Valganciclovir 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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C₁₄H₂₂N₆O₅ · HCl      390.82

L-Valine, ester with 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine, monohydrochloride.

L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl ester, monohydrochloride CAS RN: 175865-59-5; UNII: 4P3T9QF9NZ.

1 DEFINITION

Valganciclovir Hydrochloride contains NLT 97.0% and NMT 102.0% of valganciclovir hydrochloride (C₁₄H₂₂N₆O₅ · HCl), calculated on the anhydrous and solvent-free basis.

2 IDENTIFICATION

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

B. The retention times of valganciclovir diastereomeric peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

C. IDENTIFICATION TESTS-GENERAL (191), Chloride: Meets the requirements

3 ASSAY

PROCEDURE

Buffer: 11.5 g/L of monobasic ammonium phosphate in water. Adjust with phosphoric acid (85%) to a pH of 2.8 ± 0.2 prior to final dilution.

Mobile phase: Methanol and Buffer (8:92)

System suitability solution: 0.2 mg/mL of USP Valganciclovir Hydrochloride RS and 0.01 mg/mL of USP Methoxymethylguanine RS in 0.001 N hydrochloric acid

Standard solution: 0.2 mg/mL of USP Valganciclovir Hydrochloride RS in 0.001 N hydrochloric acid

Sample solution: 0.2 mg/mL of Valganciclovir Hydrochloride in 0.001 N hydrochloric acid

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 15-cm; 3.5-µm packing L1

Flow rate: 1 mL/min

Injection volume: 20 µL

Run time: NLT 2.5 times the retention time of valganciclovir diastereomer peak 2

System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for methoxymethylguanine and valganciclovir diastereomer peak 1 are 0.93 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 1.0 between methoxymethylguanine and valganciclovir diastereomer peak 1; NLT 3.0 between valganciclovir diastereomer peak 1 and valganciclovir diastereomer peak 2, System suitability solution

Tailing factor: NMT 2.0 for valganciclovir diastereomer peak 2, System suitability solution

Relative standard deviation: NMT 1.0% for the sum of valganciclovir diastereomer peak 1 and valganciclovir diastereomer peak 2, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of valganciclovir hydrochloride (C₁₄H₂₂N₆O₅ · HCl) in the portion of Valganciclovir Hydrochloride taken:

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

r_u = sum of the peak responses of valganciclovir diastereomer peaks 1 and 2 from the Sample solution

r_s = sum of the peak responses of valganciclovir diastereomer peaks 1 and 2 from the Standard solution

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

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

Acceptance criteria: 97.0%–102.0% on the anhydrous and solvent-free basis

4 IMPURITIES

RESIDUE ON IGNITION (281): NMT 0.10%

4.1 LIMIT OF ISOPROPYL ALCOHOL

Internal standard solution: Transfer 0.1 mL of 1.4-dioxane to a 100-mL volumetric flask and dilute with dimethylformamide to volume.

Standard stock solution: Transfer 1.0 mL of isopropyl alcohol and 0.1 mL of toluene to a 100-mL volumetric flask, and dilute with

dimethylformamide to volume. [NOTE-Toluene is used to verify the system suitability.]

Standard solution: Combine 2.0 mL of the Internal standard solution and 0.1 mL of the Standard stock solution.

Sample solution: Transfer 90-100 mg of Valganciclovir Hydrochloride to a vial, add 2.0 mL of the Internal standard solution, and mix.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: GC

Detector: Flame ionization

Column: 0.53-mm x 30-m capillary, coated with 3.0-pm film of phase G43

Carrier gas: Helium

Temperatures

Injection port: 250°

Detector: 300°

Column: See Table 1.

Table 1

Flow rate: 10.5 mL/min

Injection volume: 0.5 µL

Injection type: Split, split ratio 1:1

System suitability

Sample: Standard solution

Suitability requirements

Resolution: NLT 8 between 1,4-dioxane and toluene

Relative standard deviation: NMT 15% of the peak area ratio of isopropyl alcohol to 1,4-dioxane

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of isopropyl alcohol in the portion of Valganciclovir Hydrochloride taken:

Result = (R_u /R_s ) × (C_s /C_u ) × 100

R_u = peak area ratio of isopropyl alcohol to the internal standard from the Sample solution

R_s = peak area ratio of isopropyl alcohol to the internal standard from the Standard solution

C_s = concentration of isopropyl alcohol in the Standard solution (mg/mL)

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

Acceptance criteria: NMT 1.0%

Change to read:

Organic Impurities

Solution A: 11.5 g/L of monobasic ammonium phosphate in water. Adjust with phosphoric acid (85%) to a pH of 2.8 ± 0.2 prior to nal dilution.

Solution B: Methanol

Mobile phase: See Table 2.

Table 2

System suitability solution: 0.2 mg/mL of USP Valganciclovir Hydrochloride RS and 0.01 mg/mL of USP Methoxymethylguanine RS in 0.001 N hydrochloric acid

Sample solution: 0.2 mg/mL of Valganciclovir Hydrochloride in 0.001 N hydrochloric acid

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm × 15-cm; 3.5-µm packing L1

Flow rate: 1 mL/min

Injection volume: 20 µL

System suitability

Sample: System suitability solution

[Note— See Table 3 for the relative retention times.]

Suitability requirements

Resolution: NLT 1.0 between methoxymethylguanine and valganciclovir diastereomer peak 1; NLT 3.0 between valganciclovir diastereomer peak 1 and valganciclovir diastereomer peak 2

Tailing factor: NMT 2.0 for valganciclovir diastereomer peak 2

Analysis

Sample: Sample solution

Calculate the percentage of any individual impurity in the portion of Valganciclovir Hydrochloride taken:

Result = {(r_i /F_i )/[r_s + Σ(r_i /F_i )]} × 100

r_i = peak response for each individual impurity in the Sample solution

F_i = relative response factor (see Table 3)

r_s = sum of the peak responses for valganciclovir diastereomers from the Sample solution

Acceptance criteria: See Table 3.

Table 3

^a 2-Amino-1,9-dihydro-6H-purin-6-one.

^b 2-Amino-9-{[(1,3-dihydroxypropan-2-yl)oxy]methyl}-1,9-dihydro-6H-purin-6-one.

^c 3-[(2-Amino-6-oxo-1,6-dihydropurin-9-yl)methoxy]-2-hydroxypropyl L-valinate hydrochloride. _{(ERR 1-Sep-2023)}

^d 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]-3-hydroxypropyl acetate.

^e 2-Amino-9-[(2-chloro-3-hydroxypropoxy)methyl]-1,9-dihydro-6H-purin-6-one.

^f 2-Amino-9-{[(1-chloro-3- hydroxypropan-2-yl)oxy]methyl}-1,9-dihydro-6H-purin-6-one.

^g 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]propane-1,3-diyl (2S,2'S)-bis(2-amino-3-methylbutanoate).

^h 2-{[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]methoxy}-3-hydroxypropyl l-valinate hydrochloride.

ⁱ 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]-3-hydroxypropyl propionate.

^j 2-{[2-({[(7-[({1-[(l-Valyl)oxy]-3-hydroxypropan-2-yl}oxy)methyl]-4-oxo-4,5,6,7-tetrahydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]methyl}amino)-6-oxo-1,6-dihydro-9H-purin-9-yl]methoxy}-3-hydroxypropyl l-valinate dihydrochloride.

^k Includes impurities from the tests for Organic Impurities  and Limit of Ganciclovir Mono-N-methyl Valinate.

4.2 LIMIT OF GANCICLOVIR MONO-N-METHYL VALINATE

Solution A: 2.5 mL/L of triethylamine in water. Adjust with trifluoroacetic acid to a pH of 3 plus/minus 0.05

Solution B: Methanol

Mobile phase: See Table 4.

Table 4

Standard solution: 0.2 mg/mL of USP Valganciclovir Hydrochloride RS in 0.001 N hydrochloric acid

Sample solution: 0.2 mg/mL of Valganciclovir Hydrochloride in 0.001 N hydrochloric acid

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm × 15-cm; 3.5-µm packing L11

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

[Note— The relative retention times for valganciclovir diastereomeric peak 2 and ganciclovir mono-N-methyl valinate are 1.0 and 1.2, respectively.]

Suitability requirements

Resolution: NLT 1.3 between valganciclovir diastereomeric peak 1 and valganciclovir diastereomeric peak 2

Tailing factor: NMT 1.5 for valganciclovir diastereomer peak 2

Analysis

Sample: Sample solution

Calculate the percentage of ganciclovir mono-N-methyl valinate in the portion of Valganciclovir Hydrochloride taken:

Result = (r_u /r_t ) × 100

r_u = sum of the peak responses of ganciclovir mono-N-methyl valinate (diastereomers) from the Sample solution

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

Acceptance criteria: See Table 5.

Table 5

^a 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]-3-hydroxypropyl methyl-l-valinate.

^b Reported as the sum of diastereomers.

4.3 ENANTIOMERIC PURITY OF VALGANCICLOVIR

Mobile phase: 16.2 g/L of perchloric acid in water

System suitability solution: 0.2 mg/mL of USP Valganciclovir Hydrochloride RS and 0.02 mg/mL of USP D-Valganciclovir RS in 0.001 N hydrochloric acid

Sample solution: 0.2 mg/mL of Valganciclovir Hydrochloride in 0.001 N hydrochloric acid

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.0-mm × 15-cm; 5-µm packing L66

Temperature: Ambient

Flow rate: 0.8 mL/min

Injection volume: 20 µL

System suitability

Sample: System suitability solution

[NOTE-The typical retention times for the two D-valganciclovir diastereomer peaks and valganciclovir diastereomer peaks 1 and 2 are 8.9, 9.6, 13.2, and 14.7 min, respectively.]

Suitability requirements

Resolution: NLT 2.5 between the second peak of the D-valganciclovir pair and valganciclovir diastereomer peak 1

Analysis

Sample: Sample solution

Calculate the percentage of enantiomeric purity in the portion of Valganciclovir Hydrochloride taken:

Result = [r_S /(r_S + r_IM )] × 100

r_S = sum of the peak responses of valganciclovir diastereomer peaks 1 and 2 (R and S esters of l-valine) from the Sample solution

r_IM = sum of the peak responses of the d-valganciclovir diastereomeric peaks (R and S esters of d-valine) from the Sample solution

Acceptance criteria: NLT 97.0%

5 SPECIFIC TESTS

Diastereomer Ratio

Analysis:

Using the chromatogram for the Sample solution in the test for Organic Impurities, calculate the percentage of valganciclovir diastereomers (R and S esters of l-valine):

Result = [r_A /(r_A + r_B )] × 100

Result = [r_B /(r_A + r_B )] × 100

r_A = peak response for valganciclovir diastereomer peak 1

r_B = peak response for valganciclovir diastereomer peak 2

Acceptance criteria: The diastereomer ratio is 45:55–55:45

Water Determination 〈921〉, Method I: NMT 8.0%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers. Store at controlled room temperature.

USP Reference Standards 〈11〉

USP Methoxymethylguanine RS

2-Amino-9-(methoxymethyl)-1,9-dihydro-6H-purin-6-one.

C₇H₉N₅O₂                     195.18

USP D-Valganciclovir RS

2-(RS)-[(2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl d-valinate hydrochloride.

C₁₄H₂₂N₆O₅  · HCl      390.83

USP Valganciclovir Hydrochloride RS