INTRODUCTION:

The concept of mouth dissolving Drug Delivery System emerged from the desire to provide patient with more conventional means of taking their medication. In some cases such as motion sickness, sudden episodes of allergic attacks or coughing and unavailability of water, swallowing conventional tablets may be difficult. Pediatric and geriatric patients experience particularly the difficulty. Such problems can be resolved by means of mouth dissolving tablet. When put on tongue, this tablet disintegrates instantaneously, releasing the drug, which dissolves or disperses in the saliva. Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach. In such cases, bioavailability of drug is significantly greater than those observed from conventional tablet dosage form¹.

An innovative dosage form, usually uncoated tablet form, which disintegrates and dissolves in saliva within few seconds (without the need of drinking water). They are also known as fast dissolving tablets, rapid melts, melt in mouth tablets, orodispersible, quick dissolving or rapidly disintegrating tablets and porous tablets.

Loratadine is practically insoluble. For poorly soluble orally administered drugs, the rate of absorption is often controlled by the rate of dissolution. The rate of dissolution can be increased by increasing the surface area of available drug by various methods (micronization, complexation and solid dispersion)². Solid dispersion techniques have been commonly used to improve dissolution and bioavailability of poorly water soluble drugs, in general, include micronization, the use of carriers and the formation of solid dispersions². Chiou and Riegelman³ outlined 6 types of drug-carrier interactions in solid state dispersions; simple eutectic mixtures, solid solutions, glass solutions, glass suspensions, amorphous precipitates and compound or complex formation. Other factors such as increased wettability, solubilization of the drug by the carrier at the diffusion layer, and the reduction or absence of aggregation and agglomeration may also contribute to increased dissolution⁴. Among the carriers used in the formation of solid dispersions, polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP) is the most commonly used. The PEG shows excellent water solubility, low melting point, low toxicity, high viscosity, wide drug compatibility and hydrophilicity; the molecular weight range used in the formulation of solid dispersions ranges from 1000-20,000 daltons^4,5.

The basic approach used in the development of fast-dissolving tablets is the use of superdisintegrants⁶. The task of developing rapidly disintegrating tablets is accomplished by using a suitable diluent’s and superdisintegrant. The widely used superdisintegrants are sodium starch glycolate, crospovidone, and croscarmellose sodium. Like diluents, each superdisintegrant has strengths and weaknesses. Another approach used in developing such tablets is maximizing pore structure of the tablets⁷. Freeze-drying⁸, vacuum-drying techniques⁹, tablet molding¹⁰ and direct compression methods¹¹ have been tried by researchers to maximize the pore structure of the tablet matrix.

Material and methods:

Loratadine were received as gift sample from Zydus Cadila Lab, Ahmedabad, croscarmellose sodium, crospovidone, sodium starch glycolate, microcrystalline cellulose and aspartame were received as gift sample from M/s Ranbaxy Labs. Pvt. Ltd. Dewas, India. Polyethylene glycol (PEG) 6000, Polyvinyl Pyrrolidone (PVP) K-30, Talc, magnesium stearate and strawberry flavor were purchased from SD Fine Chem. Ltd., Mumbai, India. All other chemicals and reagents used were of analytical grade.

Preparation of solid dispersion by solvent evaporation method:

Loratadine and carriers were weighed accurately in the different ratios and triturated in a mortar and pestle for 5 min. This physical mixture was dissolved in 50 ml of acetone with constant stirring. The solvent was removed by heating, temperature maintained at 45 ºC. The preparations were further dried in a dessicator for 12 h and passed through sieve (# 60).

Characterization of solid dispersion:

Solubility:

The solubility studies were preformed by taking 10mg of solid dispersion from the each batch (SD-A and SD-B) and dissolve in SGF and PBS kept in mechanical shaker for 30 min at 30ºc. Samples were taken after 30min from each volumetric flask and absorbance were measured by visible spectrometer.

FTIR of solid dispersion:

FTIR spectrum of solid dispersion was taken from solid powder material and compared with pure loratadine spectra by overlapping the spectra.

Comparison of in vitro dissolution of pure loratadine and solid dispersion:

Accurately weight amount of pure loratadine (10 mg) was introduced into the dissolution medium (phosphate buffer pH 6.8) and predetermined time intervals (10 min.) 10ml sample were withdraw and replaced with fresh dissolution medium. Samples were filtered and 1 ml of this filtrate was further diluted with methanol to 10 ml and analyzed using a UV spectrometer (shimadzu UV) at wavelength of 248 nm. Similarly weight amount of solid dispersion (representing 10 mg drug) was introduced into the dissolution medium and 10 ml samples were withdrawn at predetermined time intervals (10 min.).

Further dissolution study to confirm the fastest dissolution all the solid dispersions were evaluated in the 10 min. run time by withdrawn samples at 1 min. time intervals.

Formula ®	Cumulative % released
Formula ®	SD-I	SD-II	SD-III	Drug
Wt taken (mg) ®	94	105	44.05	10
Time in min.
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18	0.00 7.20 10.40 13.11 15.17 17.13 19.21 22.09 25.13 27.59 29.97 32.40 34.37 37.14 42.23 45.03 48.23 53.19 57.37	0.00 10.80 13.19 20.34 25.00 27.19 32.40 39.13 43.21 49.21 58.93 61.33 63.71 65.19 67.37 69.43 71.97 75.17 79.21	0.00 20.39 27.59 47.00 56.13 63.59 70.79 75.13 79.20 82.80 94.79 100.23 100.23 100.23 100.23 100.23 100.23 100.23 100.23	0.00 1.19 4.70 5.40 5.99 6.23 6.64 7.04 7.35 7.89 7.94 8.09 8.25 8.51 8.70 8.92 8.98 9.08 9.19

Tablets formulation:

First tablets formulation was developed from loratadine-PEG 6000 (1:3) solid dispersion using Avicel pH 102 (microcrystalline cellulose) as diluents and superdisintigration. The tablets was found to have very less hardness, therefore other excipients were evaluated for formulation of tablet like mannitol, which gives some better strength but longer disintegration time in comparison to tablet prepared only with MCC, so the mixture of both was selected to be added to formula a tablet by direct compression in different proportion and evaluated.

Evaluation of mouth dissolving tablets

General characteristic

Formulations	Description	Thickness
FLT-1	Off white, circular shape, flat tablets.	2.0 mm
FLT-II	Off white, circular shape, flat tablets.	2.16 mm
FLT-III	Off white, circular shape, flat tablets.	2.16 mm
FLT-IV	Off white, circular shape, flat tablets.	2.20 mm

FLT= final loratadine tablet

Uniformity of weight:

Tablets prepared by all four formula, complies the pharmacopoeial specification for uniformity of weight.

Crushing Strength:

Hardness was found least where the amount of Avicel pH102 and mannitol were at the lower level, while the higher level of both the excipients produced the better hardness for tablet to withstand handling.

Formula

Hardness (kg/cm²)

Average

FLT-I

FLT-II

FLT-III

FLT-IV

1.83

1.33

2.83

2.66

Friability of tablets:

The friability was found negative for all formula but was expectable with FLT-III.

Wetting time:

Formula

Time in seconds

Average

FLT-I

FLT-II

FLT-III

FLT-IV

62.00

71 .00

80.00

78.00

0 sec. 34 sec.

68 sec. 80 sec.

Image 1. Wetting time of tablet

Modified disintegration test:

Formula

Time in seconds

Average

FLT-I

FLT-II

FLT-III

FLT-IV

68.50

65.00

72.00

69.00

Initial After 10 sec.

After 30 sec. After 60 sec.

Image 2. Modified disintegration time of tablet

RESULT AND DISCUSSION:

Solubility studies:

The solubility of loratadine in water was found to be 1.2 µg/ml, therefore, loratadine can be considered as a practically insoluble drug. The drug is also available in crystalline form. According to observations obtained from the solubility analysis of physical mixture of drug and both carriers, there were no significant changes seen in the solubility of drug as compared to that of pure drug. The solid dispersion solubility of the PEG 6000 systems were found to be maximum as compared to PVP K-30 solid dispersion systems and also it was observed that the solubility of drug enhanced with increasing the concentration of both the carriers in these solid dispersion formulations.

Fourier Transform Infrared Spectroscopy (FTIR):

The FTIR studies were carried out to investigate the possible interactions between the aceclofenac and carriers (PEG 6000 and PVP K-30) in the solid dispersion formulations. The reason might be interaction of O-H of loratadine and oxygen atom in PEG 6000. The interaction is also possible between the acidic group of drug and carbonyl group of carrier in hydrogen bonding. The absorption bands which can be assigned to the free O-H and involved in intramolecular hydrogen bonding is disappeared the reasons for interacted hydrogen bonding between O-H of loratadine.

Drug content of solid dispersions:

Percent drug content of various solid dispersion formulations was found to be 95±2% for all the solid dispersion formulations.

In vitro drug release studies of solid dispersions:

The drug release patterns of solid dispersion formulations of PEG 6000 and PVP K-30 in PBS (pH 6.8) were compared with the dissolution profile of the drug. It is evident that the rate of dissolution of pure drug is very low, only 9.19 % of the drug being dissolved within 18 min. Dispersion of the drug in the hydrophilic carrier’s considerably enhanced dissolution compared to the pure drug⁴. The dissolution rate of the solid dispersion formulations was higher compared to pure loratadine. The dissolution rate was found significantly faster when evaluated solid dispersion of PEG 6000, in different ratio. Formulation SD-III showed the fastest dissolution with the entire drug amount released within 11 min. Possible mechanisms of increased dissolution rates of solid dispersions have been proposed by Damian et al.,2000^[4] and Ford 1986¹², and include, improved wettability and dispersibility of drug from the dispersion, a solubilization effect of the carrier, absence of the aggregation of drug, reduction of drug crystallinity, dissolution of the drug in the hydrophilic carrier and conversion of the drug to the amorphous state. The increased dissolution rate observed in this case can thus be contributed by several factors such as a solubilization effect of the carrier, dissolution of the drug in the hydrophilic carrier, conversion of the drug to the amorphous state and improved wettability and dispersibility of the drug.

General characteristic of tablets:

All the prepared tablets are characterized by a uniform thickness. It was observed that the variation of thickness was insignificant (P≤0.5).

Percentage drug content of tablets:

Percent drug content of various formulations was found to be 95±5% for all the formulations.

Limit: Drug content should be in the range of 90 to 110 %.

Weight variation of tablets:

The weight variations of tablets were determined according to the specifications in USP and all the tablets were found to comply with specifications¹³. The tablets weight range of average ±7.5% produced were of uniform weight with acceptable weight variation.

Friability of tablets:

The friability of all formulations was found to be less than 1 %. The result shows resistance to loss of weight indicated the tablet ability to withstand abrasion in handling, packaging and shipment¹⁴.

Hardness of tablets:

A tablet requires certain amount of hardness to withstand the mechanical shocks in handling, packaging and at the time of application.

Wetting time of tablets:

Wetting times for tablets prepared with three superdisintegrants. Wetting times of the tablets decreased with increase in the level of crospovidone (62-80 sec). Crospovidone containing tablets shows lower wetting time as compared to another superdisintegrants. Thus wetting time of tablets with crospovidone< croscarmellose sodium< sodium starch glycolate.

Disintegration time of tablets:

In the present study, all the tablets disintegrated in less than 75 seconds (according to European Pharmacopoeia time required less than 3 min). It was observed that disintegration time of tablets in PBS (pH 6.8) decreased (73 to 59 sec) with increase in the level of crospovidone. Disintegration times of tablets follows the pattern with various superdisintegrants crospovidone <croscarmellose sodium <sodium starch glycolate. The porous structure of the tablets is responsible for faster water uptake.

SUMMARY AND CONCLUSION:

Mouth dissolving tablets get dissolve/disintegrate in mouth quickly which can be easily swallowed. This characteristic feature is useful for patient compliance. The time required for complete wetting was few seconds hence tablets disintegrate rapidly in oral cavity. Thus the release rate of loratadine can be significantly enhanced by rapidly disintegrating superdisintegrants.

Loratadine is water insoluble drug but high permeable in nature according to BCS and this refers to as class-II drug. Chemically loratadine is a weak basic drug with pKa value 5. This indicates that high amount of drug will be unionized at all pH values and therefore their absorption is pH-independent.

Poor solubility of loratadine can be attributed to its hydrophobic nature, poor wettability and evidence of particle agglomeration during the dissolution. Improvement in dissolution due to the increased wettability, decreased particle size of drug and prevention of the aggregation of drug. Loratadine is found to be suitable to formulate in complex formation to improve solubility in phosphate buffer pH 6.8.

Since results of dissolution of tablets were found similar to that of solid dispersions indicates the addition of microcrystalline cellulose (Avicel pH 102) to the solid compressing the solid dispersion and thus enhancing the disintegration and dissolution rate by rapidly swelling without destruction of contact with water. Presence of mannitol creates a better microenvironment for dissolution of the drug and provides better compressibility of the formulation. As mannitol is not hygroscopic in the nature, so suitable for stability of formulation containing moisture sensitive MCC. In this case, the presence of Ac-dil-sol with MCC and mannitol showed over an increase in hardness compared to that only with MCC. In this case, the presence of cross-carmellose sodium with MCC and mannitol showed over an increase in hardness compared to that only with MCC. Formulation (FLT-3) and (FLT-4) exhibited intermediate dissolution characteristics and showed no significant difference in dissolution time but formation (FLT-2) having lesser amount of mannitol and higher amount of MCC showed fastest release. The friability results were found of as out of specification except (FLT-3).

From the present study it may be concluded that mouth-dissolving tablets can be prepared by conventional direct compression method using solid dispersion of superdisintegrant which, shows rapid rate of disintegration. For better hardness, less friability, faster wetting and less moisture uptake combination of both MCC and mannitol is required in the formulation. It concludes formula having 72 mg MCC and 48 mg mannitol is suitable as mouth dissolving tablet.

The best formulation (FLT-3) has shown a 100% drug release in 18 min with a total disintegration time in just 72 seconds assures a desired characteristic of a mouth dissolve formulation Though the main effect is release of drug was best in formulation containing 144 mg MCC and 24 mg mannitol but the selection of formula for tablet formulation will depend on other characteristic also which indicate the formula with 72 mg MCC and 48 mg mannitol is suitable for tablet as result of release study is not varying at much extent.

ACKNOWLEDGMENT:

Authors are thankful to Zydus Cadila Pharma Labs. Ahmedabad for the gift sample of Loratidine and also thankful to Ranbaxy Labs. Pvt. Ltd. Dewas for the provided gift sample of superdisintegrants, microcrystalline cellulose and aspartame.

References:

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4. Damian F, Blaton N, Naesens L, Balzarini J, Kinget R, Augustijns P and Mooter GV. Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14. Eur. J. Pharm. 2000; 10:311-322.

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8. Corveleyn S, Remon JP. Freeze Dried disintegrating tablets. US Patent No. 456010719(2000).

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10. Dobetti L. Fast melting tablets developments and technologies. Pharm. Technol. Eur. 2000; 12:32-42.

11. Bi Y, Sunada H, Yonezawa Y, Danjo K, Otsuka A, Iida K. Preparation and evaluation of a compressed tablet rapidly disintegrating in oral cavity. Chem. Pharm. Bull. (Tokyo). 1996; 44:2121-2127.

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Received on 04.03.2011 Modified on 13.03.2011

Research J. Pharm. and Tech. 4(11): Nov. 2011; Page 1676-1681

S. No	Solvents	Pure drug mg/10ml	Drug-PEG 6000 (SD-A)			Drug-PVP K-30 (SD-B)
S. No	Solvents	Pure drug mg/10ml	SD-I (1:1) mg/10ml	SD-II (1:2) mg/10ml	SD-III (1:3) mg/10ml	SD-I (1:1) mg/10ml	SD-II (1:2) mg/10ml	SD-III (1:3) mg/10ml
1.	SGF	0.129	0.415	0.607	0.779	0.313	0.437	0.619
2.	PBS	0.121	0.413	0.585	0.738	0.411	0.419	0.617