Valacyclovir Hydrochloride

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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C₁₃H₂₀N₆O₄  · HCl           360.80

l-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy] ethyl ester, monohydrochloride;

l-Valine, ester with 9-[(2-hydroxyethoxy)methyl]guanine, monohydrochloride CAS RN: 124832-27-5; UNII: G447S0T1VC.

1 DEFINITION

Valacyclovir Hydrochloride contains NLT 95.0% and NMT 102.0% of valacyclovir hydrochloride (C₁₃H₂₀N₆O₄  · HCl), calculated on the anhydrous and solvent-free basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

Change to read:

C. IDENTIFICATION TESTS GENERAL (191), Chemical Identification Tests. Chloride

Sample solution: 50 mg/mL of Valacyclovir Hydrochloride _{(USP 1-May-2023)} in water

Acceptance criteria: Meets the requirements

ASSAY

Change to read:

PROCEDURE

Mobile phase: Methanol, water, and perchloric acid (5:95:0.5) _{(USP 1-May-2023)}

Standard solution: 0.5 mg/mL of USP Valacyclovir Hydrochloride RS in 0.05 M hydrochloric acid. [NOTE-USP Valacyclovir Hydrochloride RS contains a detectable quantity of D-valacyclovir.]

Sample solution: 0.5 mg/mL of Valacyclovir Hydrochloride in 0.05 M hydrochloric acid

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4-mm x 15-cm; 5-µm packing L66

Column temperature: 10^o

Flow rate: 0.75 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

Suitability requirements

Resolution: NLT 2.0 between valacyclovir hydrochloride and D-valacyclovir

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of valacyclovir hydrochloride (C₁₃H₂₀N₆O₄  · HCl) in the portion of Valacyclovir Hydrochloride taken:

Result = (r_u /r_s ) × (C_s /C_u ) × 100

r_u = peak response of valacyclovir from the Sample solution

r_s = peak response of valacyclovir from the Standard solution

C_s = concentration of USP Valacyclovir Hydrochloride RS in the Standard solution (mg/mL)

C_u = concentration of Valacyclovir Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 95.0%–102.0% on the anhydrous and solvent-free basis

3 IMPURITIES

RESIDUE ON IGNITION (281)

Sample: 2 g

Acceptance criteria: NMT 0.1%

Delete the following:

LIMIT OF PALLADIUM (if present) (USP 1-May-2023)

Change to read:

ORGANIC IMPURITIES, PROCEDURE 1 (for related compounds E, F, and G)

Developing solvent: Methylene chloride, methanol, tetrahydrofuran, and ammonia solution (54:34:12:3)

Standard stock solution: Transfer 5 mg each of USP Valacyclovir Related Compound D RS and USP Valacyclovir Related Compound G RS, 10 mg of USP Valacyclovir Related Compound E RS, and 8.4 mg of USP Valacyclovir Related Compound F RS into a 10-ml volumetric flask. Add 2 mL of water with swirling, followed by 6 ml of alcohol, and sonicate for 20 min. Allow to cool, and dilute with alcohol to volume.

Standard solutions: Transfer 1.0 and 0.5 mL of the Standard stock solution into two separate 10-ml volumetric flasks. Dilute the solution in both flasks with alcohol to volume.

Sample solution: Transfer 250 mg of Valacyclovir Hydrochloride into a 5-mL volumetric flask. Add 2 mL of water, and sonicate for 20 min to dissolve. Add alcohol to about 95% of the flask volume. Cool, and dilute with alcohol to volume. Pass through a suitable filter of 0.45-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: TLC

Detector: UV, long and short wavelength

Plate: TLC plate coated with a 0.25-mm layer of chromatographic silica gel mixture. Prewash the plate with methanol.

Developing distance: NLT 7 cm from the origin

Application volume: 4 µL

Analysis

Samples: Standard solutions and Sample solution

Develop the plate to the specified distance. Remove the plate from the solvent chamber, and allow to dry. Examine the plate under short-wavelength UV light, and visually estimate the valacyclovir related compounds E and G in the sample using the appropriate standard spots. The chromatograms obtained with the Standard solutions each show three clearly separated spots due to valacyclovir related compounds D, E, and G. Spray the plate with 0.01% fluorescamine in ethylene dichloride, and examine the sprayed plate under long-wavelength UV light to estimate the level of valacyclovir related compound F in the sample using the appropriate standard spot. The relative R_f values and limits for each impurity are provided in Table 1.

Acceptance criteria: See Table 1

Table 1

^a This impurity is quantitated using Procedure 2.

^b 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl N-benzyloxycarbonyl-l-valinate. _{(USP 1-May-2023)}

^c 2-Hydroxyethyl valinate 4-methylbenzenesulfonate._{(USP 1-May-2023)}

^d N,N-Dimethylpyridin-4-amine.

Change to read:

Organic Impurities, Procedure 2

Solution A: 0.3% w/w triuoroacetic acid solution in water

Solution B: 0.3% w/w triuoroacetic acid solution in methanol

Diluent: Alcohol and water(20:80) _{(USP 1-May-2023)}

Mobile phase: See Table 2.

Table 2

System suitability solution: 0.4 mg/mL of USP Valacyclovir Hydrochloride RS, 0.8 µg/mL of USP Valacyclovir Related Compound C RS, and 1.6 µg/mL of USP Acyclovir Related Compound A RS in Diluent

Sample solution: 0.4 mg/mL of Valacyclovir Hydrochloride in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm × 25-cm; 5-µm packing L11

Column temperature: 15°

Flow rate: 0.8 mL/min

Injection volume: 10 µL

System suitability

Sample: System suitability solution

Suitability requirements

Resolution: NLT 1.5 between valacyclovir and valacyclovir related compound C; NLT 1.5 between valacyclovir related compound C and acyclovir related compound A

Tailing factor: NMT 1.5 for the valacyclovir hydrochloride peak

Analysis

Sample: Sample solution

Calculate the percentage of each individual impurity in the portion of Valacyclovir Hydrochloride taken:

Result = (r_u /r_t ) × 100

r_u = peak response of any impurity in the Sample solution

r_t = sum of all the peak responses from the Sample solution

Acceptance criteria: See Table 3.

Table 3

^a This impurity is quantitated by the Procedure 3 method.

^b 9-[(2-Hydroxyethoxy)methyl]guanine. _{(USP 1-May-2023)}

^c 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl l-alaninate. _{(USP 1-May-2023)}

^d 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl N-methyl-l-valinate.

^e 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl acetate.

^f 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl N-ethyl-l-valinate.

^g 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl l-isoleucinate. _{(USP 1-May-2023)}

^h 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl N-formyl-l-valinate._{(USP 1-May-2023)}

ⁱ 2-[(6-Oxo-2-{[(6-oxo-6,9-dihydro-1H-purin-2-yl)aminomethyl]amino}-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl l-valinate. _{(USP 1-May-2023)}

^j {Methylenebis[azanediyl(6-oxo-1,6-dihydro-9H-purine-2,9-diyl)methyleneoxyethan-2,1-diyl]} di-l-valinate. _{(USP 1-May-2023)}

Change to read:

Organic Impurities, Procedure 3

Mobile phase, Standard solution, Sample solution, and Chromatographic system: Proceed as directed in the Assay.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each individual impurity in the portion of Valacyclovir Hydrochloride taken:

Result = (r_u /r_s ) × (C_s /C_u ) × (1/F) × 100

r_u = peak response of guanine plus acyclovir or acyclovir acetate or d-valacyclovir from the Sample solution

r_s = peak response of valacyclovir from the Standard solution

C_s = concentration of USP Valacyclovir Hydrochloride RS in the Standard solution (mg/mL)

C_u = concentration of Valacyclovir Hydrochloride in the Sample solution (mg/mL)

F = relative response factor (see Table 4)

Acceptance criteria: See Table 4.

Table 4

^a 9-[(2-Hydroxyethoxy)methyl]guanine. _{(USP 1-May-2023)}

^b 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl acetate.

^c 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl d-valinate. _{(USP 1-May-2023)}

Total organic impurities: NMT 5.0% for the sum of all impurities from Organic Impurities, Procedures 1, 2, and 3

4 SPECIFIC TESTS

Change to read:

Water Determination 〈921〉, Method I: For the anhydrous form: NMT 2.0% (200 mg of sample); if labeled as the hydrous form: 3.0% _{(USP 1-May-2023)} –11.0%

5 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers, and store at a temperature below 30°.

Labeling: Where it is the hydrous form, the label so indicates.

Change to read:

USP Reference Standards 〈11〉

USP Acyclovir Related Compound A RS

[Note—USP Acyclovir Related Compound A AS is equivalent.]

2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl acetate.

C₁₀H₁₃N₅O₄                          267.25 _{(USP 1-May-2023)}

USP Valacyclovir Hydrochloride RS

USP Valacyclovir Related Compound C RS

2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl N-methyl-l-valinate hydrochloride.

C₁₄H₂₂N₆O₄  · HCl                374.83 _{(USP 1-May-2023)}

USP Valacyclovir Related Compound D RS

2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9- _{(USP 1-May-2023)} yl)methoxy]ethyl N-ethyl-l-valinate.

C₁₅H₂₄N₆O₄                         352.40 _{(USP 1-May-2023)}

USP Valacyclovir Related Compound E RS

2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl N-benzyloxycarbonyl-l-valinate. _{(USP 1-May-2023)}

C₂₁H₂₆N₆O₆                        458.48 _{(USP 1-May-2023)}

USP Valacyclovir Related Compound F RS

2-Hydroxyethyl valinate 4-methylbenzenesulfonate. _{(USP 1-May-2023)}

C₇H₁₅NO₃  · C₇H₈O₃S        333.40

USP Valacyclovir Related Compound G RS

N,N-Dimethylpyridin-4-amine.

C₇H₁₀N₂                           122.17