Cyclophosphamide 10-mg/mL Oral Liquid

Cyclophosphamide 10-mg/mL Oral Liquid

Loyd V. Allen, Jr, PhD
Professor Emeritus
College of Pharmacy, University of Oklahoma
Oklahoma City, Oklahoma

US Pharm. 2010;35(3):42-43.

Method of Preparation: Calculate the quantity of each ingredient for the amount to be prepared. Accurately weigh or measure each ingredient. Reconstitute the cyclophosphamide for injection with the 0.9% Sodium Chloride Injection. Place the mixture in an appropriate graduate, add sufficient Ora-Plus or simple syrup to final volume, and mix well.

Use: Cyclophosphamide oral liquid is used in the treatment of many adult and pediatric malignancies.

Packaging: Package in tight, light-resistant containers.

Labeling: Keep out of the reach of children. Shake well. Store in a refrigerator. Discard after 56 days.1,2

Stability: A beyond-use date of 56 days can be used for this preparation only when it is stored in a refrigerator.1,2 The reported stability study used the injection as the source of the drug.

Quality Control: Quality-control assessment can include weight/volume, pH, specific gravity, active drug assay, color, rheologic properties/pourability, physical observation, and physical stability (discoloration, foreign materials, gas formation, mold growth).3

Discussion: Cyclophosphamide is a widely used chemotherapeutic drug for treating a broad range of malignancies. It is used in the treatment of Hodgkin’s disease, non-Hodgkin’s lymphoma, multiple myeloma, leukemias, cutaneous T-cell lymphoma, neuroblastoma, ovarian cancer, retinoblastoma, breast cancer, small-cell lung cancer, sarcomas, and other diseases. A former method of preparing an oral liquid involved the use of Aromatic Elixir USP and had a reported stability of 14 days. However, Aromatic Elixir USP is no longer commercially available and takes time to prepare, so the current formula is presented with a beyond-use date of 56 days when it is stored in a refrigerator.1

It should be noted that storage at room temperature resulted in 10% degradation of the drug in 10.6 days in simple syrup and in 6.0 days in Ora-Plus. Therefore, this preparation must be refrigerated.

Cyclophosphamide (C7H15Cl2N2O2P.H2O, MW 279.10) is a nitrogen mustard derivative that is used as an antineoplastic and immunosuppressant. It occurs as a white, crystalline powder that liquefies upon the loss of its water of crystallization. Cyclophosphamide is soluble in water and in alcohol.1

0.9% Sodium Chloride Injection contains not less than 95.0% and not more than 105.0% of the labeled amount of sodium chloride in water for injection. It has a pH between 4.5 and 7.0, and it contains no added antimicrobial agents. Sodium chloride solutions are chemically and physically stable. They can be sterilized by filtration or autoclaving. Aqueous sodium chloride solutions will react to form precipitates with silver, lead, and mercury salts. When acidified sodium chloride solutions are mixed with strong oxidizing agents, chlorine can be liberated. Sodium chloride will decrease the solubility of some organic compounds; methylparaben is not as soluble in sodium chloride solutions as it is in water. Sodium chloride is soluble in water to the extent of 1 g in 2.8 mL water, and it is slightly soluble in alcohol (1 g in 250 mL of 95% ethanol).4

Ora-Plus is an oral suspending vehicle that accepts dilution of up to 50% or more with water, flavoring agents, or syrups and still retains its suspending properties. It has a pH of approximately 4.2 and an osmolality of about 230 mOsm/kg. Ora-Plus is a thixotropic vehicle with a viscosity of approximately 1,000 cps at 25˚C. It contains purified water, microcrystalline cellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, sodium phosphate, and citric acid as buffering agents; simethicone as an antifoaming agent; and potassium sorbate and methylparaben as preservatives.5

Syrup (simple syrup) is a clear, sweet vehicle used as a sweetening agent and as the base for many flavored and medicated syrups. It contains 85% w/v sucrose in water and has a specific gravity of not less than 1.30. Simple syrup is generally self-preserving as long as the sucrose concentration is maintained sufficiently high. Preferably, it is prepared without the use of heat, but it can be prepared by the use of boiling water. Simple syrup should be stored in tight containers, preferably in a cool place.1
REFERENCES

1. USP Pharmacists’ Pharmacopeia. Rockville, MD: US Pharmacopeial Convention, Inc; 2005:388,775-779,1433.
2. Kennedy R, Groepper D, Tagen M, et al. Stability of cyclophosphamide in extemporaneous oral suspensions. Ann Pharmacother. 2010;44:295-301.
3. Allen LV Jr. Standard operating procedure for performing physical quality assessment of oral and topical liquids. IJPC. 1999;3:146-147.
4. Maximilien JS. Sodium chloride. In: Rowe RC, Sheskey PJ, Quinn ME, eds. Handbook of Pharmaceutical Excipients. 6th ed. London, England: Pharmaceutical Press; 2009:637-640.
5. Ora-Plus (product information). Minneapolis, MN: Paddock Laboratories, Inc; 1992.

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