Potency and Powder X-ray Diffraction (PXRD) Evaluation of Levothyroxine Sodium Tablets under Ambient, Accelerated, and Stressed Conditions

Abstract

Levothyroxine tablets, although highly prescribed in the United States, have been one of the most frequently recalled products. Because of the importance of the medication, several efforts have been put in place by the United States Food and Drug Administration (US FDA) to control the quality of levothyroxine tablets available to patients using the drug. The choice of excipients used in the formulation has been shown to impact the hygroscopicity and microenvironment, and ultimately the stability of the levothyroxine tablets formulations. Based on information generated from the US FDA Enforcement Report database, one of the main reasons for recalls is the low potency of different batches of the product. The yearly product recall trends for levothyroxine formulations were determined using the FDA Enforcement Report database. Three brands of levothyroxine tablets were selected with excipient lists similar to those products that have been historically recalled. The samples were placed at ambient (~23 °C), accelerated stability (40 °C/75% RH), and stress (50 °C/75% RH) conditions for up to 6 months. Sample potencies were determined at 0, 1.5, 3, and 6 months using the methods for assay and impurities in the United States Pharmacopeia (USP) monograph for levothyroxine tablets. Additional sample monitoring was conducted by overlaying the initial powder X-ray diffractograms (PXRD) of the samples from 0 months with the patterns generated thereafter. There has been a decline in the number of levothyroxine tablets recalled over the years. The highest numbers of recalls were recorded in the years 2013 [33] and 2020 [23]; no recalls occurred in the years 2019 and 2022. All of the brands evaluated met the USP 95.0-105.0% assay requirements at 1.5 months under accelerated conditions; only one of the brands complied at 3 months. Under ambient conditions, two brands were stable at 6 months, with borderline assay results. For stability, levothyroxine was found in microgram quantities in the formulations and PXRD could not detect changes at these low levels. However, we found some distinguishing data for samples under stress conditions.

Keywords: FDA; degradation; enforcement report; levothyroxine; reference standards; stability.

Scheme 1

Adapted from Won [23].

Figure 1

Summary of number (#) of levothyroxine formulations recalls from the US FDA Enforcement database from 8 June 2012 to 31 December 2022.

Figure 2

There were minimal overlaps in the initial PXRD from the brands (A–C) when compared with the innovator’s pattern deposited in the CCDC website.

Figure 3

Overlays comparing the PXRD of brands A, B, and C of levothyroxine tablets at 0, 1.5, 3, and 6 months. Additional diffraction patterns are observed for brands A and B at 3 and 6 months for the samples stored under stressed conditions (50 °C/75% RH).

Figure 4

Results obtained from mapping 9 points within the ovens used to place samples under accelerated stability and stress conditions for the study.