Empagliflozina: desenvolvimento analítico, identificação de produto de degradação e derivação farmacêutica para uso hospitalar

Abstract

Diabetes is a set of metabolic disorders and affects more than 400 million individuals worldwide. Type 2 diabetes is characterized by defects in insulin action and secretion, as well as in the regulation of hepatic glucose production. Empagliflozin (EMP) belongs to the gliflozines that are sodium-glucose-2 cotransporter inhibitors, used by oral route to the treatment of type 2 diabetes. The drug was approved by FDA in 2014 and is sold as coated tablets containing 10 and 25 mg (Jardiance®). EMP extemporaneous suspensions (2 mg/mL) using commercial tablets were prepared, using hydroxypropylmethylcellulose (F1) or sodium carboxymethylcellulose (F2) as polymers, to provide an alternative for patients who have difficult in swallowing tablets for hospital use. The formulations were stored at 25 °C and their stability evaluated for 60 days (t60), by the tests of assay, pH, sedimentation volume, particle size, time of redispersion and microbiological control. The EMP quantitation was performed by micellar electrokinetic capillary chromatography that was previously validated. The preparations showed unchanged pH values, which remained around 6.5 over the period; similarly, parameters such as particle size and sedimentation volume showed no difference (p > 0.05) during the study. The results showed no statistical difference (p > 0.05) between F1 and F2 content over 25-days of storage, which were 97.97 ± 1.12% and 99.92 ± 1.20% respectively; both formulations presented microbial levels within the limits specified at t25 that was considered the shelf-life. In sequence, a simple stability-indicating method by high performance liquid chromatography (HPLC) was developed to assay empagliflozin. The mobile phase was composed by methanol, acetonitrile and purified water (60:5:35 v/v), at a flow rate of 1 mL/min and detection at 225 nm. Calibration curve was linear in the range of 5 to 150 μg/mL. The method showed to be precise, accurate and robust. To forced degradation study, empagliflozin standard and tablets were exposed under stress conditions and the major degradation product evidenced after drug exposure to UV-C radiation was isolated and analyzed by high resolution mass spectrometry (HRMS). The structure of PDUVC was suggested and the route involved in the photolytic degradation of empagliflozin was proposed.