Physicochemical and microbiological stability of Spironolactone oral suspension without potentially harmful excipient

Maxime Petit 1, Sonia Mitreski 1, Julie Forget 1, Hassan Allouchi 2, Elodie Baticle 3, Eric Bailly 4, Stéphanie Provot 1, Xavier Pourrat 1
1. Pharmacy, CHRU Tours, France
2. Control Laboratory, CHRU Tours, France
3. Bacteriology and Hospital Hygiene Unit, CHRU Tours
4. Parasitology, Mycology and Tropical Medicine Laboratory, CHRU Tours, France

Introduction
In paediatrics, spironolactone (SPL) is used as an anti-hypertensive drug, however, there are no specialities suitable for administration to young children. Currently, capsules are prepared and dispensed by the pharmacy and then opened and diluted extemporaneously on the wards for per os administration.
The objective of our work is to develop an oral suspension of SPL 5mg/mL from the Syrspend SF PH4 Dry vehicle which contains no potentially harmful excipient (PHE) and to carry out a physicochemical and microbiological stability study with the aim of facilitating and securing the administration of SPL.

Materials and Methods
7 batches were prepared at a concentration of SPL 5mg/mL. Batches 1 to 6 are packaged in 10mL amber vials and are dedicated to stability before opening: 3 batches are kept at room temperature and 3 batches in the refrigerator and are checked at D0, D7, D14, D28, D56 and D84. Batch 7, dedicated to post-opening stability, was kept in the refrigerator and samples were obtained under the same conditions of use as the care service at D0, D1, D4, D7, D14 and D21.
The controls carried out at each time are a dosage by HPLC/UV, a measurement of the pH and osmolality and the monitoring of organoleptic characteristics. The microbiological quality is controlled by bacterial and fungal enumeration and by specific research of E.coli according to the European Pharmacopoeia 10th edition.

Results
Throughout the study, whatever the storage conditions, before and after opening, the SPL content remained between 95 and 105% of the initial value. It was measured at 4.79±0.14mg/mL before opening and 4.82±0.1mg/mL after opening. The osmolality remained constant (below 50 mosmol/kg) as well as the pH (4.33±0.19). No degradation products were detected and there was no change in organoleptic characteristics. The microbial count remained below Pharmacopoeia requirements and the specific test for E.coli was always negative.

Discussion-conclusion

The results show that the oral suspension is stable for 84 days before opening and 21 days after opening, allowing optimal organisation of the production and administration circuit.
The absence of PHE in the preparation allows it to be used in neonates but means that it does not contain a preservative; it was therefore essential to ensure microbiological stability. In addition, the choice to keep the preparation in the refrigerator reduces the risk of microbiological contamination.
The use in the wards will be initiated and an evaluation of the satisfaction of the nurses and the acceptability by the children is planned. The use of this excipient in oral forms should be extended to other active pharmaceutical ingredients to ensure safe administration in paediatrics.

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