Stability of Cyclophosphamide in Extemporaneous Oral Suspensions

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Stability of Cyclophosphamide in Extemporaneous Oral Suspensions

Rachel Kennedy. Pediatric Oncology Education Program Student, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN

Daniel Groepper, BS. Research Technician, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital

Michael Tagen, PhD. Postdoctoral Research Associate, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital

Robbin Christensen, BS Pharm. Clinical Research Pharmacist, Department of Pharmaceutical Services, St. Jude Children's Research Hospital

Fariba Navid, MD. Associate Member, Department of Oncology, St. Jude Children's Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee Health Sciences Center, Memphis

Amar Gajjar, MD. Member and Co-Chair, Department of Oncology, St. Jude Children's Research Hospital; Professor, Department of Pediatrics, College of Medicine, University of Tennessee Health Sciences Center

Clinton F Stewart, PharmD. Member, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital; College of Pharmacy, University of Tennessee Health Sciences Center

BACKGROUND: Cyclophosphamide, an alkylating agent, is widely used for the treatment of many adult and pediatric malignancies. The stability of cyclophosphamide in aqueous- and methylcellulose-based oral suspending vehicles is currently unknown.

OBJECTIVE: To develop and validate a stability-indicating high-performance liquid chromatography (HPLC) method to measure cyclophosphamide concentrations in simple syrup and Ora-Plus, and assess the 56-day chemical stability and physical appearance of cyclophosphamide in these suspensions at both room temperature (22 °C) and 4 °C.

METHODS: The intravenous formulation of cyclophosphamide was diluted to 20 mg/mL in NaCl 0.9%, compounded 1:1 with either suspending vehicle, and stored in the dark in 3-mL amber polypropylene oral syringes at 4 °C and 22 °C. Aliquots from each syringe were obtained on days 0, 3, 7, 14, 21, 28, 35, 42, 49, and 56 and assayed using the validated stability-indicating HPLC-UV method. A C18 analytical column was used to separate cyclophosphamide from the internal standard, ifosfamide, with a mobile phase of 21% acetonitrile in 79% sodium phosphate buffer. The suspension was examined for odor change, visually examined under normal fluorescent light for color change, and examined under a light microscope for evidence of microbial growth.

RESULTS: Samples of cyclophosphamide in both simple syrup and Ora-Plus were stable when kept at 4 °C for at least 56 days. At room temperature, cyclophosphamide in simple syrup and Ora-Plus had a shelf life of 8 and 3 days, respectively. No changes in color or odor or evidence of microbial growth were observed.

CONCLUSIONS: Cyclophosphamide can be extemporaneously prepared in simple syrup or Ora-Plus and stored for at least 2 months under refrigeration without significant degradation.