title: Physico-chemical stability of busulfan in injectable solutions in various administration packages.
abstract: OBJECTIVE
  Busulfan is used as part of a conditioning regimen prior to hematopoietic stem cell transplantation for the treatment of certain cancers and immune deficiency syndromes. Due to its instability in aqueous preparations, busulfan for infusion is prepared from a concentrate and has a relatively short shelf life once prepared. The purpose of this study was to identify the most suitable storage container and temperature to maximize the shelf life of busulfan therapeutic infusions prepared from Busilvex(®).
  
  
  METHODS
  Busilvex(®) 6 mg/mL was diluted to 0.55 mg/mL with 0.9 % NaCl and aliquots dispensed into polypropylene syringes, polyvinyl chloride bags, and glass bottles. Three storage temperatures were evaluated: 2-8 °C, 13-15 °C (thermostatically controlled chamber), and room temperature (20 ± 5 °C). At set time points, samples were analysed for busulfan content, using a high-performance liquid chromatography (HPLC) system with ultraviolet detection. The change in pH and osmolarity on storage was also determined, and solutions were inspected visually for formation of a precipitate or colour change. To determine the contribution of precipitation to loss of busulfan content on storage, samples from one time series were treated with the solvent dimethylacetamide prior to HPLC separation and quantitation of busulfan.
  
  
  RESULTS
  The results of the active substance content monitoring study over a 48-h period demonstrate that busulfan solution is stable at a 5 % threshold, at 2-8 °C for 16 h in syringes, 14 h in glass bottles, and 6 h in bags. In addition, the period of stability decreases as the temperature increases (4 h at 20 ± 5 °C). The solution is considered to be stable, subject to precipitation liable to be observed regardless of the temperature.
  
  
  CONCLUSIONS
  The best stability was observed for busulfan solutions placed at 2-8 °C in syringes. This study demonstrated that precipitation, in addition to hydrolysis, has a significant influence on the busulfan content.
authors.affiliation: Pharmacology and Drug Analysis Department, Institut de Cancérologie Gustave Roussy, 114, rue Edouard Vaillant, 94805, Villejuif Cedex, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Houot
authors.forename: Vianney
authors.initials: V
authors.lastname: Poinsignon
authors.forename: Lionel
authors.initials: L
authors.lastname: Mercier
authors.forename: Cyril
authors.initials: C
authors.lastname: Valade
authors.forename: Romain
authors.initials: R
authors.lastname: Desmaris
authors.forename: François
authors.initials: F
authors.lastname: Lemare
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
mesh_terms: D002066:Busulfan / Q000737:chemistry* / Q000592:standards*; D055598:Chemical Phenomena; D011232:Chemical Precipitation / Q000187:drug effects; D004349:Drug Packaging / Q000592:standards*; D004355:Drug Stability; D007267:Injections; D019999:Pharmaceutical Solutions / Q000737:chemistry / Q000592:standards; D013997:Time Factors
chemical_list: D019999:Pharmaceutical Solutions; D002066:Busulfan
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