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

[helvella]

There has been a tiny rivulet of papers questioning the formulation of levothyroxine products. Time and again, the papers identify problems with excipients of which a large proportion of real products contain at least one.

I'm sure it is not the entire picture. But this rivulet has been flowing for decades and yet we see even relatively new formulations containing some of these.

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

• Navpreet Kaur

and

• Raj Suryanarayanan*

Cite this: Mol. Pharmaceutics 2021, XXXX, XXX, XXX-XXX

Publication Date:June 1, 2021

doi.org/10.1021/acs.molphar...

© 2021 American Chemical Society

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.

KEYWORDS:

• levothyroxine

• salt disproportionation

• excipient compatibility

• stability

• drug product

pubs.acs.org/doi/10.1021/ac...

[Rapunzel]

I can feel another excipient fest coming on...

[crimple]

Thanks for posting helvella. It never ceases to amaze me what strange things are used as excipients. 😱 for instance acacia powder!!! Unless you are a koala bear why would you eat acacia.

[helvella Administrator in reply to crimple]

The health food and supplements food industry has many claims for acacia including as a powder.

Just one example:

healthline.com/health/7-use...

There was a quite long thread over five years ago!

healthunlocked.com/thyroidu...

And this European Food Standards Agency assessment:

efsa.onlinelibrary.wiley.co...

[crimple]

Thanks for the links helvella, interesting reading. I always check food labels anyway and avoid honey , since noting my reaction to acacia, unless it is from a named species, such as heather or orange blossom! The PIL for my Sigma Pharma T3 is in small print and you almost need a microscope to find the para about ingredients. You would have thought that the info would be more prominent and of course it isn't on the outside of the tablet box. I didn't open the boxes of Eltroxin but went straight to this page to search. Found the info in acouple of minutes, thanks again.

[helvella Administrator in reply to crimple]

Probably much easier to read online! Section 11 here:

dailymed.nlm.nih.gov/dailym...

Liothyronine Sodium Tablets, USP contain liothyronine sodium equivalent to liothyronine in 5 mcg, 25 mcg, and 50 mcg. Inactive ingredients consist of calcium sulfate dihydrate, corn starch, gelatin, magnesium stearate and mannitol.