Investigating the Influence of Excipients on the Stability of Levothyroxine Sodium Pentahydrate

Abstract

A range of tablet excipients were evaluated for their influence on the physical form and chemical stability of levothyroxine sodium pentahydrate (LSP; C15H10I4NNaO4·5H2O). LSP–excipient binary powder blends were stored under two conditions: (a) in hermetically sealed containers at 40 °C and (b) at 40 °C/75% RH. By use of synchrotron X-ray diffractometry, the disappearance of LSP could be quantified and the appearance of crystalline levothyroxine (free acid) could be identified. Under hermetically sealed conditions (40 °C) hygroscopic excipients such as povidone induced partial dehydration of LSP to form levothyroxine sodium monohydrate. When stored at 40 °C/75% RH, acidic excipients induced measurable disproportionation of LSP resulting in the formation of levothyroxine (free acid). HPLC analyses of drug–excipient mixtures revealed that lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium caused pronounced chemical decomposition of LSP. On the other hand, magnesium stearate, sodium stearyl fumarate, and alkaline pH modifiers did not affect the physical and chemical stability of the API following storage at 40 °C/75% RH. HPLC, being a solution based technique, revealed chemical decomposition of the API, but the technique was insensitive to physical transformations. Excipient properties such as hygroscopicity and microenvironmental acidity were identified to be critical determinants of both physical and chemical stability of LSP in a drug product. For drugs exhibiting both physical and chemical transformations, simultaneous solid-state and solution based analyses will enable comprehensive stability evaluation.

Poly(caprolactone)-based subcutaneous implant for sustained delivery of levothyroxine

“…The solubility of LEVO in 0.1% of BSA was measured at 37°C: 1.66 ± 0.04 mg/mL. This value is in line with previously reported solubility data (Kaur and Suryanarayanan, 2021). Each implant was immersed in 50 mL of release medium in a watertight glass vial (37°C and 40 rpm) for the first 49 days of release and every 3.5 days the release medium was analysed for LEVO sodium content (using the method described in section 2.4) and replaced with fresh medium.…”

“…This is not surprising considering the hygroscopic nature of both, PEG and LEVO (Kolská et al, 2019;Rostami et al, 2014). Similar behaviour has been reported for the formulation of LEVO with alternative hygroscopic excipients such as povidone or sodium lauryl sulfate (Kaur and Suryanarayanan, 2021). The degradation of the drug was confirmed by the visual discolouration observed and by content analysis.…”

Analysis of dose–TSH response effect of levothyroxine soft-gel formulation

“…As this drug has a narrow therapeutic index, individualization and titration of treatment are mandatory to achieve and maintain the therapeutic goal ( 25 ). The bioavailability of LT4 may depend on the characteristics of pharmaceutical preparations, such as excipient composition and stability over the shelf life ( 26 ), but also on the solubility properties that have been proven to be different among different preparations ( 4 , 5 ). Most published studies comparing different LT4 formulations have focused on TSH changes obtained by switching from tablet to liquid or soft gel preparations.…”

Levothyroxine: Conventional and Novel Drug Delivery Formulations

“…The common excipients in LT4 tablets include lactose monohydrate, cornstarch, carboxymethyl starch, gelatin, and citric acid as well as tens of other excipients that serve as binding materials, dyes, preservatives, or flavoring agents. Acid excipients, such as lactose, mannitol, and sorbitol, can induce drug instability in tablets ( 112 , 113 ), while basic excipients can be added to improve the stability of LT4 tablets ( 114 ). Manufacturers usually change formulations to avoid patent expiration.…”