Optimization and stability study of compounded oral suspension of spironolactone at 5mg/ml for infants

Background / Objective
The literature describes different formulations of spironolactone (SP) oral suspensions (OS). Depending on the safety profile of the excipients for the population, the choice of vehicle is rationalised. For neonatal use, an OS formulation of SP at 5 mg/ml in InOrpha^® is proposed. This formulation is prone to rapid sedimentation (caking), which affects the appropriate use of OS. The aim is to optimise the oral formulation of SP in InOrpha^® and assess its stability.

Material / Method
To reduce SP sedimentation rate, 0.2% xanthan (m/V) was added to the InOrpha^® formulation.
Stability (at 22°C ± 3°C [RT] and 5°C ± 3°C [refrigerated]) was investigated using a stability indicator method (HPLC-UV). Microbiological stability was also under investigation.
The study was performed before and after opening, with daily sampling of OS (RT and refrigerated storage) in triplicate at D0, D15, D30, D60, D90, D120, D135 before opening and at D0, D15, D30, D37 after opening.
The following parameters were monitored: Dosage, degradation products, organoleptic characteristics, sedimentation (concentration in unstirred bottle), viscosity (rotating rheometer), density (manual refractometer), pH (potentiometry) and osmolality (osmometer), microbial enumeration test and specific detection of E. coli according to the European Pharmacopoeia (EP).

Results
Colour and odour did not change over time regardless of storage conditions. In terms of appearance, OS appeared more viscous in the refrigerator than at RT, as measured by a rotational rheometer (218 mPa.s vs. 133 mPa.s on average up to D135).
The SP content remained between 90-110% compared to the dosage at D0, before or after opening, in the cold and at RT. No degradation products were found.
Concerning sedimentation, the SP concentration remained within the acceptability limits set at ±5% deviation up to D135.
Density (mean 1.014), pH (mean 4.76) and osmolality (mean 185 mosmol/kg) did not change over time, whatever the storage conditions.
Microbiological analysis before and after opening the vials met EP validation thresholds and no E.coli was found.

Conclusion/discussion
Physicochemical and microbiological stability of OS has been demonstrated for 135 days pre-opening (i.e. 4 effective months) and 37 days post-opening (i.e. 1 effective month) at RT and refrigerated. We validate ambient storage to simplify storage for routine use. Furthermore, at 4 months after production, no sedimentation is observed.

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