INTRODUCTION:

Tablet is the most widely used dosage form because of its convenience in terms of self-administration, compactness and ease in manufacturing. Patients often experience difficulty in swallowing conventional tablets when water is not available nearby. Furthermore, paediatric and geriatric patients may also encounter inconvenience in swallowing it¹. ‘Mouth dissolving’ (MD) or ‘melt in mouth’ tablets are a perfect fit for these patients as they immediately release the active drug, when placed on the tongue, by rapid disintegration, followed by dissolution of the drug^2-4.

Mouth dissolving tablets combine the advantage of both liquid and conventional tablet formulations allowing the ease of swallowing the drug in the form of liquid dosage form. Some drugs are absorbed from the mouth, pharynx and oesophagus as the saliva passes down into the stomach. In such cases, the bioavailability of the drug is significantly increased over those observed in the conventional tablet dosage form. The basic approach to the development of mouth dissolving tablets is the use of superdisintegrants such as crosscarmellose sodium and sodium starch glycolate. Another approach used in developing MD tablets is maximizing the pore structure of the tablet matrix. Freeze drying and vacuum drying techniques have been tried by researchers to maximize the pore structure of the tablet matrix. However, freeze drying is cumbersome and yields a fragile and hygroscopic product. Vacuum drying along with the sublimation of volatilizable ingredient has been employed to increase tablet porosity. While designing dispersible tablets, it is possible to achieve effective taste masking as well as a pleasant feel in the mouth. The main criterion for MD tablets is the ability to disintegrate or dissolve rapidly in saliva of the oral cavity in 15 to 60 seconds and have a pleasant mouth feel⁵. The drug selected for investigation is Flecainide acetate is a class IC anti arrhythmic agent. It is used to prevent and treat tachyarrhythmias, a wide variety of cardiac arrhythmias including paroxysmal atrial fibrillation, paroxysmal supraventricular tachycardia and ventricular tachycardia. For the treatment of supraventricular tachychardias and paroxysmal atrial flutter, a starting dose of 50mg twice a day was used. For the treatment of life-threatening ventricular arrhythmias, a starting dose of 100mg twice a day was used. Flecainide is almost completely absorbed after oral administration and does not undergo extensive first-pass metabolism. The bioavailability from flecainide acetate tablets has been reported to be about 90%. It is excreted mainly in the urine, approximately 30% as unchanged drug and the remainder as metabolites. Therefore, in the present study an attempt was made to formulate Flecainide acetate fast dissolving tablets and to investigate the effect of subliming agent on the release profile of the drug in the tablets. Hence formulating Flecainide acetate fast dissolving tablets leading to an increase in bioavailability of the drug, quick onset of pharmacological action and increase in patient compliance due to ease of administration.

MATERIALS AND METHODS:

MATERIALS:

Flecainide acetate was obtained as gift sample from Orchid Chemicals and Pharmaceuticals, Chennai, India. All other materials, excipients, solvents and reagents were either analytical or Pharmacopoeial grade and they were procured from S.D. fine Chemicals Mumbai.

METHODS

Drug- polymer interaction studies Fourier Transform Infra-Red (FT-IR) spectral analysis:

Fourier–Transform Infrared (FT–IR) spectrums of pure Flecainide acetate and combination of drug and excipients were obtained by a Fourier-Transform Infrared spectrophotometer, (FTIR-8300, Shimadzu, Japan) using the KBr disk method (2 mg sample in 200 mg KBr). The scanning range was 400 to 4000 cm^-1 and the resolution was 1cm^-1. This spectral analysis was employed to check the compatibility of drugs with the excipients used.

Differential Scanning Calorimetry (DSC) analysis:

DSC analysis was performed using Shimadzu DSC-60, Shimadzu Limited Japan. A 1:1 ratio of drug and excipient was weighed into aluminium crucible. And sample was analyzed by heating at a scanning rate of 20⁰C over a temperature range 40-430⁰C under nitrogen environment.

PREPARATION OF FLECAINIDE ACETATE ODTs:

Flecainide acetate ODTs were prepared using two approaches by Direct Compression method.

1. Preparation of Flecainide acetate ODTs using sublimation method:

Specified quantity of Flecainide acetate and other excipient according to formula given in the table 1 were weighed and passed through sieve no.60 and thoroughly mixed for 10 min and magnesium stearate and other ingredients were added to the blend and thoroughly mixed. The tablets were compressed using Cemach tablet punching machine. The compressed tablets were then subjected to sublimation at 60°C in oven till constant weight obtained.

2. Preparation of Flecainide acetate FDTs using superdisintegrant addition method:

Flecainide acetate tablets each containing 100 mg of Flecainide acetate were prepared by direct compression method according to formula given in the table 2. The different superdisintegrants used were Sodium starch glycollate, Crosscarmellose sodium, Indion 414 and Crosspovidone in different concentrations. Blend was prepared by first passing all the ingredients through 60-mesh sieve separately and collected. The drug and microcrystalline cellulose were mixed in small portion of both at each time and blended to get a uniform mixture and kept aside. Then the other ingredients were weighed and mixed in geometrical order and the tablets were compressed using flat face 6.3 mm size punch to get a tablets of 200 mg weight using twelve station Cemach tablet compression machine.

EVALUATION OF FAST DISSOLVING TABLETS

PRE-COMPRESSIONAL STUDIES

Angle of Repose (Ө):

The angle of repose of API powder was determined by the funnel method. The accurately weighed powder blend was taken in the funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touched the apex of the powder blend. The powder blend was allowed to flow through the funnel freely on to the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation.

Ө = tan^-1 (h/r)

Where, Ө is the angle of repose, h is the height of pile and r is the radius of the base of pile.

Table1: Composition of Flecainide acetate FDT’s using sublimation method

INGREDIENTS (mg/tablets)	FORMULATIONS
INGREDIENTS (mg/tablets)	S1	S2	S3	S4	S5	S6	S7	S8	S9
Flecainide acetate	100	100	100	100	100	100	100	100	100
Crospovidone	4	8	12	16	--	--	--	--	--
Croscarmellose sodium	--	--	--	--	4	8	12	16	--
Sodium starch glycolate	--	--	--	--	--	--	--	--	4
Indion 414	--	--	--	--	--	--	--	--	--
Camphor	2.5	5	7.5	10	2.5	5	7.5	10	2.5
Methyl cellulose	4	4	4	4	4	4	4	4	4
Magnesium stearate	2	2	2	2	2	2	2	2	2
Orange flavour	4	4	4	4	4	4	4	4	4
Talc	2	2	2	2	2	2	2	2	2
Aspartame	4	4	4	4	4	4	4	4	4
Avicel pH 102	77.5	71	64.5	58	77.5	71	64.5	58	77.5
Total weight (mg)	200	200	200	200	200	200	200	200	200

Table1 Continue……….

INGREDIENTS (mg/tablets)	FORMULATIONS
INGREDIENTS (mg/tablets)	S10	S11	S12	S13	S14	S15	S16
Flecainide acetate	100	100	100	100	100	100	100
Crospovidone	--	--	--	--	--	--	--
Croscarmellose sodium	--	--	--	--	--	--	--
Sodium starch glycolate	8	12	16	--	--	--	--
Indion 414	--	--	--	4	8	12	16
Camphor	5	7.5	10	2.5	5	7.5	10
Methyl cellulose	4	4	4	4	4	4	4
Magnesium stearate	2	2	2	2	2	2	2
Orange flavour	4	4	4	4	4	4	4
Talc	2	2	2	2	2	2	2
Aspartame	4	4	4	4	4	4	4
Avicel pH 102	71	64.5	58	77.5	71	64.5	58
Total weight (mg)	200	200	200	200	200	200	200

Table2: Composition of Flecainide acetate FDT’s using superdisintegrant addition method

INGREDIENTS (mg/tablets)	FORMULATIONS
INGREDIENTS (mg/tablets)	SD1	SD2	SD3	SD4	SD5	SD6	SD7	SD8	SD9	SD10
Flecainide acetate	100	100	100	100	100	100	100	100	100	100
Crospovidone	4	8	12	16	--	--	--	--	--	--
Croscarmellose sodium	--	--	--	--	4	8	12	16	--	--
Sodium starch glycolate	--	--	--	--	--	--	--	--	4	8
Indion 414	--	--	--	--	--	--	--	--	--	--
Methyl cellulose	4	4	4	4	4	4	4	4	4	4
Magnesium stearate	2	2	2	2	2	2	2	2	2	2
Orange flavour	4	4	4	4	4	4	4	4	4	4
Talc	2	2	2	2	2	2	2	2	2	2
Aspartame	4	4	4	4	4	4	4	4	4	4
Avicel pH 102	80	76	72	68	80	76	72	68	80	76
Total weight (mg)	200	200	200	200	200	200	200	200	200	200

Table2 Continue……

INGREDIENTS (mg/tablets)	FORMULATIONS
INGREDIENTS (mg/tablets)	SD11	SD12	SD13	SD14	SD15	SD16
Flecainide acetate	100	100	100	100	100	100
Crospovidone	--	--	--	--	--	--
Croscarmellose sodium	--	--	--	--	--	--
Sodium starch glycolate	12	16	--	--	--	--
Indion 414	--	--	4	8	12	16
Methyl cellulose	4	4	4	4	4	4
Magnesium stearate	2	2	2	2	2	2
Orange flavour	4	4	4	4	4	4
Talc	2	2	2	2	2	2
Aspartame	4	4	4	4	4	4
Avicel pH 102	72	68	80	76	72	68
Total weight (mg)	200	200	200	200	200	200

i) Bulk Density and Tapped density:

Loose bulk density (LBD) and tapped bulk density (TBD) of tablet blends were determined using bulk density apparatus. Tablet blend was passed through #18 sieve to break the clumps and transferred to 100ml graduated cylinder. Initial volume was observed. The cylinder was tapped initially 200 times from a distance of 14±2 mm. The tapped volume was measured to the nearest graduated unit. This was repeated for other tablet blends. The LBD and TBD were calculated in g/ml using following formula:

LBD = weight of the powder / volume of the packing

TBD = weight of the powder / tapped volume of the packing

ii) Carr’s Index:

The Compressibility Index of the powder blend was determined by Carr’s compressibility index. It is a simple test to evaluate the BD and TD of a powder and the rate at which it is packed down. The formula for Carr’s Index is as below,

Carr’s Index (%) = [(TBD-LBD) x100]/TBD

Where,

LBD = Loose Bulk Density and TBD = Tapped Bulk Density

iii) Hausner ratio:

The Hausner’s ratio is a number that is correlated to the flow ability of a powder or granular material. The Hausner ratio of the powder was determined by the following equation:

Hausner ratio = TBD / LBD

a) POST-COMPRESSIONAL STUDIES:

i) General appearance:

The fast dissolving tablets, morphological characterization which includes size, shape, colour, presence or absence of odour, taste surface texture was determined.

ii) Thickness and diameter:

Five tablets were picked from each formulation randomly and thickness and diameter was measured individually. It is expressed in mm and standard deviation was also calculated. The tablet thickness and diameter was measured using vernier calliper.

iii) Hardness:

Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using Monsanto hardness tester. It is expressed in kg/cm². Five tablets were randomly picked and hardness of the same tablets from each formulation was determined. The mean and standard deviation values were also calculated.

iv) Friability test:

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. Pre-weighed sample of ten tablets were placed in the Friabilator, which was then operated at 25 rpm for 4 minutes or ran upto 100 revolutions. After 100 revolutions the tablets were dusted and reweighed. Compressed tablets should not lose more than 1% of their weight. The % friability was then calculated by the following formula:

Percentage friability = (Initial weight - Final weight /Initial weight) × 100

v) Weight variation:

20 tablets were selected randomly from each formulation and weighed individually to check for weight variation. The US Pharmacopoeia allows a little variation in the weight of a tablet.

Drug content uniformity:

Twenty tablets were weighed and powdered. Powder equivalent to 100 mg drug was transferred into a 100 ml volumetric flask. Volume was made with phosphate buffer pH 6.8. After few minutes the solution was filtered; rejecting first few ml of the filtrate. 10ml of filtrate was taken in a 50 ml volumetric flask and diluted up to the mark with phosphate buffer pH 6.8 and analyzed spectrophotometrically at 300 nm. The concentration of Flecainide acetate (in µg/ml) was calculated by using the standard calibration curve of Flecainide acetate.

vi) Wetting time and water absorption ratio:

A piece of tissue paper folded twice was placed in a small petridish (i.d = 6.5 cm) containing 6 ml of water. A tablet was placed on the paper and the time required for complete wetting was then measured. The water absorption ratio, R, was determined using the following equation,

R = Wa - Wb / Wb × 100

Where,

Wb is the weight of the tablet before water absorption and Wa is the weight of the tablet after water absorption.

vii) In vitro dispersion time:

One tablet was placed in a beaker containing 10 ml of phosphate buffer pH 6.8 at 37 ±0.5ºC and the time required for complete dispersion was determined.

viii) In vitro disintegration time:

In vitro disintegration time was performed by apparatus specified in USP at 50 rpm. Phosphate buffer pH 6.8, 900 ml was used as disintegration medium, and the temperature of which was maintained at 37±2°C and the time in second taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured in seconds.

ix) In vitro drug release studies:

In vitro drug release studies were carried out using dissolution apparatus USP type XXIII at 50 rpm. The dissolution medium consisted of 900 ml of Phosphate buffer pH 6.8 maintained at 37±1⁰C. The drug release at different time intervals was measured using a double beam UV Spectrophotometer at 300 nm.

x) Scanning Electron Microscopy

Sample of one tablet (promising batch) was mounted on aluminium stub and examined using a field emission, scanning electron microscope (Joel, Japan). Photographs were taken at magnification of 500X.

xi) Data Analysis:

Various models were tested for explaining the kinetics of drug release. To analyze the mechanism of the drug release rate kinetics of the dosage form, the obtained data were fitted into zero-order, first order, Higuchi, Korsmeyer-Peppas release model and Hixson-Crowell equation.

xii) Stability Studies:

Stability of a drug has been defined as the ability of a particular formulation, in a specific container, to remain within its physical, chemical, therapeutic and toxicological specifications. In the present study, stability studies were carried out at 25⁰C±2⁰C/60% ±5% RH and 40⁰C±2⁰/75%±5% RH for a period of 90 days for the selected formulations. The formulations were then evaluated for changes in the physicochemical properties, wetting time, in vitro disintegration time and in vitro drug release.

RESULTS AND DISCUSSION:

Drug-excipient compatibility studies:

Fourier Transform Infrared (FTIR) Spectroscopy:

Physical mixture of Flecainide acetate formulative ingredients were subjected for IR spectroscopic analysis to ascertain whether there was any interaction between drug and excipients used. The IR spectras showed similar characteristic peaks at their respective wavelengths with minor differences. The similarity in the peaks indicated the compatibility of drug with formulation excipients. IR spectra of the physical mixture of drug with formulative ingredients were depicted in figure 1 to 2.

Figure 1: FTIR spectra of Flecainide acetate pure drug

Figure 2: FT-IR Spectra of physical mixture of Flecainide acetate+ S4

Differential Scanning Calorimetry:

The DSC thermograms of pure Flecainide acetate showed melting endothermic peak at 148°C indicating crystalline nature of Flecainide acetate, followed by exothermic peak which may be due to decomposition of Flecainide acetate. The endothermic peak for the drug in physical mixture, showed minor changes in the melting endotherm of drug could be due to the mixing of drug and excipients, which lower the purity of each component in the mixture and may not necessarily indicates potential incompatibility. The result showed that drugs were compatible with excipients. DSC thermograms of drug and physical mixture of drug and excipients were shown in figure 3.

Figure 3: DSC thermogram of (A) Flecainide acetate, (B) drug+CCS, (C) drug+CP, (D) drug+SSG, (E) drug+Indion 414, (F) drug + S4

EVALUATION PARAMETERS:

Pre-compressional parameters:

Powder ready for compression containing drug and various excipients were subjected for various precompressional evaluation parameters such as bulk density, tapped density, compressibility index, Hausner’s ratio and angle of repose. Pre-compressional parameters (Micromeritic properties) were studied to determine the flow properties of granules, to achieve uniformity of tablet weight. The results of all the preformulation parameters are given table 3 and 4.

Angle of repose (θ):

The data obtained from angle of repose for the formulations of sublimation method were found to be in the range of 27.52⁰ to 30.28⁰ and for superdisintegrant addition method the range was 27.52⁰ to 32.87⁰. All the formulations prepared by both the methods showed the angle of repose less than 31⁰, which reveals good flow property.

Bulk density:

Loose bulk density (LBD) for the blend was performed. The loose bulk densities for the formulations of sublimation method varied from 0.49 gm/cc to 0.55 gm/cc. For superdisintegrant addition method the range was 0.15 gm/cc to 0.55gm/cc.

Tapped density:

Tapped bulk density (TBD) for the blend was performed. The tapped bulk densities for the formulations of sublimation method varied from 0.61 gm/cc to 0.65 gm/cc. For superdisintegrant addition method the range was 0.49 gm/cc to 0.65 gm/cc respectively.

Carr’s consolidation index:

The results of Carr’s consolidation index or compressibility index (%) for the sublimation formulation blend ranged from 13% to 20% and for superdisintegrant addition method it was 15% to 21.15%.

Hausner ratio:

Hausner ratio of sublimation formulations showed between 1.14 to 1.30 and for superdisintegrant addition method formulations it was 1.14 to 1.26 indicates better flow properties.

Table 3: Pre compression evaluation of Flecainide acetate powder blend using superdisintegrant addition method

Formulation Code	Angle of Repose	Bulk Density (gm/cc)	Tapped Density (gm/cc)	Carr’s Index %	Hausner Ratio
SD1	30.1±1.70	0.53±0.007	0.64±0.02	17±1.20	1.20±0.03
SD2	30.20±0.88	0.55±0.007	0.65±0.01	15±2.51	1.18±0.03
SD3	32.77±0.70	0.39±0.007	0.47±0.07	16.56±0.82	1.19±0.01
SD4	31.87±0.46	0.15±0.206	0.49±0.01	17.07±0.63	1.25±0.03
SD5	27.52 ±1.20	0.52 ±0.007	0.63 ±0.01	17 ±2.12	1.21 ±0.04
SD6	29.19 ±1.26	0.54 ±0.007	0.64 ±0.02	15 ±1.51	1.18 ±0.03
SD7	28.26 ±1.20	0.55 ±0.007	0.65 ±0.01	15 ±1.39	1.14 ±0.03
SD8	29.03 ±1.56	0.52 ±0.007	0.62 ±0.02	16 ±1.20	1.19 ±0.04
SD9	28.72 ±1.41	0.53 ±0.007	0.63 ±0.01	15 ±1.67	1.18 ±0.02
SD10	32.11±0.12	0.42±0.009	0.52±0.08	19.67±0.72	1.24±0.0
SD11	30.25±0.89	0.39±0.005	0.49±0.01	19.36±1.51	1.23±0.02
SD12	31.62±0.52	0.40±0.007	0.51±0.07	21.15±1.97	1.26±0.03
SD13	32.87±1.32	0.51±0.007	0.62±0.38	17±1.39	1.21±0.04
SD14	28.04±1.34	0.5 ±0.007	0.65±0.02	16 ±2.20	1.20±0.03
SD15	28.43±1.48	0.50±0.007	0.6 ±0.01	20±1.58	1.26±0.03
SD16	30.72±1.22	0.52±0.007	0.63±0.02	17±1.55	1.21±0.04

*All values are expressed as mean ± SD, n=3.

Table 4: Pre compression evaluation of Flecainide acetate powder using sublimation method

Formulation Code	Bulk Density (gm/cc)	Tapped Density (gm/cc)	Angle of Repose	Carr’s Index %	Hausner Ratio
S1	0.50 ±0.007	0.63 ±0.01	26.43 ±1.48	20 ±1.58	1.26 ±0.03
S2	0.54 ±0.007	0.65 ±0.02	27.72 ±1.22	16 ±1.55	1.20 ±0.04
S3	0.52 ±0.007	0.63 ±0.38	29.87 ±1.32	17 ±1.39	1.21 ±0.04
S4	0.51 ±0.007	0.62 ±0.02	29.04 ±1.34	17 ±2.20	1.21 ±0.03
S5	0.53 ±0.007	0.63 ±0.01	30.28 ±1.26	15 ±2.01	1.18 ±0.03
S6	0.52 ±0.007	0.62 ±0.01	28.02 ±1.20	16 ±1.51	1.19±0.04
S7	0.53 ± 0.007	0.61 ±0.02	29.11 ±1.70	13 ±1.20	1.15 ±0.03
S8	0.53 ±0.007	0.64 ±0.01	30.20 ±0.88	17 ±2.51	1.20 ± 0.03
S9	0.49 ±0.007	0.65 ±0.01	29.25 ±1.56	17 ±1	1.30 ± 0.03
S10	0.53 ± 0.007	0.64 ±0.02	28.14 ± 1.67	17 ±2.51	1.20 ±0.03
S11	0.51 ±0.007	0.62 ±0.02	30.19 ±1.26	17 ±1.51	1.21 ±0.03
S12	0.55 ± 0.007	0.65 ±0.01	29.26 ±1.20	15 ±1.39	1.14 ±0.03
S13	0.52 ±0.007	0.62 ± 0.02	30.03 ±1.56	16 ±1.20	1.19 ±0.04
S14	0.53 ±0.007	0.63 ±0.01	29.72 ±1.41	15 ±1.67	1.18 ±0.02
S15	0.51 ±0.007	0.62 ±0.02	28.85 ±1.33	17 ±1.41	1.21 ±0.03
S16	0.52 ±0.007	0.65 ±0.01	27.52 ±1.20	18 ±2.12	1.25 ±0.04

*All values are expressed as mean ± SD, n=3.

Post-compressional parameters:

All the tablet formulations were evaluated for parameters such as shape, colour, thickness, hardness, friability, weight variation, drug content, in vitro disintegration time, in vitro dispersion time, wetting time, in vitro dissolution studies, model fitting of release profile and stability studies.

a) General appearance:

All the fast dissolving tablets from each batch were found to be flat, white in colour, circular in shape and having good physical appearance. There was no change in the colour and odour of the tablets from all the batches.

b) Thickness and diameter:

Thickness and diameter of all prepared fast dissolving tablets was measured by using calibrated vernier callipers. Tablet thickness should be controlled within ±0.1% variation of standard value to facilitate packaging and consumer acceptance. The mean thickness and diameter was almost uniform in all the formulations and values of tablets prepared by sublimation method were ranged from 2.57 mm to 2.62 mm, 4.01 to 4.03 mm respectively. The range for tablets of superdisintegrant addition method ranged from 2.59 mm to 2.62 mm, 4.01 to 4.03 mm respectively. The standard deviation values indicated that all the formulations were within the range.

c) Hardness:

Tablets require certain amount of strength, hardness to withstand mechanical shocks during manufacture, packaging and shipping. The hardness of all the tablets prepared by sublimation methods was maintained within the range of 2 kg/cm²to 2.8 kg/cm²and for superdisintegrant addition method the range was 2 kg/cm²to 2.8 kg/cm². In all the formulations the hardness test indicates good mechanical strength. In case of sublimation technique the hardness of tablet decreases with increase in amount of sublimable component. The obtained results revealed that the tablets were having good mechanical strength and compactness.

d) Friability:

Adequate tablet hardness and resistance to friability are necessary to prevent damage to the tablet during manufacture, packing and transport.

The friability was found in all sublimation formulations in the range 0.51 to 0.81% that of superdisintegrant addition method was 0.52 to 0.82 % to be well within the approved range (<1%) which indicates the tablets had god mechanical resistance

e) Weight variation:

The weight variation was found in the range of 196 to 205 mg for sublimation formulations and in range of 196 to 204 mg for superdisintegrant addition method. The weight variation results revealed that average percentage deviation of 20 tablets of each formula was less than ±7.5% i.e. in the Pharmacopoeial, limits which provide good uniformity in all formulations.

f) Mouth feel:

The prepared formulations were subjected for mouth feel. The volunteers felt good taste in all the formulations prepared by both the methods. As the drug is slightly bitter the presence of Aspartame and orange flavour in all the formulations showed good, palatable taste.

g) pH:

pH of the solution of all the tablets prepared by both the methods was found to be between 7.1 to 7.5, which suggest that the tablets can be conveniently administered orally and will not cause any discomfort.

h) Drug content:

To evaluate a tablet’s potential for efficacy the amount of drug in the tablet need to be monitored from tablet to tablet and batch to batch. The percentage drug content was found to be in the range of 98.56 to 100.05% for sublimation formulations and in range of 98.12 to 100.76% for superdisintegrant addition method (table 5 and 6).

i) Wetting Time:

Wetting time is an important parameter related to water absorption ratio, which needs to be assessed to give an insight to the disintegration properties of the tablets. Wetting is closely related to the inner structure of the tablets and the hydrophilicity of the excipients. Wetting time was used as a parameter to correlate with disintegration time in oral cavity. This is an important criterion for understanding the capacity of disintegrants to swell in presence of little amount of water. Since the dissolution process of a tablet depends upon the wetting followed by disintegration of the tablet, the measurement of wetting time may be used as another confirmative test for the evaluation of dispersible tablets.

As the formulation batches SD1 to SD16 comprised four different types of superdisintegrants, wetting time was found between 37to 49 seconds. Hence it was evident that selected superdisintegrants for study played vital role in wetting behaviour. Better wetting time was found with crospovidone and croscarmellose sodium with respect to batches consisting of other superdisintegrants. Thus wetting time for all these formulation batches varied in the following decreasing order: Crospovidone >Indion 414 > Sodium starch glycolate > Croscarmellose sodium. Formulation batches S1 to S16 comprised of camphor as subliming agents, wetting time was found between 32 to 49 seconds.

j) Water Absorption Ratio:

Water absorption ratio, which is an important criterion for understanding the capacity of disintegrants to swell in presence of little amount of water, was calculated. The formulations prepared by sublimation technique shows water absorption ratio in the range 46 to 85% and tablets prepared by superdisintegrant method showed water absorption ratio in range of 52 to 85%. The Water absorption ratio increased with increase in the concentration of superdisintegrant from 2-8 %. The water absorption ratio was found to be in the increasing order. This increase was due to the water up taking ability of the superdisintegrants. More the superdisintegrant concentration greater was water absorption. Water absorption ratios for all these formulation batches varied in the following decreasing order: Crospovidone > Indion 414 > Sodium starch glycolate > Croscarmellose sodium. The comparison of wetting time and water absorption ratio of formulations containing various superdisintegrants and subliming agents were depicted in figure 4 and 5 respectively.

Table 5: Post compression evaluation of Flecainide acetate FDT’s using superdisintegrant addition method

Formulation Code	Thickness (mm)*	Diameter (mm)*	Hardness (kg/cm²)*	Friability (%)**	Weight variation test (mg)***	Drug Content %)***	pH	Mouth feel
SD1	2.59±0.030	4.02±0.02	2.2 ±0.10	0.62±0.01	200 ± 1.93	99.23 ± 0.90	7.4	+
SD2	2.61±0.017	4.01±0.02	2.1 ± 0.12	0.58±0.05	196 ± 1.21	100.03 ± 1.07	7.5	+++
SD3	2.62±0.026	4.03±0.02	2.8 ± 0.18	0.57±0.02	199 ± 1.50	99.63 ± 0.39	7.4	++
SD4	2.61±0.04	4.01±0.01	2.1 ± 0.10	0.67±0.03	200 ± 0.18	99.50 ± 0.77	7.2	+
SD5	2.60±0.035	4.01±0.03	2.1 ± 0.15	0.75±0.04	203 ± 1.62	99.96 ± 0.27	7.5	+++
SD6	2.59±0.023	4.01±0.04	2.3 ± 0.21	0.78±0.02	200 ± 1.85	99.56±0.76	7.2	+
SD7	2.61±0.037	4.03± 0.04	2.2 ± 0.10	0.59±0.01	197 ± 0.96	100.09±0.76	7.1	+++
SD8	2.61±0.00	4.01±0.03	2.3 ± 0.21	0.65±0.02	196 ± 1.69	100.65±1.23	7.1	++
SD9	2.59±0.034	4.03±0.02	2.2 ± 0.15	0.60±0.01	200 ± 1.73	99.08±2.65	7.2	+++
SD10	2.60±0.035	4.02±0.01	2 ± 0.10	0.52±0.03	205 ± 1.62	100.76±0.33	7.5	++
SD11	2.61±0.037	4.01±0.02	2.1 ± 0.05	0.61±0.05	198 ± 1.45	99.99±1.79	7.2	₊₊
SD12	2.59±0.01	4.01±0.03	2.2 ± 0.20	0.73±0.04	202 ± 1.78	99.18 ± 0.72	7.5	++
SD13	2.60±0.049	4.01±0.03	2.4 ± 0.15	0.82±0.06	203 ± 1.32	99.81 ± 1.07	7.2	+++
SD14	2.61±0.025	4.03±0.02	2.5 ± 0.42	0.77±0.01	198 ± 0.56	99.54 ± 0.50	7.1	++
SD15	2.61±0.035	4.02±0.01	2.5 ± 0.11	0.56±0.02	204 ± 1.97	98.12 ± 0.73	7.3	+++
SD16	2.61±0.037	4.01±0.02	2.3 ± 0.11	0.66±0.02	201 ± 0.65	99.30 ± 0.87	7.2	₊₊

Table 6: Post compression evaluation of Flecainide acetate FDT’s using sublimation method

Formulation Code	Thickness (mm)*	Diameter (mm)*	Hardness (kg/cm²)*	Friability (%)**	Weight variation test (mg)***	Drug Content (%)***	pH	Mouth feel
S1	2.57±0.005	4.02±0.02	2.1 ± 0.10	0.68±0.21	205 ± 1.75	99.13±0.49	7.4	+
S2	2.60±0.028	4.01±0.02	2.1 ± 0.15	0.65±0.23	200 ±0.63	99.47 ± 1.47	7.5	+++
S3	2.59±0.015	4.03±0.02	2.1 ± 0.21	0.58±0.22	196 ± 1.42	99.11 ± 0.43	7.4	++
S4	2.61±0.045	4.01±0.01	2.1 ± 0.10	0.59±0.24	198 ± 0.50	98.56 ± 1.32	7.2	+
S5	2.61±0.037	4.01±0.03	2.4 ± 0.21	0.75±0.21	204 ± 1.38	99.09 ±0.10	7.5	+++
S6	2.62±0.028	4.01±0.04	2.5 ± 0.15	0.69±0.23	205 ± 0.82	100.65 ±1.43	7.2	+
S7	2.61±0.02	4.03± 0.04	2 ± 0.10	0.58±0.25	201 ±0.25	99.38 ±1.75	7.1	+++
S8	2.61±0.00	4.01±0.03	2.3 ± 0.05	0.60±0.25	199 ± 1.92	100.56 ±0.43	7.2	+++
S9	2.59±0.034	4.03±0.02	2.2 ± 0.20	0.77±0.26	197 ± 0.69	99.59 ±1.61	7.5	++
S10	2.60±0.035	4.02±0.01	2.4 ± 0.15	0.73±0.24	204 ± 1.43	99.58 ± 0.85	7.2	₊₊
S11	2.61±0.037	4.01±0.02	2.6 ± 0.42	0.81±0.24	201 ± 0.59	99.41 ± 1.57	7.5	+++
S12	2.61±0.017	4.01±0.02	2 ±0.11	0.58±0.26	198 ± 0.65	99.34 ± 1.07	7.4	++
S13	2.62±0.026	4.03±0.02	2.1 ± 0.11	0.54±0.26	200 ± 0.78	98.65 ± 0.74	7.2	+
S14	2.61±0.04	4.01±0.01	2.3 ±0.10	0.75±0.21	201 ± 1.02	99.41 ± 1.87	7.5	+++
S15	2.60±0.035	4.01±0.03	2.2 ±0.12	0.57±0.23	199 ±1.56	99.31 ± 1.08	7.2	+
S16	2.61±0.025	4.03±0.02	2.8 ±0.18	0.51±0.21	203 ± 0.97	99.43 ±1.46	7.2	₊₊

*All values are expressed as mean ± SE, n=5; **All values are expressed as mean ± SE, n=10; ***All values are expressed as mean ± SE, n=20; += Average; ++= good, +++= excellent

m) In vitro Dissolution Studies:

The in vitro drug release characteristics were studied in phosphate buffer pH 6.8 using tablet dissolution apparatus USP XXIII. The samples were withdrawn at different time intervals and analyzed at 300 nm and the cumulative percentage drug released was determined. As discussed above, differences in the particle size generated in the disintegrated tablets could affect drug dissolution since breaking tablets into finer fragments may promote drug dissolution by providing larger total surface areas for drug dissolution to take place. As the formulation batches SD1 to SD16 comprised of four different types of superdisintegrants, in vitro drug release at 15 minutes was found between 66.7 to 98.7 %. Hence it was evident that selected superdisintegrants for study played vital role in dissolution behaviour. Formulation prepared with crospovidone gave the best in vitro drug release than rest of batches consisting of other superdisintegrants. Crospovidone and Indio-414 containing tablets rapidly exhibits high capillary activity and pronounced hydration with a little tendency to gel formation and disintegrates the tablets rapidly but into larger masses of aggregated particles. Thus difference in the size distribution generated with different superdisintegrants might have contributed to difference in the drug release with the same amount of superdisintegrants in the tablets. In tablets prepared by using crospovidone as superdisintegrant showed best dissolution due to more solubility in aqueous medium. When the tablet enters into dissolution medium tablet disintegrate then the drug in molecular form releases due to which the dissolution of tablet increased and drug is released quickly from tablets. This is the reason due to which the higher concentration of superdisintegrants in formulation increases the dissolution of tablet. The formulation batches S1 to S16 comprised of camphor subliming agents, in vitro drug release at 15 minutes was found between 74.67 to 99.16 %. The tablets prepared by sublimation technique rapidly expose high pores and disintegrate the tablets rapidly in dissolution medium. It may be due to their lowest hardness and maximum pours structure was responsible for faster water uptake; hence it facilitates in bringing about faster disintegration. As the concentration of sublimable agent increased the pore structure in the tablet increases. Due to this the formulation containing highest concentration of sublimable agent shows fastest dissolution. The dissolution of the drug from the tablets was quicker this may be due to their lowest hardness and the porous structure is responsible for faster water uptake (figure 8- 12).

Figure 8: Comparison of dissolution profile of various formulations of Flecainide acetate FDT’s containing crosspovidone

Figure 9: Comparison of dissolution profile of various formulations of Flecainide acetate FDT’s containing croscarmellose sodium

Figure 10: Comparison of dissolution profile of various formulations of Flecainide acetate FDT’s containing sodium starch glycolate

Figure 11: Comparison of dissolution profile of various formulations of Flecainide acetate FDT’s containing Indion 414.

n) Data Analysis:

The results of in vitro dissolution studies obtained from optimized formulations were plotted in Zero order, First order, Higuchi and Korsmeyer-Peppas release model and Hixson-Crowell equation to study the mechanism of drug release. The correlation coefficient (r) for drug release kinetic models was tabulated in table 7. The formulations S4 formulation showed Higuchi Matrix which described the drug release, as a diffusion process based on the Fick’s law, square root time dependent.

o) SEM Scanning Electron Microscopy:

Scanning electron micrographs of the surface and cross section views of promising batch (S4) are shown in Figure 13. The micrograph shows the highly porous nature of the prepared sublimed tablet, which appear in both surface and the inner structure. The highly porous nature of the tablet explains the rapid penetration of water, which results in rapid wetting, disintegration, and dissolution in th oral cavity. These results indicate that addition of camphor followed by sublimation greatly affected the inner structure of the tablet with subsequent impact on wetting, disintegration and dissolution of final tablet.

Figure 13: Scanning Electron Micrographs of optimized flecainide acetate FDT (S4) in Surface View (A) and Cross-Section View (B)

p) Stability Studies:

Stability studies of formulation S4 was performed at 25⁰C ±2⁰C/60% ± 5% RH and 40⁰C ± 2⁰C/75% ± 5% RH for a period up to 90 days. The formulations were selected for stability studies on the basis of their high percentage cumulative drug release and also results of in vitro disintegration time, wetting time and in vitro dispersion studies. There was no change in colour and shape of the tablets when stored at 25⁰C ± 2⁰C /60% ± 5% RH and 40⁰ ±2⁰C/75% ±5% RH and observed every 20 days interval upto 90 days. Formulations S4 showed not much variation in any parameter. From these results it was concluded that formulations were stable and retained its original properties (figure 14).

Figure 14: Cumulative % Drug released from formulation S4 stored at different temperatures after 90 days

CONCLUSION:

From the study conducted and from the observations and the results obtained thereof, following conclusions were drawn:

v FTIR and DSC studies concluded that drug and excipients were compatible with each other.

v Tablet prepared by superdisintegrant addition method and sublimation methods were found to be good and were free from chipping and capping.

v The flow properties of the formulation powder have good flow property which is an important aspect for the ODT formulations.

v The formulated tablets were satisfactory in terms of hardness, thickness, friability, weight variation, drug content, wetting time, water absorption ratio, in vitro disintegration time, in vitro dispersion time and in vitro drug release.

v The in vitro dispersion time of Flecainide acetate prepared by superdisintegrant addition method and sublimation method were found to be in the range of 18 to 59 sec fulfilling the official requirements.

v Based on the in vitro disintegration time, formulation S4 (8% CP+ camphor [10%]) were found to be promising and showed a dispersion time 18 sec and wetting time of 32 sec, which facilitate the faster dispersion in the mouth.

v The formulation S4 have displayed good water absorption ratio of 85%, which indicate better and faster swelling ability of the disintegrants in presence of little amount of water.

v The drug release from optimised batches of mouth dissolving tablets of Flecainide acetate prepared by direct compression and sublimation methods showed 98.70% and 99.16% drug release within 15 minute.

v Direct compression method is the best method for the formulation of ODTs. This method is also very economical and time saving. CP was found to be the best superdisintegrant among all with 8 percent concentration yielding the best results. Similarly CP(8%) with camphor (10%) was found to be the best formulation yielding the best results.

v Formulation S4 were found to be the best on the basis of wetting time, in vitro disintegration time and in vitro drug release.

v Among the two methods used namely direct compression and sublimation, the sublimation method was found to be superior to superdisintegrant addition method.

v Short term stability studies carried out were confirmative of the drug stability in the tablets during the present study.

ACKNOWLEDGEMENTS:

The authors are thankful to Principal and Management of Karavali College of Pharmacy, Mangalore for providing all the facilities and support for this research project. The authors are also thankful to Orchid Chemicals and Pharmaceuticals, Chennai, India for generous gift samples of Flecainide acetate.

REFERENCES:

1. Koizumi K, Watanabe Y, Monita K, Utosuchi N. New method of preparing high porosity rapidly saliva soluble compressed tablets using Mannitol with camphor, a subliming material. Int. J. Pharm 1997; 152: 127-131

2. Watanabe A, Hanawa T, Yamamoto K. Release profiles of phenytoin from new oral dosage form for the elderly. Chem. Pharm. Bull.1994; 42: 1642-1645

3. Hanawa T, Watanabe A, Ikoma R, Hidaka M, Sugihara M. New oral dosage form for elderly patients: Preparation and characterization of silk fibroin gel. Chem. Pharm. Bull. 1995; 43: 284-288

4. Seager H, Drug delivery products and the Zydis fast dissolving dosage forms. J. Pharm. Pharmacol. 1998; 50: 375-382

5. Indurwade NH, Rajyaguru TH, Nahat PD. Novel approach- fast dissolving tablets. Indian drugs 2002; 39(8): 405-409

Received on 04.04.2016 Accepted on 20.04.2016

Asian J. Res. Pharm. Sci. 2016; 6(2): 116-128

DOI: 10.5958/2231-5659.2016.00017.5

Formulation Code	Mathematical Models (Kinetics)
Formulation Code	Zero Order	First Order	Higuchi Matrix	Peppas	Hixson Crowell	Best Fit Model
S4	0.976	0.765	0.977	0.865	0.912	Higuchi matrix

ABSTRACT:

Angle of repose (θ):

Bulk density:

Tapped density:

Carr’s consolidation index:

Hausner ratio: