Formulation, Characterization and Evaluation of Taste-Masked Rapid Disintegrating Tablet of Cefixime by Ion Exchange Resin Technique

 

ABSTRACT:

Cefixime is an oral third generation cephalosporin antibiotic. It is very bitter in taste. In the present work an attempt has been made to develop taste masked rapid disintegrating tablet of Cefixime by using ion exchange resins (Tulsion-335, Indion 204 and Indion 214). Different drug: resin ratios were tried to prepare taste masked complex. Depending upon the taste and drug loading efficiency the complex with Tulsion 335 in the 1:1.5 (drug: resin) ratio was selected for the formulation of tablet. Formulated DRC (Drug Resin Complex) was characterized by infrared spectroscopy. Tablets were prepared by direct compression technique using three super disintegrants e.g. croscarmellose sodium, cross povidone and sodium starch glycolate. Tablets formulated with 8% (F2) croscarmellose sodium showed low disintegration time (45 sec), wetting time (50 sec) and friability (0.28%) than the other batches. Formulated tablets of optimized batch (F2) were also compared with the marketed tablet (ZIFI 50). It was concluded from the study that Cefixime shows optimum drug loading with Tulsion-335. Among different superdisintegrants croscarmellose sodium was found suitable.

 

 

INTRODUCTION:

One of the attractive methods for oral drug delivery systems preferably is the use of ion exchange resins as carrier.¹ Taste masking technologies rely on preventing interaction between the drug molecule and the oral mucosal surface. By creating a physical barrier around each particle, drug substance can be prevented from going into solution and interacting directly with taste receptors. When an ionisable drug reacts with a suitable ion exchange resin the drug- resin complex formed is known as a drug resinate. Because the drug resinate is insoluble it has virtually no taste, so that even very bitter drugs lose their taste when converted into a drug resinate. With the correct- selection of the ion exchange resin, the drug resinate can be made sufficiently stable that it does not break down in the mouth so that the patient does not feel the taste of drug when it is swallowed. However, when the drug resinate comes into contact with the gastrointestinal fluids, usually the acid of the stomach, the complex is broken down quickly and completely. The drug is released from the resinate, directly into solution and then absorbed in the usual way. The resin passes through the GI tract without being absorbed .²

 

Cefixime (CEF) is an oral third generation cephalosporin antibiotic. Chemically, it is (6R,7R)-7-{[2-(2-amino-1,3-thiazol-4-yl)-2-(carboxymethoxyimino) acetyl]amino}-3-ethenyl-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid, clinically used in the treatment of susceptible infections including gonorrhoea, otitis media, pharyngitis, lower respiratory-tract infections such as bronchitis, and urinary-tract infection.³ It has an in vitro activity against a most common pathogens involved in the infection.⁴ Taste masking is an essential requirement for fast dissolving tablets for commercial success. Taste masking of the active ingredients can be achieved by various techniques.⁵ Among those, taste masking by use of ion exchange resin is most commonly used commercially.⁶ Most of the bitter drugs have nitrogen atom and amine as a functional group, which is the cause of their obnoxious taste. If the nitrogen atom and functional groups are blocked by complex formation the bitterness of the drug reduces drastically. Ion exchange blocks the functional group responsible for causing the bitter taste by forming complex between ion exchange drugs doesn't release in the saliva. Thus the resin reduces the drug and taste buds interaction.⁷

 

Cefixime is a BCS class IV drug. In present study an attempt has been made to prepare taste masked rapid disintegrating tablet of Cefixime by using ion exchange resins in different concentration. Taste masked complex was then further used to formulate tablet by direct compression method using sodium starch glycolate, cross povidone and crosscarmellose sodium as the super disintegrants.

 

MATERIAL AND METHODS:

Material

Cefixime trihydrate was obtained as a gift sample from Intas Pharmaceuticals Ahmedabad, Gujarat, Ion exchange resins were obtained from Emcure pharmaceuticals, Pune.

Cefixime mol. Wt. = 453.452 g/mol

Cefixime trihydrate mol. Wt. = 507.45 g/mol

So 55.95 mg of Cefixime trihydrate = 50 mg of Cefixime.

 

Preparation of drug-resin complex ratio

Fixed amount of Cefixime was mixed with different amount of powdered ion-exchange resins i.e. 1:1 and 1:1.5 ratios with the help of distilled water. Firstly the ion exchange resin was allowed to swell for 30 min. in distilled water and then drug is added in to resin and allowed for continuous stirring for a period of 8 hours and kept overnight for complete complexation. Then supernatant was removed and complex was dried in a hot air oven at a temperature of 60^o C and LOD was kept below 3. The dried complex was sifted through sieve no. 40.⁸ Ratio of drug: resin is shown in the Table 1, 2 and 3. To study the effect of stirring time and speed on the solubility of drug, pure drug was also stirred for 8 hours with water and it was taken as standard.

 

Evaluation of effectiveness of taste masking^{9, 10}

The formulation’s organoleptic properties like taste, mouth-feel and appearance are of considerable importance in differentiating products in the market and can ultimately determine the success of a product.

 

In-vivo Method

The in-vivo taste evaluation consists of a double blind crossover study, carried out on a trained taste panel of healthy volunteers with sound organoleptic senses, with their prior consent. By placing complex in the oral cavity, it was held in mouth for 60 sec by each volunteer, and the bitterness level is recorded against pure drug (control) using a numerical scale. After 60 sec, complex is spitted out and the mouth is rinsed thoroughly with mineral water. The numerical scale bears the following values: 0 = tasteless, 1= slight bitter, 2.0 = moderate bitter, 3 = strong bitter.

 

Evaluation of drug loading efficiency

The prepared resinate complex was evaluated for the drug loading efficiency. Accurately weighed 25 mg of resinate (equivalent to 10 mg of Cefixime) was dissolved in 100 ml volumetric flask and volume was made up to 100 with 0.1 N HCl. From this solution 1 ml was withdrawn in a 10 ml volumetric flask and volume was made with 0.1 N HCl and absorbance was noted, from which drug loading was calculated.

 

Selection of drug-Resin complex ratio

Six batches were prepared containing drug resin in the ratio of 1:1 and 1:1.5 for each of the ion exchange resin by above-mentioned method. On the basis of taste and drug loading efficiency resinate complex C6 having ratio 1:1.5 (with tulsion 335) was finalized for further study.

 

Characterization of Solid drug: resin complex

A. Fourier Transform Infra-Red Spectroscopy study (FTIR)

The IR spectrum of Cefixime, Tulsion 335, DRC and tablets (F2) was recorded using Fourier Transform Infra-Red spectrophotometer (Varian, 640 IR) with diffuse reflectance principle. Sample preparation involved mixing the sample with potassium bromide (KBr), triturating in glass mortar and finally placing in the sample holder. The spectrum was scanned over a frequency range 4000 - 400 cm^-1.

 

Formulation of [taste masked] rapid disintegrating tablet by disintegrant addition method^10.11

The tablet consists of resinate equivalent to 50 mg of Cefixime. Avicel (PH 102) and Mannitol were selected as diluents, different super disintegrants such as, croscarmellose sodium (Ac-Di-Sol), crospovidone and sodium starch glycolate in different concentrations.  All the nine batches were prepared by direct compression method using 10 mm flat punches on 8 station compression machine (RIMEK). The hardness of the tablets was kept constant (3-4 kg/cm²). The weight of the tablet of each batch was adjusted to 200 mg. Composition of formulated tablet has been given in the table 4.

 

Evaluation of powder blend¹⁰

The parameters like Bulk density, tapped density, Hausner’s ratio and Angle of repose were calculated for all batches.

 

Evaluation of formulated tablet^12-17

1. Tablet Hardness

For each formulation, the hardness of five tablets was determined using the Monsanto hardness tester.

 

2. Weight Variation Test

Weight variation test is done by weighing 20 tablets individually, calculating the average weight and compare the individual tablet weight to the average.

 

3. Friability

Friability test is performed to assess the effect of friction and shocks, which may often cause tablet to chip, cap or break. Roche friabilator was used for the Purpose. This device subjects a number of tablets to the combined effect of abrasion and shock by utilizing a plastic chamber that revolves at 25 rpm dropping the tablets at a distance of 6 inches with each revolution. Preweighed sample of tablets was placed in the friabilator, which was then operated for 100 revolutions. Tablets were dusted and reweighed. Compressed tablets should not lose more than 1% of their weight.

 

4. Content Uniformity

Five tablets were powdered and the blend equivalent to 50 mg of Cefixime was weight and dissolved in 0.1 N HCl, filtered and drug content analyzed spectrophotometrically at 285 nm.

Table 1: Trials with Indion 204 ion exchange resin

 

Table 2: Trials with Indion 214 ion exchange resin

 

Table 3: Trials with Tulsion 335 ion exchange resin

 

Where,

   0 = tasteless

   1 = slight bitter

   2 = moderate bitter

   3 = strong bitter

 

Fig 1: FTIR spectra of Cefixime

 

Fig 2: FTIR spectra of Tulsion 335

 

Fig 3: FTIR spectra of Cefixime-tulsion 335 complex

 

Fig 4: FTIR spectra of formulated tablet (F2)

 

Fig 5: In vitro dissolution profile of formulation batch F1-F6

 

Fig 6: In-vitro dissolution profile of Formulation batch F2 and marketed formulation

 

Table 4: formulation table of batch F1-F6

Ingredient (mg/tab)	F1	F2	F3	F4	F5	F6
D.R.C.(eq. to 50 mg of Cefixime)	140	140	140	140	140	140
MCC PH102	25	21	17	25	25	21
Mannitol	15	15	15	15	15	15
Sodium saccharine	5	5	5	5	5	5
Cros-povidone	-	-	-	12	-	-
CCS	12	16	20	-	-	-
SSG	-	-	-	-	12	16
Magnesium stearate	3	3	3	3	3	3
Total weight (mg)	200	200	200	200	200	200

DRC: Drug resin complex,

CCS: Croscarmellose sodium,

SSG: Sodium starch glycolate

 

 

Table 5: Evaluation of Powder Blend

 

Table 6: Evaluation of tablets

Parameter	Formulation Batch
	F1	F2	F3	F4	F5	F6
Hardness*  (Kg/cm2)	3.9±0.14	3.5±0.21	3.6±0.31	3.85±0.42	3.5±0.25	3.7±0.35
Friability* (%)	0.35±0.11	0.28±0.21	0.46±0.15	0.31± 0.31	0.37± 0.12	0.43± 0.11
Content Uniformity (%)	99.85	100.32	99.56	101.43	98.76	99.87
Wetting time* (sec)	63±0.65	50±0.41	45±0.72	85±0.64	78±0.56	65±0.63
Uniformity of dispersion	+++	+++	+++	+	++	+++
Disintegration time (sec)	85.33±1.5	46.43±1.3	42.45±2.1	172±1.8	92±2.3	73.32±1.6
Thickness* (mm)	1.9±0.037	2±0.027	2±0.046	1.9±0.065	1.9±0.078	2±0.045
Weight variation*(mg)	200.5±1.5	199.6±1.2	201±1.6	199.2±1.4	200.5±1.5	201±2.1
Water absorption ratio (%)	92.55	98.32	101.67	76.65	86.45	92.32

(*Represent mean ± S.D.) (n=3);  Where, + = not dispersed uniformly;     ++ = Passable dispersion (some fragment remains);

+++ = Uniformly dispersed

 

The tablets complied with the test if not more than one of the individual values thus obtained is outside the limit 90 to 110% of the average value.

 

Table 7: Comparison of evaluation parameter of F2 and Marketed formulation

 

Table 8: Dissolution profile of formulation batch F2 and Marketed formulation

 

5. Wetting Time

A piece of tissue paper folded twice was placed in a small Petri dish (10 cm diameter) containing 10 ml of water. A tablet was put on the tissue paper and allowed to wet completely. The time required for complete wetting of the tablet was then recorded.

 

6. Water Absorption Ratio

A small piece of tissue paper folded twice was placed in a small Petri dish containing 6 ml of water. A tablet was put on the paper and the time required for complete wetting was measured. The wetted tablet was then reweighed. Water absorption ratio, R was determined by using following formula were given

                              R= 100 x Wa-Wb / Wb

Wb is the weight of tablet before water absorption

Wa is the weight of tablet after water absorption

 

7. Uniformity of Dispersion

Place 2 tablet in 100 ml of water and stir gently until completely dispersed. A smooth dispersion is obtained which passes through a sieve screen with a nominal mesh aperture of 710 µm (sieve no.22).

 

8. In vitro Disintegration Study

This test is performed to ensure disintegration of tablets in water, if it is to be used as a dispersible tablet. To be in compliance with the Pharmacopoeial standards, dispersible tablets must disintegrate within 3 minutes when examined by the disintegration test for tablets.

 

9. In-Vitro Release Profile of Formulated Tablets

The dissolution of Cefixime tablets was carried out in USP Type II (Paddle) type dissolution apparatus. The dissolution medium was 900 ml 0.1 N HCL maintained 37⁰C. The basket was rotated at 100 rpm for 30 min. The sample of 5 ml was withdrawn after 5, 10, 15 and 30 min. and its absorbance was measured at 285 nm.

 

RESULT AND DISCUSSION:

Preparation of Drug-resin (resinate) complex

The resinate was prepared by batch process, six batches were prepared using three ion exchange resins. Results were shown in the table 1-3.

 

Selection of Drug: Resin ratio

Three ion exchange resins were tried i.e. Indion 204, Indion 214 and Tulsion 335. The result shows that drug: resin in the ratio of 1:1.5 with tulsion 335(batch C6) has better drug loading as compared to the other. So batch C6 was selected for the formulation of tablets. The results are shown in table 1-3.

 

Evaluation of Taste of Resinate

Resinate of all batches were evaluated for masking of bitter taste of Cefixime. The results are shown in the 1-3.

 

Characterization of Solid drug: resin complex

A)     FT-IR Study

FT-IR spectrum of Cefixime, Tulsion 335 resinate (batch C6) and formulation batch (F2) has been shown in the figure 1, 2, 3 and 4 respectively. Cefixime showed major peak at 1785 cm^-1, 3299 cm^-1, 1587 cm^-1, 1394 cm^-1. Tulsion-335 showed major peak at 1724 cm^-1, 1448 cm^-1. In the resinate also peak were found at 1786 cm^-1, 1660 cm^-1 and at 3299 cm^-1. It was observed that after complexation with tulsion- 335 there is no major shift in the IR spectrum of Cefixime. So it was concluded that the structure of Cefixime remain unchanged after complexation.

 

Evaluation of powder blend

Results of evaluation of powder blend are shown in the table 5.

Evaluation of formulated tablet

Tablets of all batches were evaluated results are shown in the table 6.

 

Three superdisintegrants viz. croscarmellose sodium, cros povidone and sodium starch glycolate were used to formulate the tablets by varying their concentration. For CCS three concentration were tried i.e. 6%, 8% and 10%. In case of cros povidone it was observed that during disintegration there is lump formation and tablet was not disintegrating properly, so only one batch taken with cros povidone.  For SSG two concentrations i.e. 6% and 8% were tried. Batch F2 formulated with CCS (8%) shows less disintegration time (46 sec), uniform dispersion, less friability (0.28%) and good content uniformity (100.32%) as compared to all other batches. In –vitro dissolution studies were also carried out for all batches. Results are shown in the figure 5. Batch F2 shows 99.45 % release of drug within 30 min. So batch F2 was selected as an optimized batch.

 

Comparison of optimized batch (F2) with marketed formulation

Tablets of optimized batch F2 were compared with the tablets of marketed formulation ZIFI 50 with respect to all evaluation parameter for tablet. Results are shown in the table 7 and 8. It was observed that the tablets of batch F2 were found equivalent with respect to the marketed tablet (ZIFI 50). In- vitro release profile of the batch F2 was also good when compared with the marketed formulation (ZIFI 50). In vitro release profile of the tablets (F2) and ZIFI are shown in the figure 6.

 

CONCLUSION:

Use of cation exchange resin offers good method for preparing taste-masked complex of Cefixime. Results obtained in this work show that drug-resin complex effectively masked bitter taste of Cefixime. Thus, complexation of Cefixime with Tulsion 335 increases acceptability and palatability of formulated rapid disintegrating tablets. So finally it is concluded that taste masked rapid disintegrating tablet of Cefixime can be prepared by using Tulsion 335 as a taste masking agent in the ratio of 1:1.5 (Drug: resin) and CCS as a superdisintegrants in the concentration of 8%. The results of this study can also be extrapolated to other intensely bitter drug by suitable selection of resin.

 

ACKNOWLEDGEMENTS:

The author would like to sincerely gratitude to the Intas Pharmaceuticals Ahmadabad, Gujarat, Emcure Pharmaceuticals, Pune, Maharashtra and Maharashtra Institute of Pharmacy, Pune Maharashtra for providing all the requirements.

 

REFERENCES:

1.       Jain N.K. et al. Advances in Controlled and Novel drug Delivery, CBS Publishers and Disributors, 2001.

2.       Jones, P. H. et al. Insoluble Erythromycin salts, Journal of Pharmaceutical Sciences 58 (3); 1969: 337–339.

3.       Sweetman S.C., Martindale, The Complete Drug Reference. Pharmaceutical Press, London 32; 1999:165-166.

4.       Quintilini R, Cefixime: A Pharmacoeconomics Perspective. Current Therapeutic Res.       57; 1996:12.

5.       Kuchekar B.S. et al. Mouth Dissolving Tablets, A novel drug delivery system, Pharmatimes 35; 2003:7-9.

6.       Sharma Vijay and Chopra Himansu, Formulation and evaluation of taste masked mouth dissolving tablets of Levocetrizine hydrochloride, Iranian Journal of Pharmaceutical Research10; 2011.

7.       Madgulkar A.R. et al. Ion Exchange resin in formulation: An update 2007.

8.       Madgulkar A.R. et al. Formulation, design and optimization of novel taste masked mouth dissolving tablets of Tramadol having adequate mechanical strength, American AAPS PharmSciTech, 10(2); 2009: 574-581.

9.       Sona. P. S., Muthulingam C. Formulation and evaluation of taste masked orally disintegrating tablets of Diclofenac sodium, International Journal of PharmTech Research, 3 (2); 2011:819-826.

10.     Dahima Rashmi, Sharma Rajesh, Formulation and invitro evaluation of taste masked ordispersible tablet of Metoclopramidehydrochloride using Indion 204, International Journal of ChemTech Research 2(1); 2010: 447-453.

11.     Ghaste R. P. et al, Fast dissolving tablets: An overview, Pharmainfo.net; 2006.

12.     Kumar R. Et al. Formulation evaluation of mouth dissolving tablets of Fenofibrate using sublimation technique, International Journal of ChemTech Research 1(4); 2009: 840-850.

13.     Patil S. B. et al. Formulation and evaluation of quick dispersible tablet of Olanzapine, International Jurnal of Pharmaceutical Research and Development 7; 2009.

14.     Venkatesh D.P., Geetha Rao C.G., Formulation of taste masked oro-dispersible tablets of Ambroxol hydrochloride, Asian Journal of Pharmaceutics 2(4); 2008: 261-264.

15.     Venkatesh D.P. et al. Formulation, development and evaluation of taste masked oro-dispersible tablets of anti emetic drug, Journal of Pharmacy Research 2(4); 2009: 606-609.

16.     Kuchekar B.S. et al. Formulation and evaluation of Norfloxacin dispersible tablets using natural substances as disintegrants, Journal of Chemical and Pharmaceutical Research, 1(1); 2009: 336-341.

17.     Niladri S.D. et al. Effect of co-processed direct compressible vehicles on fast dissolving tablets, International Journal of PharmTech Research 2(1); 2010: 771-783.

 

 

 

Received on 29.06.2012       Modified on 13.07.2012

Accepted on 29.07.2012      © RJPT All right reserved