INTRODUCTION:

Over the past three decades, Fast dissolving tablets (FDTs) have gained much attention as a preferred alternative to conventional oral dosage forms such as tablets and capsules. About 35% of the population, particularly paediatric and geriatric patients, suffer from dysphagia, have difficulty to swallow or chew conventional solid dosage forms. Recently useful dosage forms such as rapid dissolving tablets have been developed and applied clinically to assist these patients. An FDT is a solid dosage form that disintegrates and dissolves in the mouth (either on or beneath the tongue or in the buccal cavity) without water within 60 seconds or less.¹

The US Food and Drug Administration Centre for Drug Evaluation and Research (CDER) defines in the Orange Book an ODT as "A solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue"². The European Pharmacopoeia however defines a similar term, orodisperse, as a tablet that can be placed in the mouth where it disperses rapidly before swallowing^.3

Fast dissolving drug delivery (FDD) can be achieved by various conventional methods like direct compression, wet granulation, moulding⁴, spray drying⁵, freeze drying⁶, and sublimation. In order to allow fast dissolving tablets to dissolve in the mouth, they are made of either very porous and soft- moulded matrices or compressed into tablets with very low compression force, which makes the tablets friable and/or brittle, which are difficult to handle, often requiring specialized peel-off blister packaging.

In the current study, the influence of the different superdisintegrants and their concentrations on the characteristics of fast dissolving tablet of Diclofenac sodium were prepared by moulding technique was investigated. Diclofenac sodium is an acidic drug (NSAID), generally used in the treatment of acute inflammatory conditions.

MATERIALS AND METHODS:

Diclofenac sodium was purchased from Dow Chemicals, Mumbai, India. Croscarmellose sodium, Crospovidone, Sodium Starch Glycolate were obtained as gift sample from Ranbaxy, Gurgaon. Mannitol and PEG 6000 were purchased from Qualigens fine chemicals, Mumbai. All the chemicals and solvents used were of analytical grade (Merck, Mumbai, India).

Analytical Method for Estimation of the Drug: The ultraviolet spectrophotometric method was selected in the present study for the estimation of Diclofenac sodium. The drug solution was scanned in between the wavelength of 200-400nm. The wavelength of 276nm was selected as λ_max and utilized for further quantitative analysis.

Drug-Excipient Compatibility Studies: The compatibility between drug and the formulation components was investigated by Shimadzu FTIR 8300 Infrared Spectrophotometer using the KBr disc method.

Preparation of Fast dissolving Tablets: Moulding method (Fig.1 to 4) was used to prepare Fast dissolving Tablets. Weighed quantity of Diclofenac sodium (active pharmaceutical ingredient), PEG6000 (cementing agent), Croscarmellose sodium, Crospovidone, Sodium Starch Glycolate (superdisintegrant) and Mannitol (sweetening agent) were passed through 60 mesh and blended in geometric proportion .The final blend was then sieved through fine mesh (60 BSS) sieve to obtain fine powder and volumetrically filled into the blister pack. The flow property of the final blend of each formulation was characterized by Angle of Repose and Compressibility index. The powder blend was pressed slightly after filing inside the blister pack manually. These filled packs were sealed first with thin aluminium sheet and heated at 60°C in an oven. After heating for about 20 minutes the packs were allowed to cool to room temperature to get FDTs. The formulae for different formulations are shown in Table-1.

Table 1: Composition of Fast dissolving Tablets

Formulations	Diclofenac sodium (mg)	Ac-Di- sol (mg)	Polyplasdone (mg)	Explotab (mg)	PEG6000 (mg)	Mannitol (mg)	Total weight (mg)
F1	25	6	-	-	75	194	300
F2	25	12	-	-	75	188	300
F3	25	15	-	-	75	185	300
F4	25	-	6	-	75	194	300
F5	25	-	12	-	75	188	300
F6	25	-	15	-	75	185	300
F7	25	-	-	6	75	194	300
F8	25	-	-	12	75	188	300
F9	25	-	-	15	75	185	300
Control	25	-	-	-	75	200	300

Pictorial overview of moulding technique

Fig. 1 Before heating

Fig. 2 After heating for 20 minutes at 60°C

Fig. 3 Side view of the tablets formed after cooling Fig. 4 Top view of the formed tablet

Characterization of blend^5,
6

Bulk density: Powder was first passed through a standard sieve no # 20. An accurately weighed amount of blend was added to the measuring cylinder. The cylinder was fixed on the bulk density apparatus and the timer knob is set for 100 tapings. The initial volume was noted. Further, another 50 taps may be continued and the final volume was noted. For reproducible results, the process of tapings may be continued until concurrent volume was achieved. The final volume was taken as the bulk volume. Bulk density (ρ_b) was determined by using following equation,

ρ_b =M/V_b

Where, M = mass of the blend, V_b = bulk volume

All these were done in triplicate.

Compressibility index (Carr’s Consolidation Index)

Tapped density – fluff density

Carr’s index = –––––––––––––––––––––––––– × 100

Tapped density

This property is also known as compressibility. It is indirectly related to the relative flow rate, cohesiveness and particle size. It is simply fast and popular method of predicting powder flow characteristics. Carr’s index is a measure of the potential strength that a powder could build up in its arch in a hopper and also the ease with which such an arch could be broken. Carr’s index > 16 show good flow properties. All these were done in triplicate.

Angle of repose: A funnel was fixed at a particularly height, H, cm on a burette stand. A white paper was placed below the funnel on the table. The blend whose angle was to be determined was passed slowly through the funnel, until it forms a pile. Care was taken to see that the drug particles slip and roll over each other through the sides of the funnel. A circumference of the pile of the blend was drawn using a pencil without disturbing the pile. The radius of the pile, R, in cm was then determined. Angle of repose of the blend was then calculated by using the following formula.

tan a= H/R

Where a the angle of repose, H is is the height of the pile, and R is the radius of the base of the conical pile. All these were done in triplicate.

Physicochemical Evaluation of Fast dissolving Tablets ^7,8

Hardness: The hardness of the tablets (n=3) was determined by using Monsanto Hardness tester. It was expressed in Kg/cm². All these were done in triplicate.

Friability: The friability of the tablets was determined by using Roche Friabilator. Tablets corresponding to 6.5g were weighed (W_initial) and placed in the friabilator and operated for 4 min at 25 rpm. The tablets were then made free from the dust and reweighed (W_final). The percentage friability was calculated by the given formula. All these were done in triplicate.

Uniformity of Weight: Twenty tablets were selected randomly from the lot and weighed individually to check for weight variation. Percentage deviation from average weight was calculated.

Drug Content: Drug content was determined as per the assay mention in USP.

Water uptake: Ten tablets from each formulation were kept in a desicator, over calcium chloride, at 37°C for 24 hours. This was done to remove maximum amount of moisture as possible from the tablets. The tablets were weighed and exposed to 82.5% RH (which was achieved by adding 13.1ml of sulphuric acid in a dessicator and kept aside for three days) at room temperature for a week. One batch of control tablets (without superdisintegrant) was kept to assess the moisture uptake due to other excipients. The tablets were weighed and the increase in weight was reported.

Tablet disintegration time: Tablet disintegration time was noted by using disintegration tester. Tablets were placed in each tube of tablet disintegration tester and disintegration time was noted. All these were done in triplicate.

Dissolution Studies: The in vitro dissolution study was carried out using USP Type 2 dissolution apparatus at 75 rpm and 650 ml of Sorenson’s buffer (pH6.2) media. The temperature of dissolution media was maintained at 37±0.5^°C. At different time intervals, 5 ml sample was withdrawn, filtered and analyzed spectrophotometrically at 276nm for the drug release. The dissolution of the drug is expressed in percentage drug dissolved in 10 minutes. All these were done in triplicate.

Stability studies of the tablet formulations^9:The formulations were subjected to stability studies at 40°C and 75% RH in glass vials for 12 weeks. The samples were collected at weekly intervals and analyzed spectrophotometrically at 276 nm for the drug content. All these were done in triplicate.

RESULT AND DISCUSSION:

In the current study efforts were made to prepare fast dissolving tablets of diclofenac sodium with different super-disintegrants by novel and economical moulding technique. The Drug-Excipient compatibility data presented in Table-2 indicates the absence of any chemical incompatibility between drug and excipients. No considerable changes in the IR peaks of the drug were observed when mixed with excipients.

Table 3: Micromeritic properties of Various Formulations Blend (*n=3)

Formulations	Angle of Repose ± SD*	Compressibility Index± SD^*
F1	30.85 ± 0.63	19.69 ± 0.83
F2	25.76 ± 0.06	15.26 ± 0.83
F3	30.93 ± 1.13	19.39 ± 0.71
F4	33.52 ± 2.47	19.22 ± 0.95
F5	30.49 ± 0.38	19.38 ± 0.75
F6	31.20 ± 1.09	18.85 ± 0.46
F7	32.32 ± 0.43	19.57 ± 0.96
F8	30.62 ± 0.08	19.30 ± 1.37
F9	31.33 ± 1.31	19.30 ± 0.42

The cementing agent (PEG6000) provided cohesive properties to the powdered material on heating and thereby fuses the powder blend when allowed to cool to make the tablets in-situ. The disintegrant used in the present study was croscarmellose sodium, crospovidone, sodium starch glycolate which acts mainly by high capillary action and pronounced hydration capacity. The diluent used was mannitol which acts as a sweetening agent, thus masking the bitter taste of diclofenac sodium and provided a good mouth feel due to its negative heat of solution. Unlike other fast dissolving tablets, the disintegration of the moulded diclofenac tablets occurs by a combination of melting, disintegration of the tablet matrix, and dissolution of the water soluble excipient. Therefore, a dry feel does not occur.

Generally a flow characteristic is measured by angle of repose. The lower the angle of repose the better is the flow property. Blend of formulation F2 has an angle of repose of 25.76 ± 0.06 which means the blend has got a good flow property whereas the rest are in the range of fair to passable flow property. The above observation was also confirmed by Compressibility Index data.

The tablets of different formulations were subjected to various in vitro evaluation tests like hardness, friability, drug content, disintegration time, moisture uptake studies, in vitro dissolution studies and stability studies. The hardness of the tablets of all batches was ranged from 1.23 ± 0.15 to 1.63 ± 0.11 kg/cm². Disintegrants and their different levels did not show an appreciable impact on the hardness property as depicted in Table 4. The hardness reported was enough to maintain the integrity of the tablet as well as not to affect the disintegration of the tablet in the mouth. The percentage friability of various batches of tablet was ranged from 0.45 ± 0.005 % to 0.82 ± 0.04 % as depicted in Table 4. In the present study, the percentage friability for all the formulations was found below 1% indicating that friability (%) was within the acceptable limits. The drug content of various batches of tablet was ranged from 96.79 ± 2.13 to 98.73 ± 0.155 % as depicted in Table 4. Good uniformity in drug content was found among different batches of the tablets.

The disintegration time of various formulations ranged from 11± 1 to 26 ± 2 seconds as depicted in Table 4. All the formulations had a disintegration time of less than 1 minute which shows the efficiency of the superdisintegrants. Among the three superdisintegrants used, Ac-di-sol demonstrated the best disintegrating property. Tablets containing Ac-di-sol disintegrated faster when compared to others. Formulation F2 containing 4% concentration Ac-di-sol (Croscarmellose sodium) gave the least disintegrating time of 11.33 ± 0.57 seconds. This may be due to the mechanism of disintegration, which is based on swelling, water uptake and deformation. The possible mechanism of disintegration in case of Polyplasdone and Explotab comprises of capillary action with a secondary burst effect. The results also showed a decrease in disintegration time as the concentration of superdisintegrants increases. Higher levels of disintegrants probably made larger pores with continuous network or skeleton providing enough pressure within a matrix for faster disintegration.

The formulation F2 containing Ac-di-sol as the superdisintegrants released nearly 98.74% of the drug in 10 minutes. This increase in the dissolution rate may be due to improved wettability by the carrier.

At higher level (5% Ac-di-sol), the negative effect on dissolution appears (76.39% of drug was released after 10 minutes in formulation F3) because of distortion of molecular dispersion structure, which leaves an insoluble base particle and increased accumulation of carrier molecule in the bulk, to cause a saturation, by which further solubility of diclofenac sodium was retarded.

The formulations containing Polyplasdone as the superdisintegrants, showed an increase in % cumulative drug release as the concentration of the disintegrants increased from 2% to 5%. This can be correlated to tablet matrix pore size distribution created by the use of the superdisintegrants. Higher levels of disintegrants probably made larger pores with continuous network or skeleton providing enough pressure within a matrix for faster dissolution. Same trend was also observed with formulations containing Explotab as the superdisintegrants.

Table 4: Physiochemical properties of Various Formulations of Fast Dissolving Tablets of Diclofenac Sodium (*n=3)

Formulations	*Hardness± SD(kg/cm²)**	% Friability± SD*	%Drug Content± SD*	*Disintegration± SD(seconds)**	%CDR at the end of 10 minutes
F1	1.60 ± 0.1	0.63 ± 0.01	98.43 ± 0.69	19.66 ± 1.15	80.87 ± 1.04
F2	1.63 ± 0.11	0.45 ± 0.005	98.73 ± 0.155	11.33 ± 0.57	98.74 ± 0.2
F3	1.36 ± 0.15	0.76 ± 0.11	98.58 ± 0.166	13.33 ± 3.21	76.39 ± 0.83
F4	1.56 ± 0.21	0.65 ± 0.03	98.10 ± 0.44	22.00 ± 2.64	93.80 ± 0.22
F5	1.46 ± 0.11	0.74 ± 0.11	98.54 ± 0.21	17.33 ± 1.52	94.40 ± 0.12
F6	1.63 ± 0.15	0.82 ± 0.04	98.63 ± 0.14	15.66 ± 1.15	95.39 ± 0.69
F7	1.23 ± 0.15	0.73 ± 0.07	98.63 ± 0.55	26.33 ± 2.08	93.49 ± 0.45
F8	1.33 ± 0.05	0.76 ± 0.03	96.79 ± 2.13	23.66 ± 3.21	95.57 ± 0.31
F9	1.30 ± 0.26	0.80 ± 0.02	98.31 ± 0.159	19.00 ± 2.00	96.73 ± 0.55

Table 5: Percentage Moisture uptake studies of Various Superdisintegrants in different formulations of Fast Dissolving Tablets of Diclofenac Sodium

Time (days)	F1	F2	F3	F4	F5	F6	F7	F8	F9	Control
1	3.34	3.87	4.65	3.54	4.06	4.43	3.12	3.42	3.72	1.86
2	3.85	4.42	4.93	3.96	4.96	5.04	3.54	3.86	4.02	2.45
3	4.56	4.87	9.04	4.85	9.45	9.76	4.41	4.76	4.98	2.63
4	7.86	8.24	9.82	8.04	9.97	10.45	4.68	5.03	5.36	3.21
5	8.93	10.45	11.12	8.97	10.65	11.23	7.32	7.59	7.86	3.24
6	10.12	11.42	11.86	10.32	11.34	12.64	8.14	8.34	9.04	4.02
7	10.87	11.98	12.47	11.02	12.01	13.43	9.21	10.12	10.87	4.54
15	12.42	12.76	13.12	12.75	13.23	13.96	9.96	10.35	11.23	5.23

Table 6: Stability profile of Various Formulations of Fast Dissolving Tablets of Diclofenac Sodium

No. of weeks	Log % drug remaining in various formulations of diclofenac sodium
	Ac-di-sol			Polyplasdone			Explotab
	F1	F2	F3	F4	F5	F6	F7	F8	F9
0	1.9932	1.9946	1.9937	1.9916	1.9937	1.994	1.994	1.9898	1.9927
1	1.9923	1.9937	1.9922	1.9898	1.9918	1.9925	1.9933	1.9889	1.9918
2	1.9917	1.9932	1.9905	1.9889	1.9892	1.9894	1.9923	1.9874	1.9911
3	1.9907	1.9918	1.9893	1.9873	1.9878	1.988	1.9905	1.9853	1.9889
4	1.989	1.9893	1.9873	1.9853	1.9849	1.9857	1.9894	1.9835	1.9878
5	1.9873	1.9879	1.9854	1.9838	1.9832	1.9844	1.9879	1.9829	1.9862
6	1.9848	1.9875	1.9845	1.9828	1.9813	1.9808	1.9873	1.9818	1.9844
7	1.9838	1.9831	1.9829	1.9816	1.9796	1.9783	1.9867	1.9808	1.9834
8	1.9835	1.9796	1.9803	1.9803	1.9784	1.9756	1.9854	1.9799	1.9828
9	1.983	1.9786	1.9785	1.979	1.9769	1.9742	1.9844	1.979	1.9808
10	1.9812	1.9771	1.9752	1.9762	1.9753	1.9715	1.9834	1.9785	1.9789
11	1.9797	1.976	1.9742	1.9748	1.9712	1.9696	1.9817	1.9776	1.9758
12	1.9785	1.9755	1.9716	1.9737	1.969	1.9677	1.9809	1.9767	1.9744

The values of moisture uptake studies are depicted in Table 5. The moisture uptake test revealed that Polyplasdone (crospovidone) absorbed the maximum amount of moisture as the tablet weight increased by 13.96 % after 15 days of exposure to 82.5% RH. In the formulation containing Ac-di-sol (Croscarmellose sodium) and Explotab(sodium starch glycolate), the increase in weight of the tablets were found comparatively lower than Polyplasdone i.e. 13.12% and 11.23% respectively. Such a trend has been reported in the formulations containing superdisintegrants wherein the Polyplasdone has demonstrated greater moisture absorbing capacity than the other superdisintegrants (Cunningham, 2001). The percent increase in weight due to other excipients such as PEG6000, Mannitol were assessed by control, wherein the increase in weight of the tablets was comparatively low in comparison to the formulations containing the superdisintegrants.

The values of the stability testing are depicted in Table 6. Formulations F1, F2, F3 containing Ac-di-sol after the stability study of 3 months had the drug content percentage as 95.18, 94.53, and 93.68% respectively. Similarly, formulations F4, F5, F6 containing Polyplasdone after the stability study of 3 months showed the drug content percentage as 94.12, 93.12, and 92.84 %. Formulations F7, F8, F9 containing Explotab after the stability study of 3 months had the drug content percentage as 95.69, 94.79, and 94.27% respectively. It was observed that as the concentration of the superdisintegrants was increased the stability decreased. The fast rate of degradation may be attributed to the high moisture absorbing capacities of the superdisintegrants as the concentration was increased.

CONCLUSION:

The moulding method used in the present study avoids the use of expensive and non-conventional equipment. It is particularly suitable for moisture sensitive drugs because the process is solvent free. It is also suitable for the poorly compressible drugs, as the binding is provided by fusion with cementing agent rather than compression. Furthermore, as the dosage form is made in-situ in final pack, the low hardness and high friability problems normally associated with the fast dissolving dosage forms do not arise.The above study also demonstrates the potential use of superdisintegrants for the preparation of fast dissolving tablets of Diclofenac sodium by moulding method. The in vitro dissolution studies of formulations containing different percentage of superdisintegrants were found to be satisfactory. Formulation F2 with 4% Ac-di-sol showed the maximum cumulative percentage drug release (98.74%) and gave the least disintegration time of 11seconds. Stability of the formulations were found to be inversely proportional to super-disintegrant concentration. It was observed that all the superdisintegrants were able to disintegrate the tablet matrix within a minute. Therefore, further studies can be performed to find the effect of the combinations of superdisintegrants on the disintegration and the dissolution of the drug.

REFERENCE:

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Received on 14.01.2012 Modified on 13.02.2012

Research J. Pharm. and Tech. 5(4): April 2012; Page 483-489

Samples	Composition	Major peaks (Wave numbers, cm^-1)
1	Pure Diclofenac sodium	1572.61, 1508.38, 1303.92 1282.71, 775.48, 756
2	Diclofenac sodium + croscarmellose sodium + PEG6000 + Mannitol	1575.89, 1508.38,1301.99, 1282.71, 775.48, 756
3	Diclofenac sodium + crospovidone + PEG6000 + Mannitol	1575.89, 1508.38,1303.92, 1282.71, 775.48, 756
4	Diclofenac sodium + sodium starch glycolate + PEG6000 + Mannitol	1575.89, 1508.38,1301.99, 1282.71, 775.48, 756