Formulation and Control of a Pediatric Oral Hospital Preparation of 0.1% Ferrous Fumarate

Chloé Marchand[1], Elisa Marilly[1], Louise Bossy[1], Anthony Martelin[1], Samira Filali[1] [2], Damien Salmon[1] [2], Camille Merienne[1], Christine Pivot[1] , Fabrice Pirot[1] [2]
[1] Pharmacie, Hôpital Edouard-Herriot, Lyon, France.
[2] Laboratoire de Pharmacie Galénique Industrielle, ISPB, Lyon, France
[*] Coordonnées: prénom.nom@chu-lyon.fr à l’exception de damien.salmon01@chu-lyon.fr

Context
Two specialties of ferrous ascorbate (FA) or fumarate (FF) are respectively suspected, to be involved in rectal bleeding in neonatalogy, or unavailable on the national territory. Thus, our hospital pharmacy is requested to provide a pediatric oral formulation of ferrous fumarate (FF).

Objective
The main objective of this study was (i) to develop a hospital preparation (HP) of FF (0.1%) adapted for pediatric oral use and (ii) to validate an analytical method allowing the control of FF content by microwave atomic emission spectrometry (MP-AES).

Materials and methods
The dissolution of the FF (aqueous solubility: 13 mg/mL) in a ready-to-use commercial oral route vehicle was performed using a high performance dispersing device. This vehicle, claiming low osmolality (170 mOsm/kg) and facilitated acceptability, is suitable for pediatric enteral administration. The theoretical concentration of FF in the mixture was 1 mg/mL.
The FF quantification was performed using MP-AES equipped with an inert nebulizer and a cyclone nebulizer chamber. The plasma was generated by microwave heating of N2 fed by an air compressor. The quantification wavelength of iron was 371.9 nm. The analytical validation was conducted by building the accuracy profile according to the SFSTP1 recommendations. It allows estimating the linearity, the fidelity, the accuracy and the limits of quantification as well as the estimate of the measurement inaccuracy as a function of the concentrations. The development included a research for a potential matrix effect in the vehicle according to the recommendations of the Annals of Analytical Toxicology2. The oral suspension was diluted 1000 times in a 1% nitric acid solution.

Results
No evidence of instability (e.g., color change, flocculation, sedimentation) of this HP was observed during the storage time at room temperature.
The matrix effect observed in the vehicle doubled the signal intensity, therefore validation protocol V5 was then used. The parameters of accuracy, repeatability and reproducibility were in accordance with the specifications in the validity range (<10%, 5% and 8% respectively). None of the bounds of the accuracy profile tolerance threshold exceeded the acceptability limits (10%).

Discussion / Conclusion
The simplicity of implementation of this HP and the validation of a content control on the whole mixture before distribution in individual containers guarantee a safe use of the FF for pediatric use. The evaluation of rectal bleeding decrease in neonatalogy is in progress.

1 Ph. Hubert et al. Harmonization of strategies for the validation of quantitative analytical procedures, Journal of Pharmaceutical and Biomedical Analysis 45 (2007) 70–81
2 Annales de Toxicologie Analytique, vol. XVI, n° 2, 2004

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