INTRODUCTION:

Oral route has been the most popular and successfully used for controlled delivery of drugs because of convenience and ease of administration, greater flexibility in dosage form design and ease of production and low cost of such a system.¹ Pharmaceutical products designed for oral delivery are mainly immediate release type or conventional drug delivery systems, which are designed for immediate release of drug for rapid absorption. Controlled Drug Delivery (CDD) occurs when a polymer, whether natural or synthetic, is judiciously combined with a drug or other active agent in such a way that the active agent is released from the material in a predesigned manner.

The release of the active agent may be constant over a long period, it may be cyclic over a long period, or it may be triggered by the environment or other external events. In any case, the purpose behind controlling the drug delivery is to achieve more effective therapies while eliminating the potential for both under and overdosing.^2,3An irregular heartbeat is an arrhythmia (also called dysrhythmia). Heart rates can also be irregular. A normal heart rate is 50 to 100 beats per minute. Arrhythmias and abnormal heart rates don't necessarily occur together. Arrhythmias can occur with a normal heart rate, or with heart rates that are slow (called bradyarrhythmias less than 50 beats per minute). Arrhythmias can also occur with rapid heart rates.^4,5 Sotalol is a antiarrhythmic agent enhance maintenance of sinus rhythm and has a unique pharmacologic profile. It has both beta-adrenoreceptor blocking and cardiac action potential duration prolongation antiarrhythmic properties. Immediate release tablets of Sotalol are known to cause adverse gastrointestinal reactions such as nausea, vomiting. It is reported that such adverse reactions are mainly caused by abrupt increase in the blood level of the drug and differences in highest and lowest blood levels. It is important to improve the patient compliance by making it convenient to take and reduce adverse gastrointestinal reaction. To do so, first the drug should not release while residing in the stomach. Second, drug release in the small intestine should be performed at a constant rate as originally designed. To conclude, the enteric, controlled release tablet comprising Sotalol, is capable of maintaining the drug release behavior without regard to the residence time in stomach as well as reducing gastrointestinal adverse reaction such as vomiting, nausea etc. characteristic of immediate release preparation comprising Sotalol. Sotalol inhibits response to adrenergic stimuli by competitively blocking β₁-adrenergic receptors within the myocardium and β₂-adrenergic receptors within bronchial and vascular smooth muscle. The prepared formulation is usually taken 1 hour before or 2 hours after meals or antacids.^6,7

MATERIALS AND METHODS:

Materials:

Sotalol hydrochloride was received as a gift sample from GSK Ltd, Mumbai. HPMC K4M, HPMC K100M, HPMC E5, HPMC K100LV from Zydus cadila Goa. PVP K30, Isopropyl alcohol from Ranchem Ltd, Gurgaon. Aerosil 200, Acetone from Grase davison Ltd, Chennai. Instacoat II from Ideal cures Pvt.Ltd, Mumbai. Magnesium stearate from Cosme Farma Labs, Ponda. Sodium starch glycolate from FMC biopolymer, Mumbai. Compritol 888 ATO from Gattefosse pharmaceuticals, Mumbai. Lactose monohydrate from S D Finechem Ltd, Mumbai.

Methods:

Preformulation testing is the step in the rationale development of dosage forms of a drug substance. It can be investigated by physical and chemical properties of a drug substance alone and when combined with excipients.

Drug Excipient Compatibility Study:

Compatibility of Sotalol hydrochloride hemihydrate with the respective polymers and physical mixture of main formulation was established by Infrared Absorption Spectral Analysis (FTIR). Any changes in the chemical composition after combining with the excipients were investigated with IR spectral analysis.

Analytical Method:

Standard Calibration Curve of Sotalol Hydrochloride:

Calibration curve of Sotalol hydrochloride was taken in two different media i.e. in 0.1 N HCl and pH 7.4 tris buffer media.

Preparation of solution: Preparation of 0.1 N HCl solutions:

0.1N HCl was prepared by diluting 8.5 ml of concentrated Hydrochloric acid to 1000 ml distilled water.

Preparation of 7.4 pH Tris Buffer Solution:

7.27 gm of tris (hydroxy methyl) methyl amine and 5.27 gm of Nacl is dissolved in purified water, pH is adjusted and diluted with 1000ml purified water.

Standard (Stock) Solution:

The stock solution was prepared by adding 10 mg of drug in 100ml with respective buffer. From this solution serial dilutions were performed to prepare 2-10μg/ml of drug concentration were made using respective buffer solutions. All samples were analyzed by UV spectrophotometer by measuring the absorbance at 247 nm.

Formulation of Controlled Release Sotalol Tablets:

Manufacturing Procedure:

Checking Of Weights-weights of all the ingredients.

Sifting

Sift Sieve No.

Sotalol hydrochloride 24#

Lactose monohydrate 30#

HPMC K4 M 30 #

HPMC K100 M 30 #

Dry Mixing:

Materials are mixed into the blender at slow speed for 10 minutes

Granulation:

The prepared binder solution was added to the above dried mixed ingredients and makes them as wet mass. This wet mass was passed through Sieve No: # 8 and allowed to dry for 1 hour. Then it was rasped using sieve No: # 20

Mixing of Extragranular Material:

The prepared granules were mixed with extra granular material for 5 min.

Lubrication:

After mixing of extra granular material the blend was lubricated by using magnesium stearate for 5 min.

Precompressional Studies:^8,9

Angle of repose:

The angle of repose of blend was determined by the funnel method. The diameter of the powder cone was measured and angle of repose was calculated using the following equation.

tan θ = h/r

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

Table No: 1 Formula of preliminary trial batches of sotalol tablets

Ingredients (mg/tab)	FORMULATION CODE
Ingredients (mg/tab)	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	F11	F12	F13	F14
Sotalol HCl	25	25	25	25	25	25	25	25	25	25	25	25	25	25
HPMC E5	10	10	-	-	-	-	-	-	-	-	-	-	-	-
HPMC K100LV	20	-	11	-	-	-	-	-	-	-	-	-	-	-
HPMC K100M	-	-	9	11	9	9	11	11	9	11	11	11	9	11
HPMC K4M	-	20	9	14	20	14	16.5	16.5	16.5	16.5	22	22	22	22
Glyceryl Behenate	-	-	-	10	10	10	14	12	10	10	14	12	12	10
Lactose monohydrate	139	139	134	128	118	124	115.5	117.4	121.5	119.5	110	112	114	114
PVP K30	4	4	4	4	4	4	4	4	4	4	4	4	4	4
Sodium starch glycolate	-	-	-	-	6	6	6	6	6	6	6	6	6	6
Aerosil 200	-	-	2	2	2	2	2	2	2	2	2	2	2	2
Talc	-	-	4	4	4	4	4	4	4	4	4	4	4	4
Magnesium stearate	2	2	2	2	2	2	2	2	2	2	2	2	2	2
Total weight (mg)	200	200	200	200	200	200	200	200	200	200	200	200	200	200

Bulk density and Tapped Density:

Both loose bulk density (LBD) and tapped (TBD) were determined

LBD= Weight of the Granules/Untapped Volume of the packing

TBD=Weight of the Granules/Tapped Volume of the packing

Compressibility Index:

The Compressibility Index of the blend was determined by Carr’s compressibility index. It is a simple test to evaluate the LBD and TBD of a powder and the rate at which it packed down. The formula for Carr’s Index is as below:

Carr’s Index (%) = [(TBD-LBD) x100]/TBD

Hausner’s Ratio:

Hausner’s Ratio was determined by Following Equation:

Hausner’s Ratio = Tapped Density / Bulk Density

Compression:

Proceed to commence Compression operation on Rotary Tablet compression machine using Capsular shaped Standard Concave punch sets having break line on one side.

Post-compressional Studies:

Shape and appearance:

Tablets were examined under a lens for the shape of the tablet, and color was observed by keeping the tablets in light.

Uniformity of thickness:

Thickness and diameter of both core tablets and coated tablets were measured using a calibrated vernier caliper.

Weight variation test:

To study weight variation 20 tablets of each dose formulation were weighed separately using a digit al weighing balance.

Hardness test:

Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. Hardness of core tablets was determined using a validated hardness tester. It is expressed in Nkg/cm²

Friability test:

For each tablet formulation the friability of 6 tablets was determined. Friability can be determined by following equation:

F= W(I)-W(F) x100

W(I)

Tablet dosage forms assay:

Tablet containing 25 mg of drug was dissolved in 100 ml of simulated gastric fluid (SGF) pH 1.2. The drug was allowed to dissolve in the solvent, the solution was filtered, and 1ml of filtrate was suitably diluted with simulated gastric fluid pH 1.2 and analyzed spectrophotometrically at 247 nm. The amount of sotalol hydrochloride was estimated by using standard calibration curve of the drug.

Trials of Coating:

Coating was done using Instacoat EN II. Three formulations were formulated by varying the weight gain on tablet upon coating. The coated tablets were evaluated for in-vitro drug release profile.

Coating Parameter:

The coating pan was cleaned and operated.Blower was switched on so as to start hot air supply (30-35°C) on tablet bed for about 10 minutes. Tablet bed was heated to 25-30°C.

Process of coating:

Compressed air and exhaust was started. Spray of the solution was started and following parameters were maintained,

 Pan speed 25-30 rpm

 Tablet bed temperature 25 – 30°C

 Distance of gun from bed about 12 – 15 cm.

 Atomizing pressure 1.5 Kg/cm2

 Exhaust On

 Inlet air temperature 30 -35° C

 Direction of spray pattern 90° to tablet bed

Spray gun was observed for any chocking during the coating process, the coating process was stopped immediately. After spraying the total volume of solution the compressed air was stopped. Tablets are rolled for another 5 - 10 minutes for complete drying.

Disintegration Study:

Six tablets were taken and put in the disintegration apparatus, the disintegration of tablet was observed by keeping the tablets in 0.1 N HCl for 2hrs and then in tris buffer.

In-vitro drug release studies of tablets:

Drug release studies of coated tablets were carried out using a USP XXIII dissolution rate test apparatus (Apparatus 2, 150 rpm, 37 C) for 2 hr in 0.1 N HCl (900 ml) as the average gastric emptying time is about 2 hr. Then the dissolution medium was replaced with pH-7.4 Tris buffer (900 ml) for 7 hrs tested for drug release up to complete drug release. At the end of the time period 10 ml of the samples were taken and analyzed for sotalol hydrochloride content. A 10 ml Volume of fresh and filtered dissolution medium was added to make the Volume after each sample withdrawal. Sample was analyzed using UV spectrophotometer at 247 nm.

Stability study.¹⁰

The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, light, to establish re-set period for drug substances or a shelf life for the drug product and recommended storage conditions. The optimized formulation under storage condition used for stability studies are 40°C, 75±5% RH, for one month.

RESULTS AND DISCUSSIONS:

Drug - Excipient Compatibility Study:

From this Study and physical observation it was concluded that the drug does not react with the polymers and excipients under experimental conditions and affect the shelf life of product. spectras of pure drug and physical mixtures of drug and excipients were shown in Fig.1 and Fig.2 respectively.

Table No 2: Standard calibration curve of Sotalol hydrochloride in 0.1 N HCl

Sr.no	Concentration (ug/ml)	Absorbance			Average Absorbance
		1	2	3
1	2	0.172	0.175	0.170	0.172
2	4	0.312	0.315	0.318	0.315
3	6	0.476	0.476	0.475	0.476
4	8	0.630	0.632	0.634	0.632
5	10	0.772	0.773	0.774	0.773

Table No 3: Standard calibration curve of Sotalol hydrochloride in pH 7.4 Tris buffer

Sr. no	Concentration (ug/ml)	Absorbance			Average Absorbance
		1	2	3
1	2	0.195	0.193	0.191	0.193
2	4	0.337	0.337	0.336	0.337
3	6	0.493	0.491	0.489	0.491
4	8	0.651	0.657	0.654	0.654
5	10	0.794	0.797	0.796	0.796

Table No 4: Precompressional studies

Formulation	Angle of repose	Bulk density	Tapped density	Compressibility index	Hausner’s ratio	LOD
F1	33	0.6586	0.9976	28.21	1.34	2.02
F2	34	0.6576	0.997	30.05	1.36	1.98
F3	28	0.0669	0.8066	14.98	1.2	1.76
F4	27	0.6753	0.815	13.94	1.203	2.02
F5	29	0.669	0.8156	14.79	1.213	1.98
F6	27	0.6663	0.789	14.50	1.18	1.96
F7	29	0.6713	0.796	15.12	1.18	1.83
F8	28	0.6766	0.796	14.94	1.17	1.88
F9	30	0.6763	0.81	13.49	1.196	1.96
F10	27	0.6766	0.8113	15.09	1.176	2.12
F11	29	0.673	0.819	14.8	1.11	1.88
F12	28	0.6586	0.7976	14.81	1.13	2.02
F13	27	0.6576	0.797	13.5	1.2	1.98
F14	28	0.6586	0.7976	14.56	1.18	1.81

Table No 5: Post-compression evaluation of the prepared Tablets

Formulation	Thickness(mm)	Weight of tablet (mg)	Friability (%)	Hardness (N Kg/cm²)	Assay(%)
F1	Have not good flow property and compressibility index.
F2	Have not good flow property and compressibility index.
F3	4.12±0.04	200.33 ± 4.16	0.0853 ±0.016	157 ± 2	98.56
F4	4.10 ± 0.07	200.33 ± 2.51	0.082 ±0.006	157 ± 2	102.20%
F5	4.12 ± 0.07	200.33 ±3.21	0.074 ± 0.0041	151 ± 5	98.80%
F6	4.10±0.091	200 ± 3.21	0.0793 ± 0.013	155 ± 3	97.90%
F7	4.13±0.06	220 ± 3.464	0.0823 ± 0.005	152 ± 3	101.10%
F8	4.08± 0.03	200.33 ± 3.21	0.079 ± 0.009	152 ± 4	100.10%
F9	4.14±0.07	200 ± 2	0.066 ± 0.005	152 ± 4	100.20%
F10	4.09 ±0.04	198± 2.51	0.074 ± 0.001	153 ± 2	99.50%
F11	4.12±0.04	202 ± 1	0.0659 ± 0.0063	150 ± 5	99.30%
F12	4.11 ±0.04	200.3 ± 1.52	0.077± 0.014	156 ± 4	99.50%
F13	4.12±0.05	201 ± 2.64	0.078 ± 0.0075	155 ± 3	99.80%
F14	4.12 ±0.07	204 ± 2	0.069 ±0.005	154 ± 4	101.20%

Table No 6: In-vitro drug release study of tablets F3 - F6

Dissolution medium	Time(hrs)	% Cumulative drug release
Dissolution medium	Time(hrs)	F3	F4	F5	F6
0.1 N HCL	1	9.54±1.72	7.84±1.32	4.08±0.87	3.44±0.52
0.1 N HCL	2	17.46±1.23	14.8±1.34	9.02±0.51 7	7.84±0.62
7.4 Tris Buffer	3	21.6±0.51	27±0.95	18.4±0.88	15.8±0.32
	4	38.8±0.72	31.5±0.32	31.5±1.88	22±1.82
	5	49.21±0.37	47.4±0.43	44.5±1.75	39.5±0.78
	6	62.32±0.14	69±1.62	60.5±1.11	54.5±1.08
	7	86.12±0.32	84.31±0.27	73±1.79	71.09±2.23
	8	97.35±0.32	98.01±1.77	83.5±0.67	87.06±0.52
	9	--------------	---------------	96.09±2.01	98.73±0.52

Figure No 5: In-vitro drug release profile of trial batches F3 to F4

Figure No 6: In-vitro drug release profile of trial batches F5 to F6

Table No 7: In-vitro drug release study of tablets F7 – F14

Dissolution medium	Time (hrs)	% Cumulative Drug Release
Dissolution medium	Time (hrs)	F7	F8	F9	F10	F11	F12	F13	F14
0.1 N HCl	1	0	0	0	0	0	0	0	0
0.1 N HCl	2	4.89±1.8	6.76±1.61	6.06±1.40	3.52±1.23	5.78±1.06	4.21±0.97	4.84±0.73	5.12±0.52
7.4 Tris buffer	3	14.32±0.52	18.38±0.75	17.60±0.92	15.45±0.88	16.87±0.51	14.7±0.64	13.07±0.43	14.31±0.31
	4	26.87±0.74	32.63±0.54	28.34±0.32	23.93±0.68	31.33±0.49	29.15±1.76	21.53±1.54	22.23±1.84
	5	40.65±0.36	54.47±0.67	46.40±1.72	41.0±0.81	48.24±1.34	40.27±1.56	42.49±1.23	39.64±0.75
	6	59.29±0.14	62.61±1.63	61.51±1.21	59.16±1.09	63.12±1.11	59.25±0.76	58.35±1.13	57.85±1.07
	7	70.05±0.23	75.85±1.62	74.6±0.32	77.49±1.4	72.41±1.36	73.1±0.88	76.41±1.79	71.49±1.25
	8	82.90±0.31	87.7±0.52	89.30±0.88	82.21±1.79	85.34±1.62	88.44±0.67	87.63±0.72	83.42±0.54
	9	96.42±0.32	98.5±0.64	97.09±0.84	94.45±1.21	98.34±1.38	99.13±1.79	95.14±1.92	99.66±0.51

Table No 8: Comparison of dissolution profile with marketed product

Time(min)	Rt	Tt	Rt-Tt	(Rt-Tt)^2
0	0	0	0	0
1	0	0	0	0
2	4.12	4.21	0.09	0.0081
3	14.1	14.7	0.6	0.36
4	25.2	29.15	3.95	15.6025
5	43.8	40.27	3.53	12.4609
6	62.8	59.25	3.55	12.6025
7	75.21	73.1	2.11	4.4521
8	85.85	83.65	2.23	4.972
9	99.8	99.13	0.67	0.4489
Σ	410.88	403.46	16.73	50.907
Number of points		9
F1	5.01
F2	80.02

Table No 9: Effect on Physical Properties of Tablet at 40°C/ 75% RH Storage Conditions

Sr.No	Properties	Initial	Storage Conditions 40°C/ 75% RH
Sr.No	Properties	Initial	10 days	20 days	30 days
1	Appearance	White coloured, capsular shaped tablets	Whitecoloured, Capsular shaped tablets	White coloured, Capsular shaped tablets	White coloured, capsular shaped tablets
2	Hardness NKg/Cm²	150 NKg/Cm²	148 NKg/Cm²	149 NKg/Cm²	146 NKg/Cm²
3	Thickness mm	4mm±0.2mm	4mm±0.2mm	4mm±0.2mm	4mm±0.2mm
4	Weight	292 mg± 2%	292 mg± 2%	292 mg± 2%	292 mg± 2%
5	Assay	99%	98.8%	98.65%	98%

Table No 10: In-vitro drug release study for stability testing.

Dissolution medium	Time (hrs)	Initial	% Cumulative Drug Release
Dissolution medium	Time (hrs)	Initial	10	20	30
0.1 N HCl	0	0	0	0	0
	1	0	0	0	0
	2	4.21	4.56	4.40	4.60
7.4 Tris buffer	3	14.7	15.2	14.9	15.6
	4	29.15	28.05	29.95	27.15
	5	40.27	40.56	39.21	38.38
	6	59.25	57.93	58.48	59.25
	7	73.1	72.67	74	72.86
	8	88.44	86.69	87.02	86.14
	9	99.05	98.75	98.02	99.12

Figure No 11: In-vitro drug release pattern of Sotalol HCl tablets after stability study

CONCLUSION:

The study was undertaken with an aim of Formulation Development and Evaluation of Sotalol controlled release tablets using different polymers as release retarding agent. From the above results and discussion it is concluded that formulation of controlled release tablet of Sotalol hydrochloride of formulation F12 can be taken as an ideal controlled release tablets for 9 hour release as it fulfills all the requirements for controlled release tablet and our study encourages for in-vivo studies, Clinical trials on this formulation. Stability study report confirmed that formulation was not shown any colour change and no significant release profile, Assay from initial period. Thus confirms that prepared formulation was stable.

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10. ICH guidelines for Stability testing of new drug substances and products.

Received on 08.04.2015 Modified on 15.04.2015

Res. J. Pharm. Dosage Form. & Tech. 7(2): April-June, 2015; Page 134-142

DOI: 10.5958/0975-4377.2015.00020.8