Clofazimine Chemical Properties

Melting point:

210-212°

Boiling point:

616.26°C (rough estimate)

Density 

1.1342 (rough estimate)

refractive index 

1.6300 (estimate)

storage temp. 

2-8°C

solubility 

Practically insoluble in water, soluble in methylene chloride, very slightly soluble in ethanol (96 per cent). It shows polymorphism (5.9).

pka

8.37; also reported as 8.51(at 25℃)

color 

Yellow to Amber to Dark red

Water Solubility 

10mg/L(temperature not stated)

Merck 

14,2373

BCS Class

4/3

Safety Information

Hazard Codes 

Xn,Xi

Risk Statements 

22-36/37/38

Safety Statements 

36-26

WGK Germany 

3

RTECS 

SG1578000

HS Code 

35040000

Toxicity

LD50 orally in mice, rats, and guinea pigs: >4 g/kg (Stenger)

MSDS

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Clofazimine Usage And Synthesis

Chemical Properties

Red Solid

Uses

antiinflammatory, glucocorticoid

Uses

Antibacterial (tuberculostatic, leprostatic).

Definition

ChEBI: 3-Isopropylimino-3,5-dihydro-phenazine in which the hydrogen at position 5 is substituted substituted by a 4-chlorophenyl group, and that at position 2 is substituted by a (4-chlorophenyl)amino group. A dark red crystalline solid, clofazimine is an antimyc bacterial and is one of the main drugs used for the treatment of multi-bacillary leprosy. However, it can cause red/brown discolouration of the skin, so other treatments are often preferred in light-skinned patients.

Indications

Clofazimine is a weakly bactericidal dye that has some activity against M. leprae. Its precise mechanism of action is unknown but may involve mycobacterial DNA binding. Its oral absorption is quite variable, with 9 to 70% of the drug eliminated in the feces. Clofazimine achieves significant concentrations in tissues, including the phagocytic cells; it has a plasma half-life of 70 days. It is primarily excreted in bile, with less than 1% excretion in urine.

brand name

Lamprene (Novartis).

Antimicrobial activity

The mode of action is not fully understood. It has bacteristatic and weak bactericidal activity against several species of mycobacteria and some species of Actinomyces and Nocardia. In-vitro minimum inhibitory concentrations (MICs) are: M. tuberculosis 0.5 mg/L and M. leprae (assayed in a mouse model) 0.1–1 mg/L, but these MICs have limited clinical relevance as clofazimine shows marked differences in accumulation in various tissues. Activity against M. leprae is demonstrable in humans only after 50 days of therapy. Clofazimine resistance, although reported, appears to be rare.

Pharmaceutical Applications

One of a number of substituted iminophenazine dyes originally synthesized as potential antituberculosis agents. It is almost insoluble in water. It stimulates various phagocyte functions including release of free oxygen radicals, but it is not clear whether this contributes to its antimicrobial activity. It also has anti-inflammatory properties, attributed to its ability to inhibit certain patterns of intracellular T-cell receptor- mediated signaling, making it a useful drug for treating leprosy reactions and possibly other autoimmune processes.

Pharmacokinetics

Clofazimine is well absorbed by the intestine and is taken up by adipose tissue and cells of the macrophage/monocyte series, including those in the intestinal wall. It has a very long half-life (variously estimated as 10–70 days) and is eliminated, mostly unchanged, in the urine and feces.

Pharmacology

Clofazimine is a substituted iminophenazine that was first proposed for treating leprosy in 1962; however, it entered into medical practice toward the end of the 1980s. The mechanisms of its action is not definitively known, although there is the assumption that it can inhibit the formation of matrixes with DNA, which leads to a delay in the growth of mycobacteria. Clofazimine exhibits a bactericidal effect between that of dapsone and rifampicin. Synonym of this drug is lamprene.

Clinical Use

Clofazimine is given to treat sulfone-resistant leprosy or to patients who are intolerant to sulfones. It also exerts an antiinflammatory effect and prevents erythema nodosum leprosum, which can interrupt treatment with dapsone.This is a major advantage of clofazimine over other antileprosy drugs. Ulcerative lesions caused by Mycobacterium ulcerans respond well to clofazimine. It also has some activity against M. tuberculosis and can be used as last resort therapy for the treatment of MDR tuberculosis.

Clinical Use

Clofazimine (Lamprene) is a basic red dye that exerts a slow bactericidal effect on M. leprae, the bacterium that causes leprosy. It occurs as a dark red crystalline solid that is insoluble in water. Clofazimine is used in the treatment of lepromatous leprosy, including dapsone-resistant forms of the disease. In addition to its antibacterial action, the drug appears to possess anti-inflammatory and immune-modulating effects that are of value in controlling neuritic complications and in suppressing erythema nodosum leprosum reactions associated with lepromatous leprosy. It is frequently used in combination with other drugs, such as dapsone or rifampin.The mechanisms of antibacterial and anti-inflammatory actions of clofazimine are not known. The drug is known to bind to nucleic acids and concentrate in reticuloendothelial tissue. It can also act as an electron acceptor and may interfere with electron transport processes. The oral absorption of clofazimine is estimated to be about 50%. It is a highly lipid-soluble drug that is distributed into lipoidal tissue and the reticuloendothelial system. Urinary excretion of unchanged drug and metabolites is negligible. Its half-life after repeated dosage is estimated to be about 70 days. Severe gastrointestinal intolerance to clofazimine is relatively common. Skin pigmentation, ichthyosis and dryness, rash, and pruritus also occur frequently. Clofazimine has also been used to treat skin lesions caused by Mycobacterium ulcerans.

Clinical Use

Multibacillary leprosy (in combination with other anti-leprosy drugs)
Erythema nodosum leprosum (anti-inflammatory activity)
Clofazimine has been suggested as a drug for treatment of MDR tuberculosis, although its efficacy is unproven. It has been used to treat M. ulcerans infection (Buruli ulcer) but with limited responses. Use in disease caused by mycobacteria of the M. avium complex is no longer recommended as more effective and less toxic alternative agents are available.

Side effects

Clofazimine is usually well tolerated, but some patients develop nausea, abdominal pain and diarrhea, relieved to some extent by taking the drug with a meal or glass of milk. Dose-related, reversible, skin discoloration is very common and is unacceptable to some patients. Discoloration of the hair, cornea, urine, sweat and tears also occurs. Infants born to mothers receiving clofazimine are reversibly pigmented at birth. Edema of the wall of the small intestine leading to subacute obstruction is a rare but serious complication of prolonged high-dose therapy for leprosy reactions. Deposition of clofazimine in lymph nodes may interfere with lymphatic drainage, occasionally manifesting as edema of the feet.

Side effects

The most disturbing adverse reaction to clofazimine is a red-brown discoloration of the skin, especially in light-skinned persons. A rare but serious adverse reaction is acute abdominal pain significant enough to warrant exploratory laparotomy or laparoscopy. Other infrequent side effects include splenic infarction, bowel obstruction, paralytic ileus, and upper GI bleeding.

Synthesis

Clofazimine, 2-(p-chloroanilino)-5-(p-chlorophenyl)-3,5-dihydro-3-(isopropylimino)-phenazine (34.2.6), is synthesized by oxidizing 2-(p-chloroanilino)aniline using a solution of iron (III) chloride in water, which leads to the formation of 2-(p-chloroanilino)-5-(p-chlorophenyl)-3,5-dihydro-3-iminophenazine (34.2.5). Upon reacting this with a primary amine, in particular isopropylamine, the hydrogen atom in the imine region of the molecule is formally replaced with an alkyl group of the introduced amino group (in this case with an isopropyl group), forming the desired drug?aclofazimine.

Veterinary Drugs and Treatments

In small animals, clofazimine is sometimes used as part of multidrug therapy against mycobacterial diseases, primarily leprosy-like or M. avium-related disease states.
In humans, clofazimine is used primarily as part of a multi-drug regimen in the treatment of all forms of leprosy (with rifampin and dapsone), or the treatment of Mycobacterium avium complex (MAC) (with at least two of the following agents: clarithromycin or azithromycin, rifampin or rifabutin, and ethambutol). It has also been used in some treatment regimens for Crohn’s disease, pyoderma gangrenosum, etc.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: increased risk of ventricular arrhythmias with bedaquiline.

Metabolism

Because of its lipophilic nature, clofazimine is mainly distributed to fatty tissue and reticuloendothelial cells, including macrophages. Clofazimine accumulates in the body and is largely excreted unchanged in the faeces, both as unabsorbed drug and via biliary excretion. About 1% of the dose is excreted in 24 hours in the urine as unchanged clofazimine and metabolites. A small amount of clofazimine is also excreted through sebaceous and sweat glands, and in sputum.

Purification Methods

Clofazimine recrystallises from acetone as dark red crystals. Its solubility in CHCl3 and EtOH is 7% and 0.1%, respectively,at room temperature. It is insoluble in H2O. It is antibacterial. [Barry et al. J Chem Soc 859 1958, Beilstein 25 III/IV 3033.]

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