New Insights on Solid-State Changes in the Levothyroxine Sodium Pentahydrate during Dehydration and its Relationship to Chemical Instability
- 58 Downloads
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 WORDScrystal structure hydrate powder X-ray diffraction new prior knowledge levothyroxine
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.
- 1.Jameson JL, Weetman AP. Disorders of the thyroid gland. Harrisons principles of internal medicine 2001;2:2060–83.Google Scholar
- 2.Bryan J. Levothyroxine: from sheep thyroid injections to synthetic formulations. Lung Cancer. 2018;15:05.Google Scholar
- 3.Food, Administration D. Prescription drug products: levothyroxine sodium. Fed Regist. 1997;62:43535–8.Google Scholar
- 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
- 9.Byrn SR. Solid state chemistry of drugs. New York: Academic; 1982.Google Scholar
- 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.Chen J-R, Papadimitriou DC. Stable dosage of levothyroxine sodium and process of production. Google Patents. 1993.Google Scholar
- 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
- 15.Galwey AK. Structure and order in thermal dehydrations of crystalline solids. Thermochim Acta. 2000;355(1):181–238.Google Scholar
- 17.Groenewoud PJ. Stabilized thyroxine medications. Google Patents. 2001.Google Scholar
- 22.Mitra AK, Srinivas R, Thomas III CL. Stabilized thyroid hormone preparations and methods of making same. Google Patents. 2000.Google Scholar
- 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.Schreder S, Nischwitz M. Process for preparing a pharmaceutical formulation containing levothyroxine sodium. Google patents. 2003.Google Scholar
- 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.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
- 36.Carstensen J, Pothisiri P. Decomposition of p-aminosalicylic acid in the solid state. J Pharm Sci. 1975;64(1):37–44.Google Scholar
- 38.Chen LR. Solid state behavior of pharmaceutical hydrates. Minneapolis: University of Minnesota; 1999.Google Scholar
- 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.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
- 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
- 46.Liu R. Water-insoluble drug formulation. Boca Raton: CRC Press; 2000.Google Scholar
- 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.Pharmacopeia U. United States Pharmacopeia and National Formulary (USP 41–NF 36). Vol Section. 2018;2:35–117.Google Scholar
- 49.Lawrence XY. Woodcock J. FDA pharmaceutical quality oversight. Int J Pharm. 2015;491(1–2):2–7.Google Scholar
- 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.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.Campana C. Advanced crystallography - Publication of Crystal Structures. Available from: https://www.bruker.com/fileadmin/user_upload/8-PDF-Docs/X-rayDiffraction_ElementalAnalysis/SC-XRD/Webinars/Bruker_AXS_Publication_of_Crys_Structures_Webinar_20111013.pdf. Accessed 13 Dec 2018.
- 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.Patel H. The effect of formulation and processing variables on the stability of levothyroxine sodium tablets. Cincinnati: University of Cincinnati; 2003.Google Scholar
- 55.Morris KR. Structural aspects of hydrates and solvates. Drugs and the pharmaceutical sciences. 1999;95:125–82.Google Scholar
- 56.Boultif A, Louër D. Powder pattern indexing with the dichotomy method. J Appl Crystallogr. 2004;37(5):724–31.Google Scholar
- 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.Laugier J, Bochu B. CHECKCELL: a software performing automatic cell/space group determination. Collaborative computational project 2000(14).Google Scholar