Furosemide

COOH
O
NH CH2
O
NH2 S
ปรุฬห รุจนธํารงค
O Cl 4536585433
หทัยทิพย โชคสวัสดิ์ไพศาล
4536671733

1
Furosemide

COOH Empirical
O
NH CH2 C12H11ClN2O5S
O
NH2 S
Cl
Molecular weight
O 330.77

A white to slightly yellow, Elemental composition

odorless, almost tasteless C = 43.57%, H = 3.35%
crystalline powder Cl = 10.72%, N = 8.47%
O = 24.19%, S = 9.70%

2
Nomenclature

COOH
O
NH CH2
O
NH2 S
Cl
O Furosemide

5-(Aminosulfonyl)-4-chloro-2-((2-furanyl-methyl)amino)benzoic acid
4-chloro-N-furfuryl-5-sulfamoyl-anthranilic acid
4-chloro-N-(2-furylmethyl-5-sulfamoyl)anthranilic acid
4-chloro-2-furylamino-5-sulphamoyl benzoic acid

3
Physical Properties
COOH
O
NH CH2
O
NH2 S
O Cl

Melting point 206 OC

Solubility
Slightly soluble: water (10.26 mg/100 ml)1, chloroform, ether
Soluble: acetone, methanol, dimethyl formamide,
alkalide hydroxides solution

pH pH of aqueous solutions is in between 8.9 – 9.3

1Journal of Inclusion Phenomena and Molecular Recognition in Chemistry 31 (1998): 189–196 4

Physical Properties
Stability Very unstable in acidic media
Very stable in basic media
Percentage of furosemide retained in various aqueous solution after 30 days (21 days for
sugar solutions)
Solution containing Initial pH Final pH Percent retained
10% sugar 8.5 4.9 82.3
20% sugar 8.1 4.3 60.5
30% sugar 8.2 4.3 55.5
50% sugar 7.9 4.0 43.9
60% sugar 7.8 4.0 44.1
70% sugar 7.7 3.9 40.3
85% sugar 7.6 3.9 40.3
Phosphate buffer 5.0 - 88.6
Phosphate buffer 4.8 - 76.8
Phosphate buffer 4.65 - 72.1
Phosphate buffer 4.55 - 67.1
Acetate 4.2 - 11.5
Hydrochloric acid 1.2 - 0.0
Sodium hydoxide 13 - 99.5 5
Stability of furosemide in aqueous systems. Journal of pharmaceutical science. 67(1978): 808 - 811
Physical Properties
Percentage of furosemide retained in various aqueous solution
after 30 days (21 days for sugar solutions)

Percent retained after

Stored at
solution pH
(±1OC) 21 30 61 120 155 182
Days Days Days Days Days Days
50% glycerin 5.7 65OC 78.9 (4.6)a - - - - -
70% sorbitol 6.8 65OC 88.4 (5.7) - - - - -
50% sorbitol 8.5b 65OC 81.7 (4.9) - - - - -
50% sorbitol with 20% alcohol 8.5b 65OC 93.3 (4.7) - 77.4 (4.7) - - -
50% sorbitol with 20% alcohol 8.5b 24OC 99.5 (7.1) - 99.0 (6.1) - - -
50% sorbitol with 10% alcohol 8.5b 65OC 90.8 (4.6) - 81.1 (4.8) 21.7 (4.0) 10.4 (3.9) 0 (3.9)
50% sorbitol with 10% alcohol 8.5b 24OC 99.3 (4.6) 78.9 (4.6) - 97.5c (5.8) 99.2 (5.6) 99.3 (5.5)

aObserved pH
b The pH was adjusted with 0.1 N NaOH solution in water.
cIt appears that there is an error in this reading

6
Stability of furosemide in aqueous systems. Journal of pharmaceutical science. 67(1978): 808 - 811
Physical Properties
COOH
O
NH CH2
O
NH2 S H2O
O Cl

furosemide
O
COOH OH CH2
NH2
O
Furfuryl alcohol
NH2 S Other decomposition products

O Cl

4-chloro-5-sulfamoylanthranilic acid CH3COCH2CH2COOH

Levulinic acid

7
Stability of furosemide in aqueous systems. Journal of pharmaceutical science. 67(1978): 808 - 811
Physical Properties
O
Cl NH CH2
O
S COOH
H2N O Furosemide

O O
HOOC S
NH2
O CH2 NH OH O
HO NH CH2
O
S COOH
H2N O
Photoproduct of furosemide
8
Environ Chem Lett (2004) 2:155–158
Physical Properties

ตัวอยางรูปแบบยาฉีด ตัวอยางรูปแบบยาเม็ด

9
http://www.mimsonline.com/mimsonline/index.aspx?dcname=Th
Physical Properties

β-CD = β-cyclodextrin
DIMEB = dimethyl-β-cyclodextrin
HP-β-CD = dimethyl-β-cyclodextrin
RAMEB = random-methylated-β-cyclodextrin

Journal of Inclusion Phenomena and Molecular Recognition in Chemistry 31 (1998): 189–196 10

Physical Properties

β-CD = β-cyclodextrin The -β-cyclodextrin derivatives strongly

DIMEB = dimethyl-β-cyclodextrin influenced the solubility of furosemide,
HP-β-CD = dimethyl-β-cyclodextrin the solubility increasing in the sequence
RAMEB = random-methylated-β-cyclodextrin
β-CD < HP- β-CD < RAMEB < DIMEB

Journal of Inclusion Phenomena and Molecular Recognition in Chemistry 31 (1998): 189–196 11

Synthesis – Route 1
O
O
Cl S O CH3 + H2 N CH2
O O DMF Furfurylamine

S COCH3 Heated for 1 hr at 120OC

H2N O
2-(p-tolylsulfonyloxy)-4-chloro-5-sulfamoylbenzoate ester
O
Cl NH CH2
O
S COCH3
H2N O
NaOH
1.5 hr at 100OC

O
Cl NH CH2
O Furosemide
S COOH
H2N O
12
Synthesis – Route 2
O
Cl Cl + H2 N CH2
O Furfurylamine

S COOH
H2N O
2, 4-dichloro-5-sulfamoyl benzoic acid

10% HCl

O
Cl NH CH2
O Furosemide
S COOH
H2N O
13
Synthesis – Route 3
O
Cl Cl + H2 N CH2
O Furfurylamine

S COOH
H2N O
2, 4-dichloro-5-sulfamoyl benzoic acid

MeONa

O
Cl NH CH2
O Furosemide
S COOH
H2N O
14
Synthesis – Route 4
O
Cl NH2 + HO CH2
O Furfuryl alcohol

S COOH
H2N O
5-sulfamyl-4-chloro-2-amino benzoic acid

acid hydrolysis

Cl N
O N
S S
H2N OO O O
Cl NH CH2
Chlorothiazide

O Furosemide
S COOH
H2N O
15
Synthesis – Route 5
Raney Cu in MeO(CH2)2OMe
Cl Cl at 140OC

O + O Cl
O
CH2 NH CH2
S COOH HN
H2N O O
2, 4-dichloro-5-sulfamoyl benzoic acid N-Furfurylaniline
S COOH
H2N O
0OC NaNO2

NO
O
Cl NH CH2 Reflux in NaOH O
Cl NH CH2
O
S O
COOH S
H2N O COOH
Furosemide
H2N O
16
Synthesis – Route 6
O
Cl NH CH2
O
S CN
H2N O

Aqueous NaOH
at 75OC 4 hours

O
Cl NH CH2
O
S COOH
H2N O
Furosemide

17
Synthesis – Route 7
O
Cl NH2 + HO CH2
O Furfuryl alcohol

S COOCH3
H2N O
2-amino-4-chloro-5-sulfamoyl benzoate ester

Refluxing for 2 hrs

O
Cl NH CH2
O Furosemide
S COOH
H2N O
18
Synthesis – Route 8
O
Cl F + H2 N CH2
O Furfurylamine

S CN
H2N O HCON(CH3)2 at 20OC
3-sulfamoyl-4-chloro-6-cyanobenzene

O
Cl NH CH2
O
S CN
H2N O
2 hrs Reflux in 2N NaOH + Dioxane

O
Cl NH CH2
O Furosemide
S COOH
H2N O
19
Synthesis – Route 9
O
Cl F + HO CH2
O Furfuryl alcohol

S COOCH3
H2N O
3-sulfamoyl-4-chloro-6-fluorobenzoic acid

95OC 3 hrs

O
Cl NH CH2
O Furosemide
S COOH
H2N O
20
Synthesis – Route 10
O
Cl NH2 + H2 N CH2
O Furfuryl amine

S COOCH3 100OC stirring for 1 hour

H2N O
3-sulfamoyl-4,6-dichrolo benzoate ester
O
Cl NH CH2
O
S COOCH3
H2N O

5N KOH

O
Cl NH CH2
O Furosemide
S COOH
H2N O
21
Synthesis – Route 11
O
Cl NH2
C5H5N + (CH3CO)2O
Cl NH C CH3
O In steam bath
S COOH O
H2N O S
5-sulfamyl-4-chloro-2-amino benzoic acid COOH
HN O
3-acetylsulfamoyl-4-chloro-6-acetyl amino benzoic acid

C O
CH3

NaOH

Cl NH2
O
O + H2 N CH2
S COOH Furfuryl amine
HN O
C O 3-acetylsulfomyl-4-chloro-6-amino benzoic acid

CH3 22
Synthesis – Route 11
Stirring at 75OC for ½ hr

O
Cl NH CH2
O
S COOH
HN O
C O 3-acetylsulfomyl-4-chloro-6-furfuryl amino benzoic acid

CH3
Reflux for 2 hrs

O
Cl NH CH2
O Furosemide
S COOH
H2N O

23
Impurities O
O Cl NH CH2
CH2 NH Cl O
S COOH
Furosemide
O H2N O
S COOH
H2N O
2-chloro-4-(furfurylamino)-5-sulphamoylbenzoic acid
Cl NH2 Cl Cl

O O
S S COOH
COOH H2N O
H2N O
2-amino-4-chloro-5-sulphamoylbenzoic acid 2,4-dichloro-5-sulphamoylbenzoic acid
Cl Cl
O O
CH2 NH NH CH2
COOH
O
S 2,4-dichloro-benzoic acid
COOH
H2N O
2,4-bis(furfurylamino)-5-sulphamoylbenzoic acid
24
European Pharmacopoeia 5th ed. Vol.2. p1644-1645
Drug allergy
N4 site where reactive
metabolites responsible for
NH2 allergic reactions re formed
O
S
R HN O
O
Cl NH CH2
O
R=H Sulfanilamide S COOH
H2N O
Furosemide
R= CH3
Sulfamethoxazole
N O

Comparison of arylamine versus non-arylamine sulfonamide medications

Ann Pharmacother.2006; 40: 128-134 25

References
Abdulrahman M. Al-Obaid et al. Analytical profiles of furosemide.p 154-193.Analytical profiles of drug
substances. Klaus Florey (editor). New York : Academic Press, 1989

R. M. AMIN KREAZ1, GY. DOMBI2 and M. KATA. The Influence of -Cyclodextrins on the Solubility of
Furosemide. Journal of Inclusion Phenomena and Molecular Recognition in Chemistry (1998) 31:
189–196.

Greca MD et al.A new photoproduct of the drug furosemide in aqueous media. Environ Chem Lett
(2004) 2:155–158

Ghanekar AG, Gupta VD, Gibbs CW. Stability of furosemide in aqueous systems. Journal of
Pharmaceutical Sciences. 67(1978): 808 - 811

MIMS Thailand 3/2006. http://www.mimsonline.com/mimsonline/index.aspx?dcname=Th

Council of Europe (Partial Agreement) European Pharmacopoeia 5th ed. Vol.2. Strabourg: Council of
Europe, 2005 p1644-1645

Juang et al. Probable Loop Diuretic–Induced Pancreatitis in a Sulfonamide-Allergic Patient. Ann

Pharmacother.2006; 40: 128-134

26