INTRODUCTION:

Immediate release tablets are those which disintegrate rapidly and get dissolved to release the medicaments. [1] It can provide for the way of an appropriate pharmaceutically acceptable diluent or carrier, which diluent or carrier does not prolong, to an appreciable extent, the rate of drug release and/or absorption. [2] This term excludes formulations which are adapted to provide for “modified, controlled, sustained, prolonged and extended or delayed release of drug [1]

Antifungal drugs are of two kinds, systemic and topical [3]. Systemic antifungal drugs are medicines taken by mouth or by injection to treat infections caused by a fungus. Topical [4] antifungal drugs are medicines applied to the skin to treat skin infections caused by a fungus [5].

A fungus is a one-celled form of life. Common fungal infections include athlete's foot, jock itch, candidiasis (also called thrush or yeast infection), and ringworm, which is not caused by a worm, but by a fungus. [4] Topical antifungal drugs not only relieve the symptoms of fungal infection, such as itching, burning, and cracked skin, but they also eliminate the fungus. [6] However, those that occur inside the body or that do not clear up after treatment with creams or ointments may need to be treated with systemic antifungal drugs. [7] These drugs are used, for example, to treat a type of fungal infection called candidiasis also known as thrush or yeast infection), [8] which can occur in the throat, in the vagina, or in other parts of the body. [9] They may also be used to treat fungal infections [10] such as histoplasmosis, [11] blastomycosis, [12] and aspergillosis, which can affect the lungs and other organs [4]. Terbinafine is an antifungal effective against Dermatophytes, [13] Aspergillus species, [14] and Candida and Pityrosporum yeasts [15]

Figure: 1 Terbinafine hydrochloride

MATERIALS AND METHODS:

Terbinafine hydrochloride, microcrystalline cellulose, hydroxyl propyl methyl cellulose, sodium starch glycolate, magnesium stearate, colloidal silicon dioxide

PHYSICAL AND CHEMICAL:

Characterization of Innovator: Formulation:

The innovator formulation (Tablets 250mg) was tested chemically and physically to characterize it to aid formulation development.

Comparative Dissolution Profile:

Comparative dissolution profile of Innovator Tablets 250 mg was studied in four different media - 0.1 N Hydrochloric acids, Phosphate buffer pH 6.8, and Acetate buffer pH 4.5and Citrate buffer pH 3.0.

Product: Innovator Tablets 250mg

Apparatus: USP TYPE II Paddle

Speed: 50rpm

Sampling Time: 10, 20, 30, 45, and until at least 95% of label content dissolved [16]

The comparative dissolution profile [17] in four different media is given in Table No.2

Formulation of immediate release tablets by using different excipients:

The preliminary studies, innovator product physical and chemical characterization and the drug excipient compatibility study formed the basis for developing immediate release tablets containing 300mg of active ingredients. The trials were initiated with a direct compression process [18] and then with wet granulation. [19] The entire processing for all batches was carried out in controlled condition. At relative humidity: 40-50% RH and temperature: 21 - 25°C. The blend and tablets were evaluated for Physical Parameters such as loss on drying, average weight, disintegration time, hardness etc [20]. Chemical parameters such as assay, dissolution, related substances [21].

Procedure:

· Terbinafine Hydrochloride, Microcrystalline Cellulose, Sodium starch glycolate, were weighed and shifted through #40 sieves separately. All ingredients were mixed in a polybag for 10 minute[22-25]

· Binder solution will prepared by dissolving HPMC E-LV and HPLC E-MV[26] in sufficient amount of water under stirring to get clear solution (For the different trial batches different binder solution was added respectively as mentioned in the table)

· Granulation- In this step-1 blend was granulated with step-2 binder solution in additional water was added to get wet mass.

· Step-3 wet mass was dried in FBD for 40 minutes at 70ºC and checked the LOD (10 min at 90ºC). This was passed through #20 sieve and LOD was checked.

· Colloidal silicon dioxide was passed through #60 sieve and Sodium starch glycolate was passed through #40 sieve and mixed in a polybag with step-4 granules for 5 minutes

· Magnesium Stearate were passed through #60 sieve and mixed in the step-5 for 2 minutes in the polybag.

· Tablets were compressed by taking step-6 lubricated granules. It were compressed into tablets by using 11.1mm punch, biconcave, break line on one side and plain on other sides [27, 28]

Experimental Design:

Table1: Formula for various trial batches with different binder solution and extragranular agents

S. No	Ingredients	Trial batch no 1	Trial batch no 2	Trial batch no 3	Trial batch no 4	Trial batch no 5	Trial batch no 6	Trial batch no 7
S. No	Ingredients	Quantity /tab mg	Quantity /tab mg	Quantity /tab mg	Quantity /tab mg	Quantity /tab mg	Quantity /tab mg	Quantity /tab mg
1	Terbinafine hydrochloride	281.3	281.3	281.3	281.3	281.3	281.3	281.3
2	Microcrystalline cellulose	60.7	82.7	80.7	60.7	73.2	60.7	74.2
3	Sodium starch glycolate	18	10	10	18	10	18	10
4	Colloidal silicon dioxide	4	-	4	4	4	4	-
	Binder solution
5	HPMC E-MV	8	6	12	4	17.5	12	-
6	HPMC E-LV	12	-	-	6	-	8	17.5
7	Purified water	qs	100 ml	140 ml	qs	qs	qs	qs
	Extra granular
8	Sodium starch glycolate	10	8	8	10	8	10	8
9	Magnesium stearate	4	3	4	4	6	4	6
10	Colloidal silicon dioxide	2	3	2	2	-	2	3

Evaluation of immediate release tablets:

The blend and tablets of the prepared batches were evaluated for following official and unofficial in-process parameters. [29-36]

Physical evaluation:

Loss on drying:

It is an expression of moisture content [36] on a wet-weight basis, which is calculated as follows;

% LOD = W/Wt ×100 [37]

Where, W = Weight of water in sample

Wt = Total wt. of wet sample

The LOD of unlubricated and lubricated blend sample was determined by IR balance at 105°C. [38]

Bulk density:

Bulk density [39] is defined as a mass of a powder divided by the bulk volume. [40]

A blend sample (20gm) was introduced in 100ml graduated cylinder. The volume of the material was noted on graduated cylinder. The bulk density was calculated in gm/cm³ by the formula given below [41]

Bulk density (ρ₀) = M/Vo

Where,

M = Mass of the powder; v_o = Volume of the powder

Tapped density:

Tapped density of the powder is the ratio of the mass of the powder to the volume occupied by the powder after it has been tapped for a definite period of time. [42]

The blend sample under test was screened through sieve no. 18 and the weight of sample equivalent to 20 gm was filled in 100 ml graduated cylinder. The tapping of the cylinder was carried out for 500 times using Bulk Density Apparatus [43] and the tapped volume V_fwas noted. [44]

The tapped density was calculated in gm./cm³ by the formula;

Tapped density (ρ_t) = M/V_f

Where,

M = Weight of sample powder taken

V_f = Tapped volume

Compressibility index:

The compressibility index is the measure of the propensity of the powder to consolidate [44]

The bulk density and tapped density was measured and compressibility index [45] was calculated using the formula;

C.I. = {(ρ_t-ρo)/ ρt} ×100

Where,

ρ_t = Tapped density

ρ₀ = Bulk density

Hausner ratio [46]:

Tapped density and bulk density were measured and the hausner ratio was calculated using the formula,

Hausner ratio = ρt/ρo

Where,

ρt = Tapped density

ρo = Bulk density

Angle of repose of final blend:

This is the angle θ as defined by the equation below;

Tan θ = h/d

Where,

h = Powder bed height

d = Powder bed diameter

The angle of repose of final blend was determined using reposograph. [47]

Thickness:

Three tablets were selected randomly from each batch and thickness was measured by using digital vernier caliper. Thickness was measured in mm for all batches. [48]

Hardness:

Hardness of the tablets was measured using schleuniger hardness [49] tester. For each batch five tablets were tested. The hardness was measured in newton (N) for tablets of each batch. [50]

Disintegration time:

Disintegration means breakdown of the tablet into smaller particles or granules [51]. The disintegration time of the tablets was determined using disintegration test apparatus. For this six tablets were introduced into each of the cylinder of the apparatus and test carried out and disintegration time noted down. [52] The disintegration time was measured in min. sec. for tablets of each batch.

Friability [53]:

Twenty tablets were weighed and placed in the friabilator [51] (Electrolab) and apparatus was rotated at 25 rpm for 4 minutes. After revolutions the tablets were dedusted and weighed again. The percentage friability [54] was measured using the formula,

% F = {1- (Wo/W)} ×100

Where,

% F = Friability in percentage

Wo = Initial weight of tablet

W = Weight of tablets after revolution

Weight variation:

Twenty tablets were randomly selected form each batch and individually weighed. The average weight of 20 tablets was calculated. The batch passes the test for weight variation test [55] if not more than two of the individual tablet weight deviates from the average weight by more than the percentage shown in Table No.9 and none deviate by more than twice the percentage shown.

Assay (% of label claim):

Tablets from each batch were evaluated for assay (% of label claim). The assays (% of label claim) of the batches are shown in each trial. The plot of the comparative assay of various batches is shown in each trial.

In-vitro release study:

In-vitro release profile study [56] of immediate release tablet [57] was carried out using USP type II dissolution apparatus. Tablet was kept in the beginning of each test and rotated at 50rpm. Medium used for release rate study was 500ml of water. During the course of study whole assembly was maintained at 37+0.5^oC and 10ml sample was withdrawn at time interval 10, 20, 30, 45 min and until 95% of the active content is dissolved. [58]

CDER dissolution method:

CDER dissolution method was performed by following parameters such as Type II (basket) speed 30rpm and medium 3.0 citrate buffer volume 500mL and the sampling time recommended are 10, 20, 30, 45 and until at least 95% of the label content is dissolved. The results of in-vitro release profile (Dissolution profile) study of batches are shown in individual trial. The plot of comparative dissolution profile of various batches is shown in individual trial

RESULTS AND DISCUSSION:

The preliminary studies of the drug substance (Active) were complying with the prescribed standard of quality. Loss on drying 0.08% w/w obtained. Related compounds i.e. any individual unknown impurity and total impurity not detected. Assay of drug was carried out on dried basis 99.9% w/w obtained.

Physical Characterization and chemical characterization of innovator formulation:

The physical characterization of innovator formulation showed diameter is 11.22mm, weight of tablets 404.3 mg and hardness 71-95N.

The chemical characterization of innovator formulation has shown assay of 100%, highest unknown impurity of 0.10% w/w, and total known impurity of 0.3 0% w/w and total impurity of 0.40% w/w

Table 2: Comparative Dissolution Profile of in four different media of innovator formulation

Brand Name	Innovator Tablets DASKIL TABLETS 250mg
B. No.	0316
Medium	0.1 N HCL	pH 4.5 Acidic buffer	pH 6.8 Phosphate buffer	pH 3.0 Citrate buffer
Time (min)	%Release	%Release	% Release	%Release
0	0	0	0	0
5	18	27	0.0	0.0
10	50.3	34.7	0.0	79.2
20	68.7	39	0.0	91.5
30	79.7	42.8	0.0	94.7
45	86.5	44	0.0	95.3

The dissolution profile of Innovator Daskil Tablets 250 mg in 0.1N hydrochloric acid showed slow release of drugs. The dissolution profile in acidic buffer pH 4.5 showed slow release of drug [59,60]. The dissolution profile in phosphate buffer pH 6.8 showed zero release of drug .In pH 3.0 of citrate buffer showed 79-95% of drug release in 45minutes as compare to all other

Table 3: Results of the Physical Evaluation

Batch No.	TRL/01	TRL/02	TRL/03	TRL/04	TRL/05	TRL/06	TRL/07
Weight per tablet (mg)	399	406	402	407	413	402	413
In process Parameters	Uncoated	Uncoated	Uncoated	Uncoated	Uncoated	Uncoated	Uncoated
LOD	1.75%	3.0%	1.8%	1.75%	2.13%	1.8%	2.7%
Bulk Density (g/ml)	0.39	0.37	0.42	0.39	0.413	0.39	0.403
Tapped Density (g/ml)	0.51	0.52	0.55	0.51	0.511	0.5	0.525
Carr Index	23.5	28.4	23.63	23.5	19.6	22	23.23
Hausner Ratio	1.30	1.40	1.30	1.30	1.24	1.28	1.30
% fine Passed Through 60 Mesh	44	39	24	41	28	32	34
Angle of repose of final blend	27	23	23	23.9	26.56	29	30.4
Thickness (mm)	4.89-4.93	4.48-4.5	4.48-4.5	4.92-4.98	4.77-4.8	4.93-4.98	4.7-4.8
Hardness (N)	110-122	193-206	193-206	110-128	120-121	115-138	95-115
Disintegration Time (min.sec)	5min50sec 5min55sec	13min40sec 14min15sec	15min50sec 16min45sec	5min50sec 6min45sec	8min15sec 9min50sec	1min25sec 1min30sec	1min11sec 1min5sec
Friability (%) (100 rotation)	0.09%	0.09 %	0.09 %	0.09 %	0.19%	0.11 %	0.12%

Table 4: Invitro release profile (dissolution profile) of batches

Brand Name	Terbinafine hydrochloride Tablet 250 mg
	% Drug Release (pH 3.0 Citrate buffer)
Time (min)	TRL/01	TRL/02	TRL/03	TRL/04	TRL/05	TRL/06	TRL/07
10	56	69	56	89	90	92	96
20	69	75	89	95	96	94	97
30	77	76	97	96	95	95	98
45	89	87	99	97	94	96	99

Fig.2. Comparative dissolution profile of various trials

Fig.3 Assay of different trial batches

Table 5 Comparative invitro release profile of formulation with innovator formulation.

Brand name	Terbinafine hydrochloride 250mg	Innovator DASKIL tablet 250mg	Terbinafine hydrochloride 250mg	Innovator DASKIL tablet 250mg	Terbinafine hydrochloride 250mg	Innovator DASKIL tablet 250mg	Terbinafine hydrochloride 250mg	Innovator DASKIL tablet 250mg
Batch no	TRL/07	DAS 123	TRL/07	DAS 123	TRL/07	DAS 123	TRL/07	DAS 123
Medium	0.1N HCL	0.1N HCL	P^H6.8 buffer	P^H6.8 buffer	P^H4.5 buffer	P^H4.5 buffer	P^H3.0 Citrate buffer	P^H3.0 Citrate buffer
Time (min)	%Release	%Release	%Release	%Release	%Release	%Release	%Release	%Release
10	48	50.3	0	0	32.6	34.7	96	79.2
20	65	68.7	0	0	38	39	97	91.5
30	80	79.7	0	0	41	42.8	98	94.7
45	87	86.5	0	0	43	44	99	95.3