Formulation of an oral liquid solution of Carbimazole and validation of a stability indicator assay method.

E. Pinet1, C. Roessle1, V. Vasseur1, S. Benakouche1, O. Bourdon1,3,4, T. Storme1,2
1 : Pharmacy Service, Robert Debré Hospital – APHP, Paris, France; 2 : Pharmacology Laboratory Hôpital Robert Debré – APHP, Paris, France; 3 : Faculty of Pharmacy, Paris Descartes University, Sorbonne Paris Cité, Paris, France; 4 : Health Education and Practice Laboratory, EA 3412, Paris 13 University, Sorbonne Paris Cité, Bobigny, France


Introduction
Newborns of hyperthyroid mothers may have neonatal hyperthyroidism. It is a serious but transient and curable disease. Urgent treatment with Carbimazole 1mg/kg/day in 3 doses is therefore necessary. Commercial forms (5 and 20 mg tablets) are not suitable for neonatology (dose and galenic form).

Objective
Implementation of a Carbimazole formulation adapted to paediatrics, validation of a dosage method and stability study to be incorporated as a hospital preparation.

Materials & Methods
Clinical need was assessed by a retrospective method of the dosages used. Carbimazole AMDIPHARM tablets and InOrpha®, a "universal" suspension vehicle, were used for the formulation. The organoleptic characteristics were carried out over one month and a palatability study was carried out on 10 people.
The assay was performed by HPLC-UV according to the European Pharmacopoeia 9.0 method (column C18, mobile phase ACN/H20 in proportion 20/80) and validation of a stability indicator method after forced degradation tests by UV, HCl, NaOH and H2O2. The calibration standards (Carbimazole, Ph Eur) are between 0.1 and 0.5 mg/mL.
Stability was studied on the finished product (n=3) at 5±3°C and 20±5°C over 1 month with and without daily opening of the vials and 3 months without opening at 5±3°C and 20±5°C.

Results
The standardization of doses resulted in the creation of a multidose liquid oral form at 1mg/mL. InOrpha® allowed a complete solubilization of Carbimazole and the formulation of a solution adapted to the patient’s weight. The organoleptic characteristics were similar to T0 and 1 month. The palatability tests found a solution that was pleasant to taste, fluid and easy to sample.
The dosage method is linear, exact, repeatable, accurate. Forced degradation identified a degradation product, Thiamazole. The method is thus an indicator of stability.
The solution is stable for 1 month (with and without opening) at 5±3°C and 48h at 20±5°C.

Discussion & Conclusion
The extemporaneous formulation of Carbimazole meets a real clinical need. InOrpha allows the formulation of a solution without excipients with known effects and osmolarity compatible with neonatology. The assay method is exact, accurate and repeatable, allowing to validate a stability of one month at 5±3°C. Referencing in hospital preparation makes it possible to anticipate needs and therefore to respond to them as a matter of urgency.

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