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AAPS PharmSciTech

, 20:39 | Cite as

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

  • Harsh S. Shah
  • Kaushalendra Chaturvedi
  • Mazen Hamad
  • Simon Bates
  • Ajaz Hussain
  • Kenneth MorrisEmail author
Research Article Theme: Team Science and Education for Pharmaceuticals: the NIPTE Model
  • 58 Downloads
Part of the following topical collections:
  1. 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 

Notes

Acknowledgments

We gratefully thank the Lachman Institute for Pharmaceutical Analysis at Long Island University, NY for the financial support. We would like to thank William Engen for his earlier contributions to the chemical stability studies.

References

  1. 1.
    Jameson JL, Weetman AP. Disorders of the thyroid gland. Harrisons principles of internal medicine 2001;2:2060–83.Google Scholar
  2. 2.
    Bryan J. Levothyroxine: from sheep thyroid injections to synthetic formulations. Lung Cancer. 2018;15:05.Google Scholar
  3. 3.
    Food, Administration D. Prescription drug products: levothyroxine sodium. Fed Regist. 1997;62:43535–8.Google Scholar
  4. 4.
    Food, Administration D. Guidance for industry: levothyroxine sodium products enforcement of August 14, 2001, compliance date and submission of new applications. Fed Regist. 2001;66:36794–5.Google Scholar
  5. 5.
    Burman K, Hennessey J, McDermott M, Wartofsky L, Emerson C. The FDA revises requirements for levothyroxine products. Thyroid. 2008;18(5):487–90.PubMedGoogle Scholar
  6. 6.
    Hamad ML, Engen W, Morris KR. Impact of hydration state and molecular oxygen on the chemical stability of levothyroxine sodium. Pharm Dev Technol. 2015;20(3):314–9.PubMedGoogle Scholar
  7. 7.
    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(1):35–43.PubMedGoogle Scholar
  8. 8.
    Shah R, Bryant A, Collier J, Habib M, Khan M. Stability indicating validated HPLC method for quantification of levothyroxine with eight degradation peaks in the presence of excipients. Int J Pharm. 2008;360(1):77–82.PubMedGoogle Scholar
  9. 9.
    Byrn SR. Solid state chemistry of drugs. New York: Academic; 1982.Google Scholar
  10. 10.
    Andre M, Domanig R, Riemer E, Moser H, Groeppelin A. Identification of the thermal degradation products of G-triiodothyronine sodium (liothyronine sodium) by reversed-phase high-performance liquid chromatography with photodiode-array UV and mass spectrometric detection. J Chromatogr A. 1996;725(2):287–94.Google Scholar
  11. 11.
    Chen J-R, Papadimitriou DC. Stable dosage of levothyroxine sodium and process of production. Google Patents. 1993.Google Scholar
  12. 12.
    Collier JW, Shah RB, Gupta A, Sayeed V, Habib MJ, Khan MA. Influence of formulation and processing factors on stability of levothyroxine sodium pentahydrate. AAPS PharmSciTech. 2010;11(2):818–25.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Di Girolamo G, Keller GA, Antonio R, Schere D, Gonzalez CD. Bioequivalence of two levothyroxine tablet formulations without and with mathematical adjustment for basal thyroxine levels in healthy Argentinian volunteers: a single-dose, randomized, open-label, crossover study. Clin Ther. 2008;30(11):2015–23.PubMedGoogle Scholar
  14. 14.
    Fish LH, Schwartz HL, Cavanaugh J, Steffes MW, Bantle JP, Oppenheimer JH. Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. N Engl J Med. 1987;316(13):764–70.PubMedGoogle Scholar
  15. 15.
    Galwey AK. Structure and order in thermal dehydrations of crystalline solids. Thermochim Acta. 2000;355(1):181–238.Google Scholar
  16. 16.
    Garnick R, Burt G, Long D, Bastian J, Aldred J. High-performance liquid chromatographic assay for sodium levothyroxine in tablet formulations: content uniformity applications. J Pharm Sci. 1984;73(1):75–7.PubMedGoogle Scholar
  17. 17.
    Groenewoud PJ. Stabilized thyroxine medications. Google Patents. 2001.Google Scholar
  18. 18.
    Gupta VD, Odom C, Bethea C, Plattenburg J. Effect of excipients on the stability of levothyroxine sodium tablets. J Clin Pharm Ther. 1990;15(5):331–6.PubMedGoogle Scholar
  19. 19.
    Hennessey JV, Burman KD, Wartofsky L. The equivalency of two L-thyroxine preparations. Ann Intern Med. 1985;102(6):770–3.PubMedGoogle Scholar
  20. 20.
    Katrusiak A, Katrusiak A. Thyroxine revisited. J Pharm Sci. 2004;93(12):3066–75.PubMedGoogle Scholar
  21. 21.
    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(5):697–711.PubMedGoogle Scholar
  22. 22.
    Mitra AK, Srinivas R, Thomas III CL. Stabilized thyroid hormone preparations and methods of making same. Google Patents. 2000.Google Scholar
  23. 23.
    Rhodes C. Regulatory aspects of the formulation and evaluation of L-thyroxene tablets. Clin Res Regul Aff. 1998;15(3–4):173–86.Google Scholar
  24. 24.
    Schreder S, Nischwitz M. Process for preparing a pharmaceutical formulation containing levothyroxine sodium. Google patents. 2003.Google Scholar
  25. 25.
    Stoffer SS, Szpunar WE. Potency of levothyroxine products. JAMA. 1984;251(5):635–6.PubMedGoogle Scholar
  26. 26.
    Won CM. Kinetics of degradation of levothyroxine in aqueous solution and in solid state. Pharm Res. 1992;9(1):131–7.PubMedGoogle Scholar
  27. 27.
    Wortsman J, Papadimitriou D, Borges M, Defesche C. Thermal inactivation of L-thyroxin. Clin Chem. 1989;35(1):90–2.PubMedGoogle Scholar
  28. 28.
    Yu LX. Quality and bioequivalence standards for narrow therapeutic index drugs. GPhA 2011 Fall Technical Workshop. 2011. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM292676. Accessed 13 Dec 2018.
  29. 29.
    Chaturvedi K, Gajera BY, Xu T, Shah H, Dave RH. Influence of processing methods on physico-mechanical properties of ibuprofen/HPC-SSL formulation. Pharm Dev Technol. 2018:1–9.Google Scholar
  30. 30.
    Apperley DC, Basford PA, Dallman CI, Harris RK, Kinns M, Marshall PV, et al. Nuclear magnetic resonance investigation of the interaction of water vapor with sildenafil citrate in the solid state. J Pharm Sci. 2005;94(3):516–23.PubMedGoogle Scholar
  31. 31.
    Badawy SIF, Badawy S, Williams RC, Gilbert DL. Effect of different acids on solid-state stability of an ester prodrug of a IIb/IIIa glycoprotein receptor antagonist. Pharm Dev Technol. 1999;4(3):325–31.PubMedGoogle Scholar
  32. 32.
    Byrn SR, Lin C-T. The effect of crystal packing and defects on desolvation of hydrate crystals of caffeine and L-(−)-1, 4-cyclohexadiene-1-alanine. J Am Chem Soc. 1976;98(13):4004–5.PubMedGoogle Scholar
  33. 33.
    Carstensen J, Attarchi F, Hou XP. Decomposition of aspirin in the solid state in the presence of limited amounts of moisture. J Pharm Sci. 1985;74(7):741–5.PubMedGoogle Scholar
  34. 34.
    Carstensen J, Kothari R. Solid-state decomposition of alkoxyfuroic acids. J Pharm Sci. 1981;70(10):1095–100.PubMedGoogle Scholar
  35. 35.
    Carstensen J, Kothari RC. Solid-state decomposition of alkoxyfuroic acids in the presence of microcrystalline cellulose. J Pharm Sci. 1983;72(10):1149–54.PubMedGoogle Scholar
  36. 36.
    Carstensen J, Pothisiri P. Decomposition of p-aminosalicylic acid in the solid state. J Pharm Sci. 1975;64(1):37–44.Google Scholar
  37. 37.
    Carstensen JT, Musa MN. Decomposition of benzoic acid derivatives in solid state. J Pharm Sci. 1972;61(7):1112–8.PubMedGoogle Scholar
  38. 38.
    Chen LR. Solid state behavior of pharmaceutical hydrates. Minneapolis: University of Minnesota; 1999.Google Scholar
  39. 39.
    Chen LR, Young VG Jr, Lechuga-Ballesteros D, Grant DJ. Solid-state behavior of cromolyn sodium hydrates. J Pharm Sci. 1999;88(11):1191–200.PubMedGoogle Scholar
  40. 40.
    De Villiers M, Van der Watt J, Lötter A. Kinetic study of the solid-state photolytic degradation of two polymorphic forms of furosemide. Int J Pharm. 1992;88(1–3):275–83.Google Scholar
  41. 41.
    Griesser U, Burger A. The effect of water vapor pressure on desolvation kinetics of caffeine 4/5-hydrate. Int J Pharm. 1995;120(1):83–93.Google Scholar
  42. 42.
    Guillory JK, Higuchi T. Solid state stability of some crystalline vitamin a compounds. J Pharm Sci. 1962;51(2):100–5.PubMedGoogle Scholar
  43. 43.
    Hasegawa J, Hanano M, Awazu S. Decomposition of acetylsalicylic acid and its derivatives in solid state. Chem Pharm Bull (Tokyo). 1975;23(1):86–97.Google Scholar
  44. 44.
    Kachrimanis K, Griesser U. Dehydration kinetics and crystal water dynamics of carbamazepine dihydrate. Pharm Res. 2012;29(4):1143–57.PubMedGoogle Scholar
  45. 45.
    Zhang GG, Law D, Schmitt EA, Qiu Y. Phase transformation considerations during process development and manufacture of solid oral dosage forms. Adv Drug Deliv Rev. 2004;56(3):371–90.PubMedGoogle Scholar
  46. 46.
    Liu R. Water-insoluble drug formulation. Boca Raton: CRC Press; 2000.Google Scholar
  47. 47.
    Shah H. Dissolution improvement of nebivolol hydrochloride using solid dispersion adsorbate technique. Asian Journal of Pharmaceutics (AJP): free full text articles from Asian J Pharm 2015;9(1):49–55.Google Scholar
  48. 48.
    Pharmacopeia U. United States Pharmacopeia and National Formulary (USP 41–NF 36). Vol Section. 2018;2:35–117.Google Scholar
  49. 49.
    Lawrence XY. Woodcock J. FDA pharmaceutical quality oversight. Int J Pharm. 2015;491(1–2):2–7.Google Scholar
  50. 50.
    Wood SL, Lynch JG Jr. Prior knowledge and complacency in new product learning. J Consum Res. 2002;29(3):416–26.Google Scholar
  51. 51.
    Hussain A. From roadbloacks to roadmap - 2017, with a 2020 vision: Slideshare; 2016 [President’s report 2016]. Available from: https://nipte.org/wp-content/uploads/2018/10/Roadblocks-to-Roadmap-2017-with-A-2020-Vision-12182016-Final-Version.pdf. Accessed 13 Dec 2018.
  52. 52.
  53. 53.
    Gika HG, Samanidou VF, Papadoyannis IN. Development of a validated HPLC method for the determination of iodotyrosines and iodothyronines in pharmaceuticals and biological samples using solid phase extraction. J Chromatogr B. 2005;814(1):163–72.Google Scholar
  54. 54.
    Patel H. The effect of formulation and processing variables on the stability of levothyroxine sodium tablets. Cincinnati: University of Cincinnati; 2003.Google Scholar
  55. 55.
    Morris KR. Structural aspects of hydrates and solvates. Drugs and the pharmaceutical sciences. 1999;95:125–82.Google Scholar
  56. 56.
    Boultif A, Louër D. Powder pattern indexing with the dichotomy method. J Appl Crystallogr. 2004;37(5):724–31.Google Scholar
  57. 57.
    Altomare A, Giacovazzo C, Guagliardi A, Moliterni AG, Rizzi R, Werner P-E. New techniques for indexing: N-TREOR in EXPO. J Appl Crystallogr. 2000;33(4):1180–6.Google Scholar
  58. 58.
    Laugier J, Bochu B. CHECKCELL: a software performing automatic cell/space group determination. Collaborative computational project 2000(14).Google Scholar
  59. 59.
    Gerstein M, Chothia C. Packing at the protein-water interface. Proc Natl Acad Sci. 1996;93(19):10167–72.PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Harsh S. Shah
    • 1
  • Kaushalendra Chaturvedi
    • 1
  • Mazen Hamad
    • 2
  • Simon Bates
    • 3
  • Ajaz Hussain
    • 4
  • Kenneth Morris
    • 5
    • 6
    Email author
  1. 1.Department of Pharmaceutical Sciences, Arnold and Marie Schwartz College of PharmacyLong Island UniversityBrooklynUSA
  2. 2.Department of Chemistry, College of Natural and Health SciencesUniversity of Hawai’i at HiloHiloUSA
  3. 3.Triclinic Labs Inc.LafayetteUSA
  4. 4.The National Institute of Pharmaceutical Technology and Education (NIPTE)MinneapolisUSA
  5. 5.Lachman Institute for Pharmaceutical AnalysisLong Island UniversityBrooklynUSA
  6. 6.Arnold and Marie Schwartz College of Pharmacy and Health SciencesLong Island University – Brooklyn CampusBrooklynUSA

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