Publications

Introduction: Levothyroxine sodium –classified as a narrow therapeutic index drug-is one of the most prescribed medications in the world, administered orally as a thyroid hormone replacement therapy in cases of hypothyroidism. However, from literature and clinical practice, its bioavailability has been questioned and drug recalls have been issued for some formulations in sense of impaired potency and therapeutic failure. In Lebanon, due to limited availability of doses, some patients were required to split tablets to achieve the required therapeutic dose. Also, in some cases of drug shortages, some patients switched between levothyroxine formulations whether brands or generics. Both cases, when monitored showed cases of hormonal imbalance suggesting inaccurate dose administration and inadequate bioequivalence. Purpose: In light of that, this study aimed to develop novel analytical techniques for the quantification of levothyroxine, its distribution amongst the excipients and bio-waiver studies as a guide towards bio-in-equivalence risk and to better predict its bioavailability. Method: In this work, content of each part of the split tablets were quantified using UV-spectrophotometric method. Moreover, four different advanced techniques were used to quantify levothyroxine in its pharmaceutical formulations including the High-performance liquid chromatography (HPLC), Fourier transform infrared (FTIR) spectroscopy, Particle Induced X-ray Emission (PIXE) and Time of Flight-Secondary Ion Mass Spectrometry (ToF-SIMS). Additionally, the dissolution apparatus was used to conduct in vitro biowaiver study. Besides, Tof-SIMS was used as an imaging technique to check levothyroxine’s distribution amongst the excipients. Results: This study successfully developed and validated new methods for levothyroxine’s determination with high accuracy and precision. Tablets were found to comply with the labelled amount. However, the tablet splitting practice did not always give the accurate required dose as different employed splitting techniques resulted in non-uniformity of half tablet weight relating to different drug content. The sensitivity of the different proposed methods can be confirmed by the low limit of detection and quantitation values, 0.953 and 3.18g/mL, and 8.121 and 24.545 μg/ pellet for the HPLC and FTIR respectively. A detection limit of 2.70 μg/tablet was achieved using the PIXE technique demonstrating high sensitivity and accuracy in the detection. The HPLC method was used to analyze the dissolution samples in the three dissolution media for different levothyroxine pharmaceutical formulations. Results revealed dissimilar dissolution profiles suggesting bio-in-equivalence. It was found that the best fit model for levothyroxine release kinetics was the Higuchi model. Key findings from the ToF-SIMS technique was chemical characterization and behavior of levothyroxine under the experimental conditions. Results revealed the ability to quantify levothyroxine in a specific matrix. Also, chemical distribution of levothyroxine was mapped, showing a dot-like cluster distribution of the drug in the present tablet. Conclusion: Overall, due to the variation in the dissolution profiles and in the split tablets, a recommendation should be addressed to endocrinologists and pharmacist to limit such practices of switching and asking the patients to split tablets. To ensure product efficacy, stability and patient safety, not only the content of levothyroxine sodium should be considered, but also therapeutic efficacy by hormonal monitoring is highly advised.