INTRODUCTION:
The breadth and scope of ion exchange resin (IERs) seem inexhaustible. Their use as solid insoluble chemicals in the manufacturing industries is growing with today’s search for improved processing method. The IERs can be used for taste masking, stabilization of sensitive drug components, sustained release of drug and as tablet disintegrant.1-4 Ion exchange resins are solid and suitably high molecular weight polyelectrolytes that can exchange their mobile ions of equal charge with surrounding medium reversibly and stoichiometrically. Bitter drugs can get adsorbed onto ion exchange resins to form complexes, which is non-bitter. The resinates can be formulated as lozenges, chewing gum, suspension or dispersible tablets. The complex of drug and resin does not break at pH 6.7 of saliva with cation concentration of 40 meq/Lit. But at high cation concentration of stomach and pH of 1-3, free drug is immediately released. In this study Indion 204 have been used to mask the taste of bitter drug norfloxacin, a fluroquinolone antibacterial agent with superior antibacterial activity.
MATERIALS AND METHODS:
Norfloxacin was gifted by the Universal Medicament, Nagpur. Indion 204 was received as a gift sample from Ion exchange India Ltd. Mumbai. Other chemicals used were of AR grade.
Resin pretreatment:
The bed of the resin was treated with 5 to 10 bed volume of deionised water and the suspended ultrafine particles were removed to get uniform particle size. The resin was then washed consecutively with methanol, benzene and deionised water to remove organic and coloured impurities. The resin was activated by alternate treatment with 1N hydrochloric acid and 1N sodium hydroxide in order to remove the resin derived product in the solution.5 Finally the resin bed was treated with 1N HCl for 4 hrs and then rinsed with deionised water till free from excess of H+ ions which was determine by the pH meter. The resin was then drained on a Buchner funnel using mild suction and then air dried.
Preparation of drug resin complexes:
The drug resin complexes were prepared by batch process5. An accurately weighed amount of Norfloxacin (1 gm) was taken and stirred with acidified distilled water (0.4 mL acetic acid in 10 mL water) with the help of magnetic stirrer for about 5 min. Then known weight of ion exchange resin was added to this solution and stirred on magnetic stirrer for 2 hrs. Resinates obtained were washed with deionised water to remove uncomplexed drug. The complexes were dried overnight in a hot air oven at 50 C and then stored in tightly closed desiccators.
Optimization of drug loading:
Buffer solutions of varying pH were used to study the effect of pH on drug loading. One set of solutions containing Norfloxacin (1gm) were prepared in 100 mL buffer solutions. Indion 204 was added. The pH of solutions were adjusted at 3.0, 4.0, 5.0, 6.0, 7.0 and 8.0 and the solutions were stirred on magnetic stirrer till the equilibrium was achieved and the drug content was determined. The drug loading was determined by finding the difference between amount of drug present in the stock solution and amount remaining in filtrate at the end of equilibrium6. Four batches containing drug: resin in the ratio of 1:1, 1:2, 1:3, 1:4 were prepared with Indion 204 to optimize drug resin ratio. The pH of the solutions were adjusted to 7.
Determination of drug content of resinate:
About 50 mg drug equivalent resinate was weighed and taken in 100 mL volumetric flask, volume was made with 0.1M sodium hydroxide and stirred for 30 min. and then solution was filtered. The filtrate, following suitable dilution, was assayed spectrophotometrically using double beam spectrophotometer (Shimadzu Inc., Japan) at 273 nm.
Determination of properties of resin and resinate:
Size and shape of resin and resinate was determined by motic microscope. Angle of repose was determined by funnel method. Bulk density was determined by taking weighed quantity of material in measuring cylinder tapped on hard surface 100 times and volume occupied was noted before and after tapping.
Taste evaluation:
The taste of resinate was checked by panel method.6 For this purpose, 10 human volunteers were selected. In this a sample equivalent to normal dose was placed on tongue and taste evaluated after 10 sec. Bitterness level were recorded immediately and then at 1, 2, 5, 10 and 15 min.
In vitro release of Norfloxacin:
Resinates of Norfloxacin with Indion 204 and Indion 264 were subjected to in-vitro dissolution studies using USP 24 method. Weighed quantity of resinate equivalent to normal dose was suspended in 0.1N HCl using USP dissolution apparatus type II and the quantity of drug released was determined periodically by withdrawing samples from the vessels. The volume withdrawn was replaced with equal volume of 0.1N HCl.
Formulation of suspension:
The primary syrup was prepared by dissolving 40% of sugar in hot distilled water and filter through whatman filter paper. To the above syrup sodium carboxymethyl cellulose, methyl paraben and propyl paraben were added slowly with constant stirring and kept overnight. Glycerin and tween 80 were added to it. Lastly the resinate was added with the continuous stirring in small portions till complete mixing occurs. Color and flavor were added as per the requirement.
Evaluation of developed suspension:
The developed suspension was evaluated for viscosity, sedimentation volume, pH, and zeta potential.
Accelerated stability studies:
All the developed formulation subjected to accelerated stability testing for about 30 days. The accelerated stability studies were done at different temperature i.e. at 4 C, room temperature and 45 C for 30 days. The effect of aging and temperature was observed on the drug content, viscosity and pH.
RESULT AND DISCUSSION:
Masking the bitter taste of drugs has been an objective of pharmaceutical formulator. Many strategies have been adopted to achieve this goal. In the present study a bitterless suspension was developed using ion exchange resin. Norfloxacin which is a broad spectrum antimicrobial drug with very bitter taste was chosen as a drug model. For the preparation of resinates, batch method was preferred because of its convenience. Indion 204 shows maximum adsorption of Norfloxacin, which may be attributed to the difference of crosslinking, exchange capacity and form of resin.
The pH also has important role as ionization of resins are vulnerable to changes in the pH. Results of the effect of pH on drug loading study revealed that best loading occurs at pH 7 (Figure 1). The drug loading was carried at pH 7 as it showed optimum loading. The process for preparing drug resinates was optimized for drug loading at different drug: resin concentration. The study revealed that maximum drug loading occurs for drug: resin in the ratio 1:2.5 as shown in Table 1. The drug content in the resinate was found to be 99.12 %.
Figure 1: Effect of pH on drug loading.
Table 1: Effect of drug resin ratio on the drug loading
|
Drug:resin |
% drug loading |
|
1:1 |
79.84 |
|
1:1.5 |
84.90 |
|
1:2 |
95.15 |
|
1:2.5 |
98.36 |
|
1:3 |
96.60 |
Micromeritic properties such as size shape, angle of repose, bulk density were evaluated. Micromeritic evaluation showed that all the properties of the resins were retained in the complex which was important from the formulation point of view as shown in Table 2 and Figure 2.
Table 2: Physical parameter of prepared resinate with that of the Indion 204
|
Character |
Indion 204 |
Resinate |
|
Size |
Less than 200 |
Between 80-159 |
|
Shape |
Irregular |
Irregular |
|
Angle of repose |
29.74 |
11.88 |
|
Bulk density |
0.75 |
0.87 |
A) Indion 204 Resin
B) Indion 204 Resinate
Figure 2: Particle shape of A) Indion 204 resins B) resinates
For taste masking evaluation the resinate was given to the panel of healthy human volunteers. Time intensity method showed satisfactory masking of the bitter taste of norfloxacin (Table 3).
Table 3: Evaluation of taste of resinate
|
Volunteers |
Bitterness level after* |
|||||
|
10 sec |
1 min |
2 min |
5 min |
10 min |
15 min |
|
|
1 |
<2 |
<1 |
X |
X |
0 |
0 |
|
2 |
X |
X |
X |
0 |
0 |
0 |
|
3 |
X |
X |
X |
0 |
0 |
0 |
|
4 |
>1 |
X |
X |
X |
0 |
0 |
|
5 |
X |
0 |
0 |
0 |
0 |
0 |
|
6 |
<2 |
>1 |
1 |
X |
0 |
0 |
|
7 |
<1 |
X |
X |
0 |
0 |
0 |
|
8 |
X |
0 |
0 |
0 |
0 |
0 |
|
9 |
X |
0 |
0 |
0 |
0 |
0 |
|
10 |
X |
X |
0 |
0 |
0 |
0 |
This complexes were then subjected to dissolution studies in 0.1 N HCl using USP basket apparatus at 100 rpm and 37 C showed that more than 98% of the drug was released in 25 min and thus making the drug in the resinate bioavailable (Figure 3).
Figure 3: In-vitro drug release profile of resinates
The six different suspensions were prepared using varying concentration of ingredients and evaluated for physicochemical parameter (Table 4).
Table 4: Evaluation of physical properties of suspension
|
Batch No. |
Viscosity (cps) |
pH |
Sedimentation volume |
Zeta potential |
|
S1 |
132 |
5.02 |
0.58 |
0 |
|
S2 |
114 |
5.00 |
0.55 |
1.18 |
|
S3 |
109.2 |
4.99 |
0.62 |
1.18 |
|
S4 |
144.8 |
5.18 |
0.46 |
2.14 |
|
S5 |
353 |
5.12 |
0.28 |
1.82 |
|
S6 |
770 |
5.00 |
0.20 |
2.29 |
Formulation S1, S2, S3 showed acceptable values of viscosity, pH and sedimentation volume and zeta potential compared to other three formulations. The developed Norfloxacin suspension kept for accelerated stability studies to observe the effect of aging and temperature on the various parameters such as viscosity, pH and drug content. The result indicated that the viscosity decreases as temperature is increased from 4 0C to 45 0C during the 30 days period. Similar results were observed for pH and drug content. The formulation containing drug resinate was found to be stable. Thus the drug resinate complex was proved to be an efficient carrier for oral liquid taste mask suspension of Norfloxacin.
CONCLUSION:
Use of cation exchange resin offers good method for preparing taste masked substrates of Norfloxacin. Taste evaluation of the drug resinates showed complete masking of the bitterness of the drug. In vitro drug release studies revealed that more than 90% of the drug was released within 20 min from the drug resinates. Sweet palatable aqueous suspension of norfloxacin was formulated successfully with drug-resin complex and it was found to be stable
ACKNOWLEDGEMENT:
The author wish to thanks Universal Medicament Pvt.Ltd , Nagpur, India for providing the gift sample of Norfloxacin. The authors wish to thanks Ion-Exchange India ltd. Mumbai, India for providing Indion resin samples.
REFERENCES:
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2. Borodkin P, Sunderberg DP. Polycarboxylic acid ion exchange resin adsorbate for taste coverage in chewable tablets. J. Pharm. Sci. 1971; 60(5):1523-1527.
3. Fu Lu MY, Borodkin S, Woodward L. A polymer carrier system for taste masking of macrolide antibiotics. Pharm. Res. 1991;8(3):706.
4. Manek SP, Kamat VS. Evaluation of Indion CRP244 and Indion CRP254 as sustained release and taste masking agents. Int J. Pharm. Sci. 1981;.43(3):209-212.
5. Bhalekar MR, Avari JG, Umalkar RA, Markandeeywar T. Ion exchange resin for reduced hygroscopicity of ranitidine HCl. Int.J.Pharm.Excip. 2006;12(4):121-124.
6. Donfer K. Ion exchanger properties and applications. Arbur science publisher; 1972: 3rd ed:ppp. 2.
Received on 30.06.2010 Modified on 02.07.2010
Accepted on 31.07.2010 © RJPT All right reserved
Research J. Pharm. and Tech. 4(4): April 2011; Page 530-532