INTRODUCTION:

The aim of the current study was to develop once-daily sustained-release sustain release tablets of Salbutamol sulphate. An attempt has been made to evaluate the effect of various polymers on the release profile of drug from matrix system. Salbutamol sulphate, an anti-asthmatic agent and is a short-acting β₂-adrenergic receptor agonistused for the relief of bronchospasm in conditions such as asthma and chronic obstructive pulmonary disease, was used as a model drug to evaluate its release characteristics from different matrices¹. FT-IR studies showed no incompatibility between Salbutamol Sulphate, polymers and other excipients. Sustain release tablets were prepared by wet granulation method using Methocel K100M, Ethyl cellulose, Polyvinyl pyrrolidone, dicalcium phosphate and talc. The prepared granules were evaluated for various characteristics like bulk density, angle of repose, compressibility and drug content.

The prepared sustain release tablets were evaluated for various characteristics like uniformity of weight, hardness, diameter, friability, drug content, disintegration and dissolution studies and were found to be within the pharmacopoeial limits. The results of the in vitro release studies showed that the formulations with different polymers could sustain drug release for 12 hour.

From the data generated in this study, it was concluded that the used polymers were found to have the potential for sustaining the drug release from the prepared Salbutamol Sulphate sustained release tablets.

MATERIALS AND METHODS:

Materials: Salbutamol sulphate was obtained as gift sample from FDC Pvt Ltd, Walug, Aurangabad. Hydroxy propyl methyl cellulose (Methocel® K100M) was obtained as gift sample from Signet Pvt Ltd. Ethyl cellulose was purchased from MahendrasPunelaboratories, Pune. Polyvinyl pyrrolidone(K30)fromSisco research laboratories Pvt Ltd, Andheri(E). Dibasic calcium phosphate (DCP) was purchased from Cosmo chem. Magnesium stearate Research-Lab, Pune. Talc was purchased from Vishal chem, Mumbai. All the other chemicals used were of high analytical grade.

Methods:

Compatibility study: IR spectra of pure drug, drug and polymers and the formulations were obtained using IR spectrophotometer (FTIR – M 4100, Jasco) to establish the compatibility of ingredients.

Fig.01. Salbutamol sulphate

Fig.02. Methocel K100 + Salbutamol sulphate

Fig.03.Ethyl cellulose + Salbutamol sulphate

Fig.04.PVP K30 + Salbutamol sulphate

Preparation of sustain release tablets:

The tablets were prepared by wet granulation method²(table-2). The corresponding amount of drug, hydroxypropyl methylcellulose, ethyl cellulose, PVP K30, magnesium stearate and talc were accurately weighed. The powders were screened through screen #60. The screened powders were transferred to mortar and mixed for 10 minutes. The powder mixture was granulated using granulating solutions i.e. ethyl cellulose and PVP K30. The wet mass was passed through sieve # 16 and granular material was dried in oven for 12 hours at 45°C. The dried mass was passed through sieve # 20². After addition of lubricant and glidant, compression was carried out using 6 mm flat‐faced circular punches on eight station rotator press (CIP Machineries, Pvt.Ltd. Ahmedabad, India, M/C No.727). The total weight of the tablet was 200 mg. The composition of various formulations is given in Table 1.

Evaluation of granules: Granules prepared by wet granulation method were evaluated for angle of repose, bulk density, Carr’s index and drug content.

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

θ= tan ^-1 (h / r)

Where, h and r are the height and radius of the powder cone respectively³.

Bulk density: Both loose bulk density (LBD) and tapped bulk density (TBD) were determined. A quantity of 2 g of powder from each formula, previously lightly shaken to break any agglomerates formed, was introduced into a 10-ml measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall under its own weight onto a hard surface from the height of 2.5 cm at 2-second intervals. The tapping was continued until no further change in volume was noted. LBD and TBD were calculated using the following formulas⁴:

LBD= Weight of the Powder/Volume of packing

TBD= Weight of the Powder/Tapped volume of packing

Compressibility index: The compressibility index of the granules was determined by Carr’s compressibility index⁵.

Drug content: An accurately weighed amount of powdered salbutamol sulphate granules (100 mg) was extracted with water. The absorbance was measured at 276 nm after suitable dilution⁶.

Table- 01: Evaluation of granules-

Batch	Angle of repose	LBD (g/ml)	TBD (g/ml)	Carr’s Index (%)	Drug content
F1	22.95	0.398	0.440	12.70	97.75
F2	22.19	0.250	0.301	12.95	97.50
F3	22.34	0.290	0.320	12.63	96.33
F4	23.05	0.300	0.349	12.82	97.90
F5	22.84	0.291	0.325	13.02	98.05
F6	23.11	0.303	0.349	13.09	98.21

Table:02. Composition of Salbutamol sulphate sustain release tablets(200mg/tab)

Batch code	Salbutamol (mg)	Methocel K100(mg)	*DCP (mg)**	Mg-Stearate (mg)	Talc(mg)	Ethyl cellulose(%w/v)	PVP K30 (%w/v)
F1	08	20	165	2.5	2.5	02	-
F2	08	40	145	2.5	2.5	02	-
F3	08	60	125	2.5	2.5	02	-
F4	08	80	82	2.5	2.5	-	05
F5	08	100	82	2.5	2.5	-	05
F6	08	120	62	2.5	2.5	-	05

DCP=dicalcium phosphate; PVP=polyvinyl pyrrolidone

Evaluation of tablets (table-3):

Tablet crushing strength: The crushing strength of ten randomly selected tablets per batch were determined by using Monsanto hardness tester⁷.

Friability: Twenty tablets were rotated for 100 rotations in afriabilator (Lab hosp, India). The tablets were then dedusted, and the loss in weight due to fracture or abrasion was recorded as percentage weight loss (% friability)⁸.

%Friability =

Weight variation test: To study weight variation, 20 tablets of each formulation were weighed using an electronic balance (AX 200 Shimadzu) and the test was performed according to the official method⁹.

Drug content: Five tablets were weighed individually, and the drug was extracted in water. The absorbance was measured at 276 nm after suitable dilution⁶.

In vitro Disintegration Time: Disintegration time for Sustain release tablets was determined using USP disintegration apparatus with phosphate buffer of pH 6.8. The volume of medium was 900 ml and temp was 37± 0.2 °C. The time in minutes taken for complete disintegration of the tablet with no palatable mass remaining in the apparatus was measured. To comply the test all tablets should disintegrate within 70 minutes¹⁰.

Table.03: Evaluation of sustain release tablet:

Batch code	Weight variation	Hardness (kg/cm²)	Friability (%)	Disintegration (minutes)	Drug content
F1	Passes	4.2	0.88	63	96.15
F2	Passes	4.5	0.70	67	98.10
F3	Passes	4.8	0.95	69	95.98
F4	Passes	4.9	0.90	58	97.43
F5	Passes	4.5	0.79	54	97.87
F6	Passes	4.7	0.82	52	96.76

In vitro Drug Release Study: The in vitro dissolution study of the formulated salbutamolsulphatesustain release tablets were carried out using USP apparatus Type-II in 900 ml of phosphate buffer solution (pH 6.8) and in 900 ml of 0.1 M hydrochloric acid at 37ºC ± 0.5ºC at a rotational speed 50 rpm. At 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 h after starting the test, 5 ml sample of dissolution medium were withdrawn and analysed spectrophotometrically at 276 nm by using Shimadzu-1700 UV/visible spectrophotometer. An equal volume of fresh dissolution medium, maintained at the same temperature, was added after withdrawing each sample to maintain the volume. The absorbance values were transformed to concentration by reference to a standard calibration curve obtained experimentally (r =0.998)¹¹.

Table-4:In Vitro Drug Release Study OfFormulaton F1-F2

Batch (hrs)	F1	F2	F3	F4	F5	F6
1	17.5	18.18	16.16	19.53	16.18	16.84
2	25.5	27.61	24.25	28.29	23.57	25.59
3	32.3	33.0	30.98	32.33	28.96	30.31
4	37.72	41.09	37.72	39.07	37.05	39.07
5	47.15	48.50	45.80	45.80	42.44	46.48
6	54.56	55.91	53.21	51.87	48.50	53.89
7	61.97	63.30	60.62	57.26	55.91	61.97
8	67.36	70.73	68.03	65.34	63.99	74.77
9	76.79	78.14	75.44	73.42	77.47	82.85
10	84.20	85.55	82.85	79.49	85.55	88.24
11	91.61	92.96	90.26	86.90	92.96	93.63
12	98.35	97.67	96.33	95.65	96.61	97.00

RESULTS AND DISCUSSION:

The granules prepared by wet granulation method were evaluated for the Angle of repose, Carr’s index, bulk density (LBD/TBD) and Drug content. Angle of repose was in the range of22.19-23.05 which indicate good flow properties. Carr’s index was found to be in the range of 12.63-13.09%. LBD was in the range from 0.250-0.398 while TBD was found to be in the range from 0.440-0.301.Drug content in granules of all batches was found to be in the range of 96.33-98.21%.All the batches were evaluated for the hardness, friability, weight variation and drug content. Hardness of tablets was in the range of 4.2-4.9kg/cm². Friability of tablets was in the range from 0.70-0.90 .Weight variation test was found to be complying with IP standards. Disintegration time for tablets was in the range of 52-69 min. Drug content in tablets was ranges from 96.15-98.10%.Results of in vitro release of formulation F2 was found to be satisfactory because it shows better sustain release of drug from tablets for a long time due to the appropriate concentration of Ethyl cellulose as release retarding agent. Release kinetics of Salbutamol sulphate from these sustain release tablets was investigated and it was found that the drug release follows Korsmeyer-PeppasKinetics and values of R², n, k were obtained.Table:5 the mechanism of drug release was found that it was diffusion. From the FTIR studies it was concluded that there is no interaction between drug and excipients.

Table-5: Model fitting of formulation F1-F6

Batch	R²	n	K
F1	0.9891	0.6307	20.2633
F2	0.9915	0.6168	21.3184
F3	0.9918	0.6512	19.1453
F4	0.9976	0.5814	21.5387
F5	0.9836	0.6678	18.1641
F6	0.9878	0.6590	19.5537

Fig.05: Calibration curve of Salbutamol sulphate

Fig.06: In vitro Drug release of sustain release tablet

CONCLUSION:

The present study was undertaken with an aim to formulation development and evaluation of Salbutamol sulphate sustained release tablets using Ethyl cellulose as release retarding agent. Preformulation study was done initially and results directed for the further course of formulation. Based on Preformulation studies different batches of Salbutamol sulphate were prepared using selected excipients. Various formulations of sustained release tablets of Salbutamol sulphate were developed using various polymers viz, Ethyl cellulose, MethocelK100, Polyvinylpyrrolidone in different proportions and combinations by wet granulation technique.

Results of in vitro release profile indicated that formulation (F2) was the most promising formulation as the extent of drug release from this formulation was better as compare to other formulations. Tablets were evaluated for hardness, friability, in-vitro release profile and drug content. The hardness of tablets of these F2 formulation was found to be 4.5 ±0.05, friability was 0.70%, 67 min was the disintegration time of these tablet and weight variation test was passed by these tablets. Drug content of these tablets was 98.10%. From the Model fitting kinetic studies it was investigated that tablet of F2 formulation follows Korsmeyer-Peppas drug release kinetics as values of R^2,n and k were 0.9915, 0.6168, 21.3184respectively. Therefore it was concluded that mechanism of drug release was diffusion.

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Received on 12.12.2011 Modified on 05.01.2012

Research J. Pharm. and Tech. 5(2): Feb. 2012; Page 277-280