Is there a difference as far as patients are concerned?
Probably not!
We don't always know which form was used in the factory. And we have even less of an idea what form ends up in the tablets.
The rest (below) attempts to explain.
If you read about levothyroxine, especially as a medicine, you will see mention of two forms used as the Active Pharmaceutical Ingredient (API) in levothyroxine medicines: levothyroxine sodium (anhydrous) and levothyroxine sodium. The second form of words doesn’t make it clear, it could refer either to the anhydrous form or to a hydrated form. We have to try to interpret from context and any other information present.
There is a genuine difference between levothyroxine sodium (anhydrous), levothyroxine sodium monohydrate, and the most common hydrated form, levothyroxine sodium pentahydrate.
Five water molecules are attached to the pentahydrate; one to the monohydrate; none to the anhydrous.
Discussion
You can see that the image of the pentahydrate molecular formulas has ten Hydrogen atoms and five Oxygen atoms - which is five lots of H2O - water! And the monohydrate by two Hydrogen atoms and one Oxygen atom. The molecular diagram tries to represent this by showing five molecules of water.
Initially, that difference might seem important. But possibly less so as we look further. Please note that it is possible for levothyroxine monohydrate to exist – and possibly other forms with further degrees of hydration.
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).
Up to and including British Pharmacopoeia (BP) 1973 this was not the case. However, it was clearly required from British Pharmacopoeia (BP) 1980 forwards. Companies were required to reformulate their levothyroxine products which resulted in an increase in potency of around 11%. The pharmaceutical industry had to hold back new BP 1980 tablets until that BP came into force on 1st December 1980. Thereafter, BP 1973 stock could not be dispensed. New product conforming to BP 1980 was labelled “revised strength”. And a 25 microgram tablet was introduced by Thomas Kerfoot to help with the transition!
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! However, assuming it is the most common lactose monohydrate, there is potentially vastly more than enough water there to supply the 2.8 micrograms to change the levothyroxine sodium anhydrous into levothyroxine sodium pentahydrate. (There is, after all, more than a thousand times as much lactose as levothyroxine sodium, by weight.)
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 current manufacturing processes and therefore cannot know if any of them are “wet”, or not.
Even a notionally dry process could pick up water from the atmosphere. There might be limits on the humidity allowed in the factory but there will still be the possibility of some water being picked up.
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. Any was anhydrous in the tablet 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.
Conclusion
Some products do not make clear whether they were manufactured using the anhydrous or the pentahydrate form. As the manufacturer must literally weigh out the levothyroxine, they need to have known which form it was in at that point in order to correctly mix the product.
None of this proves that there could not possibly be any effective difference between products which refer to the pentahydrate and those that refer to the anhydrous form.
It should be clear that it seems less than likely to make a difference. Other factors seem likely to be more important than the hydration of the levothyroxine ingredient.
Historic Note
The British Pharmacopeia of 1980 changed the calculation of levothyroxine to specify anhydrous levothyroxine. As of 1st December 1980 this change was made across all available UK products. This represented an increase in dose of around 11%. Some patients required dose adjustments.
Prior to this, it was based on a hydrated form of levothyroxine but that was an issue as it can change between monohydrate and pentahydrate (and probably intermediate forms) while stored.
References
Partial Dehydration of Levothyroxine Sodium Pentahydrate in a Drug Product Environment: Structural Insights into Stability
Navpreet Kaur, Victor G. Young, Yongchao Su, and Raj Suryanarayanan
Molecular Pharmaceutics 2020 17 (10), 3915-3929
DOI: 10.1021/acs.molpharmaceut.0c00661
pubs.acs.org/doi/10.1021/ac...
Kaduk, J., Zhong, K., Blanton, T., Gates, S., & Fawcett, T. (2015). Powder X-ray diffraction of levothyroxine sodium pentahydrate, C15H10I4NNaO4(H2O)5. Powder Diffraction, 30(4), 370-371. doi:10.1017/S0885715615000676
cambridge.org/core/journals...
The above is more or less quoted from my Vade Mecum.
helvella - Vade Mecum for Thyroid
The term vade mecum means:
1. A referential book such as a handbook or manual.
2. A useful object, constantly carried on one’s person.
Please don't get put off by the number of pages!
In particular, it is not intended that you sit and read the document. Just that you download it and know you can look things up.
Not everything is in this one document - my major medicines document is still separate!
From Dropbox:
dropbox.com/s/vp5ct1cwc03bl...
From Google Drive:
Eltroxin contains anhydrous levothyroxine or not???
Which manufacturer?
Mercury Pharma Levothyroxine ingredients 
