Famotidine
(fam oh' ti deen).
Click to View Image

C8H15N7O2S3 337.45
Propanimidamide, N'-(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]-;    
[1-Amino-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propylidene]sulfamide;    
3-[[2-(Diaminomethyleneamino)thiazol-4-yl]methylthio]-N¢-sulfamoylpropanimidamide     [76824-35-6].
DEFINITION
Famotidine contains NLT 98.5% and NMT 101.0% of famotidine (C8H15N7O2S3), calculated on the dried basis.
IDENTIFICATION
•  A. Infrared Absorption 197
[Note—Methods described in Infrared Absorption 197K, 197M, or 197A may be used. ]
ASSAY
•  Procedure
Sample:  Dissolve 250 mg of Famotidine in 80 mL of glacial acetic acid.
Analysis:  Titrate with 0.1 N perchloric acid VS (see Titrimetry 541), using a suitable anhydrous electrode system. Perform a blank determination, and make any necessary correction. Each mL of 0.1 N perchloric acid is equivalent to 16.87 mg of C8H15N7O2S3.
Acceptance criteria:  98.5%–101.0% on the dried basis
IMPURITIES
•  Residue on Ignition 281: NMT 0.1%
Delete the following:
•  Heavy Metals, Method II 231: NMT 10 ppm(Official 1-Dec-2015)
•  Organic Impurities
Buffer:  1.882 g/L of sodium 1-hexanesulfonate in water, adjusted with acetic acid to a pH of 3.5
Solution A:  Acetonitrile, methanol, and Buffer (94:6:900)
Solution B:  Acetonitrile
Mobile phase:  See Table 1. [Note—If necessary, adjust the Mobile phase to achieve a retention time of 19–23 min for the famotidine peak and a maximum of 48 min for the famotidine related compound E peak. ]
Table 1
Time
(min)		 Solution A
(%)		 Solution B
(%)		 Flow Rate
(mL/min)
0 100 0 1
23 96 4 1
27 96 4 2
47 78 22 2
48 100 0 2
54 100 0 1
Standard stock solution:  0.5 mg/mL of USP Famotidine RS in Solution A
Standard solution:  0.5 µg/mL of USP Famotidine RS in Solution A
System suitability stock solution:  0.25 mg/mL of USP Famotidine Related Compound D RS in methanol
System suitability solution:  Transfer 1 mL of the System suitability stock solution and 0.5 mL of the Standard stock solution into a 100-mL volumetric flask, and dilute with Solution A to volume.
Sample solution:  0.5 mg/mL of Famotidine in Solution A
Identification solution:  0.5 mg/mL of USP Famotidine RS and 1.5 µg/mL of each of USP Famotidine Related Compound B RS, USP Famotidine Related Compound C RS, USP Famotidine Related Compound D RS, USP Famotidine Related Compound E RS, and USP Famotidine Related Compound F RS in Solution A
[Note—To address the poor solubility of USP Famotidine Related Compound F RS in Solution A, it may be first dissolved in a minimal amount of 0.1 N sodium hydroxide. ]
Chromatographic system 
(See Chromatography 621, System Suitability.)
Mode:  LC
Detector:  UV 265 nm
Column:  4.6-mm × 25-cm; 5-µm packing L1
Column temperature:  50
Flow rate:  See Table 1.
Injection volume:  20 µL
System suitability 
Sample:  System suitability solution
Suitability requirements 
Resolution:  NLT 3.5 between famotidine and famotidine related compound D
Analysis 
Samples:  Standard solution, Sample solution, and Identification solution
Chromatograph the Identification solution, and identify the components on the basis of their relative retention times, given in Table 2.
Calculate the percentage of each impurity in the portion of Famotidine taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100

rU== peak response of each impurity from the Sample solution
rS== peak response of famotidine from the Standard solution
CS== concentration of USP Famotidine RS in the Standard solution (mg/mL)
CU== concentration of Famotidine 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		 Acceptance
Criteria,
NMT (%)
Famotidine 1.0 — —
Famotidine related compound Da 1.1 1.0 0.3
Famotidine related compound Cb 1.2 0.53 0.3
Famotidine cyanoamidinec 1.4 0.71 0.2
Famotidine related compound Fd 1.5 0.59 0.1
Famotidine amidinee 1.6 0.53 0.2
Famotidine related compound Bf 2.0 0.40 0.3
Famotidine related compound Eg 2.1 1.0 0.3
Any other individual impurity — 1.0 0.1
Total impurities — — 1.0
a  Famotidine propanamide.
b  Famotidine sulfamoyl propanamide.
c  N-Cyano-3-[[2-(diaminomethyleneamino)thiazol-4-yl]methylthio]propanimidamide.
d  Famotidine propionic acid.
e  3-[[2-(Diaminomethyleneamino)thiazol-4-yl]methylthio]propanimidamide.
f  Famotidine dimer.
g  Famotidine disulfide.
SPECIFIC TESTS
•  Loss on Drying 731
Analysis:  Dry a sample at a pressure not exceeding 5 mm of mercury at 80 for 5 h.
Acceptance criteria:  NMT 0.5%
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in well-closed containers, protected from light. Store at room temperature.
•  USP Reference Standards 11
USP Famotidine RS Click to View Structure
USP Famotidine Related Compound B RS Click to View Structure
3,5-Bis[2-[[2-[(diaminomethylene)amino]thiazol-4-yl]methylthio]ethyl]-4H-1,2,4,6-thiatriazine 1,1-dioxide.
    C16H23N11O2S5         561.73
USP Famotidine Related Compound C RS Click to View Structure
3-[[2-(Diaminomethyleneamino)thiazol-4-yl]methylthio]-N-sulfamoylpropanamide hydrochloride.
    C8H15ClN6O3S3         374.88
USP Famotidine Related Compound D RS Click to View Structure
3-[[2-(Diaminomethyleneamino)thiazol-4-yl]methylthio]propanamide.
    C8H13N5OS2         259.35
USP Famotidine Related Compound E RS Click to View Structure
2,2¢-[4,4¢-Disulfanediylbis(methylene)bis(thiazole-4,2-diyl)]diguanidine.
    C10H14N8S4         374.53
USP Famotidine Related Compound F RS Click to View Structure
3-[[2-(Diaminomethyleneamino)thiazol-4-yl]methylthio]propanoic acid.
    C8H12N4O2S2         260.34
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Topic/Question Contact Expert Committee
Monograph Elena Gonikberg, Ph.D.
Director - Chemical Medicines
(301) 816-8251		 (SM32010) Monographs - Small Molecules 3
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USP38–NF33 Page 3437
Pharmacopeial Forum: Volume No. 39(1)