Stability indicating HPLC method development of Carbimazole tablets and stability study of the repackaged tablet

Introduction
Neonatal Graves disease, a rare but critical condition in newborns, highlights the role of Carbimazole (CBZ), a synthetic antithyroid drug. Pediatric administration of CBZ tablet is challenging, requiring conversion into an oral suspension. At our hospital, CBZ is deblistered, repackaged to ensure unitary delivery and is then used to produce the oral suspension. The 2023 French Good Manufacturing Practice (GMP) emphasize the need of a stability study and an analytical method to perform the uniformity of content test. CBZ, a prodrug rapidly hydrolyzed to the active metabolite Thiamazole (THZ), requires careful handling and protection from humidity. Ensuring the quality of CBZ is crucial before incorporating it into oral suspensions. A change in the organoleptic characteristics of repackaged CBZ tablets raised stability concerns.
We aimed to develop and validate a stability-indicating High-Performance Liquid Chromatography (HPLC) method for accurate quantification, detection of degradation products, and stability studies.

Material and method
The HPLC method was developed using an XTerra RP18 column (Waters ; 150x4.6 mm ; 5 µm), and a mobile phase composed of acetonitrile (ACN) and pH7 water (20:80, v/v) in isocratic elution (1 mL/min). Sample were prepared in a low water mixture (ACN:pH7 water ; 70:30, v/v) to minimize hydrolysis. Quantification was performed using DAD-type UV detection (from 190 to 400 nm) and analyzed at 252 nm using Chromeleon V7.2 software (ThermoFischer, USA). Forced degradation were conducted under stressed degradation conditions, such as acid, alkaline, oxidative and thermal stress. Literature data indicate CBZ is not photosensitive, thus photolytic stress was not studied. Stability studies by determining CBZ concentration followed GERPAC guidelines at various intervals throughout six months.

Results
Degradation products, THZ and oxidative derivatives, were effectively separated and identified. Method validation, following ICH Q2 guidelines, showed good repeatability, resolution, specificity, precision, accuracy, and linearity (0.6 to 1.4 mg/mL). This method analyzed repackaged CBZ tablets stored at 25 ± 2°C and 60 ± 5% relative. THZ was detectable at D0, it increased to 121% of the initial value at D28 and up to 178% at six months, indicating that repackaging may favor CBZ hydrolysis, thus altering the product shelf life. However, THZ levels stayed relatively low representing less than 1% of CBZ amount. CBZ remained therefore stable at six months (96.3% of initial value).

Conclusion
The stability of repackaged CBZ has been demonstrated up to six months with little degradation to the active metabolite THZ. This robust method ensures safer CBZ oral suspension preparation, meeting pediatric needs and new GMP requirements. The next step involves developing a content uniformity procedure for CBZ oral suspensions.