Cefdinir for Oral Suspension
DEFINITION
Cefdinir for Oral Suspension contains NLT 90.0% and NMT 110.0% of the labeled amount of cefdinir (C14H13N5O5S2). It may contain one or more suitable buffers, flavors, preservatives, stabilizing agents, sweeteners, and suspending agents.
IDENTIFICATION
Delete the following:
•  A. Thin-Layer Chromatographic Identification Test 201
Buffer:  Prepare as directed in the Assay.
Standard solution:  600 µg/mL of USP Cefdinir RS in methanol and Buffer (3:1)
Sample solution:  Transfer an equivalent to 125 mg of cefdinir, from reconstituted Oral Suspension, to a 100-mL volumetric flask, add 50 mL of Buffer, and dilute with methanol to volume. Pass a portion through a suitable filter of 0.45-µm pore size, transfer 5.0 mL of the filtrate to a 10-mL volumetric flask, and dilute with methanol to volume.
Adsorbent:  0.25-mm layer of chromatographic silica gel, preconditioned with n-hexane and tetradecane (95:5)
Application volume:  10 µL
Developing solvent system:  Methanol and water (4:1)
Visualization:  Short-wavelength UV
Analysis 
Samples:  Standard solution and Sample solution
Develop the chromatogram until the solvent front has moved about 15 cm. Remove the plate, and allow the solvent to evaporate.
Acceptance criteria:  The RF value of the principal spot from the Sample solution corresponds to that from the Standard solution.USP35
Change to read:
•  A.USP35 The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
ASSAY
•  Procedure
Buffer:  10.7 mg/mL of anhydrous dibasic sodium phosphate and 3.4 mg/mL of monobasic potassium phosphate in water. Adjust with phosphoric acid or sodium hydroxide to a pH of 7.0 ± 0.05 before final dilution.
Solution A:  7 mg/mL of citric acid monohydrate. Adjust with phosphoric acid to a pH of 2.0 ± 0.05.
Mobile phase:  Methanol, tetrahydrofuran, and Solution A (111:28:1000)
System suitability solution:  50 µg/mL of USP Cefdinir RS and 175 µg/mL of m-hydroxybenzoic acid in Buffer
Standard solution:  50 µg/mL of USP Cefdinir RS in Buffer
Sample solution:  Equivalent to 50 µg/mL of cefdinir, from constituted Cefdinir for Oral Suspension, in Buffer
Chromatographic system 
Mode:  LC
Detector:  UV 254 nm
Column:  3.9-mm × 15-cm; 4-µm packing L1
Flow rate:  1.4 mL/min
Injection size:  15 µL
System suitability 
Samples:  Standard solution and System suitability solution
Suitability requirements 
Resolution:  NLT 3.0 between cefdinir and m-hydroxybenzoic acid, System suitability solution
Tailing factor:  NMT 2.0 for cefdinir, System suitability solution
Relative standard deviation:  NMT 1.0% for cefdinir, Standard solution
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of cefdinir (C14H13N5O5S2) in the portion of Cefdinir for Oral Suspension taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response of cefdinir from the Sample solution
rS== peak response of cefdinir from the Standard solution
CS== concentration of the Standard solution (µg/mL)
CU== nominal concentration of cefdinir in the Sample solution (µg/mL)
Acceptance criteria:  90.0%–110.0%
PERFORMANCE TESTS
•  Dissolution 711
Medium:  0.05 M phosphate buffer pH 6.8; 900 mL
Apparatus 2:  50 rpm
Time:  30 min
Detector:  UV 290 nm
Standard solution:  0.14 mg/mL of USP Cefdinir RS in Medium
Sample solution:  Transfer 5 mL, by weight, of the reconstituted Cefdinir for Oral Suspension into the vessel. After the appropriate time, withdraw a portion of the solution under test, and pass through a suitable filter of 0.45-µm pore size. Dilute a portion of each filtered sample with Medium as necessary to obtain a solution having a concentration of about 0.14 mg/mL of cefdinir.
Blank:  Medium
Analysis: 
Determine the percentage of the labeled amount of cefdinir (C14H13N5O5S2) dissolved:
Result = (AU/AS) × [(CS × d × D × V)/W × L] × 100
AU== absorbance of the Sample solution
AS== absorbance of the Standard solution
CS== concentration of the Standard solution (mg/mL)
d== density of the Cefdinir for Oral Suspension (mg/mL)
D== dilution factor of the Sample solution (mL/mL)
V== volume of Medium, 900 mL
W== weight of Cefdinir for Oral Suspension taken (mg)
L== label claim (mg/mL)
Tolerances:  NLT 80% (Q) of the labeled amount of C14H13N5O5S2 is dissolved.
•  Uniformity of Dosage Units 905 (for solids packaged in single-unit containers): Meets the requirements
•  Deliverable Volume 698 (for solids packaged in single-unit containers): Meets the requirements
IMPURITIES
Change to read:
Organic Impurities 
•  Procedure
Solution A:  14.2 mg/mL of anhydrous dibasic sodium phosphate
Solution B:  13.6 mg/mL of monobasic potassium phosphate
Buffer:  Combine appropriate amounts of Solution A and Solution B (about 2:1) to obtain a solution with a pH of 7.0 ± 0.1.
Solution C:  Dilute tetramethylammonium hydroxide (10% aqueous) with water to obtain a 0.1% solution. Adjust with dilute phosphoric acid (1 in 10) to a pH of 5.5 ± 0.1.
Solution D:  37.2 mg/mL of edetate disodium
Solution E:  To 1000 mL of Solution C add 0.4 mL of Solution D.
Solution F:  Acetonitrile, methanol, Solution C, and Solution D (150:100:250:0.2)
Mobile phase:  See Table 1.
Table 1
Time
(min)
Solution E
(%)
Solution F
(%)
0 95 5
2 95 5
22 75 25
32 50 50
37 50 50
38 95 5
58 95 5
System suitability stock solution 1:  40 µg/mL of USP Cefdinir Related Compound A RS in Solution C
System suitability stock solution 2:  40 µg/mL of USP Cefdinir Related Compound B RS in Buffer
System suitability solution:  Transfer 37.5 mg of USP Cefdinir RS to a 25-mL volumetric flask. Add about 10 mL of Buffer. Add 5.0 mL each of System suitability stock solution 1 and System suitability stock solution 2, and dilute with Solution C to volume.
Standard stock solution:  750 µg/mL of USP Cefdinir RS in Buffer
Standard solution:  15 µg/mL of USP Cefdinir RS, from the Standard stock solution in Solution C
Sample solution:  Transfer a quantity equivalent to 150 mg of cefdinir from constituted Cefdinir for Oral Suspension to a 100-mL volumetric flask. Dissolve in 30 mL of Buffer, and dilute with Solution C to volume.
Chromatographic system 
Mode:  LC
Detector:  UV 254 nm
Column:  4.6-mm × 15-cm; 5-µm packing L1
Column temperature:  40
Autosampler temperature:  4
Flow rate:  1 mL/min
Injection size:  10 µL
System suitability 
Samples:  System suitability solution and Standard solution
Suitability requirements 
Resolution:  NLT 1.5 between cefdinir and the third peak for USP Cefdinir Related Compound A RS, System suitability solution
Tailing factor:  NMT 1.5 for cefdinir related compound B, System suitability solution
Relative standard deviation:  NMT 2.0% for the cefdinir peak response, Standard solution
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of each impurity in the portion of Cefdinir for Oral Suspension taken:
Result = (rU/rS) × (CS/CU) × 100/F
rU== peak response of each impurity from the Sample solution
rS== peak response of cefdinir from the Standard solution
CS== concentration of the Standard solution (mg/mL)
CU== nominal concentration of cefdinir in the Sample solution (mg/mL)
F== relative response factor (see Table 2)
Acceptance criteria:  See Table 2.
Table 2
Name Relative
Retention
Time
Relative
Response
Factor
Reporting
Threshold
(% Cefdinir)
Acceptance
Criteria,
NMT (%)
Thiazolylacetyl glycine oximea 0.10 1.1 0.1 0.5
Thiazolylacetyl glycine oxime acetalb 0.13 1.1 0.1 0.6
Cefdinir sulfoxidec 0.36 1.0 0.05 0.2
Cefdinir thiazine analogd 0.46 1.5 0.05 0.3
3-Methyl cefdinire 0.75 1.0 0.05 0.7
Cefdinir impurity 1f 0.77 1.0 0.05 0.2
Cefdinir related compound A (cefdinir open ring lactone a)g,h 0.85 1.5 0.1 3.3
Cefdinir related compound A (cefdinir open ring lactone b)g,h 0.94 1.5 0.1
Cefdinir related compound A (cefdinir open ring lactone c)g,h 1.11 1.5 0.1
Cefdinir related compound A (cefdinir open ring lactone d)g,h 1.14 1.5 0.1
7S-Cefdiniri 1.18 1.1 0.05 0.2
Cefdinir lactonej 1.23 1.2 0.05 0.8
Cefdinir related compound Bk 1.28 1.1 0.05 0.2
Cefdinir isoxazole analogl 1.37 1.4 0.05 0.5
Cefdinir impurity 2e 1.44 1.0 0.05 0.2
Cefdinir glyoxalic analogm 1.49 1.0 0.05 0.2
E-Cefdinirn 1.51 1.1 0.05 1.2
Cefdinir decarboxy open ring lactone ao,p 1.62 1.3 0.05 1.1
Cefdinir decarboxy open ring lactone bo,p 1.64 1.3 0.05
Cefdinir impurity 3e 1.82 1.0 0.05 0.2
Individual unidentified impurities 1.0 0.05 0.2
Total impurities 6.2
a  N-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetyl]glycine.
b  (Z)-2-(2-Aminothiazol-4-yl)-N-(2,2-dihydroxyethyl)-2-(hydroxyimino)acetamide.
c  (6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-5,8-dioxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
d  (R,Z)-2-{(R)-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido](carboxy)methyl}-5-ethylidene-5,6-dihydro-2H-1,3-thiazine-4-carboxylic acid.
e  (6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
f  Cefdinir impurity 1, cefdinir impurity 2, and cefdinir impurity 3 are unidentified impurities.
g  Cefdinir related compound A is a mixture of 4 isomers labeled cefdinir open ring lactones a, b, c, and d. The sum of the values is reported; the limit for the sum of the 4 isomers is 3.3%.
h  2(R)-2-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-2-[(2RS,5RS)-5-methyl-7-oxo-2,4,5,7-tetrahydro-1H-furo[3,4-d][1,3]thiazin-2-yl]acetic acid.
i  (6R,7S)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
j  (Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)-N-((3RS,5aR,6R)-3-methyl-1,7-dioxo-1,3,4,5a,6,7-hexahydroazeto[2,1-b]furo[3,4-d][1,3]thiazin-6-yl)acetamide.
k  (6R,7R)-7-[2-(2-Amino-4-thiazolyl)acetamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
l  (6R,7R)-7-(4-Hydroxyisoxazole-3-carboxamido)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
m  (6R,7R)-7-[2-(2-Aminothiazol-4-yl)-2-oxoacetamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
n  (6R,7R)-7-[(E)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
o  Cefdinir decarboxy open ring lactone is a mixture of 2 isomers labeled cefdinir decarboxy open ring lactone a and b. The sum of the values is reported; the limit for the sum of the 2 isomers is 1.1%.
p  (Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)-N-{[(2RS,5RS)-5-methyl-7-oxo-2,4,5,7-tetrahydro-1H-furo[3,4-d][1,3]thiazin-2-yl]methyl}acetamide.
USP35
SPECIFIC TESTS
•  pH 791: 3.5–4.5
Delete the following:
•  Loss on Drying 731: Dry about 1 g over phosphorous pentoxide in a vacuum not exceeding 5 mm of mercury at 70 for 4–4.5 h: it loses NMT 1.0% of its weight.USP35
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight, light-resistant containers, and store at controlled room temperature.
•  Labeling: The label specifies the directions for the constitution of the powder and states the equivalent amount of C14H13N5O5S2 in a given volume of Cefdinir for Oral Suspension after constitution.
•  USP Reference Standards 11
USP Cefdinir RS
USP Cefdinir Related Compound A RS Click to View Structure
(2R)-2-[(Z)-2-(2-Aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-2-[(2RS,5RS)-5-methyl-7-oxo-2,4,5,7-tetrahydro-1H-furo[3,4-d][1,3]thiazin-2-yl]acetic acid (three other stereoisomers are also present in this RS).
    C14H15N5O6S2        413.43
USP Cefdinir Related Compound B RS Click to View Structure
(6R,7R)-7-[2-(2-Amino-4-thiazolyl)acetamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo](4.2.0)]oct-2-ene-2-carboxylic acid.
    C14H13N4O4S2        365.41
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