INTRODUCTION:

Orally disintegrating tablet contain a wide variety of pharmaceutical actives covering many therapeutic categories, and can be a particularly good application for pediatric and geriatric treatment. These oral dosage forms dissolve/disintegrate rapidly in saliva and can be swallowed without the need of drinking water. Elimination of bitterness is an important criterion in the formulation of mouth dissolving tablets. Such a dosage form has an increased consumer acceptance due to the reason of rapid disintegration time or dissolution, self administration without water or chewing. They are also suitable for the mentally ill, bed-ridden, and patients who do not have easy access to water. The benefits, in terms of patient compliance, rapid onset of action, increased bioavailability, and good stability make these tablets popular as a dosage form of choice in the current market¹.

In recent years, mouth dissolving tablet has attracted the interest of many researchers. Many elderly patients have difficulty in swallowing tablets, capsules, or powders. To alleviate this problem, these tablets are expected to dissolve or disintegrate in the oral cavity without drinking water. The disintegrated mass can slide down smoothly along the esophagus with the help of saliva, so even people who have swallowing or chewing difficulties can take it with ease.

The basic approach used in the development of fast-dissolving tablets is the use of superdisintegrants. Freeze-drying and vacuum-drying techniques have been tried by researchers to maximize the pore structure of the tablet matrix. Freeze-drying is cumbersome and yields a fragile and hygroscopic product. On the other hand, vacuum-drying was adopted after addition of a subliming agent to increase porosity of the tablets. It is likely that a porous hydrophilic matrix will easily pick up the disintegrating medium and break quickly. Therefore, it was decided to adopt the effervescent technique in combination with a superdisintegrant in the present investigation. The major advantage with effervescent formulation approach is that it is well established, easy to implement and mask the bitter taste of the drug. The effervescent system is generally composed of dry acid and dry base which when react facilitate a mild effervescent reaction when the tablet contacts the saliva. The effervescent reaction accelerates the disintegration of tablet through the release of carbon dioxide, water, and salt. Due to evolution of the carbon dioxide bitter taste of the drug is also masked and a pleasant mouth feel is felt^1-3. The aim of present work was to develop mouth dissolving tablets of ranitidine HCl by effervescent formulation approach. In the present study tablet formulations were developed with different ratios of the effervescent agents and its effect on the disintegration time was studied. All the formulations were subjected for precompression and post compression evaluation parameters. The formulations were also subjected for the taste and mouth feel to evaluate the palatability and patient compliance.

MATERIAL AND METHODS:

Ranitidine HCl was obtained as gift sample form Strides Research pharmaceuticals, Bangalore. Sodium bicarbonate and citric acid was obtained as gift sample from SD fine chemicals, Mumbai. Low substituted hydroxy propyl cellulose was obtained as gift sample from Signet chemicals, Mumbai. All other ingredients used were of analytical grade.

Preparation of Ranitidine HCl Mouth dissolving tablets:⁴

Ranitidine HCl 150mg and 300mg tablets each containing 75mg and 150mg of ranitidine were prepared. Total six different formulations were prepared using mannitol, avicel, sucralose, sodium bicarbonate, citric acid, L- HPC, orange flavor, colloidal silicon dioxide and magnesium stearate. The sodium bicarbonate and citric acid were used in the ratio of 6:5, 7:6, 8:7, 9:8 and 10:9 in these formulations. Ranitidine HCl, mannitol, avicel, sucralose, L- HPC were accurately weighed and sifted through sieve no.44. Citric acid and sodium bicarbonate were preheated at a temperature of 80^oC to make them anhydrous and sifted through sieve no.44 then added to other ingredients. All the ingredients were thoroughly mixed in a double cone blender after adding orange flavor. Finally magnesium stearate and colloidal silicone dioxide were mixed. Composition of the developed formulations is as shown in Table 1. The prepared powder blends were evaluated for flow properties and finally punched into tablets using Rimek 10-station rotary tablet machine. The prepared tablets were evaluated for different parameters such as thickness, hardness, friability, in-vitro disintegration time, in-vivo disintegration time, taste, mouth feel and in-vitro release studies.

Pre compression evaluation:

Evaluation of the powder blend:^5-6

There are many formulation variables and process variables involved in the mixing step, and all this can affect the characteristic of the blend produced. The flow properties of blend (before compression) were characterized in terms of bulk density, tapped density, Hausner’s ratio, Carr’s compressibility index and angle of repose. For determination of angle of repose (), the blend were poured through the walls of a funnel, which was fixed at a position such that its lower tip was at a height of exactly 2.0 cm above hard surface. The blends were poured till the time when upper tip of the pile surface touched the lower tip of the funnel. The tan^-1 (height of the pile/radius of its base) gave the angle of repose. Blends were poured gently through a glass funnel into a graduated cylinder cut exactly to 10 ml mark. Excess blend was removed using a spatula and the weight of the cylinder with powder required for filling the cylinder volume was calculated. The cylinder was then tapped from a height of 2.0cm until the time when there was no more decrease in the volume. Bulk density (Db) and tapped density (Dt) were calculated. Hausner’s ratio (HR) and Carr’s index (IC) were calculated according to the two equations given below:

HR= Dt/Db

IC = (Dt- Db)/Dt x100

Evaluation of the mouth dissolving tablets of ranitidine HCl:

Uniformity of weight:^7,8

Twenty tablets were taken from each formulation and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight.

Hardness:^{7, 8}

Hardness was determined by taking six tablets from each formulation, using a Monsanto Hardness Tester.

Friability:^{7, 8}

The friability of sample of six tablets was measured using a Roche Friabilator. Six pre-weighed tablets were rotated at 25 rpm for 4 minutes. The tablets were then reweighed after removal of fine’s using 60 mesh screen and the percentage of weight loss was calculated.

% Friability = (Loss in weight / Initial weight) × 100

Drug Content uniformity:⁹

Five tablets were powdered, and 10 mg equivalent weight of Ranitidine HCl tablet powder was accurately weighed and transferred into a 100 ml volumetric flask. Initially, 10 ml of 0.01N HCl was added and shaken for 10 min. Then, the volume was made up to 100 ml with 0.01N HCl. The solution in the volumetric flask was filtered, diluted suitably, and analyzed spectrophotometrically at 225nm.

In-vitro Disintegration time:⁹

In vitro disintegration was carried by placing one tablet in each tube of the basket without disc and run the apparatus containing 0.01N HCl maintained at 37±2⁰C as the immersion liquid. The time taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured and recorded. The experiment was carried out in triplicate.

Mouth feel and In-vivo disintegration time:¹⁰

Mouth feel:

To know the mouth feel of the tablets, six human volunteers held the disintegrated particles in their mouth for 30seconds and taste sensation felt was recorded.

In-vivo disintegration time:

Six human volunteers, whose informed consent was first obtained, were selected for the study. Each volunteer randomly took one tablet from each formulation and kept on the tongue. Time taken for complete disintegration of the tablet on the tongue was recorded. It is expressed in seconds. After the test, mouth was washed with distilled water. Three trials were performed at different time intervals.

In-vitro dissolution study:¹¹

In vitro dissolution study of Ranitidine HCl effervescent mouth dissolving tablet was carried out in 0.01N HCl (900ml, 37±0.5⁰C) using USP type II dissolution test apparatus at 50rpm paddle speed. Samples (5ml) withdrawn at various time intervals were immediately analyzed for

Table No. 1. Composition Of Fast Dissolving Tablets Of Ranitidine Hydrochloride By Effervescent Method

Ingredients in (mg)	FORMULATION CODE
Ingredients in (mg)	RE1	RE2	RE3	RE4	RE5	RE6
Ranitidine HCl	84.00	84.00	84.00	168.00	168.00	168.00
Mannitol	43.22	39.22	35.22	60.60	56.60	52.60
Sucralose	0.30	0.30	0.30	0.50	0.50	0.50
Avicel	12.50	12.50	12.50	16.50	16.50	16.50
Sodium bicarbonate	12.00	14.00	16.00	16.00	18.00	20.00
Citric acid (Anhydrous)	10.00	12.00	14.00	14.00	16.00	18.00
L - HPC	9.38	9.38	9.38	18.75	18.75	18.75
Orange Flavour	2.00	2.00	2.00	2.5	2.5	2.5
CSD	0.10	0.10	0.10	0.15	0.15	0.15
Mg. Stearate	1.50	1.50	1.50	3.00	3.00	3.00
Total	150mg	150mg	150mg	300mg	300mg	300mg

L- HPC – Low-substituted hydroxyl propylcellulose, CSD – Colloidal silicon dioxide, Ranitidine Hydrochloride 84 mg is equivalent to 75 mg of ranitidine, Ranitidine Hydrochloride 168 mg is equivalent to 150 mg of ranitidine

TABLE NO. 2: Evaluation of Mixed Blend of Drug and Excipients

Formulation No.	Angle of Repose ( ⁰)	Loose Bulk Density (gm/cm³)	Tapped Bulk Density (gm/cm³)	Hausner’s Ratio	% Compressibility
RE1	30^o10’	0.476	0.548	1.151	13.13
RE2	27°52’	0.513	0.595	1.159	13.78
RE3	25°61’	0.485	0.561	1.156	13.54
RE4	29^o51’	0.489	0.563	1.151	13.14
RE5	26^o21’	0.451	0.520	1.152	13.26
RE6	23^o35’	0.539	0.631	1.170	14.58

TABLE NO. 3: Evaluation of Ranitidine HCl Effervescent Mouth Dissolving Tablets

FMC	Thickness (mm) ±SD	Hardness (Kg/cm³) ±SD	Friability (%)	Drug content (%)	Weight variation ( % RSD)	In-vitro DT (Secs)	In-vivo DT (Secs )	Mouth Feel
RE1	2.15±0.15	4.56±0.23	0.45±0.14	99.15±0.23	149.16±1.0	19.67±0.01	20.25±0.08	+
RE2	2.14±0.17	4.57±0.21	0.47±0.16	98.67±0.45	151.03±0.9	17.33±0.07	21.67±0.05	+
RE3	2.16±0.16	4.59±0.22	0.51±0.14	99.54±0.16	148.60±0.8	14.14±0.04	17.74±0.08	+
RE4	2.13±0.15	4.51±0.25	0.49±0.17	98.72±0.75	289.80±0.9	16.46±0.06	19.35±0.02	+
RE5	2.15±0.13	4.54±0.23	0.51±0.13	97.98±0.69	291.01±0.1	17.53±0.04	21.51±0.06	+
RE6	2.14±0.16	4.49±0.28	0.46±0.15	99.10±0.54	287.45±1.2	13.89±0.01	15.25±0.06	+

FMC-Formulation code, SD- standard deviation, DT- Disintegration time, ‘+’ good palatable mouth feel, ‘-’ poor palatable mouth feel

Figure 1: Drug release profile of Ranitidine HCl Effervescent Mouth Dissolving Tablets

Figure 2: Comparison of In-vitro and In-vivo disintegration time of Ranitidine HCl mouth dissolving tablets

drug concentration using ShimadzuUV-160 double beam spectrophotometer at 225nm. The withdrawn sample was replaced with equal volume of 0.01N HCl. The dissolution test was carried out in triplicate.

Stability Study:^{12, 13}

Stability testing provides evidence on how the quality of the drug substance varies with time under the influence of variety of environmental factors such as temperature, humidity, and light and enables recommended storage conditions, re-testing periods and shelf lives to be established. In the present study, stability studies were carried out at 25⁰C/60% RH and 40⁰C/75% RH for a specific time period up to 30days for selected formulations.

RESULTS AND DISCUSSION:

Six formulations of ranitidine HCl effervescent mouth dissolving tablets were prepared with varying concentration of two effervescent agents: sodium bicarbonate and citric acid using mannitol and avicel as diluents and L-HPC as a disintegrating agent. For each formulation, blend of drug and excipients were prepared evaluated for various parameters as explained earlier. The powder blends were compressed using direct compression technique. Bulk density was found in the range of 0.451-0.539g/cm³ and the tapped density between 0.520-0.631g/cm³ Table 2. The powder blends of all the formulations had Hausner’s ratio of 1.17 or less indicating good flowability. The compressibility index was found between 13.13 and 14.58 and the compressibility–flowability correlation data indicated a fairly good flowability of the powder blend. The good flowability of the powder blend was also evidenced with angle of repose (range of 23–30⁰), which is indicating good flowability.

Effervescent tablets were prepared using direct compression technique. Since the powder was free flowing, tablets were obtained of uniform weight due to uniform die fill, with acceptable weight variations as per pharmacopoeial specifications. The drug content was found in the range of 98.67 - 99.54 % (acceptable limit), the hardness of the tablets between 4.49 - 4.59 Kg/cm³ and friability of the tablets were found below 1% indicating a good mechanical resistance of tablets Table 3. The results were within the range and that indicated uniformity of mixing of the drug with excipients in the developed formulations. In-vitro and in-vivo disintegration time (DT) of all the formulations was found to be less than 22seconds respectively. Formulations RE3 and RE6 showed rapid DT than other formulations Table 3 due to higher concentration of effervescent agents in these two formulations and the comparison of in-vitro and in-vivo DT is shown in Figure 2. The acid-base reaction, water penetration into tablet and swelling of disintegrating agent (L-HPC) are suggested to be the mechanism for disintegration of the tablets.

After evaluation it was found all the tablets gave a good palatable mouth feel Table 3. Moreover, tablets containing sodium bicarbonate and citric acid in the ratio of 8:7(%w/w) were found to be optimum for producing soothing fizz, excellent palatability and good taste in oral cavity.

From the in-vitro dissolution study for all the designed formulations, tablets showed an average of 90% and above drug release at the end of 25minutes. It was observed that formulation RE6 showed the maximum drug release giving a better dissolution profile than other formulations Figure 1.

Formulations RE3, RE4 and RE6 were selected for stability studies on the basis of high cumulative % drug release, in-vitro and in-vivo disintegration time studies. These were stored at 25⁰C/60% RH and 40⁰C/75% RH. For every 10 days time interval the tablets were analyzed for drug content uniformity, hardness, disintegration time and friability up to 30 days. These formulations showed not much variation in any parameter. The results indicated formulations RE3, RE4 and RE6 are stable and retained their original properties.

CONCLUSION:

It can be concluded from the following study that a stable, effective and pleasant tasting mouth dissolving tablets, which had a good balance over the disintegration time and mechanical strength can be developed using citric acid and sodium bicarbonate as effervescent agents. Thus to improve the patient compliance, bioavailability and palatability, effervescence can be employed in the formulation of ranitidine HCL effervescent mouth dissolving tablet.

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Received on 01.01.2010 Modified on 04.02.2010

Research J. Pharm. and Tech. 3(2): April- June 2010; Page 596-599