Cefprozil

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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C₁₈H₁₉N₃O₅S · H O 407.44
5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[amino(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-(1-propenyl)-, monohydrate, [6R- [6α,7β(R*)]]-; 

(6R,7R)-7-[(R)-2-Amino-2-(p-hydroxyphenyl)acetamido]-8-oxo-3-propenyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohydrate CAS RN®: 121123-17-9. 

Anhydrous 389.43 CAS RN®: 92665-29-7. 

1 DEFINITION 

Cefprozil contains NLT 900 µg/mg and NMT 1050 µg/mg of cefprozil (C₁₈H₁₉N₃O₅S), calculated on the anhydrous basis.

2 IDENTIFICATION 

Change to read: 

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

B. The retention times of the cefprozil (Z)-isomer and cefprozil (E)-isomer peaks from the Sample solution correspond to those of the Standard solutions, as obtained in the Assay. 

3 ASSAY 

Procedure 

Buffer: 11.5 g/L of monobasic ammonium phosphate in water. Adjust, if necessary, with phosphoric acid to a pH of 4.4. Mobile phase: Acetonitrile and Buffer (100:900) 

System suitability solution: 0.125 mg/mL each of USP Cefprozil (Z)-Isomer RS and USP Cefprozil (E)-Isomer RS in water. Use this solution within 6 h. 

Standard solution 1: 0.25 mg/mL of USP Cefprozil (Z)-Isomer RS in water. Use this solution within 6 h. 

Standard solution 2: 0.025 mg/mL of USP Cefprozil (E)-Isomer RS in water. Use this solution within 6 h. 

Sample solution: 0.3 mg/mL of Cefprozil in water. Shake to dissolve. Use this solution within 6 h. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 280 nm 

Column: 4.6-mm × 30-cm; 5-µm packing L1 

Flow rate: 1 mL/min 

Injection volume: 10 µL 

System suitability 

Samples: System suitability solution and Standard solution 1 

[Note—The relative retention times for cefprozil (Z)-isomer and cefprozil (E)-isomer are about 0.7 and 1.0, respectively.] Suitability requirements 

Resolution: NLT 2.5 between cefprozil (Z)-isomer and cefprozil (E)-isomer, System suitability solution 

Tailing factor: 0.9–1.1, Standard solution 1 

Relative standard deviation: NMT 2.0%, Standard solution 1 

Samples: Standard solution 1, Standard solution 2, and Sample solution 

Result = (r_U/r_S) × (C_S /C_U) × P 

r_U = peak response of the cefprozil (Z)-isomer from the Sample solution 

r_S = peak response of the cefprozil (Z)-isomer from Standard solution 1 

C_S = concentration of USP Cefprozil (Z)-Isomer RS in Standard solution 1 (mg/mL) 

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

P = potency of the cefprozil (Z)-Isomer RS (μg/mg)

Calculate the amount (µg/mg) of cefprozil (Z)-isomer (C₁₈H₁₉N₃O₅S) in the portion of Cefprozil taken: 

r_U = peak response of the cefprozil (E)-isomer from the Sample solution 

r_S = peak response of the cefprozil (E)-isomer from Standard solution 1 

C_S = concentration of USP Cefprozil (E)-Isomer RS in Standard solution 1 (mg/mL) 

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

P = potency of the cefprozil (E)-Isomer RS (μg/mg)

Calculate the amount (µg/mg) of cefprozil (C₁₈H₁₉N₃O₅S) in the portion of Cefprozil taken by adding the values, in µg/mg, of the cefprozil (Z)-isomer and the cefprozil (E)-isomer. 

Acceptance criteria: 900–1050 µg/mg on the anhydrous basis 

4 IMPURITIES 

Organic Impurities, Procedure 1 

Use Organic Impurities, Procedure 1 when the impurity prole includes Z-cefprozil open ring, E-cefprozil open ring, and cefprozil related compound K. 

Solution A: 11.5 g/L of monobasic ammonium phosphate in water. Adjust, if necessary, with phosphoric acid or ammonium hydroxide to a pH of 4.4. 

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

Mobile phase: See Table 1. 

Table 1 

[Note—These gradient elution times are established on an HPLC system with a dwell volume of approximately 1.3 mL. The gradient elution times in Table 1 can be adjusted as necessary to achieve the separation described.] 

Standard stock solution: 0.25 mg/mL each of USP Cefprozil (Z)-Isomer RS, USP Amoxicillin Related Compound I RS, and USP Cefprozil Related Compound D RS in a mixture of 1 M hydrochloric acid and Solution A. Prepare the solution as follows. Dissolve USP Amoxicillin Related Compound I RS, USP Cefprozil (Z)-Isomer RS, and USP Cefprozil Related Compound D RS in 1 M hydrochloric acid, using 20% of the nal volume. Dilute with Solution A to volume. 

Sensitivity solution: 2.5 µg/mL each of cefprozil (Z)-isomer, amoxicillin related compound I, and cefprozil related compound D in Solution A from Standard stock solution. Store the solution at 4°, and use within 8 h. 

Standard solution: 50 µg/mL each of cefprozil (Z)-isomer, amoxicillin related compound I, and cefprozil related compound D in Solution A from the Standard stock solution. Store the solution at 4°, and use within 12 h. 

Sample solution: 5 mg/mL of Cefprozil in a mixture of 1 M hydrochloric acid and Solution A, prepared as follows. Dissolve the Cefprozil rst in 1 M hydrochloric acid using 4% of the nal volume, and then dilute with Solution A to volume. Store the solution at 4°, and use within 3 h. Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 230 nm 

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

Temperatures 

Autosampler: 4° 

Column: 40° 

Flow rate: 1 mL/min 

Injection volume: 10 µL 

System suitability 

Samples: Sensitivity solution and Standard solution 

[Note—USP Cefprozil Related Compound D RS contains the (Z)- and (E)-isomers of cefprozil related compound D. See Table 2 for relative retention times.] 

Suitability requirements 

Resolution: NLT 1.4 between the (E)-isomer of cefprozil related compound D and cefprozil (Z)-isomer, Standard solution

Relative standard deviation: NMT 10.0% for cefprozil, amoxicillin related compound I, and each isomer of cefprozil related compound D, Standard solution 

Signal-to-noise ratio: NLT 10 for cefprozil, amoxicillin related compound I, and each isomer of cefprozil related compound D, Sensitivity solution 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of amoxicillin related compound I in the portion of Cefprozil taken: 

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

r_U = peak response of amoxicillin related compound I from the Sample solution

r_S = peak response of amoxicillin related compound I from the Standard solution

C_S = concentration of USP Amoxicillin Related Compound I RS in the Standard solution (mg/mL)

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

P = potency of amoxicillin related compound I in USP Amoxicillin Related Compound I RS (mg/mg)

Calculate the percentage of cefprozil related compound D in the portion of Cefprozil taken: 

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

r_U = sum of the responses for cefprozil related compound D (Z)-isomer and cefprozil related compound D (E)-isomer from the Sample solution

r_S = peak response of cefprozil related compound D (Z)-isomer from the Standard solutionn

C_S = concentration of USP Cefprozil Related Compound D RS in the Standard solution (mg/mL)

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

P = potency of cefprozil related compound D (Z)-isomer in USP Cefprozil Related Compound D RS (mg/mg)

Calculate the percentage of each of the other impurities in the portion of Cefprozil taken: 

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

r_U = peak response of each impurity from the Sample solution

r_S = peak response of cefprozil from the Standard solution

C_S = concentration of USP Cefprozil (Z)-Isomer RS in the Standard solution (mg/mL)

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

P = potency of USP Cefprozil (Z)-Isomer RS (mg/mg)

Acceptance criteria: See Table 2. The reporting threshold is 0.05%. 

Table 2 

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

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

^c 7-Amino-3-propenylcephalosporanic acid (Z-isomer); (6R,7R)-7-Amino-8-oxo-3-[(Z)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid. 

^d The sum of the two isomers is reported. The limit for the sum is 0.3%. 

^e 7-Amino-3-propenylcephalosporanic acid (E-isomer); (6R,7R)-7-Amino-8-oxo-3-[(E)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid. 

^f (6R,7R)-7-[(R)-2-Amino-2-{4-[(R)-2-amino-2-(4-hydroxyphenyl)acetoxy]phenyl}acetamido]-8-oxo-3-[(Z)-prop-1-enyl]-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. 

^g(R)-2-{(R)-[(R)-2-Amino-2-(4-hydroxyphenyl)acetamido](carboxy)methyl}-5-[(Z)-prop-1-enyl]-3,6-dihydro-2H-1,3-thiazine-4-carboxylic acid. h N-Acyl cefprozil (Z-isomer); (6R,7R)-7-{(R)-2-[(R)-2-Amino-2-(4-hydroxyphenyl)acetamido]-2-(4-hydroxyphenyl)acetamido}-8-oxo-3-[(Z)- prop-1-enyl]-5-thia-1 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. 

ⁱ The sum of the two isomers is reported. The limit for the sum is 0.2%. 

^j N-Acyl cefprozil (E-isomer); (6R,7R)-7-{(R)-2-[(R)-2-Amino-2-(4-hydroxyphenyl)acetamido]-2-(4-hydroxyphenyl)acetamido}-8-oxo-3-[(E)- prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. 

^k(R)-2-{(R)-[(R)-2-Amino-2-(4-hydroxyphenyl)acetamido](carboxy)methyl}-5-[(E)-prop-1-enyl]-3,6-dihydro-2H-1,3-thiazine-4-carboxylic acid. l Hydroxyphenyldiketopiperazine lactone; 3-(5-Ethyl-7-oxo-2,4,5,7-tetrahydro-1H-furo[3,4-d][1,3]thiazin-2-yl)-6-(4-hydroxyphenyl)piperazine 2,5-dione. 

^m The system resolves four isomers of cefprozil related compound K. 

Organic Impurities, Procedure 2 

Use Organic Impurities, Procedure 2 when the impurity prole includes ethoxycarbonyl cefprozil, methoxycefadroxil, cefprozil delta-3 isomer, cefprozil amide, and cefprozil dimer. 

Solution A: 4 g/L of monobasic sodium phosphate adjusted with dilute phosphoric acid (1 in 10) to a pH of 4.2 ± 0.05 Solution B: Acetonitrile and Solution A (1:1) 

Mobile phase: See Table 3. 

Diluent: 0.85 g/L of monobasic potassium phosphate and 1.16 g/L of anhydrous dibasic sodium phosphate in water

System suitability stock solution: 0.15 mg/mL of USP Cefadroxil RS and 0.75 mg/mL of USP Cefprozil Related Compound D RS, prepared as follows. Dissolve USP Cefadroxil RS in Solution A, using 20% of the nal volume. Add USP Cefprozil Related Compound D RS, mix, and dilute with Diluent to volume. 

System suitability solution: 15 µg/mL of USP Cefadroxil RS and 75 µg/mL of USP Cefprozil Related Compound D RS from the System suitability stock solution and 1.5 mg/mL of USP Cefprozil RS in Solution A 

Standard solution: 15 µg/mL of USP Cefprozil RS in Solution A 

Sample solution: 1.5 mg/mL of Cefprozil in Solution A. Refrigerate the solution, and use within 1 h. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 220 nm 

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

Temperatures 

Autosampler: 4° 

Column: NMT 30° 

Flow rate: 1 mL/min 

Injection volume: 20 µL 

System suitability 

Samples: System suitability solution and Standard solution 

Suitability requirements 

Resolution: NLT 1.5 between the (Z)-isomer of cefprozil related compound D and cefadroxil; NLT 1.5 between cefadroxil and the (E)- isomer of cefprozil related compound D, System suitability solution 

Relative standard deviation: NMT 5.0% for the sum of the cefprozil (Z)-isomer and cefprozil (E)-isomer, Standard solution Analysis 

Samples: Standard solution and Sample solution 

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

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

r_U = peak response of each impurity from the Sample solution 

r_S = sum of the responses for cefprozil (Z)-isomer and cefprozil (E)-isomer from the Standard solution 

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

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

P = potency of USP Cefprozil RS (mg/mg) 

F = relative response factor (see Table 4) 

Acceptance criteria: See Table 4. The reporting threshold is 0.05%. 

a(R)-2-Amino-2-(4-hydroxyphenyl)acetic acid. 

b 7-Amino-3-propenylcephalosporanic acid (Z-isomer); (6R,7R)-7-Amino-8-oxo-3-[(Z)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid. 

c(6R,7R)-7-[(R)-2-Amino-2-(4-hydroxyphenyl)acetamido]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. d 7-Amino-3-propenylcephalosporanic acid (E-isomer); (6R,7R)-7-Amino-8-oxo-3-[(E)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid. 

e(6R,7R)-7-[(R)-2-Amino-2-(4-hydroxyphenyl)acetamido]-8-oxo-3-[(Z)-prop-1-en-1-yl]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylic acid. f N-Acyl cefprozil (Z-isomer); (6R,7R)-7-{(R)-2-[(R)-2-Amino-2-(4-hydroxyphenyl)acetamido]-2-(4-hydroxyphenyl)acetamido}-8-oxo-3-[(Z)- prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. 

g(R)-2-{(6R,7R)-7-[(R)-2-Amino-2-(4-hydroxyphenyl)acetamido]-8-oxo-3-[(Z)-prop-1-en-1-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxamido}-2-(4-hydroxyphenyl)acetic acid. 

h(6R,7R)-7-{(R)-2-Amino-2-[4-(ethoxycarbonyloxy)phenyl]acetamido}-8-oxo-3-[(Z)-prop-1-en-1-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid. 

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

5 SPECIFIC TESTS 

Crystallinity 〈695〉: Meets the requirements 

pH 〈791〉 

Sample solution: 5 mg/mL in water 

Acceptance criteria: 3.5–6.5 

Water Determination 〈921〉, Method I: 3.5%–6.5% 

Cefprozil (E)-Isomer Ratio 

Buffer, Mobile phase, System suitability solution, Standard solution 1, Standard solution 2, Sample solution, Chromatographic system, and System suitability: Proceed as directed in the Assay. 

Analysis 

Samples: Standard solution 1, Standard solution 2, and Sample solution 

Calculate the ratio of the cefprozil (E)-isomer to total cefprozil in the portion of Cefprozil taken: 

Result = E/(E + Z) 

E = amount of cefprozil (E)-isomer as determined in the Assay (µg/mg) 

Z = amount of cefprozil (Z)-isomer as determined in the Assay (µg/mg) 

Acceptance criteria: The ratio is 0.06–0.11. 

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in tight containers. 

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

USP Reference Standards 〈11〉 

USP Amoxicillin Related Compound I RS 

(R)-2-Amino-2-(4-hydroxyphenyl)acetic acid. 

C₆H₉N₂O₃ 167.16 

USP Cefadroxil RS 

USP Cefprozil RS 

USP Cefprozil (E)-Isomer RS 

USP Cefprozil (Z)-Isomer RS 

USP Cefprozil Related Compound D RS 

7-Amino-3-propenylcephalosporanic acid; 

(6R,7R)-7-Amino-8-oxo-3-[(Z)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. 

C₁₀H₁₂N₂O₃S 240.28