. Finally talc and magnesium stearate were added and mixed. The mixed blend of excipients was compressed using a single punch machine to produce convex faced tablets weighing 300 mg with 3 mm thickness and 10 mm in diameter.
Post compression parameters11-14
The thickness of the tablets was determined using a thickness screw gauge (Mitutoyo, New Delhi, India). Five tablets from each batch were used and average values were calculated.
Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using Monsanto hardness tester (Cadmach, Ahmedabad, India). It is expressed in kg/cm2. Three tablets were randomly picked and analyzed for hardness. The mean and standard deviation values were also calculated.
The friability of tablets was determined using Roche Friabilator (Campbell Electronics, Mumbai, India). The friabilator was operated at 25 rpm for 4 min(totally 100 revolutions). The % friability was then calculated by the following equation.
F= Winitial - Wfinal / Winitial X 100
F= friability (%), Winitial = initial weight and Wfinal = Final weight
Weight variation test
To study weight variation, 20 tablets of each formulation were weighed using an electronic balance (Denver APX-100, Arvada, Colorado) and the test was performed according to the official method.
Drug content uniformity
Tablet containing 10 mg of drug is dissolved in 100ml of 0.1N HCl taken in volumetric flask. The drug is allowed to dissolve and the solution was filtered, 1ml of filtrate was taken in 50ml of volumetric flask and diluted with 0.1N HCl and analyzed spectrophotometrically ( Elico SL 210, India) at 233 nm. The concentration of Cetirizine mg/ml was obtained by using standard calibration curve of Cetirizine. Drug content studies were carried out in triplicate for each formulation batch.
The tablet was placed in a petridish of 6.5 cm in diameter, containing 10 ml of water at room temperature, and the time for complete wetting was recorded. To check for reproducibility, the measurements were carried out six times and the mean value calculated.
Water absorption ratio
A small piece of tissue paper folded twice and placed in a petri dish containing 6ml of distilled water. A tablet was put on the paper and time required for complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio, R, was determined using the following equation.
R = 10 X (Wa - Wb) / Wb
Wb = weight of the tablet before water absorption
Wa = weight of the tablet after water absorption
Three tablets from each formulation were analysed performed and standard deviation was also determined.
In vitro dispersion time
Tablet was placed in 10 ml phosphate buffer solution, pH 6.8±0.50C. Time required for complete dispersion of a tablet was measured.
In vitro disintegration time
The in vitro disintegration time of tablets were performed by placing one tablet in each of the 6 tubes of the basket. Add a disc to each tube and run the apparatus using pH 6.8 (simulated saliva fluid) maintained at 37±20C as the immersion liquid. The assembly should be raised and lowered between 30 cycles per min in the pH 6.8 maintained at 37±20C. The time taken for the complete disintegration of the tablet with no palpable mass remaining in the basket was measured and recorded.
In vivo disintegration time
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Six healthy human volunteers (both sexes) were selected and their written consent was obtained. Each volunteer randomly took one tablet and kept on the tongue. The time taken in seconds for complete disintegration of the tablet on the tongue was noted. After the test, mouth was washed with distilled water. Three trials were performed with 2 days interval, between trials.
In vitro dissolution studies
In vitro dissolution studies were carried out using dissolution test apparatus USP XXIII15. The following procedure was employed throughout the study to determine the in vitro dissolution rate for all the formulations. The parameters in vitro dissolution studies were tabulated in Table No. 5.
Accelerated Stability studies:
The promising formulation (F-5) was tested stability for a period of 3 months at accelerated conditions of a temperature 400C and a relative humidity of 75% RH, for their drug content16.
RESULTS AND DISCUSSION
The FTIR spectrum of Cetirizine shown characteristic peaks at 3444.97 and 3291.18 (3300-3500) (N-H), 2922.37 (2850 - 3000) (C-H), 2854.79 and 2796.22 (3300 - 2500 (O-H), 1442.66 and 1368.13 (1350 -1550) (N=O), 1123.61 (1220 -1020) (C-N), 1287.13, 1240.80 and 1006.79 (1000 -1300) (C-O) (Figure 1). Whereas the FTIR spectrum of Cetirizine mouth dissolving tablets shown characteristic peaks at 3402.09 (3300-3500) (N-H), 2910.50 (2850 - 3000) 2910.50 (C-H), (3300 - 2500 (O-H), 1427.36, 1283.08 (1350 -1550) (N=O), 1161.61, 1081.98 (1220 -1020) (C-N), 1020.53 (1000 -1300) (C-O) (Figure 2). This indicates the characteristic peaks of Cetirizine were present even in formulated Cetirizine tablets, indicates that the drug was compatible with the polymers used.
Evaluation of powdered blend
The formulated blend was evaluated for various parameters such as angle of repose, loose bulk density, tapped bulk density, compressibility index and Hausner ratio. The values were within the official limits with less standard deviation. The results of angle of repose was ranged from 26.30±0.15 to 29.32±0.810 indicate good flow properties. Loose bulk density of the blends was ranged from 0.55±0.052 to 0.59±0.066 g/cm3 and tapped bulk density was ranged from 0.65±0.083 to 0.71±0.051 g/cm3. The LBD and TBD values were considered in calculating compressibility index, which was ranged from 12.12±0.10 to 22.50±0.02% and Hausner ratio ranged from 1.141±0.03 to 1.291±0.04. These values indicate that the formulated powder blend shows satisfactory flow property. All these values were represented in Table No. 2.
Evaluation of tablets
The mean thickness of formulated tablets was found to be uniform (2.98±0.15 to 3.05±0.02 mm), the hardness of formulated tablets was more than 5 kg/cm3 (5.94±0.26 to 7.95±0.19 kg/cm3) and the loss in friability was less than 1% (0.26±0.08 to 0.56±0.09 %) indicated the formulated tablets have good mechanical strength. All the tablets passed weight variation test as per the pharmacopoeial limits. The Wetting Time (92±8.95 to 100±5.66 s) indicates that all the formulated tablets has quick wetting, this may be due to ability of swelling and also capacity of absorption of water. The water absorption ratio (12.51±0.02 to 16.59±0.15g) favors the wetting of the tablet in saliva. The disintegration time (22±8.26 to 39±2.32 s) was within the pharmacopoeial limits aided with the presence of cross cormilose sodium and cross Povidone, in direct compression method results in hydrophilicity and swelling which in turn causes rapid disintegration. The volunteers felt good taste in all the formulations. As the formulation was not bitter due to the presence of stevia leaf powder, which is 400 times sweeter than sucrose and the Euginol in clove oil which acts as both flavoring and local anesthetic agent to block the sensation of taste buds. In oral disintegration all the formulations showed rapid disintegration in oral cavity. All these values were represented in Table 3.
In all the formulations the drug release was nearer to 100% within 6 min. This rapid dissolution might be due to fast breakdown of particles of superdisintegrants. The parameters in in vitro dissolution studies were shown in Table No. 4. The in vitro dissolution profile of formulated tablets was shown in Figure 3. The optimized formulations F-4 and F-5 were subjected to accelerated stability studies and the tablets possessed the same parameters even after the stressed conditions, indicates good stability properties of formulation. The comparative parameters of optimized formulations (F-4 and F-5) before and after the accelerated stability studies were shown in Table 5.