Formulation and Evaluation of Lacidipine Tablets Employing Lacidipine – Starch Phosphate Binary Systems

 

Prasanthi NL^* and Rama Rao N

Chalapathi Institute of Pharmaceutical Sciences, Lam, Guntur- 522034 Andhra Pradesh, India.

*Corresponding Author E-mail: prasanthi_pharm@yahoo.com

ABSTRACT:

The objective of the study is to formulate and evaluate lacidipine tablets employing lacidipine-starch phosphate binary systems. Binary systems of lacidipine in starch phosphate were prepared in different drug to carrier ratios. Lacidipine tablets were formulated employing lacidipine-starch phosphate binary systems and their corresponding physical mixtures. The compressed tablets were evaluated for various tablet characteristics including dissolution rate and efficiency. Marked increase in the dissolution rate and efficiency of lacidipine was observed with tablets of binary systems in comparison to tablets formulated with physical mixture and pure drug. Dissolution of lacidipine from the binary systems obeyed first order kinetics.

 

 

INTRODUCTION:

Starch phosphate (SP) is a modified starch that has been chemically processed to insert phosphate group in place of hydroxyl group. Though many modified starches have been studied^1-4 widely for their pharmaceutical applications, SP has not been investigated thoroughly. We have been working on the pharmaceutical applications of SP. The objective of the present investigation is to formulate and evaluate lacidipine (LAC) tablets employing LAC-SP binary systems. In the present study, LAC is used as a model drug. LAC is one of the most vascular selective of the dihydro pyridines, act as calcium channel blocker⁵. It is chemically diethyl (E) – 4 – {2-[(tert- butoxyl carbonyl) vinyl] phenyl}-1,4-dihydro-2,6-dimethyl pyridine -3,5-dicarboxylate. It is completely absorbed from the GIT. Peak plasma concentration occurs in 1 to 1.8h and it is highly protein bound. It is white to pale yellow crystalline, water insoluble (84μg/lt), freely soluble in acetone and sparingly soluble in absolute alcohol⁶.  Because of the limited aqueous solubility it exhibits, dissolution rate limited oral absorption. Hence, to improve the dissolution rate of LAC, tablets of LAC-SP binary systems were prepared and evaluated.

 

MATERIALS AND METHODS:

Materials:

Lacidipine was obtained as gift sample form Dr. Reddy’s laboratories, Hyderabad.  Starch phosphate was prepared in the laboratory using reported method ^r.

Lactose, polyvinyl pyrrolidone, talc and magnesium stearate were purchased from commercial source. All other materials were of Indian Pharmacopoeial grade.

 

Methods:

Preparation of starch phosphate (SP):

Disperse 1 mole of starch into the ½ mole of Mono sodium phosphate dehydrate solution and stir the slurry for about 10min. Swollen starch granules were collected by filtration and filter cake was broken up and dried in the air for 30min. The dried starch lumps were heated in a vacuum oven at 135^oC for 3hours. The dried mass was crushed, pulverized and sifted through mesh no. 120⁷.

 

Preparation of LAC-SP binary systems and physical mixtures:

Solid binary systems of LAC with different concentrations of starch phosphate (1:1, 1:3, 1:9 and 1:19) were prepared by kneading method. Accurately weighed quantities of LAC and Starch phosphate were taken in a mortar and mixed thoroughly. The mixture was kneaded with 2 times their amount of dichloromethane for one hour. The resulting paste was dried at 40^oC for 2 hours. The dried mass was crushed, pulverized and sifted through mesh no. 120. Physical mixtures of LAC with different concentrations of starch phosphate (1:1, 1:3, 1:9 and 1:19) were prepared by geometric mixing, by triturating LAC and starch phosphate by using the mortar and pestle, sifted through the sieve no 120 and stored in dessicator under vaccum.

 

Preparation of Lacidipine tablets:

Compressed tablets each containing 2mg of LAC were prepared by employing its physical mixtures and binary systems (in 1:1, 1:3 and 1:9) in SP by conventional wet granulation method.

Table 1: Evaluation of Various Parameters of Lacidipine Tablets Prepared

S. No	Tablet	Weight (mg)	%drug content	Hardness  (kg/cm2)	Friability (%)	D.T. (min)
Tablets prepared from solid binary systems
1	LAC-SP (1:1)	199±1.25	98.56±0.18	4.8±0.56	0.81±0.09	2.6
2	LAC-SP (1:3)	198±0.98	99.32±0.54	4.9±0.24	0.53±0.17	1.6
3	LAC-SP (1:9)	197±0.76	100.12±0.36	4.2±0.89	0.62±0.16	0.55
Tablets prepared from physical mixtures
4	LAC-SP (1:1)	200±0.99	101.15±0.09	4.1±0.75	0.55±0.11	4.5
5	LAC-SP (1:3)	201±1.52	99.26±0.27	4.6±0.16	0.64±0.23	3.3

 

Table 2: Dissolution Parameters Of Lacidipine Solid Dispersions

S. No	Tablet	Zero order ‘r’ value	First order ‘r’ value	K1 (min-1)	DE60 (%)	T50 (min)
Tablets prepared from solid binary systems
1	LAC-SP (1:1)	0.920	0.977	0.025	65.79	27.72
2	LAC-SP (1:3)	0.897	0.976	0.029	69.84	23.89
3	LAC-SP (1:9)	0.889	0.980	0.056	75.86	12.37
Tablets prepared from physical mixtures
4	LAC-SP (1:1)	0.946	0.984	0.019	49.86	36.47
5	LAC-SP (1:3)	0.925	0.979	0.024	54.53	28.87
6	LAC-SP (1:9)	0.881	0.966	0.027	61.24	25.49
7	Pure drug	0.968	0.985	0.011	45.63	63

 

Poly vinyl pyrrolidone (PVP K-30) was used as binding agent at 2% concentration in the formula; the damp mass was then granulated by passing through sieve no. 10 and the granules obtained were dried in an oven at 60^oC for 2h. The dried granules were again passed through sieve no.16 to break the aggregates. The lubricants were added to the dry granules and blended. Sufficient quantity of lactose was also added to raise the total bulk of each tablet to 200mg. The blend was compressed into tablets on a Cadmach single punch tablet machine to a hardness of 4-5Kg/Sq.cm. The prepared tablets were evaluated for the uniformity of weights, hardness, friability⁸, drug content⁹,  disintegration time and in vitro release studies^{10, 11}.

 

Estimation of Lacidipine:

An U.V Spectrophotometric method based on the measurement of absorbance at 280nm in methanol was used for the estimation of lacidipine. The method was validated for linearity, accuracy and precision. The method obeyed Beer’s law in the concentration range of 0-15µg/ml.  No interference by the experiments used in the study was observed.

 

Dissolution rate studies:

The dissolution rate of LAC tablets was studied using USP XXIII six-station dissolution rate test apparatus (DISSO 2000, LABINDIA) with paddle stirrer. The dissolution rate was studied by taking one tablet in dissolution medium (900ml of 1% tween 20 solution), maintained at 37 ± 0.5 ^o C with a speed of 50rpm. A 5ml aliquot was withdrawn at different time intervals, filtered (through 0.45µ) and replaced with 5ml of fresh dissolution medium. The samples were diluted if necessary and estimated for dissolved Lacidipine by measuring absorbance at 284nm. The dissolution experiments were conducted in triplicate.

 

Khan suggested dissolution efficiency (DE) as a suitable parameter for the evaluation of in vitro dissolution data. Dissolution efficiency is defined as the area under dissolution curve up to a certain time ‘t’ expressed as percentage of the area of the rectangle described by 100% dissolution in the same time¹².

 

RESULTS AND DISCUSSION:

A simple method to prepare starch phosphate was adopted. The method employed produced SP in fine and free flowing powder form. The SP was easily dispersible in purified water. The pH of 10% w/v slurry in water was 6.4. The density (g/cc), bulk density (g/cc), porosity (%), compressibility index (%) and swelling index (%) of SP prepared were 1.412, 0.508, 64.03, 19.13 and 98.5.

 

All the tablets prepared were found to contain the medicament with in 100±2% of labeled claim. Hardness of the tablets in all the batches was found to be in the range of 4-5kg/cm². Friability of the tablets was less than 1%. All the tablets formulated employing physical mixtures and solid binary systems disintegrated rapidly. The disintegration times were with in 5min. The evaluation data of tablets was given in Table 1. The dissolution profiles of various tablets formulated employing physical mixture and solid binary systems are studied by using USP XXIII six-station dissolution rate test apparatus. The dissolution data obtained were subjected for model fitting and the model that fits the observed dissolution data was evaluated by correlation coefficient (r) between the variables involved.  The tablets formulated employing binary systems gave rapid and fast dissolution of LAC when compared to tablets prepared with physical mixtures. The possible mechanisms responsible for increased dissolution rate form these tablets are rapid disintegration of tablets due to superior swelling capacity of SP or presence of drug in amorphous form in tablets of LAC-SP solid binary systems, since amorphous form is the highest energy form of a compound, which produce faster dissolution. The dissolution rate of LAC from the tablets increased when the proportion of SP increased. Hence, dissolution of LAC from the compressed tablets followed first order kinetics. The dissolution data is shown in Table 2 and Figure1.

 

 

Figure 1: In vitro dissolution profile of lacidipine from tablets formulated by using various binary systems and pure drug.

 

CONCLUSION:

Tablets that are formulated by employing LAC-SP solid binary systems by conventional wet granulation process gave rapid dissolution in comparison to LAC-SP physical mixtures formulations. Hence, SP (a modified starch) can be used as a carrier to formulate solid binary systems to improve the dissolution rate and efficiency of poorly water soluble drugs.

 

ACKNOWLEDGEMENTS:

The authors are thankful to Chalapathi Educational Society, Guntur for providing the necessary facilities.

 

REFERENCES:

1.       Schmidt PC, Broegmann B., Acta Pharm. Technol., 1988, 34, 22.

2.       Cohen J and Lach JL., J. Pharm. Sci., 1963, 52, 132.

3.       Tarimci N and Celebi N., Pharmaize, 1988, 43, 323.

4.       Sekulovic D and Zajic L., Pharmaize, 1987, 42, 556.

5.       Alfred G and Louis G. The Pharmacological basis of Therapeutics. 10^th ed. New York: Mc-Graw Hill Companies, Medical Publishing Divison; 2001. 907-908.

6.       British Pharmacopoeia. Vol I. 2000; 1205.

7.       United States patent 2,884,412.

8.       Leon Lachman, Lieberman HA and Kanig JL. The theory and practice of Industrial pharmacy, 3^rd ed. Varghese publishing house. 1987, 67.

9.       Indian Pharmacopoeia. Vol I. The controller of Publications, New Delhi. 1996, 736.

10.     United States Pharmacopoeia, United States Pharmacopoeial Convention, Rockville, MD. 1997.1475.

11.     Higuchi T, J. Pharm. Sci. 1961; 50: 874.

12.     Khan., K.A., J. Pharm. Pharmacol., 1975, 27, 48.

 

 

Received on 20.10.2009                             Modified on 14.12.2009

Accepted on 19.01.2010                            © RJPT All right reserved