Levothyroxine sodium – Anhydrous vs. Pentahydrate

[helvella]

There is a difference between levothyroxine sodium (anhydrous) and the most common hydrated form, levothyroxine sodium pentahydrate.

Five water molecules are attached to the levothyroxine sodium molecule in the pentahydrate; none in the anhydrous.

Levothyroxine sodium pentahydrate

Also known as: L-Tyrosine, O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-, sodium salt, pentahydrate

Molecular Weight: 888.928249 [g/mol]

Molecular Formula: C15H20I4NNaO9

Levothyroxine sodium anhydrous

Also known as: Levothyroxine sodium, Unithroid, levothroid, Euthyrox, Levoxyl, Novothyrox, Sodium thyroxinate, L-Thyroxine sodium, Sodium L-thyroxine

Molecular Formula: C15H10I4NNaO4

Molecular Weight: 798.851849

You can see that the two molecular formulas differ by ten Hydrogen atoms and five Oxygen atoms - which is five lots of H2O - water!

Initially, that difference might seem important. But possibly less so as we look further.

First: All levothyroxine products are assessed as to how much levothyroxine sodium they contain. The 25/50/100 micrograms (or whatever other dosage) printed on the pack is always assessed in terms of anhydrous levothyroxine sodium.

One UK make even clarifies:

Each tablet contains 27.8 micrograms of levothyroxine sodium equivalent to 25 micrograms of levothyroxine sodium anhydrous.

medicines.org.uk/emc/produc...

The difference between using the pentahydrate and the anhydrous forms for that tablet is just 2.8 micrograms of water (in a 25 microgram tablet).

Second: Another tablet clearly states how much lactose it contains:

Lactose 30.49mg per tablet

medicines.org.uk/emc/produc...

It doesn't even state whether that is lactose monohydrate or lactose anhydrous! But, assuming it is the most common lactose monohydrate, there is potentially more than enough water there to supply the 2.8 micrograms to change the levothyroxine sodium anhydrous into levothyroxine sodium pentahydrate.

I don't know if that happens - or not.

Third: The manufacturing process could hydrate the levothyroxine sodium anhydrous. In the document I referred to earlier, it says:

The old formulation of Eltroxin was manufactured by blending all the ingredients except for the magnesium stearate and a portion of the maize starch. The blend was wet granulated and the granules dried and blended with the magnesium stearate and remaining portion of the maize starch prior to compression into tablets.

medsafe.govt.nz/hot/alerts/...

Being a wet process, there will be plenty of water around. I do not have details of manufacturing processes and therefore cannot know if any are “wet”, or not.

Fourth: Levothyroxine sodium can both acquire and lose water molecules depending on precise circumstances such as humidity of the air both inside its packaging and when opened. We have already said what a tiny amount of water is involved.

Fifth: Usual advice is to swallow levothyroxine sodium tablets with water. (This is mandated for some tablets but is advised for most or all.) Most levothyroxine tablets are not coated. Hence, it is unlikely that much levothyroxine sodium will even get to the stomach without being hydrated. Primary absorption of levothyroxine is in the duodenum so all the levothyroxine sodium will have been in the moist or wet stomach and then passed through to the intestine before being absorbed. And that remained anhydrous in the stomach would surely be fully hydrated by then?

Sixth: Any levothyroxine oral solution would inherently have only hydrated levothyroxine sodium even if the original ingredient were levothyroxine sodium (anhydrous).

Seventh: Finally, once it has passed through the gut wall into the bloodstream, there is no doubt at all it will be hydrated.

None of this proves that there is no effective difference between the pentahydrate and anhydrous forms. Though it should be clear that it seems less than likely to make a difference.

(There was a question about this the other day but I have been unable to locate it.)

[Nanaedake]

What I'm wondering is whether there are any studies in whether taki g levothyroxine orally affects gut flora and consequently nutrient absorption? I thought it was absorped in the terminal illium and B12 is also absorped there but I could be entirely wrong.

Yes, there was a query raised the other day. Some people do seem to have trouble swapping levothyroxine from from formulation to another. It might be the fillers but it might not. Given the complexity of manufacturing levothyroxine and the vagaries of gut absorption it seems like there's plenty of potential for things to go wrong.

[helvella Administrator Thyroid UK in reply to Nanaedake]

This quote sums it up as I understand it:

Absorption and Bioavailability

Levothyroxine is mainly absorbed in the small intestine, more specifically through the duodenum, jejunum and ileum. Very little is absorbed in the stomach. Consequently, patients with shorter small intestines (bowel resection) have reduced absorption and require higher levothyroxine doses. The time to maximum concentration (Tmax) occurs at approximately 2 hours in euthyroid volunteers while it is delayed to approximately 3 hours in hypothyroid patients. Food also delays Tmax.

ncbi.nlm.nih.gov/pmc/articl...

[Nanaedake in reply to helvella]

Very interesting read. Clearly there's still more to discover about how to dose optimally with levothyroxine.