Preparation, Physicochemical Characterization, Dissolution and Formulation Studies of Immediate release tablets of Amlodipine Besylate and Hydrochlorothiazide

 

Deependra Jain¹*, Nishiprakash Jain¹, Dr. SK Jain¹, Nitin Jonwal², Shashank Mishra², Deepak Bhatt², Soham Shukla³

¹Sagar Institute of Research & Technology-Pharmacy, Bhopal, India

² Cadila Pharmaceuticals Ltd., Ahmadabad, India

³B. S. Patel Pharmacy College, Mehsana, India

*Corresponding Author E-mail: deependrajain1008@gmail.com

 

The main goal of this study was to develop a stable formulation of antihypertensive drugs amlodipine and hydrochlorothiazide (HCTZ) as an immediate release tablet and to evaluate the dissolution profile. The formulation development work was initiated with wet granulation. Lactose monohydrate and microcrystalline cellulose were used as diluents. Starch paste is prepared in purified water and was used as the binder. Sodium starch glycollate is added as a disintegrating agent. Magnesium stearate was used as the lubricant. Disintegration time and drug release were taken as the basis to optimize the formulation. The prepared granules were compressed into a single layer compression machine. Capping was observed in the formulation F1. However, in the remaining four formulations no capping was observed. The tablets thus formulated with higher proportion of sodium starch glycollate showed satisfactory physical parameters, and it was found to be stable and in vitro release studies showed that formulation F5 was 101.03% for amlodipine and 99.14% for hydrochlorothiazide respectively. The results suggest the feasibility of developing immediate release tablets consisting of amlodipine and hydrochlorothiazide for the convenience of patients with hypertension.

 

 

 

INTRODUCTION:

Oral drug delivery is the most widely utilized routes for administration that have been explored for systemic delivery of drug via various pharmaceutical products of different dosage form. Among them tablet is the most widely used dosage form because of its convenience in terms of self-administration, compactness and ease in manufacturing. In pharmaceutical industries, manufacturers of generic tablets are usually focused on the optimization of the excipient mixture composition to obtain a product that meet established standard ^[1].

 

There are many method used in the pharmaceutical industry to produce granules. however the most common is the wet granulation technique.

 

The wet granulation process offers several advantage, for example, high dose drug that experience poor flow and/or poor compatibility can be granulated to obtain suitable flow and cohesion for compaction. with low dose drugs, content uniformity in the tablets can be increased ^[2].

 

Hypertension, commonly referred to as "high blood pressure," is a medical condition where the pressure is chronically elevated; it is one of the commonly found diseases, affecting most of the populations in the world. So, treating hypertension effectively is the main criterion of this study. For treating hypertension, commonly used drugs include ACE inhibitors, alpha blockers, beta blockers, calcium channel blocker, diuretics, and combination of any of these categories if immediate action is required.^[3]

 

Amlodipine is a prototype second-generation dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. They have a longer duration of action and can be given once daily. Amlodipine is used in the treatment of mild to moderate hypertension, chronic stable angina pectoris, or vasopastic angina. In these conditions, it may be employed as monotherapy or in combination with other antihypertensives or antianginals. Amlodipine can be safely combined with other blockers, ACE inhibitors, thiazides, and nitrates. It has a half-life of 40 hours and the initial effects are cumulative over many days.^[4].[5].[6]

 

Hydrochlorothiazide, 6-chloro-3,4-dihydro-7-sulfamoyl-2H-1, 2, 4-benzothiadiazine 1,1-dioxide is a white or almost white odorless powder used for the treatment of high blood pressure and management of edema. Hydrochlorothiazide promotes water loss from the body (diuretics). It inhibits Na ⁽⁺⁾ Cl^­(-) reabsorption from the distal convoluted tubules in the kidneys. It also causes loss of potassium and an increase in serum uric acid. It causes vasodilatation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue. ^[7]

 

MATERIAL AND METHODS:

Amlodipine besilate, hydrochlorothiazide, lactose, microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycollate, magnesium stearate were provided by Cadila pharmaceutical limited. All other chemicals and reagents used were either analytical or pharmaceutical grades.

 

FORMULATION APPROACH:

Amlodipine besylate and hydrochlorothiazide mixed with lactose and sifted through 30# and placed in rapid mixer granulator. Microcrystalline cellulose previously sifted through 30 #, placed in rapid mixer granulator and mix for 10 minutes. Granulation using starch paste was performed. Drying of granules done in fluid bed dryer (FBD) at 55±5ºc for 90 min sizing of granules done through 30#. Collidal silicone dioxide mixed with microcrystalline cellulose pH 102, sodium starch glycollate and passed through 40#. To this blend mix with sized granules in double cone blender for 5 minutes. Magnesium stearate(60#) added to above step and again mix for 3 minutes.

 

EVALUATIONS:

1. Micromeretics parameters ^[8],[9]

Bulk Density (BD):

 Weigh accurately 25 g of granules, which was previously passed through #30 sieve and transferred in 100 ml graduated cylinder. Carefully level the powder without compacting, and read the unsettled apparent volume (V0).Calculate the apparent bulk density in gm/ml by the following formula :

 

Bulk density = Weight of powder / Bulk volume

 

Tapped density(TD):

Weigh accurately 25 g of granules, which was previously passed through #30 sieve and transfer in 100 ml graduated cylinder. Then mechanically tap the cylinder containing the sample by raising the cylinder and allowing it to drop under its own weight using mechanically tapped density tester that provides a fixed drop of 14± 2 mm at a nominal rate of 300 drops per minute. Tap the cylinder for 500 times initially and measure the tapped volume (V1) to the nearest graduated units, repeat the tapping an additional 750 times and measure the tapped volume (V2) to the nearest graduated units. If the difference between the two volumes is less than 2% then final the volume (V2). Calculate the tapped density in gm/ml by the following formula.

Tapped density = Weight of powder / Tapped volume

 

Carr’s Index:

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

Carr’s Index= [(TD-BD)*100]/ TD

 

Hausner’s Ratio:

The Hausner’s ratio is a number that is correlated to the flow ability of a powder or granular material.

Hausner’s ratio = TD/BD

 

2. Physical parameters ^{[9],[10] ,[ 11],}

Friability:

Friability is related to tablets ability to withstand both shocks and abrasion without crumbling during manufacturing, packing, transportation and consumer handling. Friability can be evaluated by means of friability test apparatus. Acceptable limit was not more than 1.0% of three samples.

Table 1: Formulation of tablet by wet granulation method

S.No	Ingredient	F1	F2	F3	F4	F5
1	Amlodipine Besylate	5.0	5.0	5.0	5.0	5.0
2	Hydrochlorothiazide	12.5	12.5	12.5	12.5	12.5
3	Lactose	45.0	30.0	60.0	57.0	57.0
4	Microcrystalline cellulose	45.0	60.0	30.0	35.0	35.0
5	Maize Starch	3.0	3.0	3.0	3.0	3.0
6	Microcrystalline cellulose powder pH 102	14.5	14.5	14.5	13.5	12.5
7	Colloidal silicon dioxide	2.0	2.0	2.0	2.0	1.0
8	Sodium Starch Glycollate	1.0	1.0	1.0	1.0	3.0
9	Magnesium stearate	2.0	2.0	2.0	1.0	1.0
Avg. Weight		130.0 mg	130.0 mg	130.0 mg	130.0 mg	130.0 mg

Method:

Accurately weighed 6.5 gm of tablet and transfer into Friabilator and subjected to 100 revolutions in 4 minutes. Dedusted tablets were reweighed (final wt).

 

%friability= (initial weight-final weight) X 100

                              (initial weight)

 

In vitro disintegration test:

The test was carried out on 6 tablets using Tablet disintegration tester. Distilled water at 37ºC ± 2ºC was used as a disintegration media and the time in second taken for complete disintegration of the tablet with no palable mass remaining in the apparatus was measured in seconds.

 

In vitro dissolution test:

The release rate of Amlodipine-hydrochlorothiazide from immediate release tablets was determined using united state pharmacopoeia dissolution testing apparatus II . The dissolution test was performed using 900 ml of 0.01N hydrochloric acid at 37 ±0.5°C and 50 rpm. A sample (10 ml) of the solution was withdrawn from the dissolution apparatus at 10, 15, 20, 30, 45 min. The samples were replaced with fresh dissolution medium of same quantity. Absorbance of these solutions was measured at 210 nm using a Shimadzu UV-1601 UV/Visible double beam spectrophotometer. Cumulative percentage of drug release was calculated using an equation obtained from a standard curve.

 

RESULT AND DISCUSSION:

Preformulation Study of granules:

Density was poor for API as well formulation F1-F4 for various aspects such as flow and weight variation of tablets but finalized density was achieved in F5 which is good for tablet preparations. Result was shown in Table 2

 

Table 2: Pre-formulation Study of granules

S. No	Formulation Code	Parameters
		Bulk Density	Tapped Density	Carr’s index	Hausner Ratio
1.	F1	0.178	0.213	19.66	1.196
2.	F2	0.216	0.276	27.78	1.277
3.	F3	0.305	0.401	31.47	1.314
4.	F4	0.331	0.405	22.35	1.223
5.	F5	0.384	0.428	11.46	1.114

 

Physical parameters of tablets:

Average wt of tablet was found for F1 to F5 formulation in the range of 128 to 132mg. The thickness was found uniformly for different formulation. For friability capping was found in F1 formulation. Disintegration time for F1 to F5 formulation from 1 to 7 min and % purity was found in the range. Result was shown in Table 3.

 

In-Vitro release study:

The release rate of amlodipine and hydrochlorothiazide from immediate release tablets was determined using united state pharmacopoeia dissolution testing apparatus II. The dissolution test was performed using 900 ml of 0.01N hydrochloric acid, at 37 ±0.5°C and 50 rpm. A sample (10 ml) of the solution was withdrawn from the dissolution apparatus at 10, 15, 20, 30 and 45min rpm was set 50. Result was shown in Figure 1 and 2

 

 

Fig 1. in vitro Dissolution of Amlodipine F2 to F5

 

Table 3: Physical parameters of tablets

S.No.	Formulation Code	Physical parameters
		Avg. Tab Wt.(mg )	Thickness (mm)	Hardness in kg/cm2	% Friability	D.T. (min)	Assay (%)
							Amlodipine	HCTZ
1.	F1	130	2.50±0.2mm	5-7	capping	5-6	96.21	95.33
2.	F2	130	2.55±0.2mm	4-5	0.128	3-4	94.25	97.6
3.	F3	130	2.55±0.2mm	7-8	0.134	6-7	88.32	91.57
4.	F4	130	2.58±0.2mm	3-4	0.122	5-6	95.87	96.74
5.	F5	130	2.65±0.2mm	2-3	0.101	1-2	98.74	99.87

 

 

CONCLUSION:

The prepared granules were evaluated for bulk density, tapped density, Carr’s index and Hausner's Ratio. It was found that blend had Carr’s index from 11% to 31% and Hausner's Ratio from 1.114 to 1.314, which indicate that ready for compression blend was good flow property and compressibility property. Total formulations were prepared using different percentage of lactose, microcrystalline cellulose and sodium starch glycollate in different ratios along with lubricant. The tablets were evaluated for thickness, disintegration, hardness, friability, drug release, wt. variation and assay. The thickness of the tablet varied from 2.50 to 2.65 mm. The disintegrating time was found to be between 1 to 7 min. The hardness was in range of 2 to 8 kg/cm². The formulations F2 to F5 were evaluated for assay and in vitro drug release. Based on Hence antihypertensive drug can be successfully formulated as an immediate release tablet by wet granulation method.

 

ACKNOWLEDGEMENT:

The authors are thankful to Cadila Pharmaceuticals Limited (Gujarat, India) for their support and cooperation in carrying out the research work.

 

REFERENCE:

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3.       Duarte JD, Cooper DH. Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide-like diuretics. Expert Rev Cardiovasc Ther 8 (6): 793–802.

4.       Bhowmik D, Chiranjib B, Krishnakanth P, Chandira RM. Fast dissolving tablet: An overview. Journal of Chemical and Pharmaceutical Research2009;1:163-77.

5.       Atram SC, Shahi SR, Udavant YK, Salunke RJ, Neb GB, Gulecha BS, et al. Formulation of bilayer tablet conatining metoprolol succinate and amlodipine besylate as a model drug for antihypertensive therapy. Journal of Pharmacy Research. 2; 2009: 335-47.

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7.       Tangalos EG, Zarowitz BJ. Combination drug therapy. Journal of the American Medical Directors Association. 6:2009:406-9.

8.       Leah E, Appel DT, Friesen JE, Byers MD, Crew BC, Hancock SJ, Schadtle. Immediate release dosage forms containing solid drug dispersion. United States Patent No. 424465; 2002.

9.       Lachman L, Lieberman HA, Kanig JL.The Theory and Practice of Industrial Pharmacy 3rd Ed. Varghese publishing house, Bombay. 1987:294,pp. 336, 413.

10.    Lieberman HA, Lachman L, Schwartz JB. Pharmaceutical Dosage Forms, 2nd Ed, Marcel Dekker Inc, New York.1:1989:pp 195-229.

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Received on 10.01.2013       Modified on 13.01.2013

Accepted on 15.01.2013      © RJPT All right reserved