Formulation and Evaluation of Losartan Potassium Sustained Release tablets

 

Aarti P. Nikam*, Prof. Mukesh. P. Ratnaparkhi

Marathwada Mitra Mandal’s College of Pharmacy, University of Pune, Thergaon Pune-33 India

 

ABSTRACT:

The objective of this study was to develop the Losartan potassium sustained release tablets. This can be achieved by formulating tablets by direct compression method, by employing semi-synthetic and natural polymers like HPMCK100M, Carbopol 934 and Xanthan gum in various concentrations. The powdered blend evaluated for angle of repose, bulk density, tapped density, compressibility index and Hausner’s ratio. The results obtained were satisfactory. Compressed formulations were further evaluated for thickness, friability, and hardness, swelling index and in-vitro dissolution studies. All the formulations showed good results, which were in compliance with Pharmacopoeia standards.

 

A response surface methodology was used to select the optimized formulation wherein types of polymer and concentration of polymer were taken as independent variables and amount of drug release was taken as dependent variables. Optimization studies were carried out by using the Design Expert software version 8.0.1. The in vitro drug release followed Zero Order model and the drug release mechanism was found to be Non-Fickian type.

 

 

INTRODUCTION:

Losartan potassium is an orally active non- peptide angiotensin-II receptor antagonist, used in the treatment of hypertension due to mainly blockade of AT1 receptors. The main reason for low therapeutic effectiveness of Losartan potassium is its narrow absorption window, narrow therapeutic index, poor bioavailability as 25-35%, and short biological half-life of 1.5-2 h. Historically, oral route has been the most predominant route of drug delivery due to its ease of administration, low cost of therapy, patient compliance and flexibility in its formulation. ^{[1], [2]}

 

Drugs which are easily absorbed from the gastrointestinal tract and those with short half-lives are quickly eliminated from the systemic circulation need frequent dosing. To overcome this problem, gastro-retentive drug delivery systems, which provide effective plasma drug concentration for longer periods thereby reducing the dosing frequency, are being formulated. It also has an advantage of minimizing the fluctuations in plasma drug concentration by delivering the drug in a controlled and reproducible manner.

 

Pharmaceutical research is becoming progressively more oriented towards the development of special dosage form which releases drug slowly throughout GI tract ^{[1], [3], and [4].}

 

Sustained release tablet formulated by using hydrophilic polymer like hydroxypropyl, methylcellulose, Carbopol 934, hydrophobic polymer like, ethyl cellulose and natural polymer like Xanthan Gum were used.^[5] Optimization techniques were applied in the present study to systematically study the influence of process variables on formulation of dosage forms. These designs provide effective means for studying the effects of various parameters on dependent variables. ^{[6], [7]}

 

MATERIALS AND METHODS:

Materials:

Losartan potassium was received as a gift sample from Mylan Laboratories Ltd. Magnesium stearate, Ethyl cellulose from Research Lab. Pune, Xanthan gum, Aerosil, HPMCK100M from Dow Chemicals Pvt. Ltd. Carbopol from Analab Fine Chemicals. Mumbai and Dicalcium Phosphate were obtained from Loba Chemicals Pvt. Ltd. Mumbai, India.

 

 

Methods:

Preparation of Sustained Release Tablets Losartan potassium sustained release tablets were prepared by direct compression method. Powder mix was sifted using sieve no. 80 and was lubricated by Aerosil and magnesium stearate. Finally tablets were punched using single 8 mm punch tablet machine. All tablets were stored in airtight containers at room temperature for further study. Formulation of factorial design batches is shown in Table no.1.

Evaluation:

Fourier Transform Infrared (FT- IR) Studies FT- IR spectra of pure Losartan potassium and its respective physical mixtures were taken to assure the compatibility between pure Losartan potassium and excipients. Fig.1, 2 show infrared spectrum of Losartan potassium and optimized batch bscanning the sample in KBr discs (Shimadzu FT- IR) instrument.

 

 

Fig.1: IR Spectra of Losartan Potassium

 

Fig.2: IR Spectra of Losartan Potassium and HPMCK100M

 

UV determination of drug:

Preparation of standard stock solution:

Standard stock solution containing 100 ppm of Losartan potassium was prepared in water. From the stock, different aliquots were taken and diluted to 10 ml with water to obtain series of concentrations. The solutions were scanned on spectrophotometer in UV range 200 - 400 nm. Losartan potassium showed absorbance maxima at226.5nm as shown in Fig. 3.

 

Pre Compression parameters:

Angle of repose (θ)

It is the maximum angle possible between the surface of pile of the powder and the horizontal plane. Fixed funnel method was used. A funnel was fixed with its tip at a given height (h), above a flat horizontal surface on which a graph paper was placed. Powder was carefully poured through a funnel till the apex of the conical pile just touches the tip of funnel. The angle of repose was then calculated using the formula, θ = tan-1(h/r) Where, θ = angle of repose, h = height of pile, r = radius of the base of the pile.

 

Bulk density (Db)

It is the ratio of mass of the powder taken to its bulk volume. The bulk density depends on particle size distribution, shape and cohesiveness of particles. Accurately weighed quantity of powder was carefully poured into graduated measuring cylinder through large funnel and volume was measured which is called initial bulk volume. Bulk density is expressed in gm/cc and is given by,

 

Db = M/Vo where, Db = Bulk density (gm/cc), M =Mass of powder (g), Vo = Bulk volume of powder (cc)

 

Tapped density (Dt)

Ten grams of powder was introduced into a clean, dry 100 ml measuring cylinder. The cylinder was then tapped 100 times from a constant height and tapped volume was read. It is expressed in gm/cc and is given by,

 

Dt = M/Vt Where, Dt = Tapped density (gm/cc), M =Mass of powder (g), Vt = Tapped volume of powder (cc)

 

Compressibility Index

An indirect method of measuring powder flow from bulk densities was developed by Carr. The percentage compressibility of powder was a direct measurement of the potential powder arch or the bridge strength and stability. Percent Compressibility Index of each formulation was calculated according to equation given below,

 

% Compressibility index = [(Dt – Do)/Dt] x 100.

Where, Dt = Tapped density, Do = Bulk density

 

 

Fig.3: UV Spectrum of Losartan Potassium

 

 

Fig.4.1: Dissolution profiles of Losartan Potassium sustained release tablets (F1 to F4Hauser’s ratio

 

 

Fig. 4.2: Dissolution profiles of Losartan Potassium sustained release tablets (F5 to F8)

 

Fig. 4.3: Dissolution profiles of Losartan Potassium sustained release tablets (F9 to F12)

 

Fig. 4.5: Dissolution profiles of Losartan Potassium sustained release tablets (F13 to F16)

 

Fig. 4.6: Dissolution profiles of Losartan Potassium sustained release tablets (F17 to F21)

 

Hausner’s ratio is an index of ease of powder flow; it is calculated by the following formula.

Hausner’s ratio = Dt/Do,

Where Dt = Tapped density, Do = Bulk density.

Evaluation of Powder blends is shown in Table no. 2.

 

Post compression parameters

Thickness:

Control of physical dimension of the tablet such as thickness is essential for consumer acceptance and tablet uniformity. The thickness and diameter of the tablet was measured using vernier calipers. It is measured in mm.

 

 

Fig. 5: Interaction Graph by Surface Response Method.

Hardness:

The Monsanto hardness tester was used to determine the tablet hardness. The tablet was held between a fixed and moving jaw. Scale was adjusted to zero; load was gradually increased until the tablet fractured. The value of the load at that point gives a measure of hardness of the tablet. Hardness was expressed in Kg/cm2. Three tablets were randomly picked and hardness of the tablets was determined

 

 

Friability:

Tablet strength was tested by using Roche Friabilator. 20 tablets were weighed and placed in the friabilator and operated for 100 revolutions at25 rpm for 4 min, tablets were taken out and dedusted. The percentage weight loss was calculated by reweighing the tablets. The %friability was then calculated by,

 

F = {(Wt initial) – (Wt final)/(Wt initial)} x 100

Table 1: Tablet Formulation

Formulation No.	Losartan Potassium	HPMC K100M	Carbopol 934	Xanthan Gum	Ethyl Cellulose	Dicalcium Phosphate	Magnesium stearate	Aerosil
F1	50	-	48.75	-	70	76.25	2.5	2.5
F2	50	40	-	-	60	95	2.5	2.5
F3	50	-	40	-	60	95	2.5	2.5
F4	50	-	-	57.5	53	84.5	2.5	2.5
F5	50	-	57.5	-	53	84.5	2.5	2.5
F6	50	75	-	-	50	70	2.5	2.5
F7	50	-	-	75	50	70	2.5	2.5
F8	50	57.5	-	-	53	84.5	2.5	2.5
F9	50	40	-	-	60	95	2.5	2.5
F10	50	-	40	-	60	95	2.5	2.5
F11	50	66.25	-	-	70	58.75	2.5	2.5
F12	50	-	-	66.25	70	58.75	2.5	2.5
F13	50	-	-	40	60	95	2.5	2.5
F14	50	-	-	40	60	95	2.5	2.5
F15	50	-	66.25	-	70	58.75	2.5	2.5
F16	50	75	-	-	50	70	2.5	2.5
F17	50	-	75	-	50	70	2.5	2.5
F18	50	48.75	-	-	70	76.25	2.5	2.5
F19	50	-	-	75	50	70	2.5	2.5
F20	50	-	-	48.75	70	76.25	2.5	2.5
F21	50	-	75	-	50	70	2.5	2.5

*All Ingredients are in mg per tablet

Total weight of tablet is 250mg

 

 

Table 2: Evaluation of powder blends

Formulation No.	BulkDensity (gm/cm3)	Tapped Density (gm/cm3)	Compressibility Index	Hauser’s Ratio	Angle of Repose (o)
Fl	0.4214±0.0068	0.5245±0.0013	19.64±0.5020	1.24±0.0070	34.75±0.003
F2	0.3683±0.0009	0.4473±0.0002	17.66±0.0212	1.21±0.0212	34.21±0.006
F3	0.4127±0.0180	0.4821±0.0029	14.36±0.7566	1.16±0.0000	29.24±0.008
F4	0.3925±0.0026	0.4614±0.0028	14.93±0.9545	1.16±0.0070	32.61±0.00I
F5	0.3100±0.0035	0.3655±0.0031	15.19±0.2969	1.17±0.0070	35.23±0.00I
F6	0.2896±0.0014	0.3449±0.0013	16.04±0.3676	1.18±0.0424	33.86±0.002
F7	0.3910±0.0014	0.4650±0.0036	15.90±0.3040	1.16±0.0070	34.99±0.003
F8	0.3823±0.0032	0.4852±0.0044	20.01±0.0848	1.26±0.0000	35.12±0.019
F9	0.3683±0.0009	0.4473±0.0002	17.66±0.0212	1.21±0.0212	34.21±0.006
Fl0	0.4127±0.0180	0.4821±0.0029	14.36±0.7566	1.16±0.0000	29.24±0.008
F11	0.4230±0.0020	0.4766±0.0033	11.23±0.1272	1.12±0.0035	35.15±0.041
Fl2	0.4236±0.0026	0.4854±0.0018	12.73±0.0494	1.14±0.0014	35.13±0.032
F13	0.4335±0.0016	0.4865±0.0004	10.88±0.0000	1.12±0.0084	32.39±0.091
F14	0.4335±0.0016	0.4865±0.0004	10.88±0.0000	1.12±0.0084	32.39±0.091
Fl5	0.4230±0.0034	0.5240±0.0070	19.26±0.1555	1.23±0.0063	33.94±0.028
F16	0.2896±0.0014	0.3449±0.0013	16.04±0.3676	1.18±0.0424	33.86±0.002
F17	0.4472±0.0039	0.5050±0.0035	11.88±0.1697	1.13±0.0036	31.79±0.017
F18	0.4325±0.0034	0.5025±0.0035	13.92±0.0848	1.16±0.014	30.11±0.004
Fl9	0.3910±0.0014	0.4650±0.0036	15.90±0.3040	1.16±0.0070	34.99±0.003
F20	0.4335±0.0016	0.4865±0.0004	10.88±0.0000	1.12±0.0084	32.39±0.091
F21	0.2896±0.0014	0.3449±0.0013	16.04±0.3676	1.18±0.0424	34.86±0.002

 

 

Table 3: Evaluation of Post-compression parameters

Formulation	Weight Variation	Hardness kg/cm2(n=6)	%Drug content (n=3)	%Friability
No.	(n=20)			(n=10)
F1	250.9­±1.48	7.01±0.28	97.06±0.39	0.41
F2	251.45±1..40	7.50±0.31	97.14±0.76	0.37
F3	252.4±1.40	7.24±0.22	96.54±0.46	0.39
F4	251.3±1.49	6.68±0.39	99.07±0.52	0.41
F5	250.7±1.42	7.10±0.27	98.17±0.64	0.38
F6	250.45±1.3	6.89±0.39	98.21±0.93	0.29
F7	250.85±1.3	6.90±0.39	99.27±0.78	0.36
F8	251.15±1.4	7.23±0.31	99.34±1.04	0.28
F9	251.45±1..40	7.50±0.11	98.85±0.25	0.31
F10	252.4±1.40	6.40±0.22	96.98±0.99	0.35
Fl1	250.8±1.47	7.40±0.40	95.67±0.66	0.39
F12	251.44±1.3	7.10±0.32	. 97.93±0.62	0.34
F13	251.2±1.48	7.50±0.09	95.43±0.82	0.37
F14	251.2±1.48	5.79±0.28	98.83±0.51	0.42
F15	250.6±1.41	7.08±0.31	97.65±0.44	0.47
F16	250.45±1.3	6.29±0.29	99.05±0.63	0.33
Fl7	250.87±1.5	7.24±0.35	99.37±0.97	0.58
Fl8	251.2±1.42	6.84±0.33	97.29±0.48	0.43
Fl9	250.85±1.3	7.10±0.32	97.93±0.47	0.34
F20	248.0±1.46	7.50±0.09	95.43±0.73	0.37
F21	250.9±1.44	6.89±0.39	98.21±0.84	0.29

 

 

Weight variation:

Ten tablets were selected randomly from each batch were weighed individually and together in a single pan balance. The average weight was noted.

 

Uniformity of drug content:

The drug content was performed to check the dose uniformity in the formulation. Randomly ten tablets were weighed and powdered. A quantity equivalent to 100 mg of Losartan potassium was added in a 100 ml volumetric flask and dissolved in0.1N HCI, shaken for 10 min and made up to the volume with 0.1N HCl. After suitable dilutions the drug content was determined by UV spectrophotometer (Shimadzu V 630) at 205 nm against blank.

 

In vitro Drug Release Study:

The release rate of Losartan potassium sustained release tablets was determined using USP Type II Apparatus. The dissolution test was performed using 900 ml of 0.1N HCl, at 37 °æ 0.5˚C at 50 rpm for 24 h. A 5 ml sample was withdrawn from the dissolution apparatus at specified time points and the samples were replaced with fresh dissolution medium.

 

 

Table 4: Data of Drug Release Rate Kinetics.

Formulation No.	Zero order (r2)	First order (r2)	Higuchi (r2)	Korsmeyer Peppas (r2)	Korsmeyer Peppas (n)
F1	0.989	0.715	0.958	0.956	0.374
F2	0.992	0.805	0.901	0.923	0.357
F3	0.995	0.756	0.939	0.962	0.351
F4	0.991	0.767	0.934	0.961	0.409
F5	0.994	0.767	0.918	0.919	0.336
F6	0.988	0.747	0.941	0.951	0.358
F7	0.986	0.795	0.894	0.922	0.367
F8	0.981	0.698	0.961	0.937	0.351
F9	0.992	0.805	0.901	0.923	0.357
F10	0.995	0.772	0.939	0.950	0.405
F11	0.988	0.806	0.934	0.961	0.371
F12	0.990	0.771	0.918	0.921	0.420
F13	0.994	0.751	0.925	0.950	0.337
F14	0.994	0.751	0.925	0.950	0.337
F15	0.991	0.773	0.918	0.921	0.356
F16	0.988	0.747	0.941	0.951	0.358
F17	0.990	0.720	0.900	0.923	0.380
F18	0.991	0.801	0.927	0.919	0.351
F19	0.986	0.795	0.894	0.938	0.367
F20	0.994	0.803	0.920	0.948	0.348
F21	0.993	0.799	0.945	0.951	0.343

 

 

The samples were filtered through a 0.45μm membrane filter and diluted ^{[8], [9]} Absorbance of these solutions were measured at 226.5 nm using UV Visible Spectrophotometer. Percentage cumulative drug release of optimized batches is shown in Fig.4.

 

Drug release kinetics:

To study the drug release kinetics, the data obtained from in vitro drug release studies were plotted in various kinetic models: zero order (Equation 1) as cumulative amount of drug release versus time, first order (Equation 2) as log % drug remaining versus time, and Higuchi’s model(Equation 3) as cumulative % of drug released versus square root of time.

                C=Kot………………………….. (1)

 

Where K0 is the zero order constant expressed in units of concentration/time and t is the time in hours. A graph of concentration versus time would yield a straight line with a slope equal to Ko and the  intercept origin of the axes.

                Log C= Log Co- Kt /2.303…………. (2)

 

Where Co is the initial concentration of drug, K is the first order constant, and t is the time

                Q=Kt1/2…………………….... (3)

 

Where K is the constant reflecting the design variables of the system and t is the time in hours. Hence, drug release rate is proportional to the reciprocal of the square root of time. Table no. 4shows drug release kinetics of Losartan Potassium sustained release tablets. ^[10]

 

RESULTS AND DISCUSSION:

Batches of Losartan potassium were prepared according to Table no. 1 by using HPMC and natural polymers by direct compression method. The values of pre-compression parameters evaluated were within prescribed limits and indicated good free flowing property data shown in Table no. 2.Results showed that powder blend have angle of repose from 29.24⁰ to 29.12⁰, Carr’s index from 10.88 to 19.64 and Hausner’s ratio from 1.12 to 1.24, which indicates good flow property. The data obtained from post-compression parameters such as weight variation, hardness, friability, dissolution studies, drug content are shown in table no. 3. Hardness and friability were found to be in range of 5–7.5 kg/cm2, and 0.29 to 0.41% respectively, which is an acceptable criterion in tablet formulations. In all the formulations, hardness test indicates good mechanical strength; friability is less than 1%, which indicates that tablets had a good mechanical resistance. Drug content was found to be high 99.27% and uniform in all formulations.

 

The tablets were subjected to dissolution studies. Fig. 4 depict the dissolution behavior of the tablets. It was observed that when drug and HPMCK100M, CARBOPOL 934andXanthan gum were used as polymer in the concentration of 1:2 desired dissolution behavior was achieved. The drug release was for 14 h as compared to all formulations and followed Zero Order model for drug release kinetics. The quadratic model obtained from the regression analysis used to build a 3D graphs in which the responses were represented by curvature surface as a function of independent variables presented in Fig 5,7. The response surface plots were generated using Design Expert 8.0.1 software to observe the effects of independent variables on the response studied such as percent cumulative release respectively. Graphical presentation of the data helped to show the relationship between the response and the independent variables and optimized batches were studied showing better response for 14 h duration time.

 

CONCLUSION:

The aim of the study was to study the effect of various hydrophilic and hydrophobic polymers on in vitro release rate from sustained release tablets of Losartan potassium. Different types of matrix forming polymers like HPMCK100M, Carbopol 934, Ethyl Cellulose and Xanthan Gum were studied. The use of polymer HPMCK100M was successful to achieve the sustained drug release for 14 hours from Losartan Potassium sustained release tablets. Formulation F2 as well as F9 showed sustained drug release for 14 hours, so it was selected as best formulation among all the formulations. The quadratic model obtained from regression analysis in which types of polymer and concentration of polymer show the Interaction explained in Figure 5. The kinetics of Drug release was best explained by Zero Order equation. The drug release from tablets was sufficiently sustained and Non-Fickian transport of the drug from tablets was confirmed.

 

ACKNOWLEDGEMENT:

The authors are thankful to Marathwada Mitra Mandal’s College of Pharmacy, University of Pune, India, for providing us with infrastructural facilities and moral support to carry out this research work. I sincerely express my gratitude to Mylan Lab. Nasik, India and Mr. Vinod Patil for providing Losartan Potassium as a Gift Sample.

 

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Received on 05.08.2014          Modified on 20.08.2014

Accepted on 05.09.2014          © RJPT All right reserved