Development of levothyroxine sodium pediatric oral solution driven by STEP database: Stability study and degradation products by LC-MS

• A Levothyroxine Sodium (SLT4) oral solution was developed containing pediatric-safe excipients, representing an alternative for hospital treatment of hypothyroidism. • The formulation was stable for 63 days both in sachet and amber glass bottle packaging. • SLT4 demonstrated to be unstable to alkaline condition, UVC and UVA light exposure during stress testing. • Six degradation products structures and their formation routes were suggested for SLT4 after stress testing study. • The Safety and Toxicity of Excipients for Paediatrics (STEP) database and Paediatric Excipient Risk Assessment (PERA) tool demonstrated to be very useful to select formulation’ excipients and guide a consistent development. Levothyroxine sodium (SLT4) is the sodium salt of the thyroid hormone thyroxine, being the first-choice replacement therapy in hypothyroid disease. Congenital hypothyroidism affects infants, and represents one of the most common preventable causes of intellectual disability worldwide. In Brazil and other countries, tablets are the only dosage form of SLT4 for oral use. Pediatric patients and adults unable to swallow require SLT4 extemporaneously prepared in the hospital’s routine, which can compromise safety. On the other hand, oral SLT4 solutions are available in USA, Italy, Spain, and United Kingdom. The aim of this work was to develop a SLT4 oral liquid formulation and assess its stability during 63 days under 4 °C, 25 °C and 40 °C, comparing amber glass bottles and sachet packing. In the development stage, excipients were evaluated by data tools (STEP and PERA) and the most suitable for pediatric use were chosen. An HPLC method was developed and validated to analyze SLT4 content, and forced degradation outcomes were investigated through UPLC-MS. Every 7 days, pH, drug amount, visual aspect, organoleptic properties and microbiological content were analyzed. The SLT4 30 µg/mL oral solution showed adequate physical chemical and microbiological characteristics. It was stable for 63 days when stored both in sachet and amber glass bottles at 4 °C and 25 °C. Six major degradation products structures were proposed after stress testing evaluations. It was possible to obtain a simple STL4 oral solution, with pediatric-safe excipients and dosing flexibility, representing an alternative for hospital treatment of hypothyroidism.