Cefadroxil

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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C₁₆H₁₇N₃O₅S . H₂O 381.40

5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[amino(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-, monohydrate, [6R-[6α,7β(R*)]]-;

(6R,7R)-7-[(R)-2-Amino-2-(p-hydroxyphenyl)acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohydrate

CAS RN^®: 66592-87-8; UNII: 280111G160.

Hemihydrate 372.40

CAS RN^®: 119922-85-9; UNII: J9CMF6461M.

Anhydrous 363.39

CAS RN^®: 50370-12-2; UNII: Q525PA8JJB.

1 DEFINITION

Cefadroxil has a potency equivalent to NLT 950 µg/mg and NMT 1050 µg/mg of cefadroxil (C₁₆H₁₇N₃O₅S), calculated on the anhydrous 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

Buffer: 2.7 g/L of monobasic potassium phosphate

Mobile phase: Acetonitrile and Buffer (4:96)

Standard solution: 50 µg/mL of USP Cefadroxil RS in Mobile phase prepared as follows. Transfer a suitable quantity of USP Cefadroxil RS to a suitable volumetric flask, dissolve in Mobile phase using 50% of the final volume, sonicate to dissolve, and dilute with Mobile phase to volume.

Sample solution: 50 µg/mL of Cefadroxil in Mobile phase prepared as follows. Transfer a suitable quantity of Cefadroxil to a suitable volumetric flask, dissolve in Mobile phase using 50% of the final volume, sonicate to dissolve, and dilute with Mobile phase to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

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

Flow rate: 1 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the quantity, in µg/mg, of cefadroxil (C₁₆H₁₇N₃O₅S) in the portion of Cefadroxil taken:

Result = (r_U/r_S) × (C_S/C_U) × P

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

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

P = potency of cefadroxil in USP Cefadroxil RS (µg/mg)

Acceptance criteria: 950–1050 µg/mg on the anhydrous basis

4 IMPURITIES

4.1 ORGANIC IMPURITIES

Solution A: 50 mg/mL of sodium hydroxide

Solution B: 4 g/L of monobasic sodium phosphate dihydrate adjusted with Solution A to a pH of 5.0

Solution C: Acetonitrile and Solution B (1:1)

Mobile phase: See Table 1.

Table 1

Diluent: 3.5 g/L of monobasic potassium phosphate and 4.6 g/L of dibasic sodium phosphate anhydrous

System suitability stock solution 1: 0.5 mg/mL of USP Cefadroxil Related Compound D RS in Diluent. Sonicate as needed to dissolve.

System suitability stock solution 2: 0.5 mg/mL of USP Cefadroxil Related Compound I RS in Diluent. Sonicate as needed to dissolve.

System suitability solution: 10 µg/mL of cefadroxil related compound D from System suitability stock solution 1, 10 µg/mL of cefadroxil related compound I from System suitability stock solution 2, and 1 mg/mL of USP Cefadroxil System Suitability Mixture RS in Solution B. Store the sample in the refrigerator, and discard after 14 h.

Standard solution: 10 µg/mL of USP Cefadroxil RS in Solution B. Store the sample in the refrigerator, and discard after 14 h.

Sample solution: 1 mg/mL of Cefadroxil in Solution B. Store the sample in the refrigerator, and discard after 14 h.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

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

Flow rate: 1 mL/min

Autosampler temperature: 6°

Injection volume: 20 µL

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 1.5 between cefadroxil related compound D and cefadroxil related compound I, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

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

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

r_U = peak response of each impurity from the Sample solution

r_S = peak response of cefadroxil from the Standard solution

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

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

P = potency of cefadroxil in USP Cefadroxil RS (µg/mg)

F = conversion factor, 0.001 mg/µg

Acceptance criteria: See Table 2. The reporting threshold is 0.03%.

Table 2

^a d-Hydroxyphenylglycine; (R)-2-Amino-2-(4-hydroxyphenyl)acetic acid.

^b (6R,7R)-7-[(R)-2-Amino-2-(4-hydroxyphenyl)acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5R-oxide.

^c (6R,7R)-7-[(R)-2-Amino-2-(4-hydroxyphenyl)acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5S-oxide.

^d 7-Aminodesacetoxycephalosporanic acid; (6R,7R)-7-Amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

^e This impurity is listed here for information only. It is not to be reported as an impurity in this test.

^f l-Cefadroxil; (6R,7R)-7-[(S)-2-Amino-2-(4-hydroxyphenyl)acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

^g Delta-3 cefadroxil; (6R,7R)-7-[(R)-2-Amino-2-(4-hydroxyphenyl)acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylic acid.

^h 3-(Aminomethylene)-6-(4-hydroxyphenyl)piperazine-2,5-dione.

ⁱ (6R,7R)-7-{(2R)-2-[2-Amino-2-(4-hydroxyphenyl)acetamido]-2-(4-hydroxyphenyl)acetamido}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylic acid.

^j (6R,7R)-7-[(R)-2-Amino-2-(4-hydroxyphenyl)acetamido]-3-ethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

^k (6R,7R)-7-{(2R)-2-[2-Amino-2-(4-hydroxyphenyl)acetamido]-2-(4-hydroxyphenyl)acetamido}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

^l 3-Hydroxy-4-methylthiophen-2(5H)-one.

^m (6R,7R)-7-(Ethoxycarbonylamino)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

ⁿ (6R,7R)-7-((R)-2-Amino-2-{4-[(ethoxycarbonyl)oxy]phenyl}acetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

^o (6R,7R)-7-[(R)-2-{(6R,7R)-7-[(R)-2-Amino-2-(4-hydroxyphenyl)acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxamido}-2-(4-hydroxyphenyl)acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

4.2 DIMETHYLANILINE 〈223〉: Meets the requirements

5 SPECIFIC TESTS

OPTICAL ROTATION, Specific Rotation 〈781S〉

Sample solution: 10 mg/mL in water

Acceptance criteria: +165.0° to +178.0°

CRYSTALLINITY 〈695〉: Meets the requirements

pH 〈791〉

Sample solution: 50 mg/mL suspension in water

Acceptance criteria: 4.0–6.0

WATER DETERMINATION, Method I 〈921〉: 4.2%–6.0%, except where it is labeled as being in the hemihydrate form it is between 2.4% and 4.5%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers.

LABELING: The hemihydrate form is so labeled.

USP REFERENCE STANDARDS 〈11〉

USP Cefadroxil RS

USP Cefadroxil Related Compound D RS

(6R,7R)-7-[(S)-2-Amino-2-(4-hydroxyphenyl)acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

C₁₆H₁₇N₃O₅S 363.39

USP Cefadroxil Related Compound I RS

(6R,7R)-7-[(R)-2-Amino-2-(4-hydroxyphenyl)acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylic acid.

C₁₆H₁₇N₃O₅S 363.39

USP Cefadroxil System Suitability Mixture RS

This is a mixture of cefadroxil and O-ethoxycarbonyl cefadroxil [(6R,7R)-7-((R)-2-Amino-2-{4-[(ethoxycarbonyl)oxy]phenyl}acetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid].

C₁₉H₂₁N₃O₇S 435.45