INTRODUCTION:

Patient groups such as the elderly, children and patients who are mentally retarded, uncooperative, for most therapeutic agents used to produce systemic effects, the oral route still represents the preferred way of administration owing to its several advantages and high patient compliance compared to many other routes. To fulfill these medical needs, pharmaceutical technologists have developed a novel oral dosage form known as Oral Disintegrating Tablets (ODTs) which disintegrate rapidly in saliva, usually in a matter of seconds, without the need to take water. Drug dissolution and absorption as well as onset of clinical effect and drug bioavailability may be significantly greater than those observed from conventional dosage forms¹. Orally disintegrating tablets are also called as Orodispersible tablets, quick disintegrating tablets, mouth dissolving tablets, fast disintegrating tablets, fast dissolving tablets, rapid dissolving tablets, porous tablets and rapi melts. However, of all the above terms, United States pharmacopoeia (USP) approved these dosage forms as Oral Disintegrating Tablets. Recently, European pharmacopoeia has used the term orodispersible tablet for tablets that disperses readily and within 3 min in mouth before swallowing².

Phenylephrine is 3-[(1R)-1-hydroxy-2-(methylamino) ethyl] phenol, It is freely soluble in water having plasma half life of 2.1 – 3.4 hrs. Phenylephrine is a selective α₁-adrenergic receptor agonist used primarily as a decongestant, as an agent to dilate the pupil, and to increase blood pressure. In general, α₁-adrenergic receptors mediate contraction and hypertrophic growth of smooth muscle cells. α₁-receptors are 7-transmembrane domain receptors coupled to G proteins, G_q/11. Phenylephrine decreases nasal congestion by acting on α₁-adrenergic receptors in the arterioles of the nasal mucosa to produce constriction; this leads to decreased edema and increased drainage of the sinus cavities.

In the present study, an attempt is made to improve the in-vitro dissolution of Phenylephrine Hydrochloride by development of Orodispersible tablets using super disintegrants like cross carmellose, crosspovidone and sodium starch glycolate. The resulting dosage form provides improved oral bioavailability and dissolution profile of Phenylephrine thereby, improving the patient compliance³.

MATERIALS AND METHODS:

Phenylephrine HCl was procured from Remidex Pharma., Bangalore, Mannitol from Thermo Fisher Scientific India Pvt. Ltd, Mumbai, cross povidone, cross carmellose sodium, Low substituted hydroxyl propyl cellulose from Yarrow Chem Products, Mumbai.

Table-1.Formulation of fast disintegrating tablets of phenylephrine Hydrochloride

Formulation Code	INGREDIENTS (mg)									TOTAL
Formulation Code	Phenyle-phrine HCl	Mannitol	Low- HPC	Cross-povidone	Croscarmellose sodium	Sodium starch glycolate	Aspar-tame	Aerosil	Talc	TOTAL
F₁	10	25	5	-	-	-	5	4	6	55
F₂	10	22.5	7.5	-	-	-	5	4	6	55
F₃	10	20	10	-	-	-	5	4	6	55
F₄	10	25	-	5	-	-	5	4	6	55
F₅	10	22.5	-	7.5	-	--	5	4	6	55
F₆	10	20	-	10	-	-	5	4	6	55
F₇	10	25	-	-	5	-	5	4	6	55
F₈	10	22.5	-	-	7.5	-	5	4	6	55
F₉	10	20	-	-	10	-	5	4	6	55
F₁₀	10	25	-	-	-	5	5	4	6	55
F₁₁	10	22.5	-	-	-	7.5	5	4	6	55
F₁₂	10	20	-	-	-	10	5	4	6	55

All the ingredients used were of pharmaceutical grade other materials and solvents used were of analytical grade.

Formulation of Phenylephrine Hydrochloride tablets:

Phenylephrine HCl, mannitol, low substituted hydroxy propyl cellulose, crosspovidone, cross carmellose sodium, sodium starch glycolate, aspartame, aerosil and talc were weighed and passed through #60 mesh separately. Then the ingredients were mixed and compressed in to tablet using Single rotary tablet Punching Machine, Rimek RSB-4 Minipress 6 mm punches. Formulations of phenylephrine HCl ODTs by direct compression method are shown in Table - 1.

Evaluation of tablet:

All the tablets were evaluated for different parameters like thickness, hardness, friability, uniformity of weight, disintegration time, wetting time , drug content and In vitro dissolution study.

Thickness:

The thickness of tablet was measured by screw gauge. It is expressed in mm.

Hardness:

The hardness of the tablet was determined using a Monsanto hardness tester. It is expressed as Kg/cm².

Friability:

Friability generally refers to loss in weight of tablets in the containers due to removal of fines from the tablet surface. Friability generally reflects poor cohesion of tablet ingredients. 20 tablets were weighed and initial weight of these tablets were recorded and placed in Roche friabilator and rotated at the speed of 25 rpm for 4min. Then tablets were removed from the friabilator, dedusted and weighed and the weight was recorded.

Weight variation test:

The weight of the tablet being made was routinely measured to ensure that a tablet contains the proper amount of drug. The weight variation test was done by weighing 20 tablets individually, calculating the average weight and comparing the individual weights to the average. The tablet complies the Pharmacopoeial requirements; if not more than 2 tablets are outside the percentage limits and if no tablets differ by more than 2 times the percentage limit.

Disintegration time:

The disintegration time for all formulations was carried out using tablet disintegration test apparatus. Six tablets were placed individually in each tube of disintegration test apparatus and discs were placed. The water was maintained at a temperature of 37°±2°C and time taken for the entire tablet to disintegrate completely was noted.

In vitro dissolution studies:

In-vitro dissolution was studied in USP type II dissolution apparatus. 900 ml of distilled water was used as dissolution medium at 75 rpm. The temperature of 37 ± 0.5 °C was maintained throughout the experiment. Tablet equivalent to 10 mg of phenylephrine HCl was used in each test. 5 ml of sample of dissolution medium were withdrawn at known intervals of time and analyzed for drug release by measuring the absorbance at 273.5 nm using UV-Visible Spectrophotometer (UV-1700) Shimadzu, after suitable dilution with distilled water. The volume withdrawn at each time interval was replaced with fresh quantity of dissolution medium. The amount of phenylephrine HCl released was calculated and plotted against time and compared with pure drug.

Drug content:

Five tablets from each formulation were selected randomly, crushed and mixed. From the mixture powder equivalent to 10 mg of Phenylephrine HCl was weighed and dissolved in 100ml of distilled water. The resulting solution was filtered through Whatmann filter paper ≠41 and diluted suitably with distilled water. The absorbance of the resulting solution was measured spectrophotometric ally at 273.5 nm by UV-Visible Spectrophotometer (UV-1700) Shimadzu, using distilled water as blank^4,5.

Wetting time and Water absorption ratio:

A tablet is placed on piece of tissue paper that was folded twice and kept in a Petridish (Internal diameter = 6.5 cm) containing 6 ml of water, and the time for complete wetting is measured. The wetted tablet is then weighed and the water absorption ratio, R, is determined using following equation

R = 100 (Wa×Wb)/Wb

Where,

Wa and Wb are the weights of tablet before and after water absorption, respectively.

In- vitro dispersion time:

In vitro dispersion time was measured by dropping a tablet in a 10ml measuring cylinder containing 6ml of buffer solution simulating saliva fluid (pH7.4).the time for the tablet completely disintegrate into fine particles was noted. Six tablets from each batch were randomly selected and in vitro dispersion time was performed.

Accelerated Stability studies:

The accelerated stability studies of oral disintegrating tablets were performed by Stability test chamber as per the ICH guidelines to investigate whether the oral disintegrating tablets is affected during storage conditions. In order to study the effect of aging on physico-chemical parameters and disintegration time of prepared Oral disintegrating tablets, optimized formulations F12 were kept at 40⁰C/75% relative humidity for a period of 6 months. The physical appearances, friability, disintegration time, drug content were measured for these tablets at the end of 2, 4 and 6 months. The results showed that there was no significant difference between the initial and aged orodispersible tablets. This indicated that the physico-chemical parameters, disintegration time and percentage drug content was not affected by aging. As the optimized formulations were physically and chemically stable for 6 months at accelerated stability conditions of 40^°C and 75 % RH, the shelf life can be predicted to be more than 3 years⁶.

RESULTS AND DISCUSSION:

Fourier transform infrared spectroscopy:

· FTIR was performed by using FTIR 8400S Spectrophotometer, Shimadzu, for the pure drug, physical mixture of drug and polymers to detect any sign of interaction which would be reflected by a change in the position or disappearance of any characteristic peaks of the compound.

· The IR spectra of the pure Phenylephrine HCl (Figure-1) had shown characteristic peaks at 3083.38 due to CH aromatic stretch, 3335.62 due to NH secondary stretch, 1718.26 cm^-1due to C=O stretch and 1248.86 cm^-1due to C-N stretch and CH₃rock.

· The IR spectra of Phenylephrine HCl along with the various excipients used in the formulation of oral disintegrating tablets were recorded and the IR spectra of physical mixture of inclusion complexes with excipients (Figures 2-7) showed neither shift nor disappearance of characteristic peaks suggesting that there was no interaction between drug and polymers.

Table- 2: Pre compression parameters of Phenylephrine Granules (F1 to F12) (mean±S.D (n=3)

Formulation code	Bulk density (g/ml)	Tapped density(g/ml)	Hausner’s ratio	Carr’s Index (%)	Angle of repose(q)
F1	0.41±0.002	0.615±0.002	1.5±0.002	33.3±0.11	18⁰26^’±0.115
F2	0.413±0.002	0.496±0.002	1.2±0.002	16.7±0.15	22⁰58^’±0.642
F3	0.38±0.002	0.548±0.002	1.44±0.002	30.6±0.20	26⁰56^’±0.550
F4	0.413±0.002	0.62±0.002	1.50±0.002	33.3±0.11	25⁰64^’±1.155
F5	0.364±0.002	0.51±0.002	1.401±0.011	28.6±0.10	30⁰11^’±0.818
F6	0.361±0.002	0.46±0.002	1.274±0.015	21.5±0.05	18⁰26’±0.346
F7	0.413±0.002	0.551±0.002	1.33±0.011	25.04±0.15	27⁰92^’±1.601
F8	0.42±0.002	0.63±0.002	1.5±0.020	33.33±0.20	22⁰78^’±4.215
F9	0.421±0.002	0.562±0.002	1.334±0.011	25.08±0.15	26⁰56^’±1.172
F10	0.386±0.002	0.557±0.002	1.443±0.011	30.7±0.15	27⁰47^’±0.692
F11	0.41±0.002	0.546±0.002	1.331±0.011	24.9±0.05	23⁰74^’±0.642
F12	0.413±0.002	0.62±0.002	1.501±0.011	33.3±0.15	22⁰78^’±0.692

Figure 8: Dissolution profiles for formulation F1 to F6

Figure 9: Dissolution profiles for formulation F 7 to F 12

Table - 3: Post compression parameters for phenylephrine Tablets

Formulation code	Weight variation (mg)	Friability(%)	Hardness(kg/cm²)	Percentage drug content
F1	140±2.588	0.66±0.015	5.1±0.123	99.4±0.68
F2	160±2.659	0.67±0.015	5±0.057	99.8±1.00
F3	150±1.104	0.67±0.010	5.2±0.115	100.15±1.00
F4	150±2.588	0.66±0.015	4.6±0.115	98.66±1.15
F5	150±2.588	0.66±0.017	5±0.1	98.14±1.15
F6	140±2.663	0.67±0.011	4.8±0.057	99.71±2.11
F7	160±2.472	0.66±0.005	5.5±0.115	99.9±0.92
F8	140±2.702	0.66±0.011	5.4±0.057	100.15±1.66
F9	160±2.104	0.66±0.020	5.2±0.057	99.52±1.15
F10	160±4.104	0.67±0.015	5.4±0.0115	100.28±1.61
F11	160±2.104	0.66±0.005	4.2±0.115	100±0.69
F12	140±4.104	0.66±0.015	5.4±0.0115	98.66±1.61

(mean±S.D (n=3)

Table -4: Evaluation Parameters of Phenyl ephrine Tablets

Formulation code	Wetting time(sec)	Disintegration time(sec)	In vitro dispersion time(sec)	Water absorption ratio
F1	180±3	128±4	172±8	79.56±0.68
F2	135±4	114±4	128±6	79.83±1.00
F3	120±2	108±3	122±5	81.42±1.00
F4	160±5	105±5	110±6	75.52±1.15
F5	144±4	98±6	102±5	75.99±1.15
F6	128±3	85±4	96±6	76.05±2.11
F7	210±2	138±4	182±5	72.58±0.92
F8	195±4	124±4	176±4	73.14±1.66
F9	184±4	112±5	166±5	73.68±1.15
F10	106±4	98±6	126±6	79.18±1.61
F11	100±5	86±3	106±7	79.56±0.69
F12	98±3	74±6	94±6	80.08±1.61

mean ±S.D (n= 3)

Pre-compression parameters for Phenylephrine tablets:

The pre-compression parameters for the all 12 formulations were carried out and the results were shown in the table 2. The bulk density of all 12 formulations ranged between 0.361 to 0.421g/ml and tapped density ranged from 0.51 to 0.63 g/ml. Hausner’s ratio with values less than 1.5 indicates good flow property. The Carr’s index value was between the range 16.7 to 33.33% which confirmed that all 12 formulations showing good flow properties and good compressibility. The angle of repose was found to be 24 to 36⁰ thereby confirming the good flow property of the granules. All the parameters were within the acceptable limits for powder blend with good flow properties while compressing the tablets.

Post-compression parameters for Phenylephrine tablets

Weight variation test:

The weights of all tablet formulations ranged between 50 to 55mg (Table- 3). As the weight of tablets was 55mg, it was observed that all the tablet formulations were within the pharmacopoeia limits.

Hardness:

The hardness of all formulations was determined and the results were shown in the Table -III. The values of hardness were found to be in the range of 4.2 to 5.8 kg/cm².

Friability:

The percentage friability of all the formulations was found to be not more than 0.8%, which is well within the limit of less than 1%. The results of friability indicated that the tablets were mechanically stable and the results were shown in the Table- 3.

Drug content studies:

The drug content studies for all twelve formulations was carried out in distilled water and was found to be in the range of 98.6– 101.2% of Phenylephrine HCl and the results were shown in the Table- 3.

Evaluation parameters for phenyl ephrine tablets:

Twelve formulations were formulated using direct compression method with three different concentrations of four super disintegrants like low substituted hydroxyl propyl cellulose, cross povidone, cross carmellose sodium and sodium starch glycolate. All the twelve formulations were evaluated for parameters like wetting time, in vitro dispersion time, in-vitro disintegration time and water absorption ratio (Table IV) and checked for their in-vitro drug release profiles, and figures 1-2.

Wetting time and Water absorption ratio:

Wetting time of the formulations were determined and all the formulations showed wetting time of 90 to 210 seconds. Water absorption ratio of all the formulations was calculated using the equation and all the formulations showed good water absorption ratio of 72.58 to 81.42. Wetting time of the dosage form is related to contact angle. Lower wetting time implies a quicker disintegration time and the results were shown in the Table- 4.

In-vitro dispersion time:

In-vitro dispersion time of all the formulations of orodispersible tablets was determined and was found to be 66 to 184 seconds. Formulation F12 showed good In vitro dispersion time of 66 and 94 seconds respectively and the results were shown in the Table- 4.

In-vitro disintegration time:

In-vitro disintegration time of formulations F1 to F12 were determined and all the formulations showed disintegration time of within three seconds. According to the European pharmacopoeia, the fast disintegrating or Orodispersible tablets should disintegrate within 3 minutes without leaving any residue on the screen and the results were shown in the Table- 4.

In-vitro drug release profile:

The In-vitro drug release study indicated faster and maximum drug release from formulations F-12 and dissolution profiles are shown in Figure 1 and 2.

CONCLUSION:

Thus from above results it can be concluded that the Sodium starch gycolate is having better disintegrant property than that of Croscarmellose sodium, Crospovidone, low substituted hydroxyl propyl cellulose. Sodium starch gycolate 5% gives better disintegration and dissolution profile. Stability study shows that there was no significant difference between the initial and aged orodispersible tablets. This indicated that the physico-chemical parameters, disintegration time and percentage drug content was not affected by aging of the selected formulation.The selected tablet formulation shows that In-vitro disintegration time of less than 3 minutes and 100 percentage drug release within 20 minutes. Thus Sodium starch gycolate can be successfully used in the formulation of fast disintegrating tablets.

REFERENCES:

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3. Swamivelmanickam M, Manavalan R, Valliappan K. Mouth dissolving tablets: an overview. Int J Pharm Sci Res 2010; 1 (12): 43-55.

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Received on 23.10.2013 Modified on 30.10.2013

Research J. Pharm. and Tech. 7(1): Jan. 2014; Page 12-19