Preparation and characterization of orodispersible tablets of Meclizine Hydrochloride by wet granulation method

The aim of this research is to prepare orodispersible tablets of Meclizine Hydrochloride (MHCl). MHCl is used to treat or prevent nausea, vomiting, and dizziness. Wet granulation method was used to prepare the orodispersible tablets of MHCl using different super disintegrant; crospovidone (CP), sodium starch glycolate (SSG), croscarmellose sodium (CCS), and microcrystalline cellulose (MCC) at different concentrations. Camphor and ammonium carbonate were also incorporated in preparation as subliming agents. Co processing of super disintegrant with MCC is a new approach to increase disintegration rate which we tried. The prepared tablets were evaluated for weight variation, content uniformity, hardness, disintegration time, and friability of tablets. All the formulations showed low weight variation with invitro disintegration time less than 71 s. The drug content of all the formulations was within the acceptable limits. Crospovidone shows the shortest disintegration time among super disintegrants while use of subliming agent produced friable tablets. Although use of combination of super disintegrant with MCC decreases disintegration time, the use of co processed super disintegrant (10%CP with 20% MCC) provides the optimum properties of orodispersible tablets (F11). Stability study of selected formula showed no significant changes in tablet properties.


INTRODUCTION
The disadvantages of conventional solid oral dosage forms is the necessity of water to enhance swallowing the dosage forms specially for certain groups of patients as geriatrics, pediatrics, and unconscious patients and during travelling (Venkatal et al., 2009).The continuous developing of dosage forms in the last years reveals new one which the ability to overcome the limitation of normal dosage form since it is required water for help in swallowing.The definition of orodispersible tablet in European Pharmacopoeia as "A tablet that to be placed in the mouth where it disperses rapidly before swallowing in less than three minutes" (Kamal et al., 2010).The (ODT) technology has been recently approved by United States Pharmacopoeia (USP), Centre for Drug Evaluation and Research (CDER).United States Food and Drug Administration (FDA) defined orally disintegrating tablet as "A solid dosage form containing medicinal substance or active ingredient which disintegrates rapidly usually within a matter of seconds when placed upon the tongue" (Bhupendra et al., 2010).The ODT is also known as fast melting, fast dispersing, rapid dissolve, rapid melt, and/or quick disintegrating tablet (Yourong et al., 2004).When an ODT is placed in the oral cavity, saliva quickly penetrates into the pores causing rapid disintegration.ODTs are useful in patients, such as developmentally disabled or who may face difficulty in swallowing conventional tablets or capsules and liquid orals or syrup, leading to ineffective therapy, with persistent nausea, sudden episodes of allergic attacks, or coughing for those who have an active life style (Kaushik et al., 2004;Chue et al., 2004;Shu et al., 2002;Seager et al., 1998;Gohel et al., 2004).
ODTs are also applicable when local action in the mouth is desirable such as local anesthetic for toothaches, oral ulcers, cold sores, or teething, and to deliver sustained release multiparticulate system to those who cannot swallow intact sustained action tablets/capsules (Chang et al., 2000;Shimizu et al., 2003).
Meclizine HCl, an oral antiemetic, is a white, slightly yellowish, crystalline powder which has a slight odor and is tasteless.Meclizine HCl is an antihistamine which shows slower onset and longer duration of action (24 h) than most other antihistamines used for motion sickness.Meclizine hydrochloride is an antiemetic drug indicated in prophylactic treatment and management of nausea and vomiting, and dizziness associated with motion sickness (Moffat et al., 2004).The aim of the present work was to evaluate the potential of super disintegrant and subliming agent in production of Meclizine HCl ODTs with acceptable mechanical strength and disintegration time.

EXPERIMENTAL Materials
Meclizine HCl powder was purchased from Oceanic Pharmachem, India, Crospovidone (CP), and Croscarmellose Sodium (CCS) were purchased from 3B Pharmaceutical (Wuhan) international Co. Ltd, China.Magnesium stearate, Mannitol, Ammonium carbonate were purchased from Riedel-De-Haen AG seelze, Germany.Camphor was purchased from Evans Medical Ltd, Liverpool, England.All other materials were of analytical grade.

Formulation of orodispersible tablets of Meclizine hydrochloride
All the ingredients (Except Lubricants and glidant) were passed through mesh No.44 meshes separately, then weighed and mixed in geometrical order for about 10 min.A sufficient quantity of freshly prepared starch mucilage of concentration 5% w/v was added to produce a wet coherent mass (Alebiowu et al., 2002).There after the wet mass was passed through mesh No.14 and the wet granules were dried at 50°C to constant weight in a hot air oven.Then the dried granules were passed through sieve mesh No 18.Then lubricants and glidant were added to the mixture and mixed for about 2 min.Finally an amount of the blend was compressed into tablets of 200 mg using 8 mm round flat punches using sixteen station rotary tablet machine (Vanguard Pharmaceutical, USA).Sublimation was performed from tablets contain subliming agents at 60ºC until a constant tablet weight was achieved (Koizumi et al., 1997).A minimum of 50 tablets were prepared for each batch.

Preparation of co-processed super disintegrant
The co-processed super disintegrant was prepared by solvent evaporation method (Table 1).A blend of CP and MCC (in the ratio of 1: 2) was added to 10 ml of ethanol.The contents of the beaker (250 ml capacity) were mixed thoroughly and stirring was continued till most of ethanol evaporated.The wet coherent mass was granulated through mesh No. 44.The wet granules were dried in a hot air oven at 60°C for 20 min.The dried granules were sifted through mesh No. 44 and stored in airtight container till further use (Gohel et al., 2007).

Angle of repose
Angle of repose was determined using funnel method (British Pharmacopoeia, 2007).The granules were poured through funnel that can be raised vertically until a maximum cone height (h) was obtained.Radius of the heap (r) was measured and angle of repose was calculated using the formula: where, θ is the angle of repose, h is height of pile; r is radius of the base of pile.

Compressibility (Carr's) index
An accurate weight of formula granules was poured in to a volumetric cylinder to occupy a volume (V•) and then subjected to a standard tapping procedure on to a solid surface until a constant volume was achieved (Vf).The Carr's index was calculated using following equation (British Pharmacopoeia, 2007).

Weight variation
Randomly, twenty tablets were selected after compression and the mean weight was determined.None of the tablets deviated from the average weight by more than ±7.5%.

Uniformity of content
One tablet of the prepared formula was placed in 100 ml volumetric flask, 50 ml of 0.01 N HCL was added, shaked by mechanical means for 30 min, the dilute acid added to volume, and filtered sample was analyzed for Meclizine hydrochloride in the tablet spectrophotometrically using UV-Visible spectrophotometer (Silverstein et al., 1991).The requirement for this test is met if the amount of drug in each of the ten tablets lies within the range of (85-115%) of the label claim.

Wetting time
A piece of tissue paper (12 cm × 10.75 cm) folded twice was placed in a Petri dish (Internal Diameter=9 cm) containing 10 ml of buffer solution simulating saliva pH 6.8 and amaranth.A tablet was placed on the paper and the time taken for complete wetting was noted.Three tablets from each formulation were randomly selected and the average wetting time was recorded (Hisakadzu et al., 2002).

Hardness
The crushing strength of the tablets was measured using a Monsanto hardness tester.Three tablets from each formulation batch were tested randomly and the average reading ± SD was recorded.

Friability
Twenty tablets were weighed and placed in a Roche friabilator and the equipment was rotated at 25 rpm for 4 min.The tablets were taken out, de dusted and reweighed.The percentage friability of the tablets was calculated using following equation (Rahul et al., 2009).

In vitro disintegration time
The disintegration time was defined as the time in seconds taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measure in second using artificial saliva as disintegration medium.Six tablets were placed individually in each tube of disintegration test apparatus.The values reported are mean ± standard deviation (Mohsin et al., 2010).

In vitro drug dissolution test
In vitro dissolution studies were performed only for the optimum formula and Meclizine (reference tablet, 25 mg) by using type I (Basket) dissolution apparatus (10ST+ G.B Caleva Ltd ,Dorset ,England), at 100 rpm, and 900 ml of 0.01 N HCL was used as a dissolution medium.Temperature of dissolution medium was maintained at 37 ± 0.5°C.Five millimeter aliquot of the dissolution medium was withdrawn at specific time intervals and it was filtered.Absorption of filtered solution was read by UV-visible spectrophotometer (UV-1650PC-Shimadzu, Japan) at λmax= 232 nm and drug content was determined from a standard calibration curve (United States Pharmacopoeia, 2007).The mean of three determinations was used ± SD.
The percent of drug dissolved in 15 min was considered for comparing the dissolution results.

Statistical analysis
The mean ± standard deviation of the experiments results were analyzed using one way analysis of variance (ANOVA).

RESULTS AND DISCUSSION
Meclizine HCl tablets were prepared by wet granulation method.Eleven formulations were prepared using two different subliming agents alone or with three different super disinegrants.Each super disinegrant was used in two different concentrations (5 and 10%).All batches of the tablets were evaluated for various pre and post compression parameters.Table 2 shows the data obtained from the pre compression evaluation of tablets which includes angle of repose, and Carr's index while post compression parameters such as hardness, friability, drug content, wetting time, and disintegration time were evaluated.
The results of flowability studies of the granules reveals acceptable flowability for tablet production represented by the angle of repose and Carr's index values listed in Table 2.The post compression parameters of all prepared tablets are reported in Table 3 indicate that the hardness in the range 3.9 to 7 kg/cm 2 which is appropriate except formula that contain ammonium carbonate as subliming agent shows low hardness (2.5 kg/cm 2 ).The loss in total weight of the tablets due to friability was in the range of 0.53 to 0.92% except formulas contain subliming agent (F7 and F8) produces friable tablets which mainly due to high porosity of tablets.The drug content in different formulation was highly uniform and in the range of 98.13 to 100.74%.
Wetting time is an important parameter shows the efficiency of super disintegrant regarding the swelling in presence of water was found to be 23 to 107 s.The results of in vitro disintegration time indicate that formulas which contain only super disintegrant shows efficiency in the following order; crospovidone > croscaramellose sodium >sodium starch glycolate, with superiority of 10% over 5% super disintegrant concentration for the three types and 10% is the optimum percent for good disintegration.
Although formulations used with subliming agent shows shorter disintegration time than that with super disintegrant, but the tablets produced were highly friable.Combination of best super disintegrant (CP) with MCC reduce the disintegration time and improves mechanical properties, however new approach of co processing of the super disintegrant (CP) with MCC (F11) produces the shortest disintegration time since granules of coprocessed super disintegrant possesses greater density and its particles are closer to each other than the physical mixture therefore after water uptake a greater hydrostatic pressure formed that strongly repels the particle from one another and ultimately results in quicker tablet disintegration.The results are in agreement with those of Shirsand et al. (2010).Formula (F11) was selected as best formula thus subjected for dissolution studies in comparison to conventional formula as shown in Figure 1.The results of dissolution study (Figure 1) show that the release of MHCl from selected formula and conventional tablet shows release of 100 and 49.32% respectively at 15 min which consequently indicates that enhancement of release was obtained for the selected formula.

Conclusion
Formulation of ODTs of MHCl by wet granulation method using coprocessed CP 10% with MCC exhibited fast disintegration time with good mechanical properties.

Figure 1 .
Figure 1.Dissolution profile of MHCl from selected formula and conventional tablet.

Table 1 .
Different formulas used in preparation of orodispersible tablets of MHCl