A Review on Analytical Methods for Estimation of Valacyclovir Antiviral Drug

 

Parimal Verma*, Dolly Dewangan, Jitendra Yadav, Kamraj, Krity Gupta, Manish Kumar Sahu, Prashant Kumar Sahu, Shweta Sinha, Preeti K. Suresh, S. J. Daharwal

University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur (C.G).

*Corresponding Author E-mail:  

 

ABSTRACT:

Valacyclovir hydrochloride is an antiviral prodrug that can be administered orally to increase the bioavailability of Acyclovir. Treatment for transplant patients includes herpes simplex (HSV-1, HSV-2), herpes zoster, varicella zoning, and CMV prophylaxis. The drug when taken orally, rapidly transforms into acyclovir, which inhibits viral DNA polymerase and stops viral replication. RP-HPLC and UV-Visible spectrophotometry are one of those analytical techniques used to estimate Valacyclovir in bulk, tablet formulations, and biological samples with high accuracy. These methods have the advantage of being linear, sensitive, and recoverable for use in routine quality control and pharmacokinetic studies. The purpose of this review is to provide better knowledge about valacyclovir, covering its chemistry, pharmacology, therapeutic uses, safety profile, and future perspectives in antiviral therapy.

 

KEYWORDS: Valacyclovir, Prodrug, Herpes, HPLC.

 

 

INTRODUCTION:

Valacyclovir hydrochloride is chemically L-valine, 2- [(2-amino-1,6- dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl ester and monohydrochloride.1 To overcome from this limitation, Valaciclovir was developed as the L-valyl ester prodrug of acyclovir, which shows significantly higher oral bioavailability. After administration, Valaciclovir is rapidly converted into acyclovir by first-pass metabolism and its antiviral effect by inhibiting viral DNA polymerase. Because of its improved pharmacokinetic profile, Valaciclovir contains less frequent dosing and better patient compliance compared to acyclovir.2

 

Currently, Valaciclovir is widely used in the treatment and suppression of genital herpes, herpes labialis, herpes zoster, and for prophylaxis of cytomegalovirus (CMV) in transplant patients. Its safety profile, efficacy, and ease of administration make it one of the most preferred antiviral drug in clinical practice.3. The IUPAC Name: 2-[(2-amino-6-oxo-1H-purin-9-yl) methoxy] ethyl (2S)-2-amino-3-methylbutanoate. It is approved for the treatment of various herpes virus infections and related conditions:

 

Herpes zoster (shingles), Varicella zoster virus (VZV) infections, including chickenpox, Initial episodes of genital herpes, Recurrent episodes of genital herpes, Suppressive therapy of recurrent genital herpes, Reduction of transmission of genital herpes, Herpes labialis specifically for recurrent episodes of HSV-1 infections.4

 

Figure 1: Structure of Valacyclovir

 

Physiochemical Properties:

It is a HCL salt of L-valyl ester of Acyclovir. It is [(s)-2-[(2-amino6-oxo-6, 9-dihyro-3H-purin-9yl) methoxy] ethyl-2-amino-3-methylbutanoate. It is white colour powder. Its molecular formula   C12H20N6O4•HCl with its molecular weight 360g/mol.5

 

Table 1: Solubility profile of Valacyclovir HCl 5

S. N.

Solvent

Solubility

1

Water

Freely

2

Methanol

Sparingly

3

Acidic buffer

Soluble

4

Alkaline Ph

Slightly

5

Organic solvent mixture

Soluble in mixture

 

Top of Form

Bottom of Form

Pharmacodynamic Properties:

Primary infection with varicella zoster virus (VZV) causes varicella (chickenpox). When VZV reactivates from its dormant state in sensory ganglia, it causes herpes zoster (shingles). Like other herpesviruses VZV is sensitive to acyclovir. The therapeutic benefit of valaciclovir in herpes zoster is based on establishing sufficiently high acyclovir concentrations in the blood for fast penetration to sensory nerve tissue and skin for inhibition of VZV replication.6 After oral administration and absorption of valaciclovir it is then hydrolyzed to acyclovir and L-valine. Acyclovir is then converted to acyclovir monophosphate by VZV-encoded thymidine kinase enzyme and then to the active triphosphate form by cellular enzymes. Acyclovir triphosphate inhibits VZV DNA polymerase, by terminating viral DNA chain elongation and preventing viral replication.7,8

 

In people with a healthy immune system, resistance to acyclovir from VZV is very rare.9 However, it is important to keep checking for resistance to know how common it really is. The action of Valacyclovir is exactly same as the acyclovir taken directly.10 Resistance is still uncommon; it occurs more often in people with HIV or those who have done organ transplants.11

 

Pharmacokinetic Properties:

In both healthy people and those with herpes zoster, valaciclovir is easily absorbed from the stomach and intestines. It quickly goes through the first-pass metabolism in the liver, becoming acyclovir. For people with shingles who take 1000mg of valaciclovir three times a day, the amount of acyclovir in their blood is about four times higher than when they take 800mg 5 times daily in a comparator group.12

 

In a study of patients with shingles who took valaciclovir 1000mg three times a day, the highest level of acyclovir in the blood was about 5.73 mg/L, and the average total amount in the blood over time was around 88.6 mg/L.13

 

Acyclovir is mainly eliminated from the renal route, but some is also passed in the feces. In healthy volunteers who received a single dose of valaciclovir 1000mg, the rate at which the kidney’s cleared acyclovir was higher than the rate at which the kidneys cleared creatinine, meaning the kidneys actively remove the drug. Because of this, people with kidney problems may need a lower dose.14

 

After taking single doses of valaciclovir from 100mg to 1000mg or multiple doses from 1000mg to 8000mg per day for 6 to 11 days, the plasma elimination half-life (t˝) of acyclovir ranged from 2.76 to 3.3 hours. For single doses of valaciclovir from 250mg to 2000mg in healthy Japanese men, the elimination time was similar, ranging from 2.9 to 3.59 hours.15

 

There are no reports of serious interactions between valaciclovir and other medicines including cimetidine, probenecid, digoxin, antacids or thiazide diuretics. Valaciclovir can be taken with food.

 

Mechanism of Action:

 By way of intestinal and hepatic metabolism, valaciclovir is quickly changed into acyclovir. Acyclovir is changed into acyclovir monophosphate by a special enzyme found in viruses called thymidine kinase, which is then converted into acyclovir triphosphate by other cellular enzymes. By fighting with deoxyguanosine triphosphate for antiviral DNA polymerase and getting integrated into viral DNA, acyclovir triphosphate prevents DNA synthesis and viral replication.16

 

Figure 2: Mechanism of action of valacyclovir

 

Synthesis:

Valacyclovir was made in two steps. The carbobenzoxy (Cbz) protected amino acid was attached with acyclovir using the coupling reagent called dicyclohexylcarbodiimide (DCC) in the presence of a catalytic amount of 4- (dimethyl amino) pyridine (DMAP) in DMF. Then the protection was removed by catalytic hydrogenation in the presence of Hydrogen chloride gave the desired aminoacyl ester as the hydrochloride salt. A little bit of racemization during the ester formation was observed.17

 

Requirement to Developed Analytical Method:

Analytical chemistry is divided into two main categories: qualitative evaluation, which identifies the chemical additives present in the sample, and quantitative evaluation, which calculates the quantity of positive detail or compound present in the substance, i.e., the sample.18 Drug evaluation exhibits the identity characterization and resolution of the drugs in combination like dosage forms and organic fluids. At some point of producing technique and development of drug the principal purpose of analytical strategies is to generate data regarding efficiency The main goal of analytical strategies is to produce data about efficiency (which may be directly related to the need for a specific dose), impurity (related to the medication's safety), bioavailability (which includes important drug characteristics like crystal kind, uniformity, and release), and stability (which indicates the degradation of the drug).19

 

Analytical Method development by UV- Visible Spectrophotometry:

UV Visible spectrophotometry is a widely used analytical technique that measures the absorption of ultraviolet or visible light through a substance in solution. It is applied for both qualitative and quantitative estimation of compounds. Several UV-Visible spectrophotometric methods have been reported for the estimation of Valacyclovir Hydrochloride in bulk and tablet dosage forms. These spectrophotometric methods were found to be simple, fast, and reproducible, making them suitable for routine quality control analysis of Valacyclovir in pharmaceutical formulations.20

 

Table 2: UV-Vi’s method

S. N.

Method

Sample Type

Solvent / Medium

Λ max / Detection (nm)

Linearity (µg/mL)

Correlation Coefficient (r)

Reference

1.

UV-Visible Spectrophotometric Method

Bulk and tablet

Methanol: Water (70:30)

252

2 – 10

0.9992

(21)

2.

RP-HPLC–UV Method

tablet

Methanol: Water (60:40, v/v), pH adjusted to 5.5 with glacial acetic acid

251

10–60

_

(22)

3.

UV-Visible Spectrophotometry

tablet

Britton-Robinson buffer pH 6

252.5

4×10⁻⁶ – 6×10⁻⁵

0.9994

(23)

4.

UV-Visible Spectrophotometry

tablet

Aqueous/ethanol with NaIO4-PHH-K3Fe (CN)6-NaOH-HCl

520

2–10

0.9999

(24)

5.

UV–Visible Spectrophotometry (Diazotization–Coupling, Method A)

Pharmaceutical tablet

Sodium nitrite + HCl, coupled with Orcinol (acidic medium)

440

-

0.9997

(25)

6.

UV–Visible Spectrophotometry

Bulk drug and Tablet dosage form

Methanol : 10 mM KH₂PO₄ buffer (50:50)

254

9–45

0.997

(26)

7.

Visible Spectrophotometry (Schiff base formation, Method A)

Bulk drug and Tablet dosage form

Vanillin + Nitric acid (acidic medium)

428

20–100

0.9997

(27)

8.

Visible Spectrophotometry (Schiff base formation, Method B)

Bulk drug and Tablet dosage form

p-Dimethylaminobenzaldehyde (PDAB) + Nitric acid (acidic medium)

388

100–500

0.9998

(27)

 

Analytical Method development by RP- HPLC:

RP-HPLC is most widely used analytical techniques for separation of pharmaceutical, biological, chemical and food sciences. It uses a non-polar stationary phase such as C18 and C8 and a polar mobile phase, following the principle hydrophobic interactions. Less polar analytes retained longer on the non-polar phase, while highly polar elute first. It is the popular and preferred method for most of the samples that dissolve in water- organic solvent mixture. It was reported that the technique is quick, reproducible, and suitable for routine quality control analysis of Valacyclovir in pharmaceutical formulations.28

 

Table 3: RP-HPLC method

S.N.

Method

Sample Type

column

Mobile Phase / Solvent

Λ max / Detection (nm)

Flow Rate (mL/min)

Retention Time / Rf (min)

Reference

1.

RP-HPLC

Bulk drug and Tablet dosage form

Hypersil ODS C18 (250 × 4.6 mm, 5 µm)

Acetonitrile: Phosphate buffer (pH 3.6) (50:50, v/v)

252

0.8

2.850

(29)

2.

RP-HPLC (UV detection)

Bulk drug and Tablet dosage form (Valcivir®)

RP-C18 (YMC Proc-C18, 250 × 4.6 mm, 3 µm)

Acetonitrile: Buffer (85:15)/
Methanol (Gradient mode)

250

0.6

8.0

(30)

3.

RP-HPLC (UV detection)

Bulk drug and Tablet dosage form (Valcivir®)

Phenomenex C18 (250 × 4.6 mm, 5 µm)

Phenomenex C18 (250 × 4.6 mm, 5 µm)

251

0.8

2.24 min

(31)

4.

RP-HPLC (UV detection)

Bulk drug and Tablet dosage form (Valcivir® 500 mg)

Phenomenex C18 (250 × 4.6 mm, 5 µm)

0.067 M phosphate buffer (pH 6.5) : Acetonitrile: Methanol (70:20:10 v/v)

244

0.5

3.74 min

(32)

6.

RP-HPLC (Chiral method, PDA detection)

Bulk drug and Tablet dosage form

Daicel Chiral Phase Crownpack CR (+), 150 × 4.0 mm, 5 µm

0.1% aq. Phosphoric acid: Methanol (90:10 v/v)

254

0.8 mL/min

4.9 min

(33)

7.

RP-HPLC (UV detection, Stability-indicating)

Bulk drug and Tablet dosage form

Gracesmart RP-18 C18 (250 × 4.6 mm, 5 µm)

Methanol: Citric acid buffer (60:40 v/v, pH 3.0) (250 × 4.6 mm, 5 µm)

254

1.0 mL/min

2.2 min

(34)

 

Analytical Method Development by LC-UV:

Documented LC–UV methods for estimating Valacyclovir Hydrochloride in human plasma used a Hypersil ODS C18 column with a mobile phase composed of acetonitrile and water in a ratio of 85:15 by volume, operated under isocratic conditions. The detection was at a wavelength of 265 nm, with a retention time of around 4.19 minutes. The method indicated excellent linearity within the concentration range of 50–2000 ng/mL, with a correlation coefficient of r˛ = 0.9987. The limit of quantification was determined as 50 ng/mL, indicating high sensitivity and making the method suitable for routine analysis.

 

Table 4: LC-UV method

S. No.

Method

Sample type

Mobile Phase / Solvent

Column

λ max

Rf

LOD / LOQ

Linearity range

Reference

1.

LC–UV (Liquid Chromatography with UV Detection)

Valacyclovir HCl in Human Plasma

Acetonitrile: Water (85:15 v/v), Isocratic, Flow rate 0.2–1.2 mL/min

Hypersil ODS C18 (150 mm × 4.6 mm, 5.0 μm)

265 nm

4.19 min

LOQ: 50 ng/mL

50 – 2000 ng/mL (r˛ = 0.9987)

(35)

 

Analytical Method Development by LC-MS/MS-Method:

Several liquid chromatography-tandem mass spectrometry (LC–MS/MS) methods have been developed for quantification Valacyclovir Hydrochloride (VLC) in human plasma. The reviewed studies utilized C18 or Zorbax SB C18 columns and applied solid phase extraction (SPE) for preparing the samples. 36 The mobile phase typically consisted of 0.1% formic acid and methanol in a ratio of 30:70 by volume, which helped achieve good separation and symmetrical peaks. These methods showed very high sensitivity, with detection limits as low as 0.2 picograms per milliliter and quantification limits up to 5.0 nanograms per milliliter. The linearity of the methods was evaluated across a wide concentration range from 0.5 to 1075 nanograms per milliliter, with high accuracy and reliability. Overall, the LC–MS/MS methods reported in the literature are highly specific, sensitive, and appropriate for use in pharmacokinetic and bioanalytical research involving Valacyclovir in biological samples.

 

S.N.

Method Type

Sample

Column

Extraction method

Solvent

Linearity range

LOD/LOQ

Reference

1.

LC-MS-MS

VLC in Human Plasma

C18 Column

Solid Phase Extraction (SPE)

0.1% Formic acid: Methanol (30:70 v/v)

5 – 1,075

LOQ: 5.0

(37)

2.

LC–MS-MS

VLC in Human Plasma

Zorbax SB C18 (4.6 × 75 mm, 3.5 µm)

Solid Phase Extraction (SPE)

0.1% Formic Acid: Methanol (30:70 v/v)

0.5 – 700.0 ng/mL

LOD: 0.2 pg/mL
LOQ: 0.5 ng/mL

 (38)

3.

LC–ESI–MS (Negative ion mode)

Human plasma

Porous graphitized carbon (2.1 × 125 mm, 5 µm)

-

Acetonitrile: Water (50:50) + 0.05% diethylamine

0.020 – 0.800

LOD: ~ 0.0066 µg/mL

LOQ: ~ 0.0199 µg/mL

 

(39)

 

CONCLUSION:

Valacyclovir hydrochloride is an orally administered antiviral prodrug of acyclovir, widely used for herpes zoster, simplex, and for CMV prophylaxis in immunocompromised patients. Its improved oral bioavailability and effective conversion to acyclovir make it a preferred antiviral drug in clinical practice. The literature reviews suggest that various analytical procedures have been established and verified for the estimation of Valacyclovir Hydrochloride in bulk, tablet formulations, and biological samples. Due to their ease of operation, accuracy, and reproducibility, RP-HPLC and UV-Visible spectrophotometric techniques are the most commonly used. Bioanalytical and pharmacokinetic research has advanced through the introduction of more sophisticated methods, such as LC-MS/MS and later GC-UV.

 

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Received on 05.10.2025     Revised on 30.10.2025

Accepted on 24.11.2025     Published on 28.11.2025

Available online from December 31, 2025

Research J. Engineering and Tech. 2025; 16(4):179-185.

DOI: 10.52711/2321-581X.2025.00019

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