New Insights on Solid-State Changes in the Levothyroxine Sodium Pentahydrate during Dehydration and its Relationship to Chemical Instability

[helvella]

Yes - says "levothyroxine" on the packet. They're all the same.

Ah, but maybe, just possibly, there is a reason (other than patients thinking the colour of the packs clashes with their colour scheme) for us finding the various makes as different as we do. And this abstract gives a hint.

What it doesn't do is explain why the observed differences have the effects reported by patients but that might be in the full paper.

New Insights on Solid-State Changes in the Levothyroxine Sodium Pentahydrate during Dehydration and its Relationship to Chemical Instability

Authors

Authors and affiliations

Harsh S. Sha, Kaushalendra Chaturvedi, Mazen Hamad, Simon Bates, Ajaz Hussain, Kenneth Morris

1.Department of Pharmaceutical Sciences, Arnold and Marie Schwartz College of PharmacyLong Island UniversityBrooklynUSA

2.Department of Chemistry, College of Natural and Health SciencesUniversity of Hawai’i at HiloHiloUSA

3.Triclinic Labs Inc.LafayetteUSA

4.The National Institute of Pharmaceutical Technology and Education (NIPTE)MinneapolisUSA

5.Lachman Institute for Pharmaceutical AnalysisLong Island UniversityBrooklynUSA

6.Arnold and Marie Schwartz College of Pharmacy and Health SciencesLong Island University – Brooklyn CampusBrooklynUSA

Research Article Theme: Team Science and Education for Pharmaceuticals: the NIPTE Model

First Online: 02 January 2019

Part of the following topical collections:

Theme: Team Science and Education for Pharmaceuticals: the NIPTE Model

Abstract

Levothyroxine sodium pentahydrate (LEVO) tablets have been on the US market since the mid-twentieth century and remain the most highly prescribed product. Unfortunately, levothyroxine sodium tablets have also been one of the most highly recalled products due to potency and dissolution failures on stability. In 2008, the assay limits were tightened, yet the recalls did not decline, which highlights the serious quality concerns remaining to be elucidated. The aim of the present investigation was to test the hypothesis that the solid-state physical instability of LEVO precedes the chemical instability leading to product failure. The failure mode was hypothesized to be the dehydration of the crystal hydrate, when exposed to certain humidity and temperature conditions, followed by the oxidation of the API through vacated channels. It was previously reported by the authors that LEVO degradation occurred in the presence of oxygen at a low relative humidity (RH). Furthermore, powder X-ray diffractometry shows changes in the crystal lattice of LEVO initially and through the dehydration stages. Storage of LEVO at RT and 40 °C at 4–6% RH for 12 days shows a decrease in d-spacing of the (00 l) planes. Based on a structure solution from the powder data of the dehydrated material, the basic packing motif persists to varying degrees even when fully dehydrated along with disordering. Therefore, the crystal structure changes of LEVO depend on RH and temperature and are now explicable at the structural level for the first time. This exemplifies the dire need for “new prior knowledge” in generic product development.

KEY WORDS

crystal structure hydrate powder X-ray diffraction new prior knowledge levothyroxine

link.springer.com/article/1...

[TSH110]

Interesting post, thanks. Would the T4 in NDT be more stable? Perhaps it is a different form than this one.

[helvella in reply to TSH110]

It requires research directed towards finding that out!

Your question is one reason I am usually very neutral on the idea of freezing desiccated thyroid (or any other medicine, for that matter). The process of freezing results in changes to hydration - we have surely all seen "freezer burn" and the way ice crystals form on the underside of lids in freezers?

I accept that people have reported no difference when they use previously frozen desiccated thyroid.

[TSH110 in reply to helvella]

Even more interesting so nobody knows. I do keep mine in the fridge but not frozen. It does have some silica gel in with it so I assume that helps keep any moisture at bay, not sure it is so good for me though. It seems to be ok stored this way and a 1000 grains lasts me over a year it is in there being opened and closed for quite a duration. It is good to know all this. I might be better to just keep it in the cupboard.

[helvella in reply to TSH110]

The silica gel may keep moisture at bay but this article was investigating dehydration of the levothyroxine crystals. Silica gel or other desiccant could actually be the cause of the problem!

[TSH110 in reply to helvella]

Oh thanks for alerting me helvella I had better hoik it out! Any thoughts on fridge vs cupboard? It is in the kitchen so not damp but some moisture will be wafting about. In summer it can easily go over 20. What a blooming minefield storing the stuff is.

[helvella in reply to TSH110]

Sorry - the whole issue of storage has far too many unanswered questions. Other than generally cool, dark and dry, I have no detailed understanding or knowledge. And so much depends on our individual circumstances. We don't all have truly suitable locations.

[LindaC]

Thank you helvella, another for 'the file'.

I only took Levo for weeks/couple of months, tops. Initially made me feel great, getting up singing and dancing, could have kicked my height ['back to normal' I thought... I used to be like that ] - then very weird, horrible feelings - I had to stop - Dr Skinner prescribed Armour and... then Dr P = said T3 would be needed by me for life.

Back to the point - and to TSH110 - there would seem to be variations in batches of anything - but none more so than with this kind of stuff... hypothyroidism is not taken too seriously, and no one actually seems to give a damn - with the exception of some wonderful researchers... still fine people out there.

[SilverAvocado in reply to LindaC]

Heehee, I know exactly what you mean with the "Ooh.. I must be back to normal" thoughts

I've been getting a few of them this week on a new dose of T3

[TSH110 in reply to LindaC]

I think levothyroxine has had way more recalls than NDT, in the States anyway, so I thought the T4 in it must be more stable hence my question to helvella who knows about the machinations of such technical things. Looks like no one has actually studied it in NDT.

[LindaC in reply to TSH110]

He does indeed TSH110 - point being there are a lot of quality issues - I did have some with Armour Thyroid when I took that solely [April 2010 - Dec 2012] and the GP even prescribed it via NHS resources due to my experiences with 'variability'.

Yes, seems no one of late has studied this... 'they' seem to want it out of the way for 'King Levo' Lord help us, and I'm not at all religious xox

[TSH110 in reply to LindaC]

I hated the tyrannical rule of King Levo, give me Queen NDT anyday!

[LindaC in reply to TSH110]

Wish I'd never stopped taking it... did so well for 2 1/2 years - too scared to up the grain[age] and, in the days when ranges seemed to mean something i.e. via 'The Pharma God', GP kept trying but Labs refusing [even though NHS was funding my Armour... for years], I got too concerned and went over to T3, which I'd been told a few years before that I'd need for life. Good on T3 for 2 years... then it all unravelled, of course with a bit of help from an endo_cile.

Very best of on NDT, it is without doubt superior... how could it not be!?

[TSH110 in reply to LindaC]

I totally agree. It is the closest thing we can take to what we once made ourselves with a healthy thyroid. A recent study posted here was interesting the NDT scored very high on many parameters.T4/T3 was good but not as good, in most of the measures used. They didn’t do T3 alone or T4 alone. They had moved people off T4 monotherapy who were still not well (blood tests not normalised/complaints of enduring hypo symptoms). Men who think they can create solutions that are better than nature’s own design are kidding themselves, but they don’t kid me.

[LindaC in reply to TSH110]

I was about go back to a mixture of T3 and Armour [again] to try to lessen the former a bit and up Armour [ageing with heart issues, wanting to see if I could manage on less T3... likely need more!!], but another GP stopped my longstanding Armour prescription in Jan 2017... he has no clue about it and couldn't give a damn.

They're so shoddy... I'd be embarrassed to take a pay cheque in the shoes of many of them... that's just the endos

[TSH110 in reply to LindaC]

That’s awful - I do my own thing and leave doctors completely out of my thyroid treatment. I would be furious if I had a prescription for NDT and a GP stopped it. It is criminal. I agree that for £100k+ a year plus the grotesque perks/private patients etc I expect better of medical professionals, how do some of them sleep at night? Soundly it seems.

[LindaC in reply to TSH110]

Many GP's have no clue and are best left out - besides endos NOW dictate what GPs need to be thinking which, even at the time of *Hunt*, certainly was not the case. I wish I'd known in 2007/08 what I know now - I originally paid privately for Armour Thyroid, then the GP funded this through NHS resources. Via Dr P's advice, I always sourced T3 privately to ensure the best quality.

Agreed. It feels akin to being criminal for those wholly left at their mercy - but and it's a big BUT - should any other health complaint arise [given how many systems the thyroid governs within our body], 'they' will blame the patient treating themselves... basically, I just wish I'd not gone near any of them. I needed a referral to Dr Skinner so GP had to be involved. That wonderful doctor is still ridiculed to this day in certain quarters by 'filthy misogynists'... just as lawyers, they all P in the same pot and, before you know it, they close ranks, the patient is blamed, then F*ed over. (No, not paranoid... my academic and prior work background ensures that I'm semi-saved - to this point - but they certainly try... ) I'm on their case now... too ill now to do this quickly... watch this space.

Any humane person would not sleep at night, taking a pay cheque against their own Oath, knowingly - in the name of their little 'Boys Club' expedience - harm patients, but then they're not 'mere mortal' in that sense; for me they're now creatures of the night. Someone will catch them out... one day, as being a party to one of the greatest health'care'? shams/scams in modern times: I hope I'm still around to see that day. Oh, let us not forget our CFS/ME friends.

Keep on doing what you're doing - best wishes, take care and be well xox

[TSH110 in reply to LindaC]

I am thinking today with the latest pronouncements on primary health care if they want to nip stuff in the bud as they are claiming then treating hypothyroidism in a timely manner and allowing proper treatment choice for patients would be a jolly good place to start, not cut T3, ban NDT and underdose everyone on Levothyroxine and blame the patient for still feeling unwell! Ram antidepressants and a plethora of other expensive medications down our gobs when all that’s needed it optimised throid hormone replacement therapy. As for the long term consequences of such medical negligence to the individual and the economy it beggars belief. Sadly weight gain is so common, but get this they are targeting overweight people and playing the blame game. I was shocked to read some awful comments on Michael Mossleys Twitter claiming no one ever eats 1000 calories a day and stays fat. I’d like to give them a dose of overt hypothyroidism and let them dare say that. No comprehension of this disorder at all or it’s role in metabolism and causing weight gain. Nothing a bit of T3 couldn’t rectify for the majority. The whole business makes me mad. Misogyny ++

[LindaC in reply to TSH110]

Absolutely - to everything you say! As for that 'Boys Club Pet Theories Brigade' - they ought to be prosecuted... I will publish and be damned!

[LindaC in reply to TSH110]

They have absolutely NO clue about metabolism - weight loss - it is scandalously unbelievable that in this 21st C we find ourselves in this position. That old CI-CO junk... I am by now tired of explaining why this is ludicrous but they won't have it AT ALL. I believe that every 'doctor in training' must spend long weekends being rendered, Hypothyroid, given the equiv of CFS/ME... having to wear very well made 'fat suits' in public, etc... the level of knowledge and investigative curiosity seems to have escaped them... time to 'enforce it'. Ha ha!

[Nanaedake]

Thank you. I've had lots of problems with levothyroxine quality and potency so very interesting and follows on from previous investigations into levothyroxine. I don't think the problems have been resolved yet.

[TSH110 in reply to Nanaedake]

I wonder if they can be resolved? I suppose clever chemists are working on it and yet more mice are suffering. May be one day they will get us all properly better but it seems the converse has happened and treatment is getting worse with inadequate dosage let alone that the dosage is volatile in itself.

[Nanaedake in reply to TSH110]

I think there is a great lack of monitoring at primary care level so that the problems are not being monitored properly or picked up early enough. People are left to, 'get on with it' and it's often difficult to determine what is causing the problems, especially when blood tests are infrequent. Therefore, I don't think the extent of the problems are being reported to the MHRA who should be monitoring quality of human medicines. I'm not even sure if the MHRA are acting on the information they recieve in a timely way.

[TSH110 in reply to Nanaedake]

I am sure you are right. I had never even heard of a yellow card before I came on this forum and links to info on TUK. You’d think people on life long medication that is imperative to their survival ought to be informed of its existence. I get so many weird aches and pains even now and have no idea why I have them except they seem like ones I had when I was hypothyroid/not optimised the latest is a sore lower left jaw at 5pm every day and pains in my left hip but they will suddenly stop for a week or so - drives me nuts but if I can’t determine what’s doing it I know a GP has no chance and they’d think I was nuts! I don’t feel at all undermedicated so who knows. If it were due to variations in drug quality the T4 takes so long to get used up it could be really difficult to make that link.

[helvella in reply to TSH110]

It wasn't so many years ago that they had to be submitted via medical professionals.