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

Shah, Harsh; Chaturvedi, Kaushalendra; Hamad, Mazen L.; Bates, Simon; Hussain, Ajaz; Morris, Kenneth R.

doi:10.1208/s12249-018-1264-0

Cited by 26 publications

(43 citation statements)

References 41 publications

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“…Such behaviour concerning anhydrate being more stable at lower RH and a hydrate at higher RH is a general rule. However, at very high RH , drug substances are prone to degradation and this is the reason the ICH guidelines suggest performing stability studies in accelerated conditions of 40 °C/75% RH [ 147 ]. Though, there are some exceptions, like levothyroxine sodium pentahydrate which remains stable even at high RH rates and is unstable at lower ones [ 148 ].…”

Section: Hydrates’ Stability Selected Cases Within the Last 10 Yementioning

confidence: 99%

Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances

et al. 2020

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This review discusses a set of instrumental and computational methods that are used to characterize hydrated forms of APIs (active pharmaceutical ingredients). The focus has been put on highlighting advantages as well as on presenting some limitations of the selected analytical approaches. This has been performed in order to facilitate the choice of an appropriate method depending on the type of the structural feature that is to be analyzed, that is, degree of hydration, crystal structure and dynamics, and (de)hydration kinetics. The presented techniques include X-ray diffraction (single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD)), spectroscopic (solid state nuclear magnetic resonance spectroscopy (ssNMR), Fourier-transformed infrared spectroscopy (FT-IR), Raman spectroscopy), thermal (differential scanning calorimetry (DSC), thermogravimetric analysis (TGA)), gravimetric (dynamic vapour sorption (DVS)), and computational (molecular mechanics (MM), Quantum Mechanics (QM), molecular dynamics (MD)) methods. Further, the successful applications of the presented methods in the studies of hydrated APIs as well as studies on the excipients’ influence on these processes have been described in many examples.

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Section: Hydrates’ Stability Selected Cases Within the Last 10 Yementioning

confidence: 99%

Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances

et al. 2020

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“…In 2019, Lipp and Hostalek [6] developed a new formulation of levothyroxine which is more stable, with a shelf life of three years, independent of geographic climate zones. Shah et al studied the solid-state changes that take place during LTSS pentahydrate dehydration and its correlation to chemical instability, since tablets containing this API were one of the most highly recalled products due to potency and dissolution failures on stability [12]. Also, since LTSS has a NTI, the splitting of tablet can lead at under or excessive dosage, since distribution of API in solid formulation can be heterogeneous and dependent on type of binder and the process used in the manufacture of tablets [22].…”

Section: Concordet Et Al Reported In March 2017 a New Formulatimentioning

confidence: 99%

“…It was suggested that the possible reasons for degradation of levothyroxine were the use of different excipients, the pH of the formulation, and the compression force used during tablet compaction. Therefore, a careful selection of excipients could be helpful to prevent potency loss over the shelf life of the tablets of levothyroxine [12].…”

Section: Concordet Et Al Reported In March 2017 a New Formulatimentioning

confidence: 99%

“…Several recent publications investigated the stability of levothyroxine, and the development of new formulations with better stability [6,[8][9][10][11][12][13][14][15][16][17][18][19]. The effect of excipients on the stability of levothyroxine sodium pentahydrate tablets was studied by Gupta et al and reported in 1990 [20] and aimed towards the transformations that took place in a solid formulation containing LTSS along with excipients that act as a catalyst to decomposition of API, leading to a shorter shelf-life of the product than the one mentioned by the manufacturer.…”

Section: Introductionmentioning

confidence: 99%

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Stability and Compatibility Studies of Levothyroxine Sodium in Solid Binary Systems—Instrumental Screening

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The influence of excipients on the stability of sodium levothyroxine pentahydrate (LTSS) under ambient conditions and thermal stress was evaluated. Since LTSS is a synthetic hormone with a narrow therapeutic index, the interactions of LTSS with excipients can lead to a drastic diminution of therapeutic activity. Ten commonly used pharmaceutical excipients with different roles in solid formulations were chosen as components for binary mixtures containing LTSS, namely, starch, anhydrous lactose, D-mannitol, D-sorbitol, gelatin, calcium lactate pentahydrate, magnesium stearate, methyl 2-hydroxyethyl cellulose (Tylose), colloidal SiO2 (Aerosil) and talc. As investigational tools, universal attenuated total reflectance- Fourier transform infrared spectroscopy UATR-FTIR spectroscopy and thermal analysis were chosen and used as follows: UATR-FTIR spectra were drawn up for samples kept under ambient conditions, while thermoanalytical tools (TG/DTG/HF data) were chosen to evaluate the inducing of interactions during thermal stress. The corroboration of instrumental results led to the conclusion that LTSS is incompatible with lactose, mannitol and sorbitol, and these excipients should not be considered in the development of new generic solid formulations.

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“…In hypothyroidism disease, the primary function of the human thyroid, endogenous production of thyroxine (T4), and triiodothyronine (T3) is below normal. Enough secretion of these thyroid hormones is essential to maintain cardiovascular, physical, and mental health, as well as the growth and development of children which is done via the regulation of gene transcription [1,2]. Levothyroxine (T4), as a thyroidstimulating hormone, is primarily used in the treatment of hypothyroidism.…”

Section: Introductionmentioning

confidence: 99%

Optimization and in Vitro Evaluation of Injectable Sustained-Release of Levothyroxine Using PLGA-PEG-PLGA

et al. 2020

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Purpose In situ-forming gels (semi-solid state) (ISFGs) are widely used as sustained drug delivery, but they show a high burst release as well. The purpose of the current study is to make triblock that can make a quick gel on injection with a minimum burst release. Methods In this study, to control the release of levothyroxine from ISFG, PLGA-PEG-PLGA (triblock) polymer was used. The melting method was employed to synthesize the triblock via ring-opening polymerization (ROP). Different weight percentages of triblock in the formulation were investigated to reach the minimum initial burst release of levothyroxine from ISFGs. Furthermore, the results of the in-situ forming implant (solid-state) (ISFI) of levothyroxine prepared from PLGA 504 H polymers were compared with ISFG. Results The melting method employed in this study showed a successful ROP of the triblock. As the % triblock concentration was increased from 30 to 50%, the initial burst release decreased significantly. The initial burst release levothyroxine from ISFG (6.52 ± 0.30%) was much lower than the amount of levothyroxine released from ISFI (14.15 ± 0.79%). No cytotoxicity was observed for the sustained-release formulation containing ISFG 50% according to the MTT assay. Conclusion The results indicated that this formulation was safe to be administered subcutaneously. As the synthesized triblock has thermosensitive properties, and also has the hydrogen bonding between the N-methyl pyrrolidone molecules and PEG, therefore, these properties make ISFG formulation to have a smaller initial burst release compared to ISFI formulation.

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

Cited by 26 publications

References 41 publications

Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances

Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances

Stability and Compatibility Studies of Levothyroxine Sodium in Solid Binary Systems—Instrumental Screening

Optimization and in Vitro Evaluation of Injectable Sustained-Release of Levothyroxine Using PLGA-PEG-PLGA

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