Famciclovir

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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C₁₄H₁₉N₅O₄ 321.33

1,3-Propanediol, 2-[2-(2-amino-9H-purin-9-yl)ethyl]-, diacetate (ester);

2-[2-(2-Amino-9H-purin-9-yl)ethyl]-1,3-propanediol diacetate (ester) CAS RN®: 104227-87-4; UNII: QIC03ANI02.

1 DEFINITION

Famciclovir contains NLT 98.0% and NMT 102.0% of famciclovir (C₁₄H₁₉N₅O₄), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K (CN 1-May-2020)

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

3 ASSAY

3.1 Procedure

Dilute acid: Dilute 5 mL of phosphoric acid with water to 50 mL.

Buffer: 2.72 g/L of monobasic potassium phosphate in water. Adjust with Dilute acid to a pH of 4.0 ± 0.05.

Mobile phase: Acetonitrile and Buffer (35:65)

Diluent: Water

Standard solution: 25 μg/mL of USP Famciclovir RS in Diluent

Sample solution: 25 μg/mL of Famciclovir in Diluent

3.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 25-cm; 5-μm packing L7

Column temperature: 40°

Flow rate: 1 mL/min

Injection volume: 10 μL

Run time: 5 times the retention time of famciclovir

3.3 System suitability

Sample: Standard solution

3.4 Suitability requirements

Column efficiency: NLT 2500 theoretical plates

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0%

3.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of famciclovir (C₁₄H₁₉N₅O₄) in the portion of Famciclovir taken:

Result = (r_U /r_S ) × (C_S /C_U ) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of USP Famciclovir RS in the Standard solution (mg/mL)

C_U = concentration of Famciclovir in the Sample solution (mg/mL)

Acceptance criteria: 98.0%–102.0% on the dried basis

4 IMPURITIES

4.1 Organic Impurities, Procedure 1

[Note-On the basis of the synthetic route resulting in different impurity profiles, perform Procedure 1 or Procedure 2. Procedure 1 is recommended when dimethylaminopyridine, penciclovir, deoxychloro famciclovir, propionyl famciclovir, and 6-alkylamino famciclovir may be present (see Table 2). Procedure 2 is recommended when famciclovir malonate, acetoxybutyl aminopurine, famciclovir methoxycarbonyl analog, famciclovir related compound C, famciclovir 8, N 2-dimer, and famciclovir 6,6-dimer may be present (see Table 4).]

Dilute acid, Buffer, and Diluent: Proceed as directed in the Assay.

Solution A: Buffer

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

System suitability solution: 0.5 mg/mL of USP Famciclovir System Suitability Mixture RS in Diluent

Standard solution: 0.5 μg/mL of USP Famciclovir RS, 1 μg/mL of USP Famciclovir Related Compound A RS, and 3 μg/mL of USP Famciclovir Related Compound B RS in Diluent

Sample solution: 500 μg/mL of Famciclovir in Diluent. [Note—The solution is stable for 15 h at 6°.]

4.1.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 15-cm; 5-μm packing L7

Flow rate: 1.5 mL/min

Injection volume: 20 μL

4.1.2 System suitability

Samples: System suitability solution and Standard solution

4.1.3 Suitability requirements

Resolution: NLT 1.5 between the propionyl famciclovir and 6-chloro famciclovir peaks, System suitability solution

Column efficiency: NLT 20,000 theoretical plates for the famciclovir peak, System suitability solution

Tailing factor: NMT 1.5 for the famciclovir peak, System suitability solution

Relative standard deviation: NMT 5.0% for the famciclovir peak; NMT 10.0% for the famciclovir related compound A and famciclovir related compound B peaks, Standard solution

4.1.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Famciclovir taken:

Result = (r_U /r_S ) × (C_S /C_U ) × (1/F) × 100

r_U = peak response of each individual impurity from the Sample solution

r_S = peak response of famciclovir from the Standard solution

C_S = concentration of USP Famciclovir RS in the Standard solution (μg/mL)

C_U = concentration of Famciclovir in the Sample solution (μg/mL)

F = relative response factor for each individual impurity (see Table 2)

Acceptance criteria: See Table 2.

Table 2

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

^b 9-[4-Hydroxy-3-(hydroxymethyl)butyl]guanine.

^c 2-[2-(2-Amino-9H-purin-9-yl)ethyl]propane-1,3-diol.

^d 4-(2-Amino-9H-purin-9-yl)-2-(hydroxymethyl)butyl acetate.

^e 2-[2-(2-Amino-7H-purin-7-yl)ethyl]propane-1,3-diyl diacetate.

^f 2-[2-(2-Acetamido-9H-purin-9-yl)ethyl]propane-1,3-diyl diacetate.

^g 4-(2-Amino-9H-purin-9-yl)-2-(chloromethyl)butyl acetate.

^h 2-(Acetoxymethyl)-4-(2-amino-9H-purin-9-yl)butyl propionate.

ⁱ 2-[2-(2-Amino-6-chloro-9H-purin-9-yl)ethyl]propane-1,3-diyl diacetate.

^j 2-(2-{6-[4-Acetoxy-3-(acetoxymethyl)butylamino]-2-amino-9H-purin-9-yl} ethyl) propane-1,3-diyl diacetate.

4.2 Organic Impurities, Procedure 2

Buffer: 3.85 g/L of ammonium acetate in water. Adjust with acetic acid to a pH of 5.0.

Solution A: 4.14 g/L of monobasic sodium phosphate in water. Adjust with phosphoric acid to a pH of 2.2.

Solution B: Acetonitrile and Solution A (25:75)

Mobile phase: See Table 3.

Table 3

Diluent: Acetonitrile and Buffer (5:95)

System suitability solution: 1 mg/mL of USP Famciclovir RS, 1 μg/mL of USP Famciclovir Related Compound A RS, 5 μg/mL of USP

Famciclovir Related Compound B RS, and 4 μg/mL of USP Famciclovir Related Compound C RS prepared as follows. Dissolve an appropriate amount of Standard in 5% of the final volume of acetonitrile, and dilute with Buffer to final volume.

Standard stock solution: 1 mg/mL of USP Famciclovir RS prepared as follows. Dissolve USP Famciclovir RS in 5% of the final volume of acetonitrile, and dilute with Buffer to final volume.

Standard solution: 1 μg/mL of USP Famciclovir RS in Diluent from the Standard stock solution

Sensitivity solution: 0.3 μg/mL of USP Famciclovir RS in Diluent from the Standard solution

Sample solution: 1 mg/mL of Famciclovir prepared as follows. Dissolve Famciclovir in 5% of the final volume of acetonitrile, and dilute with

Buffer to final volume.

4.2.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 4.6-mm × 15-cm; 5-μm packing L60

4.2.2 Temperatures

Column: 35°

Sample: 6°

Flow rate: 1.5 mL/min

Injection volume: 25 μL

4.2.3 System suitability

Samples: System suitability solution and Sensitivity solution

4.2.4 Suitability requirements

Resolution: NLT 0.6 between the famciclovir and famciclovir related compound C peaks; the famciclovir related compound A peak is resolved from peaks due to the solvent front, System suitability solution

Relative standard deviation: NMT 20% for famciclovir related compound A; NMT 10% for famciclovir related compound B; and NMT 10% for famciclovir related compound C, System suitability solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

4.2.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Famciclovir taken:

Result = (r_U /r_S ) × (C_S /C_U ) × (1/F) × 100

r_U = peak response of each individual impurity from the Sample solution

r_S = peak response of famciclovir from the Standard solution

C_S = concentration of USP Famciclovir RS in the Standard solution (μg/mL)

C_U = concentration of Famciclovir in the Sample solution (μg/mL)

F = relative response factor for each individual impurity (see Table 4)

Acceptance criteria: See Table 4. Disregard peaks less than 0.03%.

Table 4

^a 2-[2-(2-Amino-9H-purin-9-yl)ethyl]propane-1,3-diol.

^b 4-(2-Amino-9H-purin-9-yl)-2-(hydroxymethyl)butyl acetate.

^c Dimethyl 2-[2-(2-amino-9H-purin-9-yl)ethyl]malonate.

^d 4-(2-Amino-9H-purin-9-yl)butyl acetate.

^e 2-[2-(2-Amino-9H-purin-9-yl)ethyl]-2-hydroxypropane-1,3-diyl diacetate.

^f No individual limit but included in total impurities.

^g Methyl 2-(acetoxymethyl)-4-(2-amino-9H-purin-9-yl)butanoate.

^h 2-[2-(2-Amino-7H-purin-7-yl)ethyl]propane-1,3-diyl diacetate.

ⁱ 4-(2-Amino-9H-purin-9-yl)-2-methylbutyl acetate.

^j 2-{2-[7-Acetyl-2-amino-7H-purin-9(8H)-yl]ethyl}propane-1,3-diyl diacetate.

^k 2-[2-(2-Acetamido-9H-purin-9-yl)ethyl]propane-1,3-diyl diacetate.

^l 2-[2-(2-Amino-6-methoxy-9H-purin-9-yl)ethyl]propane-1,3-diyl diacetate.

^m 2-[2-(2-Amino-6-chloro-9H-purin-9-yl)ethyl]propane-1,3-diyl diacetate.

ⁿ 2-{2-[2-(1-{9-[4-Acetoxy-3-(acetoxymethyl)butyl]-2-amino-9H-purin-8-yl}ethylamino)-9H-purin-9-yl]ethyl}propane-1,3-diyl diacetate.

^o 2,2′-[2,2′-(2,2′-Diamino-6,6′-bipurine-9,9′-diyl)bis(ethane-2,1-diyl)]bis(propane-3,2,1-triyl) tetraacetate.

4.3 Famciclovir Related Compound E and Famciclovir Related Compound F

Perform this test if Organic Impurities, Procedure 2 is used.

Buffer: 15.6 g/L of monobasic sodium phosphate in water. Adjust with 0.1 M sodium hydroxide to a pH of 4.5 ± 0.1 before final dilution.

Solution A: Methanol and Buffer (20:80)

Solution B: Methanol and Buffer (60:40)

Mobile phase: See Table 5.

Table 5

Standard stock solution: 28 μg/mL each of USP Famciclovir Related Compound E RS and USP Famciclovir Related Compound F RS prepared as follows. Transfer 7 mg of USP Famciclovir Related Compound E RS and USP Famciclovir Related Compound F RS to a 250-mL volumetric flask. Add 1 mL of 0.1 M sodium hydroxide and 50 mL of Solution A. Sonicate to dissolve, cool to room temperature, and dilute with Solution A to volume.

Standard solution: 0.28 μg/mL each of USP Famciclovir Related Compound E RS and USP Famciclovir Related Compound F RS in Solution A from the Standard stock solution

Sample solution: 30 mg/mL of Famciclovir in Solution A

4.3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 4.6-mm × 25-cm; 5-μm packing L1

Column temperature: 30°

Flow rate: 1.7 mL/min

Injection volume: 20 μL

4.3.2 System suitability

Sample: Standard solution

4.3.3 Suitability requirements

Resolution: NLT 5.0 between famciclovir related compound E and famciclovir related compound F

Tailing factor: NMT 2.0 for the famciclovir related compound F peak

Relative standard deviation: NMT 5.0% for famciclovir related compound F

Signal-to-noise ratio: NLT 30 for the famciclovir related compound E and famciclovir related compound F peaks

4.3.4 Analysis

Samples: Standard solution and Sample solution

Calculate, in ppm, the amount of famciclovir related compound E and famciclovir related compound F in the portion of Famciclovir taken:

Result = (r_U /r_S ) × (C_S /C_U ) × 106

r_U = peak response of famciclovir related compound E or famciclovir related compound F from the Sample solution

r_S = peak response of famciclovir related compound E or famciclovir related compound F from the Standard solution

C_S = concentration of USP Famciclovir Related Compound E RS or USP Famciclovir Related Compound F RS in the Standard solution (μg/mL)

C_U = concentration of Famciclovir in the Sample solution (μg/mL)

Acceptance criteria: NMT 10 ppm for famciclovir related compound E and NMT 5 ppm for famciclovir related compound F

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry under vacuum at a pressure not exceeding 20 mm of mercury at 60° for 2 h.

Acceptance criteria: NMT 0.5%

Residue on Ignition 〈281〉: NMT 0.1%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Store in a well-closed container at controlled room temperature.

Labeling: If a test for Organic Impurities other than Procedure 1 is used, the labeling states the test with which the article complies.

USP Reference Standards 〈11〉

USP Famciclovir RS

USP Famciclovir Related Compound A RS

[2-[2-(2-Amino-9H-purin-9-yl)ethyl]propane-1,3-diol] hydrochloride.

C₁₀H₁₅N₅O₂ · HCl 273.72

USP Famciclovir Related Compound B RS

4-(2-Amino-9H-purin-9-yl)-2-(hydroxymethyl)butyl acetate.

C₁₂H₁₇N₅O₃ 279.30

USP Famciclovir Related Compound C RS

4-(2-Amino-9H-purin-9-yl)-2-methylbutyl acetate.

C₁₂H₁₇N₅O₂ 263.30

USP Famciclovir Related Compound E RS

2-Aminopurine.

C₅H₅N₅ 135.13

USP Famciclovir Related Compound F RS

2-Amino-6-chloropurine.

C₅H₄ClN₅ 169.57

USP Famciclovir System Suitability Mixture RS

Contains famciclovir, propionyl famciclovir, and 6-chloro famciclovir.