Excipients and Levothyroxine

[helvella]

A few links to papers which have looked at the effects of excipients on levothyroxine. Notably lactose and all acidic excipients.

One paper actually suggests that changing the standards is the appropriate way of handling an out-of-specification result. My view is that while they might be right about the relative unimportance of the substance found, the formulation should be re-considered from scratch.

Advancing drug safety and mitigating health concerns: High-resolution mass spectrometry in the levothyroxine case study

Abstract

Levothyroxine is a drug with a narrow therapeutic index. Changing the drug formulation composition or switching between pharmaceutical brands can alter the bioavailability, which can result in major health problems. However, the increased adverse drug reactions have not been fully explained scientifically yet and a thorough investigation of the formulations is needed. In this study, we used a non-targeted analytical approach to examine the various levothyroxine formulations in detail and to reveal possible chemical changes. Ultra-high-performance liquid chromatography coupled with a data-independent acquisition high-resolution mass spectrometry (UHPLC-DIA-HRMS) was employed. UHPLC-DIA-HRMS allowed not only the detection of levothyroxine degradation products, but also the presence of non-expected components in the formulations. Among these, we identified compounds resulting from reactions between mannitol and other excipients, such as citric acid, stearate, and palmitate, or from reactions between an excipient and an active pharmaceutical ingredient, such as levothyroxine-lactose adduct. In addition to these compounds, undeclared phospholipids were also found in three formulations. This non-targeted approach is not common in pharmaceutical quality control analysis. Revealing the presence of unexpected compounds in drug formulations proved that the current control mechanisms do not have to cover the full complexity of pharmaceutical formulations necessarily.

Quote:

Hence, lactose is an example of an inappropriate excipient.Surprisingly, it is still used in some levothyroxine formulations

sciencedirect.com/science/a...

Lactose intolerance and levothyroxine malabsorption: a review of the literature and report of a series of patients treated with liquid L-T4 without lactose.

Abstract 

In hypothyroid patients needing large doses of levothyroxine (L-T4) (>1.7-2 μg/kg/day) to reach euthyroidism, lactose intolerance (LI) needs to be excluded, owing to the high prevalence in the population. If LI is present, a lactose-free diet decreases the rate of L-T4 malabsorption. However, an increased requirement of L-T4 is described in patients with LI, which can be beneficially treated using lactose-free L-T4 formulation. The lactose-free liquid L-T4 formulation is able to circumvent LI malabsorption leading to the normalization of thyroid-stimulating hormone (TSH) in patients with subclinical hypothyroidism and long-term stable TSH levels.

europepmc.org/article/MED/3...

Investigating the Influence of Excipients on the Stability of Levothyroxine Sodium Pentahydrate

Abstract

A range of tablet excipients were evaluated for their influence on the physical form and chemical stability of levothyroxine sodium pentahydrate (LSP; C15H10I4NNaO4·5H2O). LSP–excipient binary powder blends were stored under two conditions: (a) in hermetically sealed containers at 40 °C and (b) at 40 °C/75% RH. By use of synchrotron X-ray diffractometry, the disappearance of LSP could be quantified and the appearance of crystalline levothyroxine (free acid) could be identified. Under hermetically sealed conditions (40 °C) hygroscopic excipients such as povidone induced partial dehydration of LSP to form levothyroxine sodium monohydrate. When stored at 40 °C/75% RH, acidic excipients induced measurable disproportionation of LSP resulting in the formation of levothyroxine (free acid). HPLC analyses of drug–excipient mixtures revealed that lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium caused pronounced chemical decomposition of LSP. On the other hand, magnesium stearate, sodium stearyl fumarate, and alkaline pH modifiers did not affect the physical and chemical stability of the API following storage at 40 °C/75% RH. HPLC, being a solution based technique, revealed chemical decomposition of the API, but the technique was insensitive to physical transformations. Excipient properties such as hygroscopicity and microenvironmental acidity were identified to be critical determinants of both physical and chemical stability of LSP in a drug product. For drugs exhibiting both physical and chemical transformations, simultaneous solid-state and solution based analyses will enable comprehensive stability evaluation.

Abstract only (full paper behind paywall)

pubs.acs.org/doi/10.1021/ac...

Levothyroxine Sodium Pentahydrate Tablets − Formulation

A B S T R A C T

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.

jpharmsci.org/article/S0022...

Preclinical toxicological assessment of levothyroxine and liothyronine Maillard impurities.

Abstract 

Background

Following the introduction of new stability-indicating related substances methods, an unknown impurity was observed in levothyroxine (LeMI) and liothyronine (LiMI) tablets (ADVANZ PHARMA) in concentrations ≥1.0%, from 6 months of storage onwards. The impurity was identified as a Maillard condensation product between lactose and LeMI/LiMI in the LeMI and LiMI tablets, respectively.

Materials and methods

To establish the toxicity profile of LeMI and LiMI in humans and to define appropriate shelf-life specification limits, a comprehensive nonclinical toxicological assessment was performed, including in silico (Leadscope and Derek Nexus analyses), in vitro (Ames test), and in vivo tests (7-day dose range finding and 90-day dose repeat studies in rats). In silico analyses indicated that potential LeMI and LiMI structures should not be considered bacterial mutagens or in vitro/in vivo clastogens, and that at the low oral exposure levels expected, the impurities are unlikely to cause harm.

Results

In vitro testing showed that neither LeMI nor LiMI were cytotoxic or mutagenic at up to 5000 μg/plate, both in the presence and absence of metabolic activation. The 2 in vivo studies further confirmed that no systemic toxicity or other notable negative effects were evident at up to 200 μg/kg/day for LeMI and 45 μg/kg/day for LiMI, the highest doses tested. These doses represent 120-122 times the maximum daily exposures of LeMI and LiMI, based on body surface area (μg/m2).

Conclusions

Based on these results, a proposal has been formulated to increase the limits of Maillard condensation products to ≤8.0% for LeMI and ≤6.0% for LiMI at shelf life.

europepmc.org/article/MED/3...

helvella - Excipients and Levothyroxine

A few links to papers which have looked at the effects of excipients on levothyroxine. Notably lactose and all acidic excipients.

Last updated 20/10/2024

helvella.blogspot.com/p/hel...

[helvella Administrator]

The following excipients are expressly mentioned in these papers:

Mannitol

Lactose

Povidone

Microcrystalline cellulose

Croscarmellose sodium

Every UK-licensed levothyroxine includes at least one of these! Most contain two or more.

[BB001]

Recognition at last that:

'Changing the drug formulation composition or switching between pharmaceutical brands can alter the bioavailability, which can result in major health problems.'

Patients have being saying this for ages.

A fair bit of this went over my head.

However I was concerned about the following statement.

'Based on these results, a proposal has been formulated to increase the limits of Maillard condensation products'.

So, based on only one set of results, a formulation standard should be changed! I personally would want the results to be verified by other research before standards were changed. Also, it would be good to see these results reproduced by using actual people, not just by chemical analyses.

[helvella Administrator in reply to BB001]

Certainly I agree with your sentiment!

However, the human testing came before the substances were even identified! As I read it, the people are from Advanz Pharma and - with new methods - they found things they had not previously seen. Likely they have been present forever. Therefore human tested in everyone who takes Mercury Pharma levothyroxine or liothyronine.

But I absolutely agree that chemists from one manufacturer should not be used to justify changes to standards. It is a nonsense. And I hope that chemists from other manufacturers - who do NOT see these substances at all , or only at much lower levels - would jump in and argue against changes to standards.

Maillard reactions are between reducing sugars and amino acids. Make products without any sugars and you solve this problem. I note that Aristo Vencamil has no sugar content - no lactose, no sucrose, no mannitol. Therefore it can be done.

[Tina_Maria]

Sadly, excipients are necessary, as no pharmaceutical ingredient can be administered in its pure form. To make a pharmaceutical substance ready to be administered to a patient, it needs to be me made into a formulation, so it can be easily absorbed and therefore increase the bioavailability of the pharmaceutical ingredient in the body (it helps to get it to where it is needed). Most formulations are already determined in pre-clinical trials and can be adapted in clinical trials (preferred formulations are tablets or capsules for oral application).

Excipients are inert substances and only added to the pharmaceutical compound to increase bioavailability, in the lowest possible concentration. Most manufacturers add in excipients that are well known, hence lactose is often added (as it is tried and tested), even when it seems an unnecessary addition. If you would like to add a new excipient to your formulation, manufacturers have to perform new clinical trials and the excipient also has to have a licence (FDA, EMA, MHRA approval) to be able to be used in a formulation. As this is an expensive business and especially if you are in the generics business, you would not want to have this expenditure and would therefore rather rely on tried and tested substances.

[helvella Administrator in reply to Tina_Maria]

A major part of the issue is that excipients are NOT inert. Specifically lactose. And even more specifically lactose use in formulation of levothyroxine.

[Tina_Maria in reply to helvella]

Problem is though how do you prove that lactose for example is not inert (not saying that it isn't) - if it has been tested before and the regulator has accepted it, it is very difficult to challenge that. And like I said, sadly unless you design trials to show that it isn't inert, you would have no comeback.

That's really the whole problem with excipients, some people are fine with them, but some are not - and those that are not will have to see if they can find a different formulation they can tolerate better. Agree, some excipients such as lactose should be kept out of formulations, especially as more and more people are intolerant - but unless you find something that does the same job at a similar cost, it will be difficult.