Chemical Stability of Cyclophosphamide in Parenteral Solutions

Brooke, Dana; Bequette, RJ; Rm, Davis

doi:10.1093/ajhp/30.2.134

Cited by 14 publications

(10 citation statements)

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“…As expected, 1 was significantly more stable in solutions kept at 20 °C (Figure 2), and only a small amount of compound 13 was formed (Table 2). After 6 days at 37 °C, 45% of 1 was hydrolyzed leading to 30% of compound 13 and 15% of eight unknown phosphorylated compounds.…”

Section: T H I S C O N T E N T Imentioning

confidence: 99%

Chemical and Biological Evaluation of Hydrolysis Products of Cyclophosphamide

Gilard¹,

Martino²,

Malet‐Martino³

et al. 1994

J. Med. Chem.

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31P NMR spectroscopy was used to study the products of the decomposition of cyclophosphamide (1) in buffered solutions at pH's ranging between 1.2 and 8.6 at 20 degrees C and at pH 7.4 at 37 degrees C. At pH 1.2, 1 undergoes a rapid breakdown (t1/2 = 1.4 days) of the two P-N bonds, giving compounds 2 [HN(CH2CH2Cl)2] and 3 [H2N(CH2)3OP(O)(OH)2] as hydrochlorides. No intermediates were detected. At pH's between 5.4 and 8.6, hydrolysis of 1 during 17 days leads to the sole and previously unknown nine-membered ring compound 13. 13 results from the intramolecular alkylation of 1 giving the bicyclic compound 7 followed by the exothermal hydrolytic breakdown of the P-N bond of its six-membered ring. At pH 2.2 and 3.4, the two hydrolytic pathways coexist since, beside compounds 2 and 3, the hydrochloride of compound 9 [Cl(CH2)2NH(CH2)2NH(CH2)3OP(O)(OH)2] is formed, resulting from the acid-catalyzed breakdown of the P-N bond in the nine-membered ring compound 13. At pH 2.2, the presence of chloride ion affected neither the stability of 1 nor the contribution of the two competing hydrolytic pathways. At pH's ranging from 3.4 to 8.6, there is little degradation of 1 since more than 95% of initial 1 was still present after 7 days at 20 degrees C. Under physiological conditions (pH 7.4, 37 degrees C) after 6 days, 45% of 1 is hydrolyzed (t1/2 = 6.6 days), leading essentially (30% of initial 1) to the nine-membered ring compound 13. The rate of hydrolysis of 13 and the nature of its hydrolysis products were found to depend on pH over the range 0-8.6. After a single ip injection to mice, compounds 3, 9, and 13 were less toxic than 1. They did not exhibit any direct cytotoxic efficacy on the colony-forming capacity of L1210 cells in vitro, and they had no antitumor activity in vivo against P388 leukemia.

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Section: T H I S C O N T E N T Imentioning

confidence: 99%

Chemical and Biological Evaluation of Hydrolysis Products of Cyclophosphamide

Gilard¹,

Martino²,

Malet‐Martino³

et al. 1994

J. Med. Chem.

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“…Antineoplabtic drugs. The intravenous admixture literature is not very rich in data describing the compatibility of antineoplastic agents (74)(75)(76)(77)(78)(79)(80)(81)(82).…”

Section: Problems Associo T Ed With In Traveno Iis Odni Iu T Iires 289mentioning

confidence: 99%

“…Methotrexate (75). mercaptopurine as the sodium salt (74) and cyclophosphamide (74,78) were found to be stable in isotonic dextrose or isotonic sodium chloride solutions for at least 24 h at room temperature. Also 5-fluorouracil sodium could be added to the same infusion fluids (77).…”

Section: Problems Associo T Ed With In Traveno Iis Odni Iu T Iires 289mentioning

confidence: 99%

Incompatibility and Stability Problems Associated With Intravenous Admixtures: A Survey

Lundgren

Landersjö²

1980

J Clin Pharm Ther

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In intravenous therapy the use of infusion fluids as vehicles or carriers for other parenteral drugs is now common. The extent of use of this drug administration method has been illustrated in many papers (1-8). A report from the early sixties shows that one or more drugs were added to about 10% of the infusion fluids administered (9). In the late sixties, however, the frequency of intravenous prescriptions containing additives had increased and figures of between 50 and 907; have been reported in several papers (2, 4, 5, 8). Reports over the last 5 years indicate that drugs are now less frequently administered as additives.The drugs added to infusion fluids are mainly antibiotics, electrolytes, heparin, vitamins and, to a lesser extent, several other drugs such as aminophylline and corticosteroids. Some of these drugs, for example, electrolytes, are available as sterile stock solutions designed for use as additives in infusion fluids. Usually, however, neither infusion fluids nor injections are formulated to be diluted or mixed with further drugs. The practice of adding drugs to large volume parenteral solutions may therefore result in incompatibility or stability problems.Several authors have reviewed the literature concerning addition of drugs to large volume solutions and provided references, tables and recommendations to reduce the occurrence of problems (10-16). There have been many studies on such incompatibilities; however, the literature in this area is often inconsistent and does not reflect clinically applicable situations. Several stated incompatibilities, reported in compatibility charts, are based on single observations. The influence of pH, the concentration of the drug and other factors have not been evaluated. Some are based only on the observation that no visible change has taken place in the admixture within a stated time.In some papers (6,17-27) the prediction ofcompatibility and stability ofdrugs added to infusion fluids was based on relevant physico-chemical principles. This more theoretical approach has allowed quantitative approximations to be made from kinetic data. Such a technique may be the best way to attack incompatibility problems. The success of this approach, however, depends on the available physicochemical information on the drug *Apoteksbolaget AB, (National Corporation of Swedish Pharmacies,) 105 14 Stockholm, Sweden. 29. Lebmnnn, H. (1959) uber pH-Werte von Infusionslosungen. dsterreichische Apotheker-Zeitung, 13, 30. Vogt. H. P Cklche, C. (1961) pH-Studien an den gebrauchlichsten Infusionslosungen, inbesondere die Ennittlung ihrer Pufferkapazitiit im Vergleich mit der des Blutes. Mitteilirngen der Deutschen Pharmaceutischen Gesellschaft. 31,97-107. 3 I . Cklche, G. (1966) Uber die Bedeutung de pH und Puferwertes von lnfusionslosungen fur Kombinationen mit weiteren Anneistoffen. Krankenhausact. 39.80-86. 32. hndgrm, P. P hndasj6, L. (1970) Studieson the stability and compatibility of drugs in infusion fluids. 1. pH and buffer capacity of infusion fluids. Acta Pharmacewica Sue...

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“…A number of the hydrolysis products have been isolated and used a s standards in chromatographic analyses of urine and plasma metabolite mixtures. toxan for injection) when stored a t room temperature (24 to 27°C) showed no more than 2.8% change in composition in 24 h r and approximately 18% decomposition after 1 week [6]. In unbuffered, aqueous solutions C P slowly hydrolyzes to nor-HN2 and the phosphoric acid ester of N-propanolamine [7].…”

Section: Hydrolytic Productsmentioning

confidence: 99%