INTRODUCTION:

Valsartan is an angiotensin II receptor antagonist utilized in remedy excessive blood pressure. Treat high blood pressure blocks vasoconstriction and aldosterone. Effect of Selective Secretion of Angiotensin II by blocks the binding of angiotensin II and angiotensin I receptor in many tissues. The most preferred route of administration for this drug is oral tablets. Valsartan has low water solubility, low bioavailability (approx.20-25%) and a shorter half-life (nearly 6 hours).¹

Oral administration of drugs has been known for decades as the most common route of administration. Routes of systemic drug delivery were tested.

The reason why the oral route has become so popular can be attributed in part to its ease of administration, as well as the traditional belief that the drug is taken orally is absorbed in the same way as food eaten daily. Common dosage forms such as tablets and capsules are key oral formulations in all dosage forms to achieve wide acceptance of 50-60%. Short bioavailability and short half-life of valsartan took over the development of the enhanced version modules desired. The sustained-release system is a type of modified drug delivery system that can be used as an alternative to conventional drug delivery system. These systems maintain drug delivery maintains the plasma concentration of the drug therapeutic window without fluctuation and increase the therapeutic effectiveness of the drug.²

Among the different approaches used for a new drug. The Matrix tablet from Delivery Systems is one of them. The maximum famous and extensively used method. The to develop an extended or controlled release. Valsartan Matrix Tablet Drug Delivery Systems is designed to reduce dosing frequency, or an increase the effectiveness of the drug or Localization at the site of action, dose reduction required or provided controlled drug administration.³

METHODS AND MATERIALS:

Materials:

Valsartan is bought from Dhamtec Pharma and Consultants, Taloja MIDC, Navi Mumbai, Maharashtra, India. HPMC K100M was purchased form Balaji Drugs, Nashik, Maharashtra, India. All other Reagents obtained from research lab.

Instrumentation:

The work was done on the UV visible spectrophotometer (Model EQ-826, Equiptronics), Tablet compression machine (Model no. 8 station, D, Cemach Machineries Ltd). The FTIR spectra of API and its excipients were secure by Fourier Transform Infrared Spectrophotometer (Bruker). All weighing was done on electronic precision balance (Wenser PGB220).

Drug excipients interaction Compatibility of the drug with excipients was determined by differential scanning calorimeter (DSC-60, Shimadzu, Japan). This study was carried out to detect any change on chemical constitution of the drug after combination with the excipients. The samples taken for DSC study were physical mixtures of Valsartan: HPMC K100M (1: 1)

Formulation and Devlopment:

Valsartan tablets in different strengths polymers were made wet Granulation Technique. All the ingredients were present in the required quantities individually weighed. All ingredients were first sifted. Mixed by isopropyl alcohol was added dropwise until a mass suitable for granulation was obtained. The wet mass was prepared and granulated through an 8# screen and the granules produced were dried at 60°C for 1 hour. The dried granules are passed through 10# sieve and retained granule fractions. The mesh was discarded and then mixed with talc and magnesium stearate for diffusion granules. Which were then pressed into individual pellets perforated tablet press with 8mm rounds punch. tablet weight suitable for 250mg, each tablet contains 40 mg of valsartan and others excipients listed in Table 1.0.⁴

Table 1.0 Formulation Table for Valsartan Tablet:

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8
Valsartan	40	40	40	40	40	40	40	40
HPMC K100M	90	65	40	65	65	65	65	90
Ethyl Cellulose	40	40	30	30	40	40	40	50
PVP K30	20	15	15	20	15	15	15	15
Magnesium Stearate	2	2	2	2	2	2	2	2
Talc	8	8	8	8	8	8	8	8
MCC	Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg
Iso-Propyl Alcohol	Q.S.	Q.S.	Q.S.	Q.S.	Q.S.	Q.S.	Q.S.	Q.S.

F9	F10	F11	F12	F13	F14	F15	F16	F17
40	40	40	40	40	40	40	40	40
65	90	65	65	90	65	40	40	40
40	30	50	50	40	30	50	40	40
15	15	10	20	10	10	15	20	10
2	2	2	2	2	2	2	2	2
8	8	8	8	8	8	8	8	8
Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg
Q.S.	Q.S.	Q.S.	Q.S.	Q.S.	Q.S.	Q.S.	Q.S.	Q.S.

RESULT AND DISCUSSION:

Characterization of physicochemical properties of drug:

Organoleptic properties:

Valsartan has white, odorless and Bitter in taste. That the entire drug characteristic complies with official standards.

Pre-formulation study:

Determination of Physical constant:

The physical constant was determined by capillary method and it was found to be in range of 108-112⁰C which complies with I.P.

Analysis of drug:

Calibration Curve Method:

The calibration curve of Valsartan was performed in 0.1N NaOH. The absorbance of the solution was measured at 248nm using UV-visible spectrophotometer.

· Line Equation: y = 00253X + 0.0117

· Regression Coefficient: R² = 0.9913

Table 2.0 Concentration and Absorbance:

Sr. No.	Concentration (In PPM)	Absorbance
1	5	0.010
2	10	0.040
3	15	0.070
4	20	0.089
5	25	0.112

Drug –Excipients compatibility studies:

The drug excipient interaction study was carried out by using the physical observation of drug and excipient materials. The mixture of drug and each excipient (1:1) ratio are place on vials with the rubber closures, which is hermetically sealed are placed in the environmental test chamber (Stability chamber, 40⁰C at 75% RH) for 30 days.

Fig 1.0 Calibration Curve of Valsartan

Table 3.0 Compatibility Study of Valsartan and Excipients:

Sr. No.	Composition	Caking	Liquification	Discoloration	Odour	Conclusion
1.	Drug + HPMC K100M	No	No	No	No	Compatible
2.	Drug + Ethyl Cellulose	No	No	No	No	Compatible
3.	Drug + PVP K30	No	No	No	No	Compatible
4.	Drug + Magnesium Stearate	No	No	No	No	Compatible
5.	Drug + Talc	No	No	No	No	Compatible
6.	Drug + MCC	No	No	No	No	Compatible

FTIR Studies of Valsartan:

FTIR stands for “Fourier Transform Infrared Spectroscopy” this type of spectroscopy work on the principle of infrared radiation passing through the sample and this sample absorb some amount of infrared radiation passing through the material. It is a useful analytical technique used to verify the drug and excipient interaction in the formulation.⁵

Table 4:0 Interpretation of FTIR peak present in Valsartan

Sr. No.	Wave number in formulation (cm-1)	Characteristic Wave number range cm-1	Bond nature and bond attributed
1.	1204.36	1200-1300	C-N Stretching
2.	1598.28	1585-1600	C-C Stretching
3.	1731.10	1720-1740	C=O Stretching
4.	2957.38	2850-3000	C-H Stretching

Fig 2.0 FTIR Spectra of Valsartan

Fig 3.0 FTIR Spectra of Valsartan + HPMC K100M.

DSC studies of Valsartan:

Differential Scanning Calorimetry (DSC) is the thermal analytical technique that measures the heat against time and check the how physical properties of sample changes with increasing temperature with time.⁶

Differential Scanning Calorimetry of Valsartan:

Thermal analysis of Valsartan is carried using DSC. The DSC curve of Valsartan shows sharp exothermic peak at 98.87⁰C at 6.22 min.

Fig 4.0 Differential Scanning Calorimetry of Valsartan

Fig 5.0 Differential Scanning Calorimetry of Valsartan and All Excipients:

Pre-Compression Evaluation of Granules:

Prior to compression, the formula combination changed into evaluated for pre-compression parameters are tapped density, bulk density, hausner ratio, carr’s index and angle of repose.

Evaluation of granules:

Angle of Repose:

The angle of repose of the granules was determined by the funnel method. Carefully weighed granules were removed from the funnel. Height In the funnel was adjusted so that the end of the funnel has just touched the tip stacks of granules. Granules allowed flow freely through the funnel Area. Diameter of powder cones and angles were measured remainder was calculated using the following formula Equation.⁷

Tan θ = h/r

Were,

h = Height

r = radius of the powder.

Bulk Density:

Bulk Density (BD) and Tap Bulk Density (TBD) to be determined. Amount 2gm powder of each formula, light at first was shaken to break up the resulting agglomerations introduced in a 10ml graduated cylinder. After observing the initial volume. Cylinder may have fallen under itself on hard ground from a height of 2.5 cm in 2-second intervals. The tapping has continued to rattle until there are no more modifications. Volume is annotated. BD and TBD were calculated with the following formulas.^8,9

BD = Bulk Density.

TBD = Tapped Bulk Density.

Compressibility index:

The compressibility index of the granules became decided through Carr’s compressibility index.

Carr’s index (%) = [(TBD – BD) × 100] / TBD¹⁰

Table 5: 0 Pre-Compression Evaluation of Granules:

Formulation code	Bulk density (gm/ml)	Tapped density	Hausner ratio	Carr’s index (%)	Angle of repose (θ)
F1	0.38	0.43	1.13	11.62	39.00
F2	0.40	0.46	1.16	13.03	33.02
F3	0.41	0.47	1.14	12.60	40.69
F4	0.37	0.41	1.12	11.05	35.52
F5	0.41	0.47	1.09	12.76	28.81
F6	0.41	0.47	1.09	12.76	28.81
F7	0.41	0.47	1.09	12.76	28.81
F8	0.49	0.45	1.12	11.11	33.82
F9	0.41	0.47	1.09	12.76	28.81
F10	0.38	0.45	1.19	15.55	31.58
F11	0.40	0.45	1.12	11.11	38.65
F12	0.43	0.5	1.16	14.00	30.54
F13	0.42	0.46	1.10	8.69	31.58
F14	0.38	0.48	1.28	20.83	33.02
F15	0.37	0.50	1.36	26.00	33.82
F16	0.37	0.45	1.21	17.77	37.23
F17	0.39	0.48	1.23	18.75	31.78

Post Compression Evaluation of Valsartan Tablets:

a) Weight Variation: Twenty weighed tablets were calculated as the average weight of the tablets individually and then together.

b) Hardness: Hardness tests were performed on each lot of tablets using a Monsanto’s hardness tester and average values were calculated.

c) Friability: The tablets were tested for friability using a Roche friability tester run at 25rpm for 4 minutes

d) Thickness: Tablet thickness was determined using a micrometre gauge.^11,12

In-vitro Dissolution Study:

In-Vitro Dissolution research of solubility greater dispersions have been achieved in a calibrated eight station dissolution test equipment. Equipped with paddles (USP II apparatus paddle type) in 900 ml of phosphate buffer with pH of 6.8. The paddles were operated at speed of 50 rpm and temperature was maintained at 37ºC±2ºC throughout the experiment.¹³

Table 6.0 Post Compression evaluation for Valsartan Tablet:

Formulation code	Weight Variation (mg)	Diameter (mm)	Thickness (mm)	Hardness (kg/cm²)	Friability (%)
F1	253	8.00	4.76	5.54	0.80
F2	252.5	8.00	4.65	6.19	0.81
F3	251.5	8.00	5.06	5.98	1.20
F4	251.5	8.00	5.06	5.98	1.20
F5	251.5	8.00	5.06	5.98	1.20
F6	251.5	8.00	5.06	5.98	1.20
F7	251.5	8.00	5.06	5.98	1.20
F8	251	8.00	5.03	6.14	0.80
F9	251.5	8.00	5.06	5.98	1.20
F10	252	8.00	5.33	6.39	1.32
F11	253	8.00	5.29	6.23	0.40
F12	252.5	8.00	5.13	6.46	0.80
F13	253.5	8.00	5.44	6.43	0.32
F14	256.50	8.00	5.34	6.66	0.72
F15	251	8.00	5.16	6.26	0.48
F16	252.5	8.00	5.35	6.32	0.60
F17	250	8.00	5.04	6.1	0.56

Table 7.0 In-vitro % Drug Release of Valsartan in Phosphate Buffer 6.8.:

Time (Hrs.)	Dissolution Medium	F1	F2	F3	F4	F5	F6	F7	F8
1	0.1 N HCL	15.14	14.7	18.96	21.99	27.50	27.50	27.50	17.9
2		23.06	17.9	30.79	30.61	34.35	34.35	34.35	31.41
3		30.79	30.61	41.11	39.24	39.06	39.06	39.06	35.86
4		41.11	36.57	48.92	51.34	46.27	46.27	46.27	41.91
5	Phosphate Buffer 6.8	48.93	46.21	56.85	59.76	60.3	60.3	60.3	45.47
6		56.85	57.92	70.55	67.88	72.77	72.77	72.77	54.72
7		63.7	66.45	80.15	78.37	84.42	84.42	84.42	65.21
8		70.04	78.64	88.95	83.53	88.69	88.69	88.69	75.70
9		77.04	83.62	98.36	90.56	98.20	98.20	98.20	82.64
10		83.08	88.78	-	96.78	-	-	-	87.26
11		90.56	97.67	-	-	-	-	-	90.56
12		95.89	-	-	-	-	-	-	98.56

F9	F10	F11	F12	F13	F14	F15	F16	F17
27.50	18.79	31.06	27.86	18.08	33.46	21.45	26.61	24.66
34.35	29.99	41.02	35.59	31.06	35.86	28.66	33.19	30.53
39.06	38.08	51.25	42.18	37.20	45.47	41.20	35.59	39.15
46.27	48.40	58.45	49.02	45.02	60.23	45.47	45.38	46.18
60.3	58.09	65.92	56.58	52.76	65.30	55.96	55.16	57.47
72.77	67.70	71.17	64.85	65.74	75.70	66.19	68.77	68.68
84.42	78.28	78.37	73.12	70.99	83.53	75.70	72.15	75.08
88.69	90.56	84.95	83.71	78.55	88.78	83.17	83.08	87.62
98.20	95.89	88.78	91.44	81.31	90.56	95.00	93.22	95.71
-	-	95.00	-	87.18	96.78	-	95.89	-
-	-	-	-	89.04	98.56	-	-	-
-	-	-	-	89.40	-	-	-	-

Fig 6.0 In Vitro Drug Release Batch F1 to F8

Fig 7.0 In Vitro Drug Release Batch F9 to F17

CONCLUSION:

This study was conducted to preform and formulate the pure drug valsartan. The result of the preformulation showed that the drug was genuine and pure and therefore there was no sign of drug alteration. Valsartan showed poor flow properties and show good compressibility. It was found soluble in organic solvent like methanol and slightly soluble in water, and drug loading was maximal in the lipophilic phase compared to the hydrophilic phase. The physicochemical compatibility of the drug with all ingredients was determined by DSC. The study showed that the drug is well tolerated with it. The granules produced also retained the physio-chemical properties of the tablets, such as thickness, hardness, weight variation, friability. The optimized formulation F8 which release the valsartan in sustained manner in 1st hour it releases 17.90% but remaining drug release up to12hours. Compared to other formulation it gives better release of drug in 12hours. Hence it may be concluded that F8 formulation prepared by wet granulation method for sustained release tablets might be a perfect and effective formulation to treat the hypertension.

ACKNOWLEDGEMENT:

We express our gratitude to the teachers and Principal of Loknete Dr. J. D. Pawar College of Pharmacy, Manur, Tal. Kalwan, for their valuable guidance and support.

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Received on 07.05.2023 Modified on 22.07.2023

Res. J. Pharma. Dosage Forms and Tech.2023; 15(4):241-246.

DOI: 10.52711/0975-4377.2023.00039