Rapid, quantitative and qualitative control of oxaliplatin in G5% using a separative HPLC method

Guillaume HILY (1), Jean-Marc BERNADOU(1), Maïté SANGNIER(1), Guillaume BOUGUEON(1,2), Fabien XUEREB(1,3), Aude BERRONEAU(1), Sylvie CRAUSTE-MANCIET(1,2)
1 Pharmaceutical Technology Department, Bordeaux University Hospital, France
2 ARNA ChemBioPharm U1212 INSERM – UMR 5320 CNRS, Bordeaux University, France
3 Univ. Bordeaux, INSERM, Biologie des maladies cardiovasculaires, U1034, F-33600 Pessac, France

Standardization and series production of cytotoxic drugs are growing interests in hospital pharmacies. In accordance with the French good manufacturing practices in pharmaceutical healthcare establishments(1), the batches release includes, among other controls, physico-chemical controls. An UV-visible/Raman spectrometer (QCRx®) was used to analyze those batches. However, the interference with glucose absorption led to quantitative assay non-conformities. In the absence of a suitable method, the objective was to develop an analytical and separative method to solve this interference with a limited choice of solvent and a short analysis time for routine use.

Materials and Methods
An analytical method using HPLC-UV (Dionex Ultimate 3000® - Chromeleon®) analysis, has been developed. A review of literature highlights the need of a polar mobile phase, an apolar stationary phase like a C18 column. Parameters of the method are described as follows: the mobile phase was composed of acetonitrile/formic acid solution (0.01M) (10/90; v/v) and the flow rate was 1,5 mL/min. A C18 column has been chosen (Prontosil® C18 AQPlus 150x4.6mm). The detector was a photodiode array ultraviolet-light detector set at 248 nm. Oxaliplatin 5mg/mL was provided from Accord®. Validation of the method was carried out in accordance with ICH Q2 R(1) international guideline(2) using specificity, linearity, accuracy and precision. The calibration range has been constructed over three days using 6 samples of different concentrations (0,1 to 2,5 mg/mL), analyzed twice. Each day, 3 quality control samples (QC1=0.15, QC2=1.2 and QC3=2.0mg/mL) were analyzed 3 times.

Results and Discussion
The linear range of the method was 0,1-2,5 mg/mL. Coefficients of correlation was respectively 0.9999;1;1 at D1, D2 and D3. The retention time of oxaliplatin was 1.7627±0.0016 min. Coefficients of variation over the three days were 0,67%, 0.4% and 0.16% for QC1, QC2 and QC3. Accuracy over the three days was 101.21%, 99.75%, 100.24% for QC1, QC2 and QC3. Specificity has been validated by obtaining representative chromatograms and spectrums.

Our HPLC method allowed to quantify oxaliplatin without glucose interference and showed adequate linearity and accuracy according to international guidelines. This method is simple, fast and precise which is compatible with routine dosage for batches release with a smallest withdrawal of 20 µL compared to the 1 mL of the alternative method.

1. ANSM. French Good Manufacturing Practices for hospital and community pharmacies. 2007.
2. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Brouder A, éditeurs. Validation of analytical procedures: text and methodology Q2(R1). 2005

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