INTRODUCTION:

Valsartan is an antihypertensive drug, belongs to a group of Angiotensin Receptor Blockers (ARBs). It is used for the treatment of hypertension. Valsartan is poorly water soluble drug with low bioavailability (25%) and half life of 6 h [1]. Dosing frequency of Valsartan tablet once in day makes it an ideal candidate for sustained release dosage form. From the literature survey it was found that the Valsartan floating tablets were formulated and evaluated using various polymers [2-6]. Preparation and Evaluation of Valsartan Sustained Release Matrix tablets were also reported by various polymers [7-16]. Drug release of Valsartan through pulsatile drug delivery system was reported in the method [17], fast dissolving tablets were reported in the method [18] and mucoadhesive film of Valsartan reported [19]. But for the treatment of hypertension, prolonged effect of drug is required which can maintain the concentration of drug in the body for long period of time. The Valsartan tablets available in the market are conventional tablets which provide the drug release only for few hours.

Formulation of matrix tablets using Cyclodextrin alongwith HPMC hydrophilic polymers is the simplest method for extended release tablet. Cyclodextrin is water soluble polymer containing hydroxyl groups in its chemical structure. It form water soluble complexes with drugs and increase its solubility. It enhances the bioavailability of drugs by increasing the dissolution rate. It acts as hydrophiliser for sustained release tablets [20]. The HPMC hydrophilic polymer has been widely used because of its excellent stability within wide pH range, pH-independent drug release and suitability of various drugs. HPMC is water swellable polymer and increases the size of the tablet thereby retains in the stomach for the long time and provide the extended action [21,22].

The aim of the presented work is to formulate and evaluate matrix tablets containing Valsartan as sustained release using Beta-Cyclodextrin and HPMC in different amounts the by wet granulation method. The prepared tablets were subjected to drug release study by validated UPLC-PDA method.

MATERIALS AND METHODS:

Materials:

The pure sample of Valsartan was kindly supplied by Systopic Pharmaceuticals Ltd. (New Delhi, India). Beta-Cyclodextrin, HPMC K100, Talc and Magnesium stearate was purchased from S.D. Fine Chemicals Ltd., Mumbai, India. HPLC grade water, methanol, and ammonium acetate were used throughout the analysis. All other chemicals and reagents were of analytical grade.

Method of Preparation of Tablets:

The wet granulation method was applied for tablet preparation as per the following procedure. The composition of different formulations for the SR tablets is given in Table 1. Beta-Cyclodextrin was blended with drug and HPMC K100 polymer in a planetary mixer for 5 min. The powders were granulated, sieved by 20 mesh screen, dried at 30ºC for 1 h and mixed with talc and magnesium stearate. Prepared granules were compressed in to 150mg tablets to an average hardness of 7Kg/cm² using tablet punching machine (Cadmach, Mumbai, India). Tablets were named as F1, F2 and F3.

Table 1. Composition of Various Formulations of Valsartan

Ingredients (mg)	Formulation Code
Ingredients (mg)	F1	F2	F3
Valsartan	80	80	80
HPMC K100	50	40	20
Beta-Cyclodextrin	10	20	40
Talc	5	5	5
Magnesium Stearate	5	5	5
Total weight	150	150	150

Evaluation of Physical Properties of Tablets:

The tablets were evaluated for various quality control tests. The weight variation was carried out on 20 tablets using an electronic balance. 10 tablets were used for friability test in a Roche friabilator at the speed of 25 rpm for 5 min. Similarly 10 tablets were used for hardness testing with the help of Mosanto tester. The thickness was measured on 10 tablets by Vernier caliper.

Drug Content Studies:

Twenty tablets were weighed, powdered and equivalent amount of 80mg of valsartan was taken in a 50mL volumetric flask. The powder was dissolved with 25mL of methanol, sonicated and final volume was made up with methanol. Solution was filtered by 0.45mm membrane filter to remove all the excipients. The resultant filtrate was further diluted with methanol: water (50:50, v/v) to give a sample solution containing 800 ng/mL of Valsartan. Solutions were again filtered by 0.20mm syringe filter and injected in to the UPLC/PDA system for analysis. The amount of valsartan in tablets was determined by calibration equations obtained from the calibration curve.

UPLC Conditions:

The ultra performance liquid chromatography (UPLC) with PDA detector was employed for drug release study. The Waters Acquity UPLC system (Waters Corporation, MA, USA) with a binary solvent manager, auto-sampler, and column manager was used for analysis. Chromatographic separation was performed on a Waters Acquity UPLC BEH C₁₈ (100.0×2.1mm, 1.7mm) column. The detection was carried out at 295nm. For isocratic separation the mobile phase was acetonitrile-2 mM ammonium acetate (50:50, v/v), sonicated and filtered through 0.45mm membrane filter. The flow rate of the mobile phase was kept at 0.20mL/min and the total chromatographic run time was 2.50 min.

Validation of the Method:

The developed method was validated according to ICH validation guidelines [23]. For the determination of linearity and range, different standard concentrations of the drug ranging from 1-1000ng/mL were prepared separately in methanol: water (50:50, v/v). Solutions filtered by 0.20mm syringe filter and injected in to the UPLC-PDA system for analysis. Linearity graph was plotted by taking peak areas. The other parameters which were evaluated are limit of detection (LOD) and limit of quantitation (LOQ), precision and accuracy.

Drug Release Studies:

Drug release studies from the tablet were performed using USP paddle apparatus, Veego VDR-8DR (Veego Instruments, Mumbai, India). The dissolution medium consisted hydrochloric acid buffer of pH 1.2 (0.1N) with 1% w/v sodium lauryl sulfate (SLS) as solubiliser maintained at 37ºC with a rotation speed of 100 rpm. One tablet was added to each vessel filled with dissolution medium. Ever hour 5 mL of samples were taken and equivalent amount of medium was added to the dissolution vessel. The solutions were filtered by 0.45 mm membrane filter to remove all the excipients. The filtrates were further diluted with methanol: water (50:50, v/v) to get the sample solution containing required concentration of drug. The samples were again filtered by 0.20 mm syringe filter and injected in to the UPLC-PDA system for analysis. The amount of the drug dissolved in different time intervals was calculated from the peak areas and finally the release profile of drug in terms of percentage was calculated.

RESULTS AND DISCUSSION:

Physical Properties of Tablets:

The tablets formulations were tested for various quality control tests such as weight variation, thickness, hardness, friability, and drug content studies. The results of evaluation tests are given Table 2. Tablets were passed all the tests in accordance with the specification limits of United States Pharmacopoeia (USP, 2002) that is less than 1% all for weight variation, thickness, hardness, friability and 98% drug content studies [24]. The developed analytical method was applied to study the drug content from prepared tablets containing 80 mg of Valsartan.

Validation of the Method:

The retention time (R_t) of Valsartan was 2.0 min with the total chromatographic run time of 2.5 min as shown in Figure 1. The calibration curve was linear in the concentration range of 1-1000ng/mL with correlation coefficient was more than 0.999. The LOD and LOQ of the drug was 0.1 and 1ng/mL, respectively.

Figure 1- UPLC-PDA Chromatogram on Valsartan (1 ng/ml)

Drug Release Studies:

Dissolution study was carried out by validated UPLC-PDA method. The drug solubility study was carried out by mixing drug with Beta-cyclodextrin and HPMC grade with higher molecular weight polymer such as HPMC K100 in different proportions. The study showed that tablet formulation-3 (F3) provided the best effect of drug release as compared to other formulation. Beta-Cyclodextrin improves the solubility of drug due to presence of hydroxyl groups. HPMC polymer provide faster rate of polymer hydration and gel formation occurs within the tablet matrix. From the study it was observed that when the content of Beta-cyclodextrin polymer increases in the formulation, it increases the solubility of drug and at the same time decrease in the amount of HPMC, provides the sustained release effect over the extended period of time. Formulation F3 was found to release Valsartan in sustained manner up to 24 h. The brief chemistry of cyclodextrin and mechanism of complexation with drug is explained in the separate Section, which is Cyclodextrin and Complexation Phenomenon. Drug release mechanism of SR Valsartan from matrix tablet, the data was fitted to Higuchi’s equation. The kinetics of drug release from tablets was studied according to the method described in literature [25,26]. Valsartan release kinetic parameters from the tablets (F1 to F3) showed good linearity (R²: 0.9994-0.999). Formulation F3 was found to release Valsartan in sustained manner up to 24 h. The in-vitro release profile of Valsartan release from matrix tablets in F1, F2 and F3 formultions are shown in Figure 2. Hence formulation F3 was selected the optimum formulation and compared with the Valsartan marketed tablets. The optimized tablets showed the better sustained release of Valsartan (99.95%) up to 24 h when compared to the marketed tablets (92.52%) for 1 h as shown in Figure 3.

Cyclodextrin and Complexation Phenomenon:

Cycodextrins are belongs to cyclic oligosachharides with a hydrophilic outer surface and a lipophilic central cavity. They are available as three types such as alpha, beta and gamma. Structurally they are not perfectly cylindrical molecule but are cone shaped. They are useful for their ability to encapsulate hydrophobic molecules in their toroidal or cone shaped cavity, whose selectivity depends on a number of glucose units (i.e., 6, 7, and 8-glucose units, respectively). In pharmacy research, cyclodextrins have mainly been used as complexing agent to increase aqueous solubility of poorly soluble drugs and to increase their bioavailability. Cyclodextrins have the ability to alter the physical, chemical and biological properties of drug molecules through the formation of inclusion complexes. Due to their chemical structure and shape, they possess a unique ability to act as molecular containers by entrapping drug molecules in their internal cavity. Cyclodextrins increase the aqueous solubility of drugs by forming inclusion complexes with their apolar molecule. The resulting complex prevents the hydrophobic group in the interior cavity of the Cyclodextrin while hydrophilic hydroxyl groups on the external surface remain exposed to the environment. This ultimately gives water soluble Cyclodextrin-Drug complex. In aqueous solution, the complexes are readily dissociates to give free drug molecule. This further leads to enhanced dissolution rate and absorption rate of drug [20].

Figure 2. The In-vitro Release Profile of Valsartan Release from Matrix Tablets in F1, F2 and F3.

Figure 3. In-vitro Release Profile of Valsartan Release from Marketed Tablets (Bars ± SD [n=3]).

CONCLUSIONS:

Matrix tablets containing Valsartan as Sustained Release first time have been prepared by selecting Beta-cyclodextrin along with HPMC hydrophilic polymer. It has been concluded that the rate of dissolution enhanced when the amount of Beta-Cyclodextrin is highest and HPMC K100 is lowest in the prepared tablets. The study showed that the optimized tablet formulation (F3) allowed its prolonged and sustained release with highest drug solubility. In-vitro drug release from prepared tablets showed better effect up to 24 h when compared with marketed tablets.

ACKNOWLEDGEMENTS:

The author is grateful to Systopic Pharmaceuticals Ltd., New Delhi, India, for providing gift sample of Valsartan. Author is also thankful to In-charge of Instrumentation Facilities, Faculty of Pharmacy, Hamdard University, New Delhi, India, for providing opportunities to work on UPLC-PDA system.

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Received on 15.01.2020 Modified on 21.03.2020

Res. J. Pharma. Dosage Forms and Tech.2020; 12(4):245-248.

DOI: 10.5958/0975-4377.2020.00040.3

Formulation Code	Weight Variation (%)^b	Thickness (mm)^a	Hardness (Kg/cm²)^a	Friability (% w/w)^a	Drug Contents (%)^b
F1	1.25 ± 0.42	7.00 ± 0.01	7.10 ± 0.10	0.42 ± 0.35	98.32 ± 0.25
F2	1.55 ± 0.45	7.10 ± 0.03	7.20 ± 0.11	0.62 ± 0.32	98.54 ± 0.92
F3	1.75 ± 0.25	7.00 ± 0.04	7.00 ± 0.24	0.24 ± 0.25	99.12 ± 0.65