INTRODUCTION:

Patients often experience inconvenience in swallowing conventional tablets when water is not available. Furthermore, patients who have swallowing problems encounter difficulties in taking tablets, particularly pediatric and geriatric patients. Such problems can be resolved by means of mouth disintegrating tablet. This tablets disintegrate instantaneously when put on tongue, releasing the drug which dissolves or disperse in to the saliva. Some drugs are absorbed from the mouth, pharynx and oesophagus as the saliva passes down into the stomach. In such cases, bioavailability of drug is significantly greater than those observed from conventional tablet dosage form ^1-3.

Sertraline hydrochloride, a white crystalline powder, slightly soluble in water and isopropyl alcohol and sparingly soluble in ethanol which is official in Martindale Extra Pharmacopoeia. Sertraline is slowly absorbed from the gastrointestinal tract with peak plasma concentration occurring about 4.5 to 8.5 hours after ingestion. The plasma elimination half-life of sertraline is reported to be 24 to 26 hours.

It is a selective serotonin reuptake inhibitor which inhibit the reuptake of serotonin and used as antidepressant. In the management of obsessive-compulsive disorder, the usual initial dose of Sertraline is 50mg daily for adults. For children greater than 12 years, the dose 50mg once daily and for children 6 to 12 years the usual initial dose is 25mg once daily ^4,5.

Although, fast dissolving tablets prepared using crystalline cellulose and low-substituted hydroxyl propyl cellulose(L-HPC) rapidly disintegrated in the saliva of humans, the tablets thus manufactured were found to have a gritty mouth feel because of the insoluble nature of crystalline cellulose. To overcome this problem, we attempted the use of water soluble diluent, mannitol. But the tablets prepared with mannitol took long time to disintegrate probably for the fact that tablets prepared with mannitol often tend to dissolve rather than disintegrate. Thus, a novel diluent, a combination of mannitol and silicified microcrystalline cellulose(SMCC) in the ratio of 70:30 was employed in the study⁶.

MATERIALS AND METHODS:

Sertraline hydrochloride was supplied by Amoli Organics Pvt. Ltd., Vadodara. Crospovidone, Croscarmellose sodium(Ac-Di-Sol), sodium starch glycolate (Primogel) and Aspartame was obtained from the Rajesh Chemicals, Mumbai. D-mannitol-SD 200 DC was procured from Merck Ltd (Mumbai), silicified microcrystalline cellulose(SMCC) was procured from Penwest (England). Pregelainized starch was obtained from Colorcon Asia pvt Limited, Goa. Low substituted hydroxypropyl cellulose (L-HPC) was procured from shin-Etsu Chemical Co. Ltd (Japan). All the ingredients received were of pharmaceutical grade and were used as received. Other materials and solvents used were of analytical grade.

EXPERIMENTAL:

Preparation of tablets:

Sertraline hydrochloride tablets each containing 56mg of sertraline hydrochloride (equivalent to 50mg of sertraline) were prepared by direct compression as per the formulae given in Table-1. The tablets were formulated employing direct compression method using 9.5mm flat-faced punches. The drug, diluent, superdisintegrant, sweetener and flavor were passed through sieve number 40. All the above ingredients were properly mixed together (in a poly-bag). 1.5% of magnesium stearate and 1.5% talc were then passed through mesh number 60, mixed and blended with the initial mixture in a poly-bag followed by compression of the blend (Rimek II minipress). Prior to compression the granules were evaluated for several tests.

Evaluaion of Blend:

Bulk Density(Db):⁷

It is the ratio of total mass of powder to the bulk volume of powder. It was measured by pouring the weighed powder(passed through standard sieve #20)into a measuring cylinder and the initial volume was noted. This initial volume is called the bulk volume. From this, the bulk density is calculated according to the formula mentioned below. It is expressed in g/ml and is given by

Db=

Where, M is the mass of powder, Vo is the Bulk volume of the powder

Tapped Density(Dt):⁷

It is the ratio of total mass of powder to the tapped volume of powder. The volume was measured by taping the powder for 500times. Then the tapping was done for 750times and the tapped volume was noted if the difference between these two volumes is less than 2%. If it is more than 2%, tapping is continued for 1250 times and tapped volumes was noted. Tapping was continued until the difference between successive volume is less than 2% (in a bulk density apparatus). It is expressed in g/ml and is given by

Dt =

Where, M is the mass of powder, Vt is the tapped volume of the powder

Angle of repose(θ):⁷

The frictional force in a loose powder can be measured by the angle of repose, θ. It is an indicative of the flow properties of the powder. It is defined as the maximum angle possible between the surface of a pile of powder and the horizontal plane.

Tanθ =h/r

θ=tan^-1(h/r)

Where, θ is the angle of repose

h is the height in cone

r is the radius in cms.

The powder mixture was allowed to flow through the funnel fixed to a stand at definite height (h). The angle of repose was then calculated by measuring the height and radius of the heap of powder formed. Care was taken to see that the powder particles slip and roll over each other through the sides of the funnel.

Values of angle of repose ≤ 30º usually indicate a free flowing material and angles ≥ 40º suggest a poorly flowing material.

Carr’s index(I):⁷

It indicates powder flow properties. It is expressed in percentage and is given by

D_t-D_b

I= × 100

D_t

Where, D_t is the tapped density of the powder and D_b is the bulk density of the powder.

Hausner’s ratio⁷

Hausner’s ratio is an index of ease of powder flow. It is calculated by following formula. Hausner’s ratio = ρ_t/ρ_b

ρ_t-Tapped density

ρ_b-untapped bulk density

Evaluation of Tablets:

Thickness⁸:

Thickness of tablets was measured using digital vernier caliper. It is expressed in mm.

Hardness⁸:

For each formulation, six tablets were used for the study. The hardness of the tablet was determined using a Monsanto hardness tester(Cadmach). It is expressed in Kg/cm².

Friability(F)⁸:

The friability of the tablet was determined using Roche Friabilator. It is expressed in percentage(%). Twenty tablets were initially weighed (W_initial) and transferred into the friabilator and the apparatus was operated at 25rpm for 4min. The tablets were weighed again(W_final ). The % friability was then calculated by

W_{initial -}W_{final
× 100}

_F
=W_initial

Weight Variation⁸:

Twenty tablets were selected randomly from the lot and weighed individually to check for weight variation.

Table-1:Formulae of Fast disintegrating tablets of Sertraline hydrochloride

Ingredients	Quantity present(mg)in
Ingredients	S1	S2	S3	S4	S5	S6	S7	S8	S9	S10
Sertraline hydrochloride	56	56	56	56	56	56	56	56	56	56
Silicified MCC	38.46	36.96	38.46	36.96	38.46	36.96	38.46	36.96	38.46	36.96
Mannitol SD200DC	89.74	86.24	89.74	86.24	89.74	86.24	89.74	86.24	89.74	86.24
Crospovidone	5	10	-	-	-	-	-	-	-	-
Croscarmellose sodium	-	-	5	10	-	-	-	-	-	-
Sodium starch glycolate	-	-	-	-	5	10	-	-	-	-
L-HPC	-	-	-	-	-	-	5	10	-	-
Pre-gelatinized starch	-	-	-	-	-	-	-	-	5	10
Aspartame	4	4	4	4	4	4	4	4	4	4
Magnesium stearate	3	3	3	3	3	3	3	3	3	3
Talc	3	3	3	3	3	3	3	3	3	3
Flavor(orange)	0.8	0.8	0.8	0.8	0.8	0.8	0.8	0.8	0.8	0.8
Total wt	200	200	200	200	200	200	200	200	200	200

Table- 2:Evaluation of blend properties of fast disintegrating tablet.

Formulation	Bulkdensity (g/ml)	Tapped density(g/ml)	Angle of repose	Carr’sindex(%)	Hausner ratio(%)
S1	0.425±0.02	0.515±0.05	28.85±0.01	17.48	1.21
S2	0.435±0.02	0.522±0.02	25.66±0.02	16.67	1.20
S3	0.430±0.01	0.524±0.02	30.86±0.01	17.94	1.22
S4	0.434±0.03	0.521±0.05	26.08±0.02	16.69	1.20
S5	0.435±0.04	0.526±0.04	28.45±0.01	17.30	1.21
S6	0.438±0.04	0.527±0.04	26.58±0.02	16.89	1.20
S7	0.415±0.03	0.532±0.05	33.06±0.04	21.99	1.28
S8	0.432±0.03	0.540±0.04	32.08±0.02	20.00	1.25
S9	0.434±0.03	0.541±0.05	29.06±0.04	19.77	1.24
S10	0.431±0.04	0.521±0.02	27.06±0.02	17.27	1.20

Table No.3:Evaluation of physical properties of fast disintegrating tablet

Formulation	Thickness (mm)	Hardness (Kg/cm2)	% friability	Weight variation (g)
S1	3.06±0.02	3.40±0.201	0.498±0.02	199±2
S2	3.16±0.06	3.34±0.23	0.470±0.02	201±3
S3	3.26±0.04	3.44±0.14	0.431±0.03	205±2
S4	3.16±0.02	3.24±0.25	0.476±0.05	202±4
S5	3.04±0.06	3.50±0.01	0.448±0.02	205±2
S6	3.16±0.02	3.34±0.01	0.411±0.06	201±2
S7	3.26±0.04	3.50±0.02	0.447±0.04	200±3
S8	3.06±0.02	3.40±0.18	0.521±0.03	202±2
S9	3.16±0.06	3.32±0.14	0.476±0.05	198±3
S10	3.04±0.02	3.35±0.16	0.470±0.06	201±2

±-standard deviation

Table No.4:Evaluation of physical properties of fast disintegrating tablet

Formulation	Disintegration time ( sec)	Wetting time(sec)	Invitro Dispersion Time (sec)	%drug content
S1	11.34±1.15	14.6±2.16	12.2±1.20	98.60±0.03
S2	10.34±1.12	12.5±2.12	11.9±1.15	99.53±0.02
S3	12.1±2.10	15.8±3.16	14.8±3.12	98.82±0.05
S4	11.4±1.05	14.1±1.08	13.3±2.10	99.60±0.04
S5	15.2±2.16	18.6±1.18	15.3±1.15	97.54±0.08
S6	13.6±2.15	14.5±2.12	14.2±3.10	99.23±0.06
S7	14.34±2.16	35.0±2.42	29.3±1.81	97.0±0.04
S8	13.34±1.21	24.3±1.28	24.8±3.51	99.23±0.06
S9	15.2±1.06	20.6±1.16	18.3±2.31	98.56±0.04
S10	13.2±1.18	17.0±2.15	16.8±3.25	99.50±0.02

Disintegration time⁸:

The invitro disintegration time was determined using disintegration test apparatus (veego,2D). A tablet was placed in each of the six tubes of the apparatus and one disc was added to each tube. The time in seconds taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured in seconds.

Wetting time⁹:

The wetting time of tablets was measured using a simple procedure. A piece of tissue paper folded twice was placed in a small Petri-dish containing 10ml of distilled water. A tablet having small amount of amaranth powder on the upper surface was placed on the filter paper. Time required to develop red color on the upper surface of tablet was recorded as wetting time.

Drug content ^4,5:

Ten tablets were weighed and triturated. The tablet triturate equivalent to 50mg of the drug was weighed accurately and dissolved in 0.1M hydrochloric acid and diluted to 100ml with 0.1M hydrochloric acid. Absorbance was read at 228nm against the reagent blank.

Invitro Dispersion time²:

In vitro dispersion time was measured by dropping a tablet in a measuring cylinder containing 6ml of pH 6.8 simulated saliva fluid. Three tablets from each formulation were randomly selected and in vitro dispersion time was performed.

Invitro Dissolution studies ¹⁰:

The release rate of sertraline hydrochloride from fast dissolving tablet was determined using USP dissolution testing apparatus TypeII (Paddle )with a dissolution medium of 900ml of 0.1 M hydrochloric acid at 50rpm(37±0.5ºC ). 5ml of sample was withdrawn at predetermined time intervals replacing with an equal quantity of drug free dissolution fluid. The samples withdrawn were filtered through 0.45μm membrane filter, and the drug content in each sample was analyzed after suitable dilution by UV/VIS spectrophotometer at 228nm, and cumulative percent drug release was calculated using an equation obtained from a standard curve.

Accelerated stability studies¹¹:

Stability studies were carried out at 25º/60%RH and 40º/75%RH for a specific time period upto 30days for selected formulations according to ICH guidelines.

RESULTS AND DISCUSSION:

The present study was carried out to prepare sertraline hydrochloride mouth dissolving tablets using various disintegrants like crospovidone, croscarmellose sodium, sodium starch glycolate, L-HPC and Pregelatinized starch in 5% and 10% concentrations. Tablets were prepared along with other additives. Direct compression method was used for the preparation of tablets. A total number of ten formulations were prepared and evaluated.

Evaluation of blend properties:

For each designed formulation, blend of drug and excipients was prepared and evaluated for micrometric properties shown in Table-2. The bulk densities of all formulations were between 0.415-0.438g/cc. The tapped densities of all formulatios were between 0.515-0.540g/cc. The Carr’s index and Hausner ratio which ranges between 16.67 to 21.99 and 1.20 to 1.28 respectively. All formulations showed good flow properties except formulation containing L-HPC as disintegrant which had carr’s index value of 21.99%. The angle of repose values again conformed the above findings. The angle of repose values ranged from 25.66 to 33.06º. Formulations with crospovidone, croscarmellose sodium, sodium starch glycolate and pregelatinized starch as disintegrants showed angle of repose values ≤30º where as formulation containing low substituted hydroxyl propyl cellulose (L-HPC) showed angle of repose values ≥30º indicating only fair flow property of the powder mixture. This “Not-so-good” flow property of the formulation containing L-HPC may be because of the fact that L-HPC being fibrous hinders the flow.

Tablets mean thickness (n=3) was almost uniform in all the ten formulations. The thickness varies between 3.04 to 3.26mm. In all the ten formulations (n=3) the hardness was uniformly maintained and it was found to be 3.24 to 3.50Kg/cm². No much variation in the hardness was found which clearly indicates that the blending was uniform. The prepared tablets in all the formulations possessed good mechanical strength with sufficient hardness. Percent friability was less than 1% in the entire ten formulations and the values obtained lies between 0.431 and 0.521.

All the tablets from each formulation passed weight variation test, as the % weight variation was within the pharmacopoeial limits of ± 7.5% of the weight. The weight variation in all the ten formulations was found to be 198mg to 205mg which was within the pharmacopoeial limits. The percentage drug content of all the tablets was found to be between 97.54% and 99.60% of sertraline hydrochloride, which was within the acceptable limits.

Fig.1:Dissolution profiles for formulations containing 5% disintegrants of crospovidone,croscarmellose sodium,sodium starh glycolate, L-HPC and pregelatinized starch( S1,S3,S5,S7and S9 )

Further the tablets were subjected for the evaluation of invitro disintegration time. The invitro disintegration time for all the ten formulations varied from 10.34±1.12 to 15.2±2.16 seconds. The rapid disintegration was seen in the formulations containing crospovidone and croscarmellose sodium. This is due to rapid uptake of the water from the medium, swelling and burst effect. It was also noticed that as the disintegrant concentration was increased from 5% to 10% the time taken for disintegration was reduced. The results are shown in Table-4. The wetting time for all the ten formulations was performed in triplicate. The values lies between 12.5±2.12 to 35.0±2.42. The wetting time was rapid in crospovidone followed by croscarmellose sodium, sodium starch glycolate, Pregelatinized starch and L-HPC. Here also it was observed that as the concentration of disintegrant increased the time taken for wetting was reduced. L-HPC took a little more time (5%-time taken 35.0±2.42 and 10%-time taken 24.34±1.28) for complete wetting in both the concentrations when compared to other formulations. The values are shown in Table-4.

Fig.2: Dissolution profiles for formulations containing10% disintegrants of crospovidone,croscarmellose sodium,sodium starh glycolate, L-HPC and pregelatinized starch( S2,S4,S6,S8and S10 )

In vitro dispersion is a special parameter in which the time taken by the tablet for complete dispersion is measured. The time for all the ten formulations varied between 17.0±2.81and 37.0±3.94. The time taken by all the tablets to produce a uniform dispersion was within the limits. The invitro dispersion was rapid in crospovidone followed by croscarmellose sodium, sodium starch glycolate, pregelatinized starch and L-HPC. The same sequence was observed in all the three parameters related to disintegration. The results are tabulated in Table - 4.

The cumulative percentage drug released by each tablet in the in vitro release studies was based on the mean content of the drug present in the respective tablet. Formulations S1, S3, S5, S7 and S9 which contains 5% disintegrant concentration releases 88.76%, 85.40%, 80.80%, 81.26% and 80.65% drug respectively, at the end of fifteen minutes. An increase in the drug release was observed when 10% disintegrant concentration was used in formulations S2, S4, S6, S8 and S10. The drug release was found to be 99.88%, 98.65%, 89.12%, 90.68% and 89.92% respectively at the end of fifteen minutes. The rapid drug dissolution might be due to easy breakdown of particles and rapid absorption of drug into the dissolution medium. This signifies that disintegrant concentration in 10% is suitable for the formulation of mouth disintegrating tablets of sertraline hydrochloride.

Next, the release rates obtained were subjected for kinetic treatment to know the order of release. The values obtained signify that the release rate follows first order kinetics. Good correlation of 0.9971, 0.9948 and slope values of 1.65, 1.92 was obtained in case of formulations S2 and S4 respectively.

Stability studies were conducted for the formulations S2 and S4. The reason for selection is, these two formulations have shown good results in invitro disintegration, wetting time and invitro drug release studies. The tablets were analysed for hardness, uniformity of drug content, disintegration time and invitro at a time interval of 10days till a period of 30days. Both the formulations showed no significant variations in all the parameters and were stable for a period of 30days.

In conclusion, overall results suggests that a 10% disintegrant concentration is suitable for the preparation of sertraline hydrochloride mouth disintegrating tablets and the tablets containing disintegrants Crospovidone (S2) and croscarmellose sodium(S4) are the best. It can also be concluded that Fast disintegrating tablets (FDT) of sertraline hydrochloride with sufficient crushing strength and disintegration time can be formulated by direct compression by using a combination of silicified microcrystalline cellulose and mannitol (30:70) as a diluent.

ACKNOWLEDGEMENT:

The authors are thankful to The Management, Sankaralingam Bhuvaneswari College of Pharmacy, for providing necessary facilities to carry out this work.

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Received on 15.06.2009 Modified on 18.08.2009

Research J. Pharm. and Tech. 3(2): April- June 2010; Page 412-416