Journal of Applied Pharmaceutical Science 01 (04); 2011: 12-19

ISSN: 2231-3354
Received: 27-05-2011 Pharmacological and Pharmaceutical Profile
Accepted: 10-06-2011
of Valsartan: A Review

Nadeem Siddiqui, Asif Husain, Lakshita Chaudhry, M Shamsher

Alam, Moloy Mitra and Parminder S. Bhasin

ABSTRACT

Angiotensin II Receptor type 1 antagonists have been widely used in treatment of

diseases like hypertension, heart failure, myocardial infarction and diabetic nephropathy. Their
beneficial effects are related to inhibition of Angiotensin II by blockade of AT 1 receptor.
Nadeem Siddiqui, Asif Husain, Lakshita
Valsartan is an orally active Angiotensin II receptor type 1 antagonist which causes reduction in
Chaudhry, M Shamsher Alam
blood pressure and is used in treatment of hypertension. It was first developed by Novartis and has
Department of Pharmaceutical
Chemistry, Faculty of Pharmacy, a wide market in the developed and the developing countries. It is also available in combination
Jamia Hamdard (Hamdard with other antihypertensive drugs. It is a lipophilic drug and possesses moderate onset of action
University), New Delhi, India than other drugs of the same category. The drug is a very good target for the generic industries.
This review evaluates the pharmacological properties of Valsartan and its efficacy and tolerability
in the treatment of patients with hypertension. A brief discussion has also been made on the
Moloy Mitra and Parminder S. Bhasin current and future aspects of the drug in the market.
Analytical Research, Ranbaxy Research
Laboratories, Gurgaon, India Key words: Valsartan, hypertension, diabetes mellitus, spectrophotometry, ACE inhibitors

INTRODUCTION
Valsartan is a potent, orally active nonpeptide tetrazole derivative and selectively inhibits
Angiotensin II Receptor type 1 (Flesch et al., 1997) which causes reduction in blood pressure and is
used in treatment of hypertension. It was first developed by Novartis and has a wide market in the
developed and the developing countries. It is also available in combination with other antihypertensive
drugs. It is a lipophilic drug and possesses moderate onset of action than other drugs of the same
category. The drug is a very good target for the generic industries. It is soluble in the neutral pH range.
It belongs to the BCS class III drug classified as low permeability and high solubility drug. Valsartan is
soluble in acetonitrile and methanol. The drug is rapidly absorbed orally and has limited volume of
distribution and is extensively bound to plasma proteins. Valsartan is not extensively metabolized and
is mainly excreted by non-renal routes. Valsartan is effective in treatment of pediatric, adolescents and
the elderly patients with mild to moderate hypertension. Monotherapy with Valsartan with 80 mg as the
starting dose has shown considerable efficacy in patients with CHF and renal impairment alongwith
hypertension and add on therapy helped control BP in large population of patients with severe
hypertension not responding sufficiently to β-blockers, ACE inhibitors or diuretics. The importance of
aggressive blood pressure control is undisputed, but the therapeutic focus is now extending to end-
organ protection as a treatment goal of equal importance to BP reduction. Thus, the value of ARBs like
Valsartan in slowing the progression of kidney disease due to high blood pressure or diabetes has very
positive medical as well as commercial implications. Many clinical trial studies like VALUE,
VALIANT, VAL-Heft, PREVAIL and many more have been conducted of which valsartan
*For Correspondence: administration is a part. From these studies comparison of valsartan with other antihypertensives
E-mail: [email protected]
 Journal of Applied Pharmaceutical Science 01 (04); 2011: 12-19

have been made extensively. Valsartan was well tolerated in PHYSICOCHEMICAL PROPERTIES
clinical studies and with most treatment related adverse effects Valsartan is 3-methyll-2-[pentanoyl-[[4-[2-(2H-tetrazoyl-
related to the drugs of same category and ACE inhibitors. Many 5-yl)phenyl]phenyl]methyl]amino]-butanoic acid (Structure
analytical methods have been developed for the quantitation and 1)with empirical formula C24H29N5O3. Its molecular weight is
determination of valsartan in biological fluids and pharmaceutical 435.519g/mol (Flesch et al., 1997). Valsartan is a white coloured
dosage form. powder that is freely soluble in ethanol, methanol, acetonitrile and
HISTORY sparingly soluble in water. The drug is listed officially in USP
Valsartan was first developed by Novartis and was sold monograph alongwith its three impurities (R)-N-valeryl-N-{[2’-
under the brand name DIOVAN and it currently holds the largest (1H-tetrazole-5-yl)biphenyl-4-yl]-methyl}valine, (S)-N-butyryl-N-
{[2’-(1H-tetrazole-5-yl)biphenyl-4-yl]-methyl}valine and (S)-N-
market share for the drug of its kind in the market. In the USA,
valeryl-N-{[2’-(1H-tetrazole-5-yl)biphenyl-4-yl]-methyl}valine
valsartan is registered by the Food and Drug Administration
benzyl ester. Valsartan appears in the melting range of 105-110˚C
(FDA) for use in the treatment of hypertension in children of 6
and the specific rotation [α]D/20 in methanol being 68˚. The
years and older and adolescents in the December 2008.
partition coefficient of Valsartan is 0.033 (log P=1.499),
suggesting that the compound is hydrophilic at physiological pH.
Present and Future Scenario
The compound is stable under storage in dry conditions (Saydam
Diovan (valsartan) was labelled as the world’s number-
et al., 2007).
one selling high blood pressure medication and accounted for $6
billion in sales in 2010 worldwide. In near future its patent
protection on its active ingredient is ready to expire in most of the
major territories.There are two types of dosage forms of valsartan
OC
available in the market. One comprising of single-active
component valsartan and other comprising three dosage froms N
HN NH
containing a combination of valsartan with one or more active N N C
ingredients hydrochlorothiazide, amlodipine besylate, aliskiren (Z) O OH
hemifumarate. Ranbaxy Laboratories filed a Paragraph IV (structure 1: Valsartan)
certification in 2007 and claimed the US5399578 patent as invalid
and thereby pledged not to make, use, sell, offer to sell, or import Valsartan is a tetrazole derivative that contains acid
Valsartan until November 2012 expiry date. Ranbaxy along with (pKa=4.73) and carboxylic (pKa=3.9) groups making the
Teva has got tentative approval for many strengths of the tablet compound soluble in the neutral pH range (Flesch et al., 1997).
and is expecting 180 days exclusivity and being first to file upon Hence, it exists as solution at physiological pH values as the
the expiry of the US5399578 patent. Data exclusivity (DE) delays undissociated acid, the mono-anion and the di-anion. On
generic competition even if the patented period has expired and increasing the pH from 4 to 6 the solubility of valsartan increases
hence is a cause for trouble for companies interested in developing by a factor of about 1000, but it favors the anionic form and
a generic equivalent. As the DE periods for the combination decreases lipophilicity, hence the rate of absorption of valsartan is
periods by Novartis are scheduled to expire in US influenced by intestinal pH along the (GI)tract. In vitro dissolution
(Valsartan/Hydrochlorothiazide expiring in 2011; Valsartan/ is complete and rapid at pH 5.0 and above. As valsartan has pH
Hydrochlorothiazide/Amlodipine and Valsartan/ Aliskiren dependent solubility it belongs to a special case in a proposed
expiring in 2012). Similarly in Europe, data exclusivity for general classification system that categorises drugs with respect to
Valsartan alone has expired, and the combination products are their biopharmaceutical and absorption properties.In the
scheduled to expire as follows: Valsartan/Aliskiren expiring in biopharmaceutical classification system, valsartan has been
2017 and Valsartan/Hydrochlorothiazide/Amlodipine expiring in classified as Class III drug with low permeability, poor
2019. Hence, the originator of Valsartan, ‘Novartis’ aims to secure metabolism and high solubility (Saydam et al., 2007). The pKa of
its credentials in the market by focusing the combination products Valsartan varies with the percentage of acetonitrile in ACN:water
by convincing the medical practitioners and patients with their mixtures, with 60% ACN, pKa of carboxyl group is 5.321 and that
benefits. of tetrazole is 6.189 with 55% ACN, pKa of carboxyl group is
The combination of Valsartan and Hydrochorothiazide is 5.143 and tetrazole group has pKa of 6.163. Under the influence of
not protected by any patent but only the Valsartan molecule, 50% ACN pKa of carboxyl group is 4.982 and that of tetrazole is
hence the generic versions of this product is expected to be 6.6130. These studies help in selection of mobile phases for the
launched at the same time as the single active product. development in RP-HPLC (Demiralay et al., 2010). Valsartan has
From the past eight years, it has been observed that there bioavailability of about 25% due to its acidic nature. Being acidic
has been an increase in the patent filing of Valsartan and its in nature it is poorly soluble in the acidic environment of GIT and
combination products clearly indicating the importance of the is absorbed from the upper part of GIT that is acidic in nature and
drug molecule. where its solubility is low.
 Journal of Applied Pharmaceutical Science 01 (04); 2011: 12-19

Valsartan is 0.18 g/L soluble in water at 25˚C.In a buffered According to the AUC values obtained, the
solution a dianion salt is formed due to which its solubility is bioavailability of capsule was 23% and that of solution was 39%.
increased. In phosphate buffer (pH 8.0), valsartan is 16.8 g/L The deconvolution results of the plasma levels, measured after
soluble at 25˚C (Saydam et al., 2007). administration of the two oral formulations with the i.v. bolus dose
as three unit impulse response showed that valsartan was 24%
PHARMACOLOGY
absorbed from capsule and 41% from the solution. Valsartan is
Valsartan belongs to the family of angiotensin II type1
absorbed rapidly, 50% of it in capsule being absorbed within 1.6 h
receptor (AT1) antagonists and posseses about 20,000 fold greater
and 90% within 4.6 h. The absorption occurs by a passive
affinity for it than for the angiotensin II type 2 receptor (AT2) diffusion process. Food has not been reported to affect the
(Saydam et al., 2007). This action exert effects on blood pressure absorption of valsartan. Hence, it can be administered with or
(BP) reduction, as well as decreases vascular smooth muscle
without food (Iqbal et al., 2010).
contraction, inhibits sympathetic outflow, improves renal function
and also leads to reduction in progression of atherosclerosis Distribution
lesions (Burnier et al., 2000). Also blockade of AT1 receptor by Valsartan has only limited distribution outside the plasma
valsartan leads to increase in local angiotensin II concentration compartment and is extensively bound to the plasma proteins (94-
that stimulates the unblocked AT2 receptor (McInnes et al., 1999). 97%) and hence is only limited distributed outside plasma
compartment. Because of the presence of carboxylic groups
The increase in AT2 receptor stimulation causes vasodialation
through local production of bradykinin which in turn leads to a Valsartan is soluble in neutral pH range and is mainly present in
signaling cascade that increases the production of nitric oxide and the ionized form at physiological pH. The volume of distribution
cyclic guanosine 3’-5’-monophosphate at the endothelial level that at steady state is about 17l (Flesch et al., 1997).
provides protection against vascular dysfunction (Verdechhia et Metabolism and Elimination
al., 2004). Valsartan does not require any metabolism in the body to
PHARMACOKINETIC PROFILE become active. After the oral administration of 80 mg of [14C]-
The pharmacokinetics of valsartan had been examined in radiolabelled valsartan (Waldmeier et al., 1997) only one
healthy male volunteers after administration of 20 mg of valsartan pharmacologically inactive metabolite was found in plasma nearly
as an i.v bolus injection and 80 mg of valsartan as capsule about 11%. The primary metabolite was identified as valeryl 4-
formulation and as a buffered solution (Flesch et al., 1997). hydroxy Valsartan (M1) accounted for about 9% of the dose and is
(Table 1) inactive in hypertension. M1 has about 200 fold lower affinity for
Table 1: Pharmacokinetic Profile of Valsartan
the AT1 receptor than valsartan (Waldmeier et al., 1997).
Dose Cmax Tmax AUC f(%) t1/2 Ae(%of
Valsartan is mainly excreted in faeces via biliary excretion and
administered (mg/l) (h) (mg/l/h) (h) dose) hence it is not recommended for patients with hepatic dysfunction
20mg of Valsartan 4.02 1 9.39 - 9.45 4.02 and biliary cirrhosis (Martin et al., 2005). After the administration
administered as of an i.v. dose in healthy volunteers, plasma clearance of Valsartan
an i.v bolus
80mg of valsartan 1.64 2 8.54 23 7.05 7.34
was found to be ~2 l/h (Iqbal et al., 2010). Renal Clearance (0.62
administered l/h) was found to be only 30% of the total plasma clearance.
as an oral capsule Hence, it is clear that Valsartan is eliminated mostly by non-renal
80mg of valsartan 3.25 1 14.32 0.39 7.50 12.55
administered routes. It is only slightly metabolized and excreted mainly
as an oral solution unchanged in bile (<80%) and urine (20%). M1 is formed by
Cmax= maximum plasma Concentration f(%)= oxidative biotransformation and accounts for 9±3 % of the dose in
percentage bioavailability excreta. Dose adjustment is not needed based on age, but for an
t(max)= time to reach maximum t1/2= half life in average 70year old patient, plasma concentration generally falls by
terminal phase
plasma concentration Ae(%of dose)= 22% compared with an average 55 year old patient (Martin et al.,
amount of drug 2005). Hence, dose reduction needs to be considered in this group.
AUC= area under curve indicating excreted
unchanged) THERAPEUTIC EFFICACY
concentration of valsartan in body with time
The therapeutic efficacy of valsartan has been evaluated
Absorption in a number of dose ranging and comparative studies in patients
Valsartan is rapidly absorbed orally. After oral with varying degrees of hypertension, diabetes and renal
administration of Valsartan 80mg capsule and solution formulation in impairment.
12 healthy volunteers, maximum plasma concentrations (Cmax) of Comparison of Valsartan with
Valsartan (1.64mg/l and 3.25 mg/l) were respectively reached in placebo Hypertension
~ 1-2 h. Plasma levels and the area under the plasma Efficacy had been studied from nine double-masked,
concentration-time curve were not linearly related to dose, randomized, placebo-controlled, parallel studies on 4067 patients.
indicating a saturable first pass metabolism (Flesch et al., 1997). Patients with mild-to-moderate hypertension were given a range of
 Journal of Applied Pharmaceutical Science 01 (04); 2011: 12-19

doses of valsartan 10-320 mg once daily or placebo. The integrated that valsartan gave almost same response as that of amlodipine
analysis resulted in a linear relationship between increasing dose of (Ferdinand et al., 2009).
valsartan 10 to 320 mg and blood pressure-lowering efficacy. Another clinical trial study VALIANT (Valsartan in Acute
(Placebo-subtracted mean changes from baseline to endpoint for Myocardial Infarction) conducted on about 10,000 patients, patients
valsartan were reported to be systolic diastolic blood pressure were treated beta blockers and ACE inhibitors or Valsartan or both.
(SDBP), -1.3 to -9.0 mm Hg in a dose dependent manner). The resulted showed that there were no concerning differences
The dose recommended for starting the medication is 80 between the two strategies (Ferdinand et al., 2009).
mg o.d or hydrochlorothiazide may be added (Martin et al., 2005). In the PREVAIL study conducted on about 1200 patients
In nine double-masked, randomized, placebo-controlled studies of showed that 82.7% of the patients receiving valsartan showed
similar design conducted on 4067 patients with mild-to-moderate control in BP than 81.6% patients with lisinopril therapy. Adverse
hypertension, administration of valsartan doses > 8 0 mg showed effects were observed in about only 5.1% patients receiving
reduction in supine or seated diastolic blood pressure(SDBP) and Valsartan than with 10.7% patients receiving lisinopril (Malacco
systolic blood pressure (SSBP) as compared with placebo et al., 2004).
(P<0.05) (Pool et al., 1998).
Chronic Heart Failure
Chronic Heart Failure
In general, Angiotensin Receptor Blockers like Valsartan
Valsartan had favourable acute and chronic
are more effective inhibitors of the rennin-angiotensin-aldosterone
neurohormonal and haemodynamic actions in CHF according to a
system than ACE inhibitors. Valsartan appears to be better
large randomized, double blind placebo study (Val HeFT-
tolerated in context with side effects like cough and angidoedema
Valsartan Heart Failure Trial) conducted on a 5010 group of
as seen with the ACE inhibitors (Martin et al., 2005). .
patients and had no effect on mortality among patients but patients
receiving valsartan showed 13.2% reduction in morbidity. This Post myocardial infarction
study proved the fact that valsartan is a good treatment for patients A study named VALIANT (valsartan in acute myocardial
with hypertension receiving ACE inhibitors as Valsartan has infarction) conducted on patients with LV systolic dysfunction,
shown to decrease hospitalization(27.5%) in such patients HF, or both following an acute myocardial infarction, compares
(Ferdinand et al., 2009). the efficacy and safety of long-term treatment with Valsartan,
Renal Impairment Captopril and their combination in 14,703 high risk patients after
A study was conducted in a randomized, double-blinded MI. It is a multi centre, double blind, randomized, active
group of patients with chronic renal failure and hypertension. It controlled parallel group study. The study showed no differences
showed that Valsartan (80 mg) considerably lowered the mean in mortality among patients being treated with captopril 50 mg
arterial blood pressure, when compared to placebo. It had no TID, Valsartan 160 mg BID, or the combination of Valsartan 80
affect on the GFR (glomerular filtration rate) or renal blood flow mg BID with Captopril 50 mg TID (Pool et al., 1998).
when compared to placebo, but showed significant reduction in Diabetes Mellitus
proteinuria(26%) and albuminuria(41%) (Martin et al., 2005). Valsartan (80 mg) gives similar response as compared to
Amlodipine (5 mg) in blood pressure reduction. But Valsartan
Comparison of Valsartan with other agents
shows a significantly greater reduction in urinary albumin
The antihypertensive efficacy of Valsartan is quite similar to
excretion ratio when compared to amlodipine. (Spinola et al.,
that of the other antihypertensive agents like thiazide diuretics, beta-
2009) A clinical trial study named MARVAL (MicroAlbuminaria
blockers, ACE inhibitors and calcium channel blockers.
Reduction with VALsartan) conducted on 332 patients, showed
In treatment of moderate hypertension 80 mg Valsartan
that Valsartan considerably decreased albuminaria in patients with
is as effective as 20 mg Enalapril.
diabetic nephropathy. Patients were randomized and received
In elderly patients Valsartan 80-160 mg daily provides
either valsartan or amlodipine in a 24-week period. Patients of the
comparative short and long term anti-hypertensive efficacy as
group receiving valsartan showed significant reduction in urinary
compared to lisinopril 10-20 mg (Malacco et al., 2004; Martin et
albumin excretion (Pool et al., 1998).
al., 2005).
Valsartan (80 mg) has been as effective as Left Ventricular Hypertrophy
Hydrochlorothiazide and amlodipine in treatment of mild-to- In a randomized double-blind study of 69 previously
moderate hypertension. untreated hypertensive people, it was shown that Valsartan (80 mg
In a clinical trial study VALUE (Valsartan Antihypertensive daily for 8months) reduced left ventricular mass index by 21 g/m 2
Long-term Use Evaluation) conducted on hypertensive patients ≥50 as compared to 10 g/m2 with atenolol (Martin et al., 2005).
years of age, blood pressure reduction for valsartan and amlodipine Valsartan with other antihypertensives
based treatment strategies were compared for fatal or non-fatal In a randomized, double-blind, parallel-group superiority
myocardial infarction. It was shown study conducted on 838 patients, it was found that combination of
 Journal of Applied Pharmaceutical Science 01 (04); 2011: 12-19

valsartan 160 mg + simvastatin 40 mg was statically superior to Side-effects

that of valsartan 160 mg + simvastatin 20 mg in reduction of LDL- According to a post marketing surveillance study
C (low density level cholesterol) in patients with conducted on 12881 patients in England (the largest safety study
hypercholesterolemia and essential hypertension (Verdechhia et conducted on valsartan as reported from MEDLINE and EMBASE
al., 2008). (Table 2) criteria), malaise was the most frequently reported event (13.7
percent per 1000 patient-months of exposure). Dizziness (11.7%),
Table 2: Summary chart for clinical studies conducted with lsartan
headache and migraine (10.3%) followed thereafter. Epistaxis
Trial Drug compared No. of Results (0.5%), fatigue (10%), rash (1.1%) appeared the labeled adverse
patients
drug reactions associated with Valsartan. Joint stiffness, muscle
VALIANT Valsartan(160mg BD) vs 14703(with Adverse events Î in
captopril(50mgTD) vs acute MI valsartan/captopril cramps, myalgia added to the list (Biswas et al., 2002).
Valsartan(160mg or Heart vs valsartan group Renal functions alongwith creatinine clearance,
BD)+captopril(50mgTD) Failure) or captopril
VALUE Valsartan(80mg) vs 15245(with Valsartan group electrolyte excretion and uric acid excretion are not influenced on
Amlodipine(5mg) treated or had lesser no. of administration of valsartan (Saydam et al., 2007). Other reported
untreated incidences of
hypertension) diabetes as adverse
side effects of the drug are dose-related orthostatic hypotension,
effect and was rash, hyperkalemia(5%), respiratory tract disorders, nausea,
better tolerated vomiting(1.4%), intolerance, diarrohea, dyspnoea,
Valsartan(160mg) vs 1213(with Valsartan alone impotence/ejaculation failure, dyspepsia, oedema as listed in the
PREVAIL Lisinopril(20mg) mild to was better tolerated
(alone or combined with moderate Summary of Product Characteristics.(Figure 1)
HCTZ) hypertension)

VAL-Heft Titrated doses from 5010(with Valsartan was well

Valsartan 40mg BD history of tolerated and
to 160mg BD vs Placebo heart failure) mortality and
morbidity was
significantly
reduced

SAFETY AND TOLERABILITY

The safety of antihypertensives deserves a special
importance because they are likely to be used long term in general
practice in a number of patients. Valsartan has a good tolerability
profile consistent over the wide dose range (Verdechhia et al.,
Fig 1: Various side-effects of Valsartan
2004) with a side effect profile almost indistinguishable from
placebo and is superior to that of other comparable
Contraindications
antihypertensive drugs. Valsartan doesnot cause cough and
Valsartan is contraindicated in patients with severe
angioneurotic oedema as associated with ACE inhibitors, the
hepatic impairment, liver cirrhosis, and biliary obstruction. In a
reason being the site specificity and the greater selectivity of the
study conducted it was seen that liver function tests (LFTs),
drug (Biswas et al., 2002).
billirubin levels were found to be raised after the valsartan
In a Val-HeFt (the VALsartan Heart Failure Trial) study
administration in patients (Biswas et al., 2002).
conducted on 2511 patients adverse drug reactions occurred in
Valsartan in contraindicated throughout pregnancy and
9.9% of the patients receiving valsartan and 7.2 % occurred in
lactation as the drug acts directly on the rennin-angiotensin
patients receiving placebo and not the drug showing that the drug
system, so can cause some injury or even death to the developing
is generally safe for use in patients with hypertension (Malacco et
foetus.Though no controlled studies have been conducted in
al., 2004) .
women about the effect of valsartan on foetus, on detection of
In one study conducted on 11191 patients valsartan was
pregnancy the therapy should be discontinued as soon as possible
found to be 81.1% as effective as losartan that was 84.8%
and should only be used until it justifies the risk associated with it.
effective. Thus, both have almost same tolerability (Biswas et al.,
2002). Valsartan is also well tolerated in children, adolescents and Drug Interactions
elderly both in males and females as proved by a post-marketing Valsartan is contraindicated with NSAIDs and ciclosporin
surveillance study conducted in England (Herder et al., 2010). as it causes increased risk of renal impairment and hyperkalemia.
According to the Summary of Product Characteristics, in With general anaesthetics, clozapine, dopamine agonists and other
the patients on valsartan alongwith with renal impairment, the hypertensives valsartan causes increased risk of hypotension.
elderly or those on potassium supplements, serum potassium Hyperkalemia can be caused during valsartan therapy with
levels should be monitored regularly as the clinical trials have potassium-sparing diuretics, potassium supplements, ACE
shown incidences of hyperkalemia (Biswas et al., 2002). inhibitors and heparin.
 Journal of Applied Pharmaceutical Science 01 (04); 2011: 12-19

Table 3: Quantification and determination methods

S. no. Sample Column Method Mobile phase Reference
1 Valsartan in human LC-MS/MS Koseki et al., 2007
plasma

2 Valsartan in p’ceutical BEH C18(100mm X RP-UPLC Gradient mixture of solvent A Krishnaiah et al., 2010.
dosage form 2.1mm,1.7µ) and B
3 Valsartan in tablet UV Gupta et al., 2010
dosage form
4 Valsartan in Venusil XBP C-18,5µ RP-HPLC 0.1 M Phosphate Thanusha et al., 2010
Pharmaceutical dosage Buffer:Acetonitrile(20:80)
form
5 Valsartan in Tablet Thermohypersil ODS RP-HPLC Water:acetonitrile:glacial Reddy et al., 2010
Dosage Form (150mm x 4.4mm)5µ acetic acid(500:500:01)
6 Valsartan and its HIQ sil C18 ODS RP-HPLC Methanol:water[70:30v/v]pH Bhatia et al., 2009
degradation products (250mm X 4.6mm)5µ 7.2
Methanol:water[60:40v/v]pH
7.2
7 Valsartan and its Atlantis C18(100mm x SPE-HPLC-UV Gradient: ACN with 0.025% Iriarte et al., 2006
metabolites in human 3.9mm)3µ TFA and 5mM phosphate
plasma buffer with 0.025% TFA pH
2.5
8 Valsartan or candesartan Tandem mass Levi et al., 2009
in human plasma spectroscopy
9 Valsartan and other Bondapak C18 HPLC- Gradient: Acetonitrile-5mM Gonzalez et al., 2002
ATII antagonists in flourescence acetate buffer(pH4)
plasma
10 Valsartan and HCTZ Precoated silica gel HPTLC Chloroform:methanol:toluene Shah et al., 2009.
60F254 :glacial acetic acid(6:2:1:0.1
v/v/v/v)
11 Valsartan and HCTZ in Precoated silica gel G HPTLC Chloroform:ethyl Kadam et al., 2007.
tablets 60F254 acetate:acetic acid(5:5:0.2v/v)
12 Valsartan, Aliskiren, Purosphere Star RP HPLC 0.2%v/v TEA buffer(pH Pachauria et al., 2010
Ramipril,HCTZ 18(250mmX4.6mm) 3.0):ACN
13 Valsartan and HCTZ in HIQ sil ODS (250 Ion pair Methanol:0.0025M Bhatia et al., 2010
tablet dosage form mmX4.6mm) chromatography orthophosphoric acid(70:30)
pH 4.6: 0.1%hexane
sulphonic acid
14 Valsartan and Kromasil C18(250 X RP-HPLC Acetonitrile:phosphate Chitlange et al., 2008.
Amlodipine 4.6mm) buffer(0.02M,pH3.0),(56:44v/
v)
15 Valsartan and Precoated silica gel TLC Toluene:methanol:acetic Dhaneshwar et al., 2009
Amlodipine 60F254 acid(7:3:0.1 v/v/v)
16 Valsartan and HICHROME Nucleosil RP-HPLC Phosphate buffer(pH Celebier et al., 2008
Amlodipine 100-5,C18(250X4.5mm) 3.6;0.01M):acetonitrile:metha
nol(50:40:10v/v)
17 Valsartan and X Terra RP18, 5µ, RP-HPLC Mixture of solution A and Patel et al., 2009
Amlodipine 150mm X 4.6mm solution B
18 Valsartan, HCTZ, Hypersil C18 (250mm X RP-HPLC ACN:Phosphate buffer pH6.8 Younus et al., 2010.
Amlodipine 4.6mm) (55:45)

Dosage significant as compared with placebo. As compared placebo

changes in systolic BP (SBP) and diastolic BP (DBP) in response
Valsartan is available in the dose range of 10, 20, 40, 80,
to valsartan 80, 160, 320 mg were found to be -6.8/-3.9, -8.6/-5.1,
160, and 320 mg. All doses of Valsartan have been found to be safe
and tolerable (Oparil et al., 1996). Special care should be exercised and -9.0/-6.4 mm Hg respectively (Verdechhia et al., 2004).
when initiating treatment with Valsartan in the elderly or patients with Quantification and Determination Methods
mild to moderate renal or hepatic dysfunction,although dosage There have been reports in the literature regarding the
adjustments are not required in such patients. In general clinical determination of valsartan in pharmaceutical dosage forms and
practice, therapy is initiated with 80 mg once daily appropriate dosage biological fluids using various analytical techniques including
in hypertensive patients as a functional blockade of AT2 receptor has spectrophotometry. Many UV and second derivative
been shown to occur in humans after single doses of 80 mg valsartan spectrophotometric and high-performance liquid chromatographic
in 2 to 24 h (Saydam et al., 2007). A randomized, double-blind, techniques for the determination of valsartan in pharmaceutical
placebo-controlled study was conducted by Pool et al on 4067 adult dosage forms have been developed and presented. It is reported
hypertensive patients who received various oral doses of valsartan ( that the proposed second derivative spectrophotometric method
10, 20, 40, 80, 160, 320 mg) for 4 weeks. It was found that the provided a better precision and accuracy, and also determined a
response to valsartan was dose related and clinically relevant and also lower concentration of valsartan capsules than the UV-
clinically spectrophotometric method. The main advantage of this method is
shorter analysis time, the low cost of analysis and widespread
 Journal of Applied Pharmaceutical Science 01 (04); 2011: 12-19

availability of the apparatus. The HPLC methods used for routine CONCLUSION
analysis are rather time consuming, cumbersome and require too Valsartan is an effective and well tolerated once daily
many solvents and are expensive (Tatar et al., 2002). antihypertensive agent in patients with mild to moderate
Various analytical methods have been developed for the hypertension. In addition, the drug may reduce BP when used as
determination of valsartan in the biological fluids and they mainly monotherapy in patients with severe hypertension or when used
use the liquid chromatographic techniques. Various HPLC adjunctively in patients with resistant hypertension. Importantly,
methods have been described in the literature for determination of Valsartan appears to be at least as effective and well tolerated as
valsartan in biological fluids with photometric (Soldner et al., other commonly used antihypertensive agents. The drug therefore
1998), fluorimetric (Kondo et al., 1996; Gonzalez et al., 2002) or represents a useful therapeutic option in the management of
mass spectrometric (Danaeshtalab et al., 2002) detection after patients with hypertension and will be particularly useful in
extraction from plasma. patients not responding to, or intolerant of, anti-hypertensive
Very few methods have been reported in literature for the agents from other drug classes. Valsartan is an appropriate choice
determination of valsartan in pharmaceutical dosage form that are for first-line treatment of patients with mild-to-moderate
based on liquid chromatography-tandem mass spectrometry(LC- hypertension, and its predictable dose-responsive efficacy
MS/MS) (Koeski et al., 2007; Selvan et al., 2007; Levi et al., provides a rational basis for titration in clinical practice.
2009).
Direct UV-Vis spectrophotometric method did not give REFERENCES
much impressive results for the simultaneous determination of Agrahari V., Kabra V., Gupta S., Nema RK., Nagar M.,
drugs with spectral overlapping. Application of derivative Karthikeyan C. and Trivedi P. Determination of Inherent Stability of
Valsartan by Stress Degradation and it’s Validation by HPLC. Int J Pharm
technique of spectrophotometry has reported a powerful tool for Clin Res 2009; 1(2): 77-81.
quantitative analysis of multi-component mixtures (Rojas et al., Bhatia M., Bhatia MS., Choudhari PB., Ingale KB.
2009). Development and validation of spectrophotometric and ion pair
Over the years, many methods have been developed for chromatographic technique for estimation of valsartan and
hydrochlorothiazide. J Pharm Res and Health Care 2010; 2(1): 2-14.
the determination of valsartan in pharmaceutical dosage forms Bhatia MS., Uttamrao KS. Determination and validation of
based on HPLC (Agrahari et al., 2009; Thanusha et al., 2010; valsartan and its degradation products by isocratic HPLC. J Chem
Bhatia et al., 2009; Reddy et al., 2010) and UV-derivative Metrology 2009; 3(1)1-12.
Biswas PN., Wilton LV., Shakir SW. The safety of valsartan:
spectrophotometry (Gupta et al., 2010) and have been reported.
results of a postmarketing surveillance study on 12881 patients in
Many methods for the simultaneous determination of England. J Hum Hyper 2002; 16: 795-803.
valsartan and hydrochlorothiazide in biological matrices and Burnier M. and Brunner HR. Angiotensin II receptor
pharmaceutical dosage forms have been reported by the use of antagonists. Lancet 2000; 355: 637-645.
Carlucci G., Carlo V. and Mazzero P. Simultaneous
HPLC (Satana et al., 2001; Carlucci et al., 2000; Li et al., 2007) determination of valsartan and hydrochlorothiazide in tablets by high
and UV-derivative spectrophotometry (Satana et al., 2001; performance chromatography. Analytical Letters 2000; 33(12): 2491-
Carlucci et al., 2000). 2500.
LC-MS/MS and capillary electrophoresis methods have been Çelebier M., Kaynak MS., Altınöz S., Şahin S. Validated HPLC
Method Development: The Simultaneous Analysis of Amlodipine and
developed and reported for simultaneous determination of valsartan Valsartan in Samples for Liver Perfusion Studies. Hacettepe Uni J Faculty
and hydrochlorothiazide in pharmaceutical dosage forms (Li et al., of Pharmacy 2008; 28: 15-30.
2007; Hillaert et al., 2003) Some reverse phase high-performance Chitlange SS., Bagri K., Sakarkar DM. Stability indicating RP-
HPLC method for simultaneous estimation of valsartan and amlodipine in
liquid chromatography(RP-HPLC) methods have also been developed
capsule formulation. Asian J Res Chemistry 2008; 1(1): 15-18.
of the simultaneous for determination valsartan and amlodipine Daneshtalab, Lewanczuk RZ., Jamali F. High performance
(Celebier et al., 2008; Chitlange et al., 2008). liquid of chromatographic analysis of angiotensin II receptor antagonist
(Table 3) Valsartan using liquid extraction method. J Chrom B 2002; 766: 345-349
Demiralay EC., Cubuka B., Ozkanb SA., Alsancaka G.
Combined effect of polarity and pH on the chromatographic behavior of
Formulation Types some angiotensin II receptor antagonists and optimization of their
A variety of conventional dosage forms are commercially determination in pharmaceutical dosage forms. J Pharm Biomed Anal
2010; 53: 475-482.
available consisting of tablets and capsules. A constant
Dhaneshwar SR., Patre NG. and Mahadik MV. Validated TLC
programmable chronotherapeutic controlled delivery pulsatile Method for Simultaneous Quantitation of Amlodipine Besylate and
capsule dosage form has been prepared. It consists of a precoated Valsartan in Bulk Drug and Formulation. Chromatographia 2009; 69: 157-
capsule consisting of a drug tablet and erodible tablet (L- 161.
Ferdinand KC., Taylor C. The Management of Hypertension
hydroxypropyl cellulose (L-HPC) or guar gum) made of swellable With Angiotensin Receptor Blockers in Special Populations. Clin
polymer (L-HPC), xanthan gum, polyethylene oxide or sodium Cornerstone 2009; 9(3): S5-S17.
alginate (Saydam et al., 2007). Flesch G., Muller Ph., Lloyd P. Absolute bioavailability and
Fast dissolving tablets of Valsartan were also prepared pharmacokinetics of valsartan, an angiotenin II receptor antagonist in
man. Eur J Clin Pharmcol 1997; 52: 115-120.
using different disintegrants. It was found that drug release Gonzalez L., Lopez JA., Alonso RM., Jimenez RM. Fast
increased with increasing concentrations of the distintegrant with screening method for the determination of angiotensin II receptor
Crospovidone showing the highest amount of drug release. antagonists in human plasma by high-performance liquid chromatography
with fluorimetric detection. J Chrom A 2002; 949: 49-60.
 Journal of Applied Pharmaceutical Science 01 (04); 2011: 12-19

Gupta KR., Wadodkar AR., Wadodkar SG. UV- Pachauria S., Paliwalb S., Srinivasa KS., Singha Y., Jain V.
Spectrophotometric methods for estimation of Valsartan in bulk and tablet Development and Validation of HPLC Method for Analysis of Some
dosage form. Inter J ChemTech Res 2010; 2(2): 985-989. Antihypertensive Agents in their Pharmaceutical Dosage Forms. J Pharm
Herder SD., Weber E., Winkemann A., Herder C., Morck H. Sci Res 2010; 2(8): 459-464.
Efficacy and safety of angiotensin II receptor type 1 antagonist in children Patel SB., Chaudhari BG., Buch MK. and Patel AB. Stability
and adolescents. Paed Neph 2010; 25: 801-811. indicating RP-HPLC method for simultaneous determination of Valsartan
Hillaert S., Bossche VW. Simultaneous determination of and amlodipine from their combination drug product. Inter J ChemTech
hydrochlorothiazide and several angiotensin-II receptor antagonists by Res 2009; 1(4): 1257-1267.
capillary electrophoresis. J Pharm Biomed Anal 2003; 31(2): 329-339. Pool J., Oparil S., Hedner T., Glazer R., Oddou-Stock P. Dose-
Iqbal M., Khuroo A., Batolar LS., Tandon M., Monif T., Sharma Responsive Antihypertensive Efficacy of Valsartan, a New Angiotensin II-
PL. Pharmacokinetics and Bioequivalence Study of Three Oral Receptor Blocker. Clin Therap 1998; 20(6): 1106-1114.
Formulations of Valsartan 160 mg: A Single-Dose, Randomized, Open- Reddy BN., Reddy UC., Nagarjuna P. and Kumar CD. RP-
Label, Three-Period Crossover Comparison in Healthy Indian Male HPLC method development and validation of Valsartan tablet dosage
Volunteers. Clin Therapeutics 2010; 32: 588-596. form. J Chem Pharm Res 2010; 2(4): 878-886.
Iriarte G., Ferreirós N., Ibarrondo I., Alonso RM., Maguregi Rojas FS., Ojeda CB. Recent development in derivative
MI., Gonzalez L., Jiménez RM. Optimization via experimental design of ultraviolet/visible absorption spectrophotometry. Analytica Chimica Acta
an SPE-HPLC-UV-fluorescence method for the determination of valsartan 2009; 635: 22-44.
and its metabolite in human plasma samples. J Separation Sci 2006; Satana E., Altinay S., Goger NG., Ozkan SA., Sentruk Z.
29(15): 2265-2283. Simultaneous determination of valsartan and hydrochlorothiazide in
Kadam BR, Bari SB. Quantitative analysis of valsartan and tablets by first derivative ultraviolet spectrophotometry and LC. J Pharm
hydrochlorothiazide in tablets by high performance thin-layer Biomed Anal 2001; 25(5): 1009-1013.
chromatography with ultraviolet absorption densitometry. Acta Saydam, Takka. Bioavailability File: Valsartan. FABAD J
Chromatographica 2007; 18: 260-269. Pharm Sci 2007; 32:185-196.
Koeski N., Kawashita H., Hara H., Niina M., Tanaka M., Kawai Selvan PS., Gowda V., Mandal U., Solomon WDS., Pal TK.
R., Nagae Y., Masuda N. Development and validation of a method for Simultanoeus determination of fixed dose combination of nevobiolol and
quantitative determination of valsartan in human plasma by liquid valsartan in human plasma by liquid chromatographic-tandem mass
chromatography tandem mass spectrometry. J Pharm Biomed Anal 2007; spectrometry and its application to pharmacokinetic study. J Chrom B
43: 1769-1774. 2007; 858: 143-150
Kondo T., Yoshida K., Yoshimura Y., Motohashi M., Tanayama Shah NJ., Suhagia BN., Shah RR., Patel NM. HPTLC Method
S. Characterization of conjugated metabolites of a new angiotensin II for the Simultaneous Estimation of Valsartan and Hydrochlorothiazide in
receptor antagonist, candesartan cilexetil, in rats by liquid Tablet Dosage Form. Ind J Pharma Sci 2009; 71(1): 72-74.
chromatography/electrospray tandem mass spectrometry following Soldner A., Spahn-Langguth H., Mutschler E. HPLC assays to
chemical derivatisation. J Mass Spectrometry 1996; 31: 873-878. simultaneously determine the angiotensin AT1 antagonist losartan as well
Koseki N., Kawashita H., Hara H., Niina M., Tanaka M., Kawai as its main and active metabolite EXP 3174 in biological material of
R., Nagae Y. Development and validation of a method for quantitative humans and rats. J Pharm Biomed Anal 1998; 16: 863-873. Spinola ACF.,
determination of valsartan in human plasma by liquid chromatography- Almeida S., Filipe A., Neves R., Trabelsi F., Farré A. Results of a Single-
tandem mass spectrometry. J Pharm Biomed Anal 2007; 43(5): 1769- Center, Single-Dose, Randomized-Sequence, Open-Label, Two-Way
1774. Crossover Bioequivalence Study of Two Formulations of Valsartan 160-
Krishnaiah A., Reddy R., Kumar R., Mukkanti K. Stability- mg Tablets in Healthy Volunteers under Fasting Conditions. Clin Therap
indicating UPLC method for determination of valsartan and their 2009; 31(9): 1992-2001.
degradation products in active pharmaceutical ingredient and Tatar S., Saglik S. Comparison of U.V and second derivative-
pharmaceutical dosage forms. J Pharm Biomed Anal 2010; 53(3): 483- spectrophotometric and LC methods for determination of valsartan in
489. pharmaceutical formulation. J Pharm Biomed Anal 2002; 30(2): 371-375.
Levi M., Wuerzner WG., Ezan E., Pruvost A. Direct analysis of Thanusha G., Jose C., Babu G., Basavaraj KPC, Panditi VR. and
Valsartan candesartan in human plasma and urines by on-line solid phase Sharadha C. Validated RP-HPLC Method for the Quantitative Estimation
extraction coupled to electrospray tandem mass spectrometry. J Chrom B of Valsartan in Bulk and Pharmaceutical Dosage Forms. Int J ChemTech
2009; 877(10): 919-926. Res 2010; 2(2): 1194-1198.
Li H., Wang Y., Jiang Y., Tang Y., Wang J., Zhao L. A liquid Verdecchia P., Angeli F. Assessment of the optimal daily dose
chromatography/tandem mass spectrometry method for simultaneous of valsartan in patients with hypertension, heart failure, or Both. Clin
determination of valsartan and hydrochlorothiazide in human plasma. J Therapeutics 2004; 26(4): 460-472.
Chrom B 2007; 852: 436-442. Verdecchia P., Angeli F. Co-administration of Valsartan 160 and
Malacco E., Santonastao M., Vari NA., Gargiulo A., Spagnuolo 320 mg and Simvastatin 20 and 40 mg in Patients with Hypertension and
V., Bertocchi F., Palatini P.. Comparison of Valsartan 160mg with Hypercholesterolemia: A Multicenter, 12-Week, Double-Blind, Double-
Lisinopril 20mg, Given as Monotherapy or in Combination with a Dummy, Parallel-Group Superiority Study. Clin Therap 2008; 30(10):
Diuretic, for the Treatment of Hypertension: The Blood Pressure 1782-1793.
Reduction and Tolerability of Valsartan in Comparison with Waldmeier F., Flesh G., Muller P., Winkler T., Kriemler HP.,
Lisinopril(PREVAIL) Study. Clin Therap 2004; 26(6): 855-865. Buhlmayer P., Gasparo MD. Pharmacokinetics disposition and
Martin J., Krum H. Role of Valsartan and other angiotensin biotransformation of [14C]-radiolabelled valsartan in healthy male
receptor blocking agents in the management of cardiovascular disease. volunteers after a single oral dose. Xenobiotica 1997; 27(1): 59-71.
Pharmacol Res 2005; 46(3): 203-212. Younus M., Reddy TK., Reddy YR., Arif MF. RP-HPLC
McInnes GT. Angiotensin II antagonism in clinical practice: Method Development and Validation for Simultaneous Estimation of

Oparil S., Dyke S., Harris F. The efficacy and safety of valsartan form. J Pharmacy Res 2010; 3(11): 2647-2650.
compared with placebo in the treatment of patients with essential
hypertension. Clin Therap 1996; 18: 797-810.