Stability of cyclophosphamide in extemporaneous oral suspensions

Abstract

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 degrees C) and 4 degrees 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 degrees C and 22 degrees 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 degrees 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.

Figure 1

Example HPLC chromatograms of cyclophosphamide assay. Chromatograms of blank simple syrup (A) and simple syrup spiked with 10 mg/mL cyclophosphamide and internal standard (B). Chromatograms of blank Ora-Plus (C) and Ora-Plus spiked with 10 mg/mL cyclophosphamide and internal standard (D).

Figure 2

Chemical stability of cyclophosphamide in oral suspending agents. Cyclophosphamide (10 mg/mL) was extemporaneously prepared in simple syrup (A) and Ora-Plus (B) and stored at either 22°C or 4°C. Aliquots of the suspension were assayed for cyclophosphamide concentrations in triplicate at the indicated time-points for up to 56 days.