Cyclophosphamide

Cyclophosphamide Properties

Melting point	41-45°C
Boiling point	336.1±52.0 °C(Predicted)
Density	1.33±0.1 g/cm3(Predicted)
storage temp.	Keep in dark place,Inert atmosphere,Store in freezer, under -20°C
solubility	≥11.85 mg/mL in H2O with gentle warming and ultrasonic; ≥13.05 mg/mL in DMSO; ≥50.8 mg/mL in EtOH
form	solid
pka	2.84±0.20(Predicted)
color	White to off-white
Water Solubility	Soluble. 1-5 g/100 mL at 23 ºC
BCS Class	1,3
Stability	Stable, but light sensitive. Incompatible with oxidizing agents.
CAS DataBase Reference	50-18-0(CAS DataBase Reference)
IARC	1 (Vol. 26, Sup 7, 100A) 2012
NIST Chemistry Reference	2-[Bis(2-chloroethylamino)]-tetrahydro-2h-1,3,2-oxazaphosphorine-2-oxide(50-18-0)
EPA Substance Registry System	Cyclophosphamide (50-18-0)

SAFETY

Risk and Safety Statements

Symbol(GHS)	GHS08,GHS06
Signal word	Danger
Hazard statements	H301-H360-H340-H350
Precautionary statements	P264-P270-P301+P310-P321-P330-P405-P501
Safety Statements	22-24/25
RIDADR	UN 1851
HazardClass	6.1(b)
PackingGroup	III
Toxicity	LD50 oral in rat: 100mg/kg

Cyclophosphamide Chemical Properties,Uses,Production

Chemical Properties

Endoxan is a white crystalline powder (monohydrate). It may be used or shipped in solution. Darkens on exposure to light. Odorless

Uses

Cyclophosphamide USP is used to treat acute and chronic lymphocytic leukemia; lung cancer; rhabdomyosarcoma; neuroblastoma; ovarian and mammary carcinoma; multiple myeloma; lymphosarcoma; Burkitt’s lymphoma; Hodgkin’s disease; retinoblastoma; mycosis fungoides

Indications

Cyclophosphamide (Cytoxan) is the most versatile and useful of the nitrogen mustards. Preclinical testing showed it to have a favorable therapeutic index and to possess the broadest spectrum of antitumor activity of all alkylating agents. As with the other nitrogen mustards, cyclophosphamide administration results in the formation of cross-links within DNA due to a reaction of the two chloroethyl moieties of cyclophosphamide with adjacent nucleotide bases. Cyclophosphamide must be activated metabolically by microsomal enzymes of the cytochrome P450 system before ionization of the chloride atoms and formation of the cyclic ethylenimmonium ion can occur. The metabolites phosphoramide mustard and acrolein are thought to be the ultimate active cytotoxic moiety derived from cyclophosphamide.

Definition

ChEBI: Cyclophosphamide is a phosphorodiamide that is 1,3,2-oxazaphosphinan-2-amine 2-oxide substituted by two 2-chloroethyl groups at the amino nitrogen atom. It is an alkylating agent used in the treatment of several forms of cancer including leukemias, lymphomas and breast cancer.

General Description

Cyclophosphamide is a fine white crystalline powder. Odorless with a slightly bitter taste. Melting point 41-45 °C. A 2% solution has pH of 4 to 6. Used medicinally as an antineoplastic agent.

Air & Water Reactions

Water soluble.

Reactivity Profile

Cyclophosphamide is sensitive to exposure to light (darkens). Also sensitive to oxidation. Aqueous solutions may be kept for a few hours at room temperature, but hydrolysis occurs at temperatures above 86°F. Solutions in DMSO, 95% ethanol or acetone are stable for 24 hours under normal lab conditions. Incompatible with benzyl alcohol. Undergoes both acid and base hydrolysis at extreme pHs

Fire Hazard

Flash point data for Cyclophosphamide are not available; however, Cyclophosphamide is probably combustible.

Mechanism of action

Cyclophosphamide can be given orally, intramuscularly, or intravenously. The plasma half-life of intact cyclophosphamide is 6.5 hours.Only 10 to 15% of the circulating parent drug is protein bound, whereas 50% of the alkylating metabolites are bound to plasma proteins. Since cyclophosphamide and its metabolites are eliminated primarily by the kidneys, renal failure will greatly prolong their retention.
Cyclophosphamide has a wide spectrum of antitumor activity. In lymphomas, it is frequently used in combination with vincristine and prednisone (CVP [or COP] regimen) or as a substitute for mechlorethamine in the MOPP regimen (C-MOPP). High dosages of intravenously administered cyclophosphamide are often curative in Burkitt’s lymphoma, a childhood malignancy with a very fast growth rate.Oral daily dosages are useful for less aggressive tumors, such as nodular lymphomas, myeloma, and chronic leukemias.

Pharmacology

Besides being used as an alkylating agent in cancer chemotherapy, cyclophosphamide is a unique drug when used as an immunosuppressant. First, it is the most powerful of all such drugs. Second, it kills proliferating cells, and evidently alkylates a certain region of remaining cells. Finally, its action on T-cells is such that despite its overall suppressive effect, it can, in certain environments, suppress the response of these cells to antigens.
Cyclophosphamide is successfully used for bone transplants. In small doses, it is effective for autoimmune disorders.

Pharmacokinetics

The drug is metabolized in the liver and is eliminated via the kidney, with approximately 15% of a given dose being excreted unchanged. Doses should be reduced in patients with levels of creatinine clearance less than 30 mL/min. Interestingly, hepatic dysfunction does not seem to alter metabolism of this drug, but caution should be exercised in patients with inhibited cytochrome P450 (CYP450) enzymes or with a combination of factors that could negatively impact drug activation/inactivation pathways.

Clinical Use

Cyclophosphamide is a component of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) and other drug combinations used in the treatment of breast cancer. Cyclophosphamide in combination may produce complete remissions in some patients with ovarian cancer and oat cell (small cell) lung cancer. Other tumors in which beneficial results have been reported include non–oat cell lung cancers, various sarcomas, neuroblastoma, and carcinomas of the testes, cervix, and bladder. Cyclophosphamide also can be employed as an alternative to azathioprine in suppressing immunological rejection of transplant organs.

Side effects

Chloroacetaldehyde toxicity is accompanied by glutathione depletion, indicating that, as expected, this electrophilic by-product alkylates Cys residues of critical cell proteins. Alkylation of Lys, adenosine, and cytidine residues also is possible. The CYP-generated carbinolamine undergoes nonenzymatic hydrolysis to provide the aldophosphamide either in the bloodstream or inside the cell. If this hydrolysis occurs extracellularly, the aldophosphamide is still able to penetrate cell membranes to reach the intracellular space. Once inside the cell, acrolein (a highly reactive α,β-unsaturated aldehyde) splits off, generating phosphoramide mustard. With a pKa of 4.75, the mustard will be persistently anionic at intracellular pH and trapped inside the cell.

Safety Profile

Confirmed human carcinogen producing leukemia, Hodgkin's dsease, gastrointestinal and bladder tumors. Experimental carcinogenic, neoplas tigenic, and teratogenic data. A human poison by ingestion and many other routes. Human systemic effects: hdney changes (hepatic dysfunction), leukopenia (reduced white blood cell count), nausea and alopecia (loss of hair), liver changes, agranulocytosis. Human reproductive and teratogenic effects by multiple routes: spermatogenesis, testicular changes, epiddymis and sperm duct changes, menstrual cycle changes, fetal developmental abnormahties of the craniofacial area, musculoskeletal and cardiovascular systems. Experimental reproductive effects. Human mutation data reported. A powerful skin irritant. Used as an immunosuppressive agent in nonmalignant diseases. When heated to decomposition it emits hghly toxic fumes of PO,, NOx, and Cl-.

Potential Exposure

Exodan is used as an immunosuppressive agent in nonmalignant diseases; treatment of malignant lymphoma, multiple meyloma; leukemias, and other malignant diseases. Exodan has been tested as an insect chemosterilant and for use in the chemical shearing of sheep. Exodan is not produced in the United States.; manufactured in Germany and imported into the United States since1959. The FDA estimates that 200,000300,000 patients per year are treated with exodan. It is administered orally and through injection. The adult dosage is usually 15 mg/kg of body weight daily or 1015 mg/kg administered intravenous every 710 days

Carcinogenicity

Cyclophosphamide is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.

Metabolism

The initial metabolic step is mediated primarily by CYP2B6 (and, to a much lower extent, by CYP3A4) and involves hydroxylation of the oxazaphosphorine ring to generate a carbinolamine. This hydroxylation reaction must occur before the molecule will be transported into cells. CYP3A4 (but not CYP2B6) also catalyzes an inactivating N-dechloroethylation reaction, which yields highly nephrotoxic and neurotoxic chloroacetaldehyde.

Shipping

UN3464 Organophosphorus compound, solid, toxic, n.o.s, Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials. UN1851 Medicine, liquid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials

Incompatibilities

Should be protected from exposure to temperatures above 30°C/86°F.

Waste Disposal

Consult with environmental regulatory agencies for guidance on acceptable disposal practices. Generators of waste containing this contaminant (≥100 kg/mo) must conform with EPA regulations governing storage, transportation, treatment, and waste disposal

Cyclophosphamide Preparation Products And Raw materials

Raw materials

3-Aminopropanol Triethylamine

Preparation Products

Cyclophosphamide Suppliers

Global( 337)Suppliers

Supplier	Tel	Country	ProdList	Advantage	Inquiry
AVD pharmaceuticals Pvt Ltd	+919860835260	Pune, India	102	58	Inquiry
Varanous Labs Pvt Ltd	+91-7036248882 +91-7036248882	Hyderabad, India	1541	58	Inquiry
Aarti Industries Limited (AIL)	+91-84596144931 +91-9920899935	Maharashtra, India	235	58	Inquiry
Hetero Drugs Limited	+91-4023704923 +91-4023704923	Telangana, India	296	58	Inquiry
Shilpa Medicare Limited (SML)	+91-8532238704 +91-9320649838	Karnataka, India	61	58	Inquiry
Basil Drugs AND Pharmaceuticals Pvt Ltd	+91-2249700250 +91-9619320820	Mumbai, India	108	58	Inquiry
Stellar Chemical Laboratories Pvt., Ltd.	+91-66662691 +91-2266662690	Maharashtra, India	11	58	Inquiry
Narmada Organics	+91-9601758907 +91-9409133000	Gujarat, India	19	58	Inquiry
Ralington Pharma	+91-7948911722 +91-9687771722	Gujarat, India	1350	58	Inquiry
Sakar Healthcare	+91-8976292690 +91-9967572302	Gujarat, India	47	58	Inquiry

Supplier	Advantage
AVD pharmaceuticals Pvt Ltd	58
Varanous Labs Pvt Ltd	58
Aarti Industries Limited (AIL)	58
Hetero Drugs Limited	58
Shilpa Medicare Limited (SML)	58
Basil Drugs AND Pharmaceuticals Pvt Ltd	58
Stellar Chemical Laboratories Pvt., Ltd.	58
Narmada Organics	58
Ralington Pharma	58
Sakar Healthcare	58

Cyclophosphamide Spectrum

Cyclophosphamide(50-18-0)MS Cyclophosphamide(50-18-0)¹HNMR Cyclophosphamide(50-18-0)¹³CNMR Cyclophosphamide(50-18-0)IR1 Cyclophosphamide(50-18-0)IR2 Cyclophosphamide(50-18-0)Raman

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2-(Bis(2-chloroethyl)amino)-2H-1,3,2-oxazaphosphorine 2-oxide 2H-1,3,2-Oxazaphosphorin-2-amine, N,N-bis(2-chloroethyl)tetrahydro-, 2-oxide 2-H-1,3,2-Oxazaphosphorinane 2H-1,3,2-Oxazaphosphosphorin-2-amine, N,N-bis(2-chloroethyl) tetrahydro-, 2-oxide 1-(Bis(2-chloroethyl)amino)-1-oxo-2-aza-5-oxaphosphoridine 2-(Di(2-chloroethyl)amino)-1-oxa-3-aza-2-phosphacyclohexane 2-oxide Cyclophosphamide 2-Bis(2-chloroethyl)aminotetrahydro-2H-1,3,2-oxazophosphorine-2-oxide Aids002314 Aids-002314 Clafen(CyclophosphaMide) CyclophosphaMide COS 2-(Bis(2-chloroethyl)amino)-2H-1,3,2-oxazaphosphorine 2-oxid N,N-bis(2-chloroethyl)-2-oxo-1,3,2$l^{5}-oxazaphosphinan-2-amine 2H-1,3,2-Oxazaphosphorine, 2-(bis(2-chloroethyl)amino)tetrahydro-,2-oxide 2H-1,3,2-Oxazaphosphorine, 2-(bis(2-chloroethyl)amino)tetrahydro-,2-oxide, monohydrate Asta B 518 B 518 Bis(2-chloroethyl)phosphoramide cyclic propanolamide ester CB 4564 Clafen Claphene Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphoramide Cyclostin Cyklofosfamid Cytophosphan Endoxan R Endoxana Endoxanal Endoxan-Asta Endoxane Enduxan Genoxal Mitoxan N,N-Bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide N,N-Bis(2-chloroethyl)-N',O-propylenephosphoric acid ester diamide N,N-Bis-(beta-chloraethyl)-N',O-propylen-phosphorsaeure-ester-diamid N,N-Bis(beta-chloroethyl)-N',O-trimethylenephosphoric acid ester diamide N,N-Di(2-chloroethyl)-N,O-propylene-phosphoric acid ester diamide NCI-C04900 NSC 26271 Phosphorodiamidic acid, N,N-bis(2-chloroethyl)-N'-(3-hydroxypropyl)-, intramol. ester Rcra waste number U058 Semdoxan Sendoxan Senduxan SK 20501 Zyklophosphamid 2-(bis(2-chloroethyl)amino)-1,3,2-oxazaphosphorinane 2-oxide Cyclophosphamide USP/EP/BP Cyclophosphamide DISCONTINUED, offer C988580 2-(Bis(2-chloroethyl)amino)-1,3,2-oxazaphosphinane 2-oxide CyclophosphamideQ: What is Cyclophosphamide Q: What is the CAS Number of Cyclophosphamide Q: What is the storage condition of Cyclophosphamide Q: What are the applications of Cyclophosphamide (Bis(chloro-2-ethyl)amino)-2-tetrahydro-3,4,5,6-oxazaphosphorine-1,3,2-oxide-2 hydrate ASTA