Partial Dehydration of Levothyroxine Sodium Pentahydrate in a Drug Product Environment: Structural Insights into Stability

[helvella]

Over the years we have seen many discussions about storing levothyroxine.

◾ Should we refrigerate it?

◾ Can we freeze it?

◾ Does it make any difference if it is in a blister pack or "loose" in a pot?

◾ Can we put it into dosettes or other ways of organising medicines?

We have also seen questions over the difference between "levothyroxine sodium anhydrous" identified as an ingredient in some products. Indeed, that has cropped up often enough for me to have written a document which tries to explain how I see the issue:

dropbox.com/s/pqwuga75fxvkd...

I still don't have sufficient understanding to fully answer the questions! But I do appreciate that we need to think about what we do and not make assumptions.

This paper points out that there are issues. Many have realised that humidity affects levothyroxine. But fewer see that dryness might be just as big an issue.

Partial Dehydration of Levothyroxine Sodium Pentahydrate in a Drug Product Environment: Structural Insights into Stability

Navpreet Kaur 1 , Victor G Young Jr 2 , Yongchao Su 3 , Raj Suryanarayanan 1

Affiliations

• PMID: 32960611

• DOI: 10.1021/acs.molpharmaceut.0c00661

Abstract

Levothyroxine sodium pentahydrate (LSP; C15H10I4NNaO4·5H2O) gradually loses one molecule of water of crystallization as the water vapor pressure is decreased from 90% to 15% RH (40 °C), a behavior characteristic of nonstoichiometric hydrates. LSP loses four molecules of water of crystallization to form levothyroxine sodium monohydrate (LSM; C15H10I4NNaO4·H2O) under realistic storage conditions (40 °C/0% RH for 3 h). The crystal structure of LSP was determined following which the specimen was partially dehydrated in situ to form LSM. The crystal structure of LSM provided insight into its potential for high reactivity. Thus, its presence in a drug product is undesirable. In LSP-oxalic acid mixtures stored in a hermetic container at 40 °C, there was moisture transfer from drug to excipient. Synchrotron X-ray diffractometry revealed dehydration of LSP resulting in LSM, while anhydrous oxalic acid transformed to its dihydrate. In formulations of LSP, chemical degradation of levothyroxine sodium may be preceded by its partial dehydration.

Keywords: chemical stability; crystal structure; drug product; levothyroxine sodium; physical form.

pubmed.ncbi.nlm.nih.gov/329...

[nightingale-56]

Curiouser and curiouser, but thanks for this information helvella .

[TSH110]

I wonder if dehydration might also affect NDT....

[helvella Administrator Thyroid UK in reply to TSH110]

There are differences - we think that the thyroid hormone in desiccated thyroid is largely bound to proteins which could make a difference.

It is feasible that the same or similar effects might occur in desiccated thyroid.

But it would be very wrong to assume they do.

I have always had reservations about freezing desiccated thyroid products. But to me, the most obvious issue has always been the possibility of condensation as it is defrosted. And I have read several accounts of people who do freeze desiccated thyroid and claim it makes no difference.

[TSH110 in reply to helvella]

Thanks for your interesting reply. I have read advice to freeze it but I just keep it in a cool place to store it long term and the bottle I’m on I keep in the fridge always careful not to get any moisture in it. I had a pill cutter with some in that got damp and when I opened it the NDT was all mouldy 😱. I remember there was something you may have posted or commented on a while back about silica gel degrading NDT.