*Corresponding Author:
Purnima Amin
Pharmaceutical Division, University Institute of Chemical Technology, Matunga, Mumbai-400 019, India
E-mail: [email protected]
Date of Submission 16 November 2004
Date of Revision 25 April 2005
Date of Acceptance 25 February 2006
Indian J Pharm Sci, 2006, 68 (1): 117-119  

Abstract

The present research paper introduces Indion 414, an ion exchange resin, as a new superdisintegrant for pharmaceutical dosage forms. Indion 414 is a pharmaceutical grade weak acid cation exchange resin. Model drugs belonging to various classes were taste masked and formulated into palatable mouth dissolve tablets. Experiments were carried out to evaluate the disintegrant property of Indion 414 by incorporating Indion 414 in fast disintegrating dosage form like mouth dissolve tablets. Indion 414 was compared with the conventional disintegrants to determine its relative efficacy.

Fast dissolving drug delivery is rapidly gaining acceptance as an important new drug delivery technology [1,2]. Not all fast dissolving technologies actually dissolve; some use different disintegration mechanisms such as high levels of disintegrants [3,4] and/or effervescent agents that cause the dosage form to disintegrate rapidly in the patient’s mouth within a minute and can be gulped easily without the need of water. Thus, it offers increased patient compliance and convenience. The present work was aimed to formulate and evaluate efficacy of Indion 414 in formulation of palatable fast disintegrating dosage form like mouth dissolve tablets. Mouth dissolve tablets are dosage forms, which when placed in the mouth, disintegrate or dissolve in the saliva within a minute without the aid of water or chewing [5]. Indion 414 is a high-purity pharmaceutical grade weak acid cation exchange resin available as a dry powder in potassium form. It is manufactured in an FDA-approved manufacturing facility. The parent material is manufactured in an ISO 9001 and ISO 14001 certified facility. Indion 414 is safe for oral consumption, costeffective and is easily available. The advantages of ion exchange resins as superdisintegrants as compared to conventional ones are that they swell on getting hydrated but do not dissolve or have an adhesive tendency, a feature commonly encountered with gums. Thus the tablet disintegrates evenly. Ion exchange resins are efficient at considerable lower levels than recommended for conventional disintegrants. They facilitate the compression phase by conferring greater hardness to the tablets [6]. Ion exchange resins work equally efficiently with hydrophilic and hydrophobic formulations, especially with the latter where the conventional disintegrants are ineffective [6].

Indion 414 appears as a white-to-pale coloured powder, free from foreign matter. It is insoluble in water and in common solvents. Its matrix is made of cross-linked acrylic copolymer and is available in potassium form with carboxylic acid functional group. The specifications of Indion 414 are as given in Table 1. For effective disintegration of the tablet, 0.5 to 2% of Indion 414 is recommended. The advantages of Indion 414 as a tablet disintegrant include remarkable swelling tendency on wetting, thus causing rapid disintegration; there is no lump formation on disintegration; and it is compatible with commonly used therapeutic agents and excipients. Indion 414 does not stick to punches and dies.

Parameter Specification
Particle size distribution  
Retained on 100 BSS mesh 1% maximum
Retained on 100 BSS mesh 30% maximum
Moisture content 10% maximum
Sodium content 0.2% maximum
Potassium content 20.6 to 25.1%
pH of 10% slurry 7-9
Iron content, as Fe 100 ppm, maximum
Heavy metals, as Pb 20 ppm, maximum
Arsenic content 3 ppm maximum

Table 1: Specifications For Indion 414

Indion 414 was obtained as a gift sample from Ion Exchange India Ltd, Mumbai. Excipients for tablets were gifted by Signet Chemical Corporation, Mumbai. All solvents used were of analytical grade and were purchased from S. D. Fine Chemicals, Ltd, Mumbai.

The drugs selected for the study were roxithromycin, dicyclomine hydrochloride and montelukast sodium. Roxithromycin, chemically erythromycin 9 [o-(2-methoxyethoxy)- methyl-1]–oxime, is a macrolide antibiotic, widely used in the treatment of mild to moderate infections of the ear, nose and respiratory tract. Dicyclomine hydrochloride is an antispasmodic agent. Montelukast Sodium is an oral antiasthmatic agent. Bitter drugs like roxithromycin and dicyclomine hydrochloride were taste masked using ion exchange resins. The complexes along with the diluent were granulated with PVP K29/32 in Isopropyl alcohol. The wet mass was screened through 16 mesh and dried at 60° for 30 min. The dried granules were then screened through 40 mesh. Indion 414 was added extragranularly. Excipients were screened through 60 mesh. The blend was then compressed on a Cadmach single-stroke punch machine to give tablet weight of 460 mg [7] containing 50 mg of roxithromycin per tablet, and 200 mg containing 20 mg of dicyclomine hydrochloride respectively. Various formulations were tried to achieve a palatable formulation. Optimized formulations are as shown in Tables 2 and 3.

Ingredients F1 F2 F3 F4
mg/tab mg/tab mg/tab mg/tab
Roxithromycin: Indion 330 330 330 330
204 complex        
Sodium saccharin 3 3 3 3
Monoammonium 3 3 3 3
glycerrhizinate        
Aspartame 15 15 15 15
PVP K29/32 20 20 20 20
Indion 414 10 - - -
Croscarmellose sodium - 10 - -
Sodium Starch Glycolate - - 10 -
Crospovidone - - - 10
Avicel PH  101 59 59 59 59
Menthol 2 2 2 2
Mixed fruit flavor 6 6 6 6
Talc 6 6 6 6
Magnesium stearate 3 3 3 3
Aerosil 3 3 3 3

Table 2: Formulation Of Roxithromycin Mouth Dissolve Tablets And Comparison Of Indion 414 With Existing Super disintegrants

Ingredients F5 F6 F7 F8
Mg/tab Mg/tab Mg/tab Mg/tab
Dicyclomine Hydrochloride: 80 80 80 80
Indion 204 (O) complex        
Sodium saccharin 5 5 5 5
Aspartame 8 4 4 4
PVP K29/32 20 20 20 20
Avicel PH 101 63 63 63 63
Strawberry flavour 6 6 6 6
Indion 414 10 - - -
Croscarmellose sodium - 10 - -
Sodium Starch Glycolate - - 10 -
Crospovidone       10
Talc 4 4 4 4
Magnesium stearate 2 2 2 2
Aerosil 2 2 2 2

Table 3: Formulation Of Dicyclomine Hydrochloride Mouth Dissolve Tablets And Comparison Of Indion 414 With Existing Super disintegrants

Montelukast Sodium, an antiasthmatic agent, was geometrically mixed with excipients including Indion 414 and the blend was directly compressed on a Cadmach single-stroke punch machine. The tablet weight was fixed at 150 mg. Each tablet contained montelukast sodium equivalent to 5 mg of montelukast. Optimized formulations are shown in Table 4.

Ingredients F9 F10 F11 F12
mg/tab mg/tab mg/tab mg/tab
Montelukast Sodium 5.19 5.19 5.19 5.19
(equivalent to 5 mgof        
Montelukast)        
Aspartame 4 4 4 4
Talc 4 4 4 4
Aerosil 2 2 2 2
Magnesium stearate 2 2 2 2
Indion 414 5 - - -
Croscarmallose sodium - 5 - -
Sodium Starch Glycolate - - 5 -
Crospovidone       5
Avicel PH 102 123.31 123.31 123.31 123.31
Menthol 0.5 0.5 0.5 0.5
Strawberry flavour 4 4 4 4

Table 4: Formulation Of Montelukast Sodium Mouth Dissolve Tablets And Comparison Of Indion 414 With Existing Superdisintegrants

The tablets were evaluated for various quality control parameters like appearance, taste, mouth feel, hardness, weight variation, in vitro dispersion time, in vivo dispersion time, drug content and drug release. Hardness of the tablets was determined with a Monsanto hardness tester. One tablet was placed in a beaker containing 6 ml of water. The time required for uniform dispersion of tablet was noted. In vivo dispersion time was determined by placing tablet in the mouth. The results of evaluation of the optimized formulations are depicted in Table 5.

Parameter F1 F5 F9
Appearance Biconvex tablets Off white flat Off white flat
  offwhite in colour bevelled tablets beveled tablets
Texture Smooth Smooth Smooth
Taste Non bitter Non bitter Sweet
Dimensions 12 mm in diameter 9 mm in diameter 9 mm in diameter
Weight variation (mg) ± SD 460 ± 2.87 200 ± 2.15 150 ± 1.87
Hardness (kg/sq-cm) 3-4 3-4 3-4
In vitro dispersion time (s) 15 20 20
Drug content (%) ± RSD 100.12 ± 1.46 101.09 ± 1.28 99.18 ± 1.28
Drug release% (30 min) 87.26 92.89 95.49

Table 5: Evaluation Of Optimized Mouth Dissolve Tablets For Various Quality Control Parameters

Swelling index of the superdisintegrants was studied in simulated saliva. One gram of each sample was transferred to a 100 ml measuring cylinder. Simulated saliva was added up to 25 ml. The measuring cylinder was shaken intermittently for the first 1 h and then kept aside for next 3 h. Volume occupied by the material at the end of 4 h was measured. Swelling index was calculated by the formula: (final volume-initial volume/ initial volume)×100. Complete taste masking of bitter drugs like roxithromycin and dicyclomine hydrochloride was achieved using 1:5 and 1:3 ratio of Indion 204 and Indion 204 (O) respectively. The mouth dissolve tablets were non-bitter with a good mouth feel. F1, F5 and F9 exhibited good dispersion time as compared to others. The results of comparison of in vitro dispersion time of Indion 414 with croscarmellose sodium, sodium starch glycolate and crospovidone are shown in Table 6. The formulations F4, F8 and F12, showed pitted surface, whereas F1, F5 and F9 appeared smooth. The hardness of the formulations was 3-4 kg/sq cm. Drug content of the formulations was within limits with more than 80% of drug release in 30 min. Swelling index of the superdisintegrants is given in Table 7, with Indion 414 showing good swelling.

Superdisintegrants Roxithromycin mouth dissolve tablets Dicyclomine Hydrochloride mouth dissolve tablets Montelukast sodium mouth dissolve tablets
Indion 414 (Ion Echnage India Ltd) 15s 20s 20s
Sodim Starch Glycolate (Primojel) 20s 100s 15s
Crospovidone (Polyplasdone XL) 15s 35s 10s
Croscarmellose sodium (Ac-Di-Sol) 25s 30s 15s

Table 6: Comparative Evaluation Of In Vitro Dispersion Time Of Mouth Dissolve Tablets Containing Various Superdisintegrants

Superdisintegrant   Initial Volume Final Volume Swelling power
Indion 414 1ml 9ml 800
Sodim Starch Glycolate 1ml 17ml 750
Crospovidone 5ml 5ml 20
Croscarmellose sodium 2ml 16 ml 700

Table 7: Comparative Evaluation Of Swelling Volumes Of Various Superdisintegrants In Simulated Saliva

Thus, Indion 414 exhibited very good superdisintegrant action resulting in a cost-effective formulation. Their use can be extended to various other fast disintegrating dosage forms.

Acknowledgements

This work has been sponsored by Ion Exchange (India) Ltd, Mumbai and was presented at the fifth International Symposium on Advances in Technology and Business Potential of New Drug Delivery Systems organized by Controlled Release Society (Indian Chapter) 2004, Mumbai.

References