Development & optimization of fast Dissolving tablet of levocetirizine HCL

Mehul Dekivadia1, Avinash Gudigennavar2, Chandrashekar Patil1, Bhaskar Umarji1*
  1. 1Dept. of Pharmaceutics, B.L.D.E.A's College of Pharmacy, BLDE University Campus, Bijapur- 586 103, Karnataka, India.
  2. 2Dept. of Pharmaceutics, HSK College of Pharmacy, BVVS Campus, Bagalkot-587101, Karnataka, India.
Corresponding Author: Bhaskar UmarjiDept. of Pharmaceutics, BLDEA's College ofPharmacy, BLDE University Campus, Bijapur-586103, Karnataka, India.E-mail: [email protected]
Received: 13 April 2012 Accepted: 02 May 2012
Citation: Mehul Dekivadia, Avinash Gudigennavar,Chandrashekar Patil, Bhaskar Umarji*"Development & optimization of fast Dissolvingtablet of levocetirizine HCL", Int. J. Drug Dev. &Res., April-June 2012, 4(2): 237-246
Copyright: © 2012 IJDDR, Bhaskar Umarji etal. This is an open access paper distributed under thecopyright agreement with Serials Publication, whichpermits unrestricted use, distribution, andreproduction in any medium, provided the originalwork is properly cited.
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Abstract

Levocetirizine (as Levocetrizine hydrochloride) is a third-generation non-sedative antihistamine, developed from the second-generation antihistamine Cetirizine. Levocetirizine Hcl works by blocking histamine receptors. It does not prevent the actual release of histamine from mast cells, but prevents it binding to its receptors. Fast dissolving tablets of Levocetrizine HCl were prepared using sodium starch glycolate, Croscarmellose sodium and Crosspovidone as superdisintegrants by direct compression method. The tablets prepared were evaluated for various parameters like weight variations, hardness, friability, in vitro dispersion time, drug content, wetting time, in vitro drug release, FTIR and XRD. The tablets prepared by direct compression method possess a weight variation below ±7.5%, hardness of 3 to 4.0 Kg/cm², percentage friability of 0.51 to 0.85, in vitro dispersion time of 17 to 58 seconds, Wetting time of 13 to 48 seconds, and in vitro drug release showed 94% to 99.00% within 20 min. The formulation (MD6) contains Crosspovidone and Sodium Starch Glycolate shows better Disintegration time and 99% drug release within 20 min.

Key words

In vitro dispersion time, Levocetrizine HCl, Fast dissolving tablets, Superdisintegrants.

INTRODUCTION

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. Tablets are the most widely used dosage form because of its convenience in terms of self-administration, compactness and easy in manufacturing1.
Drinking 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 bronchitis2.
Advantages 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.3
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 firstline therapy, but not effective in nasal congestion.4

Primary requirements to manufacture fast dissolving tablets

• Selection of the API(Active Pharmaceutical Ingredients): Ideally the API selection should be dependent upon the potency and therapeutics range of the drug. As the drug load is the major factor to consider for this dosage form as the size of the tablet is dependent upon the dose, potent API may be appropriate to select.
Taste masking: - Most fast dissolvable films must include substance to mask the taste of the active ingredient as with all immediate release products coming in contact with tongue. E.g.: menthol, peppermint, thymol, eucalyptol, fruit punch, bubble gum, fructose, aspartame, sucralose, sucrose.
Selection of a carrier: The properties of the carrier have a major influence on the dissolution characteristics of the dispersed drug. A carrier should meet the following criteria to be suitable for increasing the dissolution rate of a drug.

MATERIAL AND METHODS

Levocetirizine HCl was obtained from Dagon pharmaceuticals pvt. Ltd, Vadodara, (Gujarat), Croscarmellose sodium were obtained from Metro chemical Pvt. Ltd, Solan (H.P.), Crosspovidone and Sodium starch glycolate were obtained from Shreeji chemicals, Mumbai (Maharashtra), microcrystalline cellulose, magnesium stearate, aerosol were obtained from loba chemie pvt. Ltd. Mumbai (Maharashtra).

METHODS

Fast dissolving tablets of Levocetrizine Hcl were prepared by direct compression method according to the formula given in Table-1. All the ingredients were weighed and kept separately. Then the weighed ingredients were mixed in geometrical order with weigh Levocetrizine Hcl and blend together to get uniform mixture. Then tablets were compressed using 6.5mm sizes biconvex round punch to get tablet using Rimek Compression machine.

EVALUATION

Analytical method for estimation of Levocetrizine HCl

Identification of drug was carried out by FTIR (Perkin Elmer Instruments, USA). Standardization of the drug was carried out by using UV visible spectrophotometer (1700-Shimadzu, Japan). XRD (X-ray Diffraction) studies were also carried out to assess drug excipient compatibility.

Standard calibration curve of Levocetrizine HCl in acetate buffer pH 6.87

Solution ranging from 2 to 10 mg/ml were prepared using buffer (pH 6.8); separately, absorbance was measured for each solution at lmax of 231nm using Shimadzu UV/visible 1700 spectrophotometer, graph was plotted for absorbance versus concentration of Levocetrizine HCl.

FTIR Studies:

IR spectra for pure drug Levocetrizine HCl and Levocetrizine HCl fast dissolving tablet formulations like MD1, MD2, MD3, MD4, MD5 and MD6 were recorded in a Fourier transform infrared (FTIR) spectrophotometer (Shimadzu corporation 8600, Japan) with KBr pellets.

XRD Studies

The spectra were recorded using a Philips, PW-171, xray diffractometer with Cu-NF filtered CuKa radiation. Quartz was used as an internal standard for calibration. The powder x-ray diffractometer was attached to a digital graphical assembly and computer with Cu-NF 25 KV/20 mA tube as a CuKa radiation source in the 2q range 0-50o.

Physical Characterization

The fabricated tablets were characterized for weight variation (n=10), hardness (n=5, Monsanto hardness tester), and % friability (n=5, Roche friabilator, ElectroLab, Mumbai, India).

Wetting time

The method was applied to measure tablet wetting time. A piece of tissue paper folded twice was placed in a small petri dish (i.d. = 6.5 cm) containing 10 ml of water, a tablet was placed on the paper, and the time for complete wetting was measured. Three trials for each batch were performed and standard deviation was also determined.

Drug content uniformity

Ten tablets were weighed and powdered. An amount of the powder equivalent to 10mg of Levocetrizine HCl was dissolved in 100ml of pH 6.8 buffer, filtered, diluted suitably and analyzed for drug content at 231nm using UV-Visible spectrophotometer (UV 160 Shimadzu, Japan).

In-vitro disintegration time

I.P. Specifications: Place 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°±2°C as the immersion liquid. The assembly should be raised and lowered between 30 cycles per minute in the pH 6.8 maintained at 37°±2°C. The time in sec. taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured and recorded.

In-vitro dissolution studies

Dissolution rate was studied by using USP type-II apparatus (USP XXIII Dissolution Test Apparatus at 50 rpm) using 900ml of buffer pH (6.8) as dissolution medium. Temperature of the dissolution medium was maintained at 37±0.5°C, aliquot of dissolution medium was withdrawn at every 5 min interval and filtered. The absorbance of filtered solution was measured by UV spectrophotometric method at 231 nm and concentration of the drug was determined from standard calibration curve.

RESULTS AND DISCUSSION

FTIR was used to determine the drug-polymer compatibility; Table 2 shows the FTIR spectra of pure Levocetirizine Hcl and mixture of pure drug and disintegrating agent. The spectra of pure Levocetirizine Hcl shows characteristic peaks at 1742 cm-1 due to stretching vibrations of –COOH group, the peak at 2947 cm-1 due to CH2 stretching and the peaks at 758 cm-1 due to C-CL stretching. The similar peaks were also observed in the spectra of mixture of Levocetirizine Hcl and polymers with slight deviations. This indicate that the drug is stable and there is no drug-disintegrating interaction.
The X-ray diffractograms of pure Levocetirizine Hcl, formulation MD4 and MD6 are presented in fig no 5- 7. Levocetirizine Hcl has shown characteristic intense peaks between 2R of 15° and 25° due to its crystalline nature. Whereas, in the MD4, MD5 and MD6 formulation shows intense peak between 2R of 15° and 30°

Angle of repose (θ)

The data obtained from angle of repose for all the formulations were found to be in the range of 23°.75 and 27°.47. All the formulations prepared by the direct compression technique showed the angle of repose less than 30°, which reveals good flow property.

Bulk density

Loose bulk density (LBD) and tapped bulk density (TBD) for the blend was performed. The loose bulk density and tapped bulk density for the entire formulation blend varied from 0.44 gm/cm3 to 0.49 gm/cm3

Hausner ratio

Hausner ratio of entire formulation showed between1.20 to 1.30 indicates good flow properties.

Carr’s consolidation index

The results of Carr’s consolidation index or compressibility index (%) for the entire formulation blend ranged from 17.85% to 24.13%. The directly compressible granulations had shown excellent compressibility index values up to 15% result in good to excellent flow properties.

Hardness

The hardness of the tablets prepared by direct compression method was maintained within the range of 3.00 kg/cm2 to 4.00kg/cm2 was considered adequate for mechanical stability.

Friability test

The friability was found in all designed formulations in the range 0.51 to 0.85% to be well within the approved range (<1%).The friability study results were tabulated in Table 4.

Weight variation test

The weight variation was found in all designed formulations in the range 98 to 102 mg. The mean weight variation test results are tabulated in Table 4. All the tablets passed weight variation test as the average percentage weight variation was within 7.5% i.e. in the pharmacopoeia limits.

Thickness

The mean thickness was (n=3) almost uniform in all the formulations and values ranged from 2.73 ± 0.020 mm to 3.21 ± 0.017 mm. The standard deviation values indicated that all the formulations were within the range. The results of thickness for tablets were shown in Table 4. The tablet prepared with aerosil showed highest thickness because of their least density.

In- vitro disintegration time

The in-vitro disintegration time is measured by the time taken to undergo complete disintegration. Rapid disintegration within several minutes was observed in all the formulations. The in-vitro disintegration time of fast dissolving tablets prepared by direct compression method were found to be in the range of 19 to 58 sec fulfilling the official requirements. By the addition of super disintegrants the disintegration time increased significantly (P<0.05) tablets prepared. Based on the in-vitro disintegration time, formulation MD4 and MD6 were found to be promising and showed a disintegration time of 19 and 25 sec respectively.

Wetting time

Wetting time is closely related to the inner structure of the tablet. The wetting time of Levocetirizine Hcl tablets prepared by direct compression method were found to be in the range of 13 to 47 sec. Promising formulations MD4 and MD6 showed a wetting time of 16 and 13sec respectively, which facilitate the faster dispersion in the mouth.

Drug Content

The drug content uniformity was performed for all the 9 formulations. All samples were analyzed spectrophotometrically. The percentage drugs content of the tablets were found to be between 93.76 ± 0.9 to 100.0 ± 0.5% of Levocetirizine HCL.

In-vitro dissolution studies

Dissolution rate was studied by using USP type-II apparatus (USP XXIII Dissolution Test Apparatus at 50 rpm) using 900ml of phosphate buffer pH (6.8) as dissolution medium. Temperature of the dissolution medium was maintained at 37±0.5°C, aliquot of dissolution medium was withdrawn at every 5 min. interval and filtered. The absorbance of filtered solution was measured by UV spectrophotometric method at 231nm and concentration of the drug was determined from standard calibration curve.
The dissolution of Levocetirizine Hcl from the tablets is shown in (Fig. 9-10) and (Table 6) shows the drug release profiles. These values changed with change of method of preparation of tablets.In case of tablets prepared by direct compression technique the values decreased with increase in the concentration of croscarmellose sodium, crospovidone and sodium starch glycolate. The rapid increase in dissolution of Levocetirizine Hcl with the increase in sodium starch glycolate may be due to rapid swelling and disintegrating tablets rapidly into apparently primary particles.

STABILITY STUDY

Stability studies for the developed formulations were carried out as per ICH guideline by storing the selected formulations at 40°C/75% RH up to one month. The formulation MD6 was selected on the basis of their high cumulative percentage drug release, and also results of in-vitro disintegration time, wetting time, and in-vitro dispersion studies.
The tablets were analyzed for the colour, hardness, drug content uniformity and cumulative % drug released in-vitro disintegration time up to one month. From the obtained data of tablet evaluation parameters indicated that stable formulations can be developed by direct compression method.

CONCLUSION

Orodispersible tablets of Levocetirizine Hcl were successfully formulated by employing direct compression method. Percentage weight variation and drug content uniformity were found to be within the approved range (Indian Pharmacopoeia Standards) for all the formulations.
The in-vitro disintegration, in-vitro dispersion, wetting time parameters revealed that sodium starch glycolate, croscarmellose sodium, crospovidone alone and in combinations. This acts as superdisintegrants, reveals good results in all the formulations. Among the formulation, MD6 exhibited 99% of drug release within 20 minutes and also less Dis-integration time i.e 19 secs. Therefore MD6 was found to be optimized formulation.The accelerated stability studies carried out for MD4 and MD6 formulation at 400C and 75%RH for one month, after 15 days interval the formulation was examined for physical appearance, hardness, friability, thickness, drug content, disintegration time, dispersion time, wetting time.
The formulation exhibited no change in physical appearance, hardness, friability, thickness, drug content, disintegration time, dispersion time, wetting time revealing excellent stability of the formulated formulation.

Conflict of Interest

NIL

Source of Support

NONE
 

Tables at a glance

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Table 1 Table 2 Table 3 Table 4
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Table 5 Table 6 Table 7
 

Figures at a glance

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Figure 1 Figure 2 Figure 3 Figure 4 Figure 5
Figure 6 Figure 7 Figure 8 Figure 9 Figure 10
Figure 6 Figure 7 Figure 8 Figure 9 Figure 10
 

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