FORMULATION AND EVALUATION OF SUBLINGUAL TABLETS OF NIFEDIPINE

About Authors:
^*DINESH BABU GOTTIPATI¹, SREE DEVI ANANDHAM¹, NANNAPANENI VENKATA BALAKRISHNA RAO².
¹ Department of pharmaceutics, M.E.S.college of pharmacy, Aradeshally gate, Bangalore -562110,India.
² Research and Development Department, Natco Pharma Limited, Kothur.
*babu.dinesh89@live.in

ABSTRACT:
The aim of this study was to evaluate the effect of increasing nifedipine on the characteristics of fast-disintegrating sublingual tablets for the potential emergency treatment of anginal pain and hypertension. Nifedipine undergoes first pass metabolism in liver and gut wall which has oral bioavailability of 43-77%. Sublingual dosage form bypasses the metabolism of the nifedipine in liver and offers a fast relieve from anginal pain and hypertension. An attempt has been made to prepare fast dissolving tablets of nifedipine were prepared by wet granulation technique using Crospovidone and croscarmellose sodium (CCS) as super disintegrants as super disintegrants, Flavor and sweetener impart the taste to the formulation. The porous granules were compressed in to tablets by 8mm punch rotary tablet machine. All the formulations were evaluated for weight variation, hardness, friability, content uniformity, wetting time, and disintegration time and dissolution rate. Among the formulations, F9 one containing to be the best acceptable in terms of palatability, fast dissolving tablet having adequate strength. The disintegration time was found to be 56 ± 0.4 seconds, hardness of 4.6 ± g /cm², wetting time of 31sec   and drug release of 99.85 % in 9 mins. All the formulations showed low weight variation. The present study demonstrated potentials for rapid absorption, improved bioavailability, effective therapy and patient compliance.

Reference Id: PHARMATUTOR-ART-1303

INTRODUCTION:
Tablet administration difficulties are common among all patient groups and can exacerbate compliance problems and undermine treatment efficacy. Physical problems with swallowing (dysphasia) can occur at any age but are particularly prevalent in the elderly and those with dementia, whereas refusal to swallow is often encountered in geriatric, pediatric, and psychiatric patients ¹.Nonetheless, oral dosing remains the preferred mode of administration for many types of medication due to its simplicity, versatility, convenience, and patient acceptability. In recent years, sub-lingual oral drug formulations have been developed to overcome problems related to swallowing difficulties. It is dose dependently absorbed after oral administration and undergoes excessive first pass metabolism, thereby making it a suitable candidate for sublingual dosage form².Sincethe drug can be absorbed partially or entirely into the systemic circulation from blood vessels in the sublingual mucosa, the sublingual route bypasses the hepatic first pass metabolic processes, thus producing rapid onset of action. The sublingual route is appropriate for drugs with Short delivery period requirements, for drugs which are inactivated by first pass – intestinal or hepatic metabolism
E.g. : Nifedipine , nitroglycerin.

These dosage forms dissolves or disintegrate in oral cavity within a minute without the need of water or chewing³. Nifedipine is a dihydropyridine calcium channel antagonist originally introduced for the treatment of angina pectoris⁴ hypertension and anti-atherosclerotic activity⁵. The sublingual⁶ dosage form offers fast release of drug from the formulation and it reaches the systemic circulation directly, which bypasses the metabolism of the nifedipine in the liver and offers a fast relive form the anginal pain, hypertension which will be worth in such conditions. The objective of study was to enhance safety and efficacy of drug molecule, achieve better compliance, solve swallowing problem, enhance onset of action and provide stable dosage form.

MATERIALS AND METHODS:

Materials: Nifedipinewas procured from MEDOPHARM, Karnataka. Aerosil ,talc, Aspartame, PVP ,mannitol, croscarmellose sodium ,Crospovidone, Raspberry flavor were procured from Karnataka fine chemicals, Bangalore. All other reagents and solvents used were of analytical grade.

Methods:  The sublingual tablets of Nifedipine were prepared using different combinations of Crospovidone and croscarmellose sodium (CCS) as super disintegrants, mannitol as a diluents, Aspartame as sweetening agent, alcoholic solution of PVP(10 % w/v) as binder and aerosil with talc as a flow promoters (Table 1). The drug and other ingredients were mixed together, and a sufficient quantity of alcoholic solution of PVP (10 %w/v) was added and mixed to form a coherent mass. The wet mass was granulated using sieve no. 12 and dried at 60⁰ C for 30 min. The dried granules were re-granulated by passing through sieve no. 16. The dried granules were then blended with talc, aerosil and compressed into tablets using a 8mm punch rotary tablet machine (Rimek, RSB-4minipress Cadmach, Ahmedabad, India).Experiments were carried out systematically to analyze the effect of different concentrations of disintegrants on the wetting time and In vitro dispersion time of the tablets, using a response surface methodology and to develop an optimized formulation.

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EVALUATION OF TABLETS:
The flow properties of blends (before compression) were characterized in terms of Angle of repose⁷, Bulk density and tapped density ⁸, Carr’s index⁹and Hausner’s ratio¹⁰ and evaluation of tablets can be divided into physical and chemical parameters. Physical appearance ,Tablet size and thickness, Average weight of tablets, Hardness test, and chemical parameters like content uniformity, in vitro dispersion time and in-vitro drug release.

Hardness: The crushing strength of the tablets was measured using a Monsanto hardness tester.          Three tablets from each formulation batch were tested randomly and the average reading was noted ^11,12

Friability: Ten tablets were weighed and placed in a Roche friabilator (Veego, India). Twenty pre weighed tablets were rotated at 25 rpm for 4 min. The tablets were then de-dusted and reweighed and the percentage of weight loss was calculated. The percentage friability of the tablets was measured¹³.

Weight variation:Randomly, twenty tablets were selected after compression and the mean weight was determined. None of the tablets deviated from the average weight by more than ±10% ¹⁴.

Drug content:Ten tablets were randomly sampled from each formulation batch, finely powdered and individually estimated for the drug content after suitable dilution, using UV-VIS spectrophotometer (UV-1601, Shimadzu) at 235 nm after suitable dilution with distilled water ¹⁵. The mean percent drug content was calculated as an average of three determinations.

Wetting time:A piece of tissue paper (12cmx10.75cm)folded twice was placed in a Petri dish (Internal Diameter=9cm) containing 9ml of buffer solution simulating saliva pH 6.8, which had the following composition, NaCl (0.126g), KCl (0.964g), KSCN (0.189g),KH2PO4 (0.655g) and urea (0.200g) in 1Litre of distilled water. A tablet was placed on the paper and the time taken for complete wetting was noted ¹⁶. Three tablets from each formulation were randomly selected and the average wetting time was noted.

In vitro dispersion time: In vitro dispersion time was measured by dropping a tablet in a 10ml measuring cylinder containing 6ml of buffer solution simulating saliva fluid (pH 6.8) ^17,18.

Dissolution study:In-vitro dissolution study was performed by using USP Type II Apparatus (Paddle type)[Veego Tablet Dissolution Tester] at 50 rpm. Phosphate buffer pH 6.8, 900 ml was used as dissolution medium which maintained at 37±0.5°C. Aliquot of dissolution medium (10 ml) was withdrawn at specific time intervals(2 min) and was filtered. The amount of drug dissolved was determined by UV spectrophotometer (Shimadzu,Japan) by measuring the absorbance of the sample at 235 nm ¹⁹.

RESULTS AND DISCUSSION:
Among the soluble diluents, mannitol was selected as a diluent considering its advantages in terms of easy availability and negative heat of dissolution.Table 2 shows us the granule properties of all the batches which are within the limits. Table 3 shows that all the formulated tablets exhibited low weight variation . The drug content of all the formulations was found to be between 98.52 - 101.67 % which was within the acceptable limits as per USP XXVII. The batches F2 and F3 were prepared using low concentrations of super disintegrants to study its effect on disintegration time. Batch F9 , containing 10% of both super disintegrants in their ratios, showed the least disintegrating time.  Tablets with lower friability (0.7%) may not break during handling on machines and/or shipping . In vitro release studies were carried out using USP XXIII tablet dissolution test apparatus paddle method at 37±0.5^oC, taking 900 ml of dissolution medium. Speed of rotation of the paddle was set at 50 rpm. Sample of 10 ml were withdrawn after 1,2,3,4,5,6,7,8,9 min and analyzed spectrophotometrically at 235 nm. Formulation F9  prepared by wet granulation technique showed good release from final tablets showed release 99.85% drug  at the end of 9 min when compared to other batches. The in vitro dissolution profile (Fig.2) indicated faster and maximum drug release from formulation F9. Table 4 shows the wetting time and In-vitro dispersion time of all the batches and for F9 the values are 20 sec and 31 sec respectively.

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ACKNOWLEDGEMENTS:
We thank Venkata Balakrishna rao. N of Research and Development Department, Natco Pharma Limited, Kothur for his constant encouragement and support.

TABLE : 1 FORMULATION VARIABLES FOR NIFEDIPINE SUB-LINGUAL TABLETS:

TABLE 2: GRANULE PROPERTIES OF ALL THE BATCHES:

TABLE 3: EVALUATIONS OF ALL BATCHES OF NIFEDIPINE TABLETS

*All reading are average + (SD)

TABLE 4: TABLE SHOWING WETTING TIME AND IN-VITRODISPERSION TIME.

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