Levothyroxine sodium pentahydrate tablets - formulation considerations

[helvella]

Levothyroxine is reaching retirement! It has been available for just over sixty-five years.

Despite that, we still have to accept formulations which are problematic. This review paper summarises in its abstract two major causes of these problems. It then identifies shortcomings in the United States Pharmacopeia's methods of testing products.

This is despite many previous papers identifying formulation issues. Even specific excipients (inactive ingredients) that are known to cause problems.

Why does no-one seem to listen? Not to the science. Not to patients.

But do note that the suggested effects are separate to any personal sensitivity to the excipients. We might be entirely tolerant of all the excipients when they are used in foods, supplements or other medicines. But when used in levothyroxine, it appears they affect the actual active ingredient, the levothyroxine, itself.

(Obviously we need to avoid excipients to which we are sensitive.)

Perhaps this is why we stare at list of excipients, comparing them to other things we take, and however much we scratch our heads, we fail to confidently identify why one product is more acceptable than another.

J Pharm Sci. 2021 Aug 9;S0022-3549(21)00405-6.

doi: 10.1016/j.xphs.2021.08.006. Online ahead of print.

Levothyroxine sodium pentahydrate tablets - formulation considerations

Navpreet Kaur 1 , Raj Suryanarayanan 2

Affiliations

• PMID: 34384799

• DOI: 10.1016/j.xphs.2021.08.006

Abstract

Even though levothyroxine sodium pentahydrate tablets have been in the market since 1955, there continue to be recalls due to sub potency. We have comprehensively reviewed the factors affecting its stability in solid oral dosage forms. A compilation of marketed formulation compositions enabled the identification of the potential 'problem excipients'. Two excipient properties, hygroscopicity and microenvironmental acidity, appeared to be responsible for inducing drug instability. In drug products, depending on the formulation composition and storage conditions, the pentahydrate can dehydrate to highly reactive levothyroxine sodium monohydrate, or undergo salt disproportionation to the free acid form of the drug. The USP assay method (HPLC based) is insensitive to these different physical forms of the drug. The influence of physical form of levothyroxine on its chemical stability is incompletely understood. The USP has five product-specific dissolution tests reflecting the complexity in its evaluation.

Keywords: Levothyroxine sodium; drug product stability; excipients; tablets.

Abstract linked below but full paper is behind a paywall:

pubmed.ncbi.nlm.nih.gov/343...

[TSH110]

It annoys me to think of the way NDT has been rubbished as being of poor and unreliable potency complancently trotted out as a fact that applies to all NDT all the time everywhere, which is a complete lie. Yet Levothyroxine is anything but the perfect replacement drug it has been made out to be but it is now the only option offered by the NHS.

[Hidden]

At a similar age, NDT was said to be out-of-date and needing to be replaced with a more modern product. A single incident of sub-potency when the affected NDT pills, as far as I am aware, never even reached the market is still, many decades later, still quoted by some doctors as proof it should be banned. This review will undoubtedly be ignored and swept under the carpet.When presented with this and even more damning evidence, the reaction I have always received is simply to quote the information received from others that NDT is not recommended.

Even when I quote THEIR OWN RULES to the General Medical Council that every doctor MUST inform the patient of the existence of any medicine or equipment if they believe this might be of benefit, even if they are forbidden to prescribe it, I am ignored.

The desperate victims of this unbelievable rotten and totally avoidable treatment deserve better than this!

[BB001]

Nice find! Would you ok with me posting it in thyroidpatientscanada Facebook support group?

[helvella Administrator in reply to BB001]

Of course - anything I post can be copied and posted elsewhere.

But thanks for asking.

I refuse to touch facebook. I much prefer to fact that, having done my post, anyone, anywhere can read it. So I'll never know if you re-post it!

[BB001 in reply to helvella]

There are lots of really good articles you might like on thyroidpatients.ca which is their public website

[helvella Administrator in reply to BB001]

Yes - well aware and I've even posted links to Tania's articles.

[nellie237]

Am I right in thinking that this is basically the same as the MHRA Levothyroxine review in 2013, apart from being more forthright in saying "We still don't know how stable Levo is" ?

If you read between the lines of the MHRA report, and the statements about GP's being occasionally permitted to prescribe particular brands you know we have not been given a definitive answer, but...........these statements are a bit of a bomb if I ever need to argue a point with a Dr...

The USP assay method (HPLC based) is insensitive to these different physical forms of the drug. The influence of physical form of levothyroxine on its chemical stability is incompletely understood. The USP has five product-specific dissolution tests reflecting the complexity in its evaluation.

💣💣💣💣💥💥💥

[helvella Administrator in reply to nellie237]

Yet there are papers which say that lactose and mannitol are inappropriate excipients for levothyroxine. But every single UK product (except Aristo) contains one or the other.

At least some ingredients are absolutely known to be problematic.

[nellie237]

But at least if we need to we can say to Dr's No, you don't know