Skip to main content
SpringerLink
Log in

Influence of Formulation and Processing Factors on Stability of Levothyroxine Sodium Pentahydrate

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Stability of formulations over shelf-life is critical for having a quality product. Choice of excipients, manufacturing process, storage conditions, and packaging can either mitigate or enhance the degradation of the active pharmaceutical ingredient (API), affecting potency and/or stability. The purpose was to investigate the influence of processing and formulation factors on stability of levothyroxine (API). The API was stored at long-term (25°C/60%RH), accelerated (40°C/75%RH), and low-humidity (25°C/0%RH and 40°C/0%RH) conditions for 28 days. Effect of moisture loss was evaluated by drying it (room temperature, N2) and placed at 25°C/0%RH and 40°C/0%RH. The API was incubated with various excipients (based on package insert of marketed tablets) in either 1:1, 1:10, or 1:100 ratios with 5% moisture at 60°C. Commonly used ratios for excipients were used. The equilibrium sorption data was collected on the API and excipients. The API was stable in solid state for the study duration under all conditions for both forms (potency between 90% and 110%). Excipients effect on stability varied and crospovidone, povidone, and sodium laurel sulfate (SLS) caused significant API degradation where deiodination and deamination occurred. Moisture sorption values were different across excipients. Crospovidone and povidone were hygroscopic whereas SLS showed deliquescence at high RH. The transient formulation procedures where temperature might go up or humidity might go down would not have major impact on the API stability. Excipients influence stability and if possible, those three should either be avoided or used in minimum quantity which could provide more stable tablet formulations with minimum potency loss throughout its shelf-life.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Goodman L, Gilman A. The pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill; 2001.

    Google Scholar 

  2. Rhodes C. Regulatory aspects of the formulation and evaluation of levothyroxine tablets. Clin Res Regul Aff. 1998;15:173–86.

    Article  Google Scholar 

  3. FDA. Regulatory history and current issues. Health & Human Services; 2006.

  4. Post A, Warren R. Sodium levothyroxine. In: Florey K, editor. Analytical profiles of drug substances. New York: Academic Press; 1976. p. 226–81.

    Google Scholar 

  5. Won CM. Kinetics of degradation of levothyroxine in aqueous solution and in solid state. Pharm Res. 1992;9:131–7.

    Article  CAS  PubMed  Google Scholar 

  6. Kazemifard AG, Moore DE, Aghazadeh A. Identification and quantitation of sodium-thyroxine and its degradation products by LC using electrochemical and MS detection. J Pharm Biomed Anal. 2001;25:697–711.

    Article  CAS  PubMed  Google Scholar 

  7. Wortsman J, Papadimitriou DC, Borges M, Defesche CL. Thermal inactivation of l-thyroxin. Clin Chem. 1989;35:90–2.

    CAS  PubMed  Google Scholar 

  8. Patel H, Stalcup A, Dansereau R, Sakr A. The effect of excipients on the stability of levothyroxine sodium pentahydrate tablets. Int J Pharm. 2003;264:35–43.

    Article  CAS  PubMed  Google Scholar 

  9. Das Gupta V, Odom C, Bethea C, Plattenburg J. Effect of excipients on the stability of levothyroxine sodium tablets. J Clin Pharm Ther. 1990;15:331–6.

    Article  CAS  PubMed  Google Scholar 

  10. Burger A, Griesser UJ. Physical stability, hygroscopicity and solubility of succinyl-sulfathiazole. Eur J Pharm Biopharm. 1991;37:18–24.

    Google Scholar 

  11. Morris KR, Griesser UJ, Eckhardt CJ, Stowell JG. Theoretical approaches to physical transformations of active pharmaceutical ingredients during manufacturing processes. Adv Drug Deliv Rev. 2001;48:91–114.

    Article  CAS  PubMed  Google Scholar 

  12. Otsuka M, Hasegawa H, Matsuda Y. Effect of polymorphic transformation during the extrusion-granulation process on the pharmaceutical properties of carbamazepine granules. Chem Pharm Bull. 1997;45:894–8.

    CAS  Google Scholar 

  13. Phadnis NV, Suryanarayanan R. Polymorphism in anhydrous theophylline—implications on the dissolution rate of theophylline tablets. J Pharm Sci. 1997;86:1256–63.

    Article  CAS  PubMed  Google Scholar 

  14. Monkhouse DC. Stability aspects of preformulation and formulation of solid pharmaceuticals. Drug Dev Ind Pharm. 1984;10:1373–412.

    Article  CAS  Google Scholar 

  15. Kandarapu R, Grover V, Chawla HPS, Garg S. Evaluation of the compatibility of ketorolac tromethamine with selected polymers and common tablet excipients by thermal and isothermal stress testing. S T P Pharma Sci. 2001;11:449–57.

    CAS  Google Scholar 

  16. Serajuddin AT, Thakur AB, Ghoshal RN, Fakes MG, Ranadive SA, Morris KR et al. Selection of solid dosage form composition through drug-excipient compatibility testing. J Pharm Sci. 1999;88:696–704.

    Article  CAS  PubMed  Google Scholar 

  17. Gu L, Strickley RG, Chi LH, Chowhan ZT. Drug-excipient incompatibility studies of the dipeptide angiotensin-converting enzyme inhibitor, moexipril hydrochloride: dry powder vs wet granulation. Pharm Res. 1990;7:379–83.

    Article  CAS  PubMed  Google Scholar 

  18. Shah RB, Bryant A, Collier J, Habib MJ, Khan MA. Stability indicating validated HPLC method for quantification of levothyroxine with eight degradation peaks in the presence of excipients. Int J Pharm. 2008;360:77–82.

    Article  CAS  PubMed  Google Scholar 

  19. Kopelman SH, Augsburger LL. Excipient compatibility study of Hypericum perforatum extract (St. John’s Wort) using similarity metrics to track phytochemical profile changes. Int J Pharm. 2002;237:35–46.

    Article  CAS  PubMed  Google Scholar 

  20. Patel N, Patel I, Cutie A, Wadke D, Monkhouse D, Reier G. The effect of selected direct compression excipients on the stability of aspirin as a model hydrolysable drug. Drug Dev Ind Pharm. 1998;14:77–98.

    Article  Google Scholar 

  21. van Dooren AA, Duphar BV. Design for drug–excipient interaction studies. Drug Dev Ind Pharm. 1983;9:43–55.

    Article  Google Scholar 

  22. Kowalski J, Kalb O, Joshi YM, Serajuddin ATM. Application of melt granulation technology to enhance stability of a moisture sensitive immediate-release drug product. Int J Pharm. 2009;381:56–61.

    Article  CAS  PubMed  Google Scholar 

  23. Andre A, Domanig R, Riemer E, Moser H, Groeppelin A. Identification and thermal degradation products of l-triiodothyroxine sodium (liothyroxine sodium) by reversed phase HPLC with photodiode-array UV and mass spectrometric detection. J Chromatogr A. 1996;725:287–94.

    Article  CAS  Google Scholar 

Download references

Disclaimer

The opinions expressed in this work are only of the authors, and do not necessarily reflect the policy and statements of the FDA.

Author information

Authors and Affiliations

  1. Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave, Life Sciences Bldg 64, Silver Spring, Maryland, 20993-0002, USA

    Jarrod W. Collier, Rakhi B. Shah, Abhay Gupta & Mansoor A. Khan

  2. Department of Pharmaceutical Sciences, School of Pharmacy, Howard University, Washington, District of Columbia, USA

    Jarrod W. Collier & Muhammad J. Habib

  3. Division of Chemistry III, Office of Generic Drugs, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA

    Vilayat Sayeed

Authors
  1. Jarrod W. Collier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rakhi B. Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abhay Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vilayat Sayeed
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Muhammad J. Habib
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mansoor A. Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mansoor A. Khan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Collier, J.W., Shah, R.B., Gupta, A. et al. Influence of Formulation and Processing Factors on Stability of Levothyroxine Sodium Pentahydrate. AAPS PharmSciTech 11, 818–825 (2010). https://doi.org/10.1208/s12249-010-9434-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-010-9434-8

Key words

Search

Navigation