INTRODUCTION:

Solid dosage forms are popular because of low cost, ease of administration, accurate dosage self-medication, pain avoidance, and the most importantly the patient compliance. The most popular solid dosage forms are being tablets and capsules. Many conventional oral drug and products, such as tablets and capsules, are formulated to release the active drug immediately after oral administration. Such immediate products results in relatively rapid and complete systemic drug absorption and onset of accompanying pharmacodynamic effects.^1,2Orodispersible tablets are those when put on tongue disintegrate instantaneously releasing the drug which dissolves or disperses in the saliva. The faster the drug into solution, quicker the absorption and onset of clinical effect.^3,4,5Levocetirizine, the active isomer of its parent compound, cetirizine, is one of the newest second-generation antihistamines.

After only 1 dose, it has been found to suppress the cutaneous allergic response to a significantly greater extent than similar drugs in its class. In addition, levocetirizine is effective in the treatment of nasal congestion.⁶Drinking water plays an important role in the swallowing of oral dosage forms. Often times people experience inconvenience in swallowing conventional tablets and capsules. When water is not available, in the case of motion sickness (kinetosis) and sudden episodes of coughing during the common cold, allergic conditions and bronchitis.^7,8Advantages of this drug delivery system include administration without water. Some drug are absorbed from mouth, pharynx and esophagus as the saliva passes down in to the stomach and in such cases bioavailability of drug is increased, pre-gastric absorption can result in improved bioavailability and as a result to reduce dosage form, improved reduction of unwanted effects.^9.10,11

Antihistamines are effective in reducing pruritis, sneezing and watery rhinorrhea, and are a mainstay therapy for allergic rhinitis. Second generation antihistamines have shown favorable effect on sleep in patients with allergic rhinitis and are in general recommended for mild to moderate disease as first line therapy, but not effective in nasal congestion.¹²Some drugs are absorbed from the mouth, pharynx and esophagusas the saliva passes down into the stomach. The basic approach in development of ODT is the use of superdisintegrants like cross linked carboxymethyl cellulose (crosscarmellose), Indion 414, cross povidone etc, which provide instantaneous disintegration of tablet after putting on tongue, there by release the drug in saliva.^13,14

MATERIALS AND METHODS:

Materials:

Levocetirizinedihydrochloride API, MCC, Cross povidone, Cross carmillose, Magnesium stearate, Talc, and all other excipients were obtained from pharmaceutics laboratory of RCPSR, KohkaKurud Road, bhilai.

Selection of Excipients:

Excipients are critical to the design of any drug delivery system and play a major role in determining its quality and performance. The following excipients were selected for the formulation of Orodispersible tablets.¹⁵

Diluents:

Tablet prepared using insoluble nature of crystalline cellulose were found to have a gritty mouth feel. To overcome this problem we attempted the use of water-soluble diluents mannitol but the tablet prepared with mannitol often tends to dissolve rather than disintegrate. Thus, novel diluents, a combination of mannitoland microcrystalline cellulose (102) in the ratio of 70:30 wereemployed in the study.¹⁶

Disintegrants:

Short disintegration time with good dispersibility is the most important characteristics of an orodispersible tablets. The necessity of an orodispersible tablet is to disintegrate 145-150 seconds, in limited amount of the water available in the form of saliva. This demands the use of special type of disintegrantscalled as “Superdisintegrants”. In the present study, crosscarmellose sodium, crosspovidone, was used as superdisintegrants.¹⁷

Flavoring agent:

Mint flavor are intended as flavoring agent and to accelerate the mouth feel of tablet imparting their cooling sensation.

Lubricants/Glidants:

Lubricants are intended to reduce the friction during compression and ejection of tablets. In the present study, magnesium stearate and talc were used as Lubricants/glidants.

Preparation of standard calibration curve of levocetrizine:

Preparation of Standard stock solutions:

Levocetrizinedihydrochloride (10 mg each) were separately weighed and transferred to a 10 ml volumetric flask and drugs were dissolved in methanol to get a solution of 1000 μg/ml. 1 ml of stock solution was diluted up to 10 ml using methanol to give 100 μg/ml ofdrug separately. After proper dilutions, 10 μg/ml Levocetrizinedihydrochloride were scanned in the UV-region i.e. 400 to 200 nm (Table 1).

Calibration Curve:

A calibration curve was plotted over a concentration range of 5-25 μg/mL for Levocetrizinedihydrochloride individually. Accurately measured standard stock solution of Levocetrizinedihydrochloride (0.5, 1, 1.5, 2 and 2.5 mL) and were transferred to a separate series of 10 mL of volumetric flasks and diluted to the mark with Methanol. The absorbance of each solution was measured at the wavelengths of 230nm. Calibration curves were constructed for Levocetrizine dihydrochloride by plotting concentration versus absorbance at both wavelengths. Each reading was average of five determinations.¹⁸(Fig 1)

Levocetirizine was found to be soluble in organic solvents such as methanol. Calibration curve of Levocetrizine was prepared in methanolA simple reproducible method of estimation was carried out in methanol ranging from 0.5-2.5 µg/ml solutions at 231.5nm . The standard graph obtained was linear, with regression coefficient of 0.9993.The slope of the graph was found to be 0.2144 and intercept with 0.4356.

Table 1: Calibration curve data of Levocetrizine

Concentration (µg/ml)	Absorbance
0.5	0.54
1	0.65
1.5	0.76
2	0.87
2.5	0.966

Preparation of Orodispersible Tablet:

Levocetirizine dihydrochloride (5 mg), super disintegrants in different ratios and excipients were blended using mortar and pestle. The drug and the superdisintegrantswere sieved through mesh # 120 before blending. The mixture was evaluated for angle of repose, bulk density and compressibility. The mixture was mixed with 1% magnesium stearate as lubricant and saccharine sodium as sweetening agent. The granules were then compressed by using tablet-compressing machine using 8 mm punch. The hardness was adjusted to 2-5 kg/cm. (Table 2 and 3).

Figure 1: Standard calibration curve of levocetrizine

Table2: Formulation of Levocetrizineorodispersible

Ingredient (in mg )	F1	F2	F3	F4	F5	F6
LevocetrizinediHCl	5	5	5	5	5	5
MCC	30	30	30	30	30	30
Crosscarmillose sod	6	13	20	-	-	-
Cross povidone	-	-	-	6	13	20
Mannitol	98	91	83	98	91	83
Talcum powder	1%	1%	1%	1%	1%	1%
Magnesium stearate	1%	1%	1%	1%	1%	1%

Table3:Preformulation studies of formulated tablet Levocetrizine

Batch	Angle of repose (θ)	Bulk density (g/cc)	Tapped density (g/cc)	Compresssibility %
F1	29˚12	0.55	0.73	23.60
F2	30˚56	0.59	0.79	25.22
F3	32˚70	0.58	0.78	23.61
F4	30˚23	0.53	0.70	20.00
F5	29˚81	0.57	0.71	19.42
F6	32˚76	0.52	0.67	21.57

RESULT:

Evaluations of Powder blends:

Powders were evaluated for all pre-compression parameters like angle of repose, bulk density, tapped density, Hausner’s ratio and compressibility index. The evaluations were done using all the methods as per specified in pharmacopoeias.

Angle of repose:

It is measured using fixed funnel method. The funnel is kept vertically attacked to a stand at a specific height, below which a paper is kept on a horizontal surface. The funnel is first filled with the powder and then opened to release the same in a form of conical heap, the height of heap is measured with scale and then angle of repose is calculated using formula below:

θ = tan^-1 h/r

Where h = height of heap, r = radius of heap

Tapped density:

It was determined by placing the powder in a measuring cylinder and tapping it 100times, the total mass of powder was determined and density was calculated using the formula:

Tapped density = Vb/Vf

Where

Vb = initial volume,

Vf = tapped volume

Bulk density:

A known quantity of powder blend is putted into a measuring cylinder and levelled, note the bulk volume and calculate the bulk density using formula below:

Bulk density = m/Vo

Where

m = unsettled,

Vo = apparent volume

Compressibility index:

It was calculated using measured values of bulk and tapped density as:

Carr’s index = [(Vt-Vb)/Vt] x 100

Where

Vt = tapped volume and

Vb = bulk volume

Hausner’s ratio:

It is also calculated from using measured values of bulk and tapped density as:

Hausner’s ratio = Dt/Do

Where

Dt = tapped density,

Do = bulk density

Evaluation of tablets:

Prepared tablets were evaluated for certain properties like tablet weight variation,hardness, friability, dissolution study, etc.

Tablet weight variation:

Every individual tablet in a batch should be in uniform weight and weight variation within permissible limits. Twenty tablets were randomly selected and accurately weighted using an electronic balance. The results are expressed as mean values of 20 determinations.

% wt. variation = avg. wt. – initial wt. / avg. wt. of tablets

For 80-250 mg. it should be within the limit of ±7.5%.

Hardness:

The hardness of tablets is defined as “the force required in breaking a tablet” and it is determined using Monsanto hardness testing apparatus. The tablet is placed vertically in the tester and the force required to break the tablet is measured.

Friability:

The friability of tablets was measured in a Roche friabilator. 20 tablets of known weight (Wo) were taken in a drum for a fixed time (100 revolutions) and weight (W) again. Percentage friability was calculated from the loss in weight as given in equation below. The weight loss should not be more than 1% w/w.

Tablet thickness:

Thickness of the tablet is important for uniformity of tablet size. Thickness was measured using Vernier Calipers. It was determined by checking the thickness of ten tablets of each formulation.

Wetting time:

This is carried out to measure the time, which is required for the complete wetting of tablet formulations. A piece of tissue paper folded twice was placed in small Petri dish containing 6 ml of water. A tablet was placed on the paper. When water completely wets the tablet, the time was noted.

In vitro dissolution studies:

The In- vitro dissolution study of the prepared formulations was carried out in USP dissolution test apparatus type2 (paddle). The following conditions are maintained such as dissolution medium: 900 ml of (pH 6.8 buffer), Temperature : 37 ± 0.5° C, at 50 RPM.

Drug content:

Ten tablets of each formulation were weighed and powdered. A quantity of powder equivalent to 5 mg of Levocetirizinedihydrochloride taken into 50 ml volumetric flask. The amount of drug present in a 5 mg equivalent amount of powder was determined by, dissolving the powder mixture in 10ml of methanol and suitably diluted with methanol and UV absorbance was measured at 231.5 nm. Drug concentration was determined from standard graph (Table 4).

Disintegration time:

Tablet disintegration is an important step in drug absorption. The test for disintegration was carried out in Electro lab USP disintegration test apparatus. It consists of 6 glass tubes which are 3 inches long, open at the top, and held against a 10 mesh screen, at the bottom end of the basket rack assembly.Saliva fluid (pH 6.2-6.8) as the disintegrating medium. The time taken for the complete disintegration of the tablets was noted (Table 5).

Table 5: Comparative study of % drug release from orodispersible tablet

Time (Min)	% Drug release
Time (Min)	F1	F2	F3	F4	F5	F6
30sec	7.38	8.38	16.23	7.83	9.23	11.54
60sec	65.60	67.33	49.32	54.34	57.86	56.67
90sec	72.10	73.32	75.67	67.63	67.56	68.67
2	76.0	77.54	78.97	76.56	78.67	79.75
4	79.45	80	81.1	80.32	83.12	85.34
6	81.23	83.13	83.65	84.0	86	87.78
8	83.02	86.37	87.32	86.75	88.34	89.76

DISCUSSION:

Levocetrizine tablets were formulated by direct compression method using MCC, cross carmellose, crosspovidone Talc, Magnesium stearate, and mannitol for developing controlled release solid dosage form. The granules were subjected to various preformulation study tests before compression and are show in table 3the angle of repose from formulation F1 to F6 varied between 29.12to 32.76 showing very good flow properties. The tapped density varied from 0.73 to 0.67 while bulk density ranged from 0.55 to 0.52 both showing good flow ability of powder blends among which F1 and F6 have very good flow property. The punched tablets of different formulation were also subjected to several evaluation parameters like tablet weight variation, assay, hardness, friability, dissolution study, etc. which is shown in table no.4. All the tablets passed weight variation test as all of then weighed within given pharmacopoeial limits. The hardness of tablets ranged between 3.6 to 4 which indicated good mechanical strength and ability to withstand physical pressure and stress. The friability was between 0.26 to 0.23 which is within limits and shows good resistance of tablets to mechanical stress.The drug release profile of all the formulation was givenin table 5. Among all the formulations formulation F6 was found to have better release profile when compared to others. The formulation F4 showed89.76 release in 8minute in accordance with USP dissolution criteria for Levocetrizine or dispersibletablet. A decrease in release kinetic was observed on increasing polymer concentration. Higher concentration of the polymer delayedthe release profilethereof.

CONCLUSION:

The overall study was done to formulate and evaluated Levocetrizine orodispersible tablet using different disintegrating ratio and the present study showed that it can be easily formulated using direct compression technique for fast release, improved bioavailability, patient compliance with effective therapy.All the formulations showed acceptable release among which F6was best selected out. The study revealed that cross carmelloseand providonecan be used in different ratio for a better drug release profile.

ACKNOWLEDGMENT:

Authors want to acknowledge the facilities provided by the Rungta College of Pharmaceutical Sciences and Research, Kohka, Kurud Road, Bhilai, Chhattisgarh, India. The authors also wants to acknowledge Chhattisgarh Council of Science and Technology (CGCOST) for providing financial assistance under mini research project (MRP) vide letter no. 1124/CCOST/MRP/2015; Dated: September 4, 2015 and 1115/CCOST/MRP/2015; Dated: September 4, 2015.

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Received on 15.08.2017 Modified on 13.09.2017

Research J. Pharm. and Tech 2018; 11(6): 2429-2433.

DOI: 10.5958/0974-360X.2018.00448.1

Code	Wt variation (mg)	Hardness (kg/cm)	Thickness (mm)	Friability (w/w)	WettingTime(sec)	Disintegration time (sec)
F1	139±1.6	3.6	4.5	0.26	52	35
F2	139.2±2	4.2	4	0.72	46	30
F3	139±0.8	3.8	3.8	1.16	43	26
F4	139±1.3	3.7	3.7	0.57	49	38
F5	139±0.9	3.7	4	0.42	40	25
F6	139±0.7	4	4	0.23	37	20