Comparative Pharmaceutical Evaluation and Bioavailability Assessment of Levothyroxine Sodium in Different Dosage Forms
Abstract
Levothyroxine sodium is recognized as a narrow-therapeutic-index drug, making its clinical performance highly sensitive to formulation variables that can influence systemic bioavailability. This study focused on the development, physicochemical evaluation, and comparative bioavailability assessment of levothyroxine sodium formulated into three distinct dosage forms: tablets, HPMC based capsules, and soft gelatin capsules. Each formulation was manufactured using optimized processing strategies to ensure stability and dose accuracy. Physical evaluation and comprehensive in vitro testing, including assay, content uniformity, dissolution profiling, and analysis of related substances, were conducted in accordance with compendial standards. All three dosage forms exhibited satisfactory predefined quality criteria, indicating acceptable pharmaceutical performance. In vivo characterization was carried out in healthy volunteers using a randomized, open-label, two-treatment, two-period crossover design to compare the test products with the reference capsule. Blood samples were collected over an extended sampling period, and levothyroxine plasma concentrations were quantified using a validated analytical method. Pharmacokinetic parameters, including Cmax, AUC0–t, and AUC0–∞, were derived through non-compartmental analysis and evaluated for bioequivalence using standard statistical approaches. The in vivo results demonstrated that the soft gelatin capsules exhibited bioavailability parameters closely aligned with those of the reference product, with 90% confidence intervals for both rate and extent of absorption falling within accepted regulatory bioequivalence limits. Conversely, the directly compressed tablets and HPMC-based capsule formulations displayed higher inter-subject variability and did not consistently meet equivalence criteria across all pharmacokinetic endpoints. Among the dosage forms investigated, soft gelatin capsule provided the most reliable pharmaceutical quality and bioavailability performance relative to the reference product. These findings highlight the critical role of formulation design in achieving consistent levothyroxine exposure and support the liquid-filled soft gelatin system as a promising alternative for clinical application.
Keywords: Levothyroxine sodium; Different dosage forms; Soft-gelatin capsules; Bioavailability; Bioequivalence.
Keywords:
Levothyroxine sodium, Different dosage forms, Soft-gelatin capsules, Bioavailability, BioequivalenceDOI
https://doi.org/10.22270/jddt.v16i1.7517References
1. Oteri V, Volpe S, Lopes M. Therapeutic efficacy and patient compliance of levothyroxine liquid and softgel formulations taken with meals: a systematic review. Endocrine 2025; 87: 48-58. https://doi.org/10.1007/s12020-024-04016-7.
2. Liu H, Lu M, Hu J, Fu G, Feng Q, Sun S, Chen C. Medications and Food Interfering with the Bioavailability of Levothyroxine: A Systematic Review. Ther Clin Risk Manag 2023;19: 503-523. https://doi.org/10.2147/tcrm.s414460.
3. Liu H, Li W, Zhang W, Sun S, Chen C. Levothyroxine: Conventional and Novel Drug Delivery Formulations, Endocrine Reviews 2023; 44(3):393–416. https://doi.org/10.1210/endrev/bnac030.
4. 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 Pharm Sci Tech 2010;11(2):818–825. https://doi.org/10.1208/s12249-010-9434-8.
5. Tanguay M, Girard J, Scarsi C, Mautone G, Larouche R. Pharmacokinetics and Comparative Bioavailability of a Levothyroxine Sodium Oral Solution and Soft Capsule. Clin Pharmacol Drug Dev 2019; 8(4):521-528. https://doi.org/10.1002/cpdd.608.
6. AlBathish M, Gazy A,Jamal MA. A Comparative pH-Dissolution Profile Analysis of Selected Commercial Levothyroxine Formulations in Lebanon Using Anion-Exchange HPLC Method: Implication on Interchangeability 2025; 8833028. https://doi.org/10.1155/adpp/8833028.
7. Okezue MA, Byrn SR, Probost J, Lucas M, Clase KL. Potency and Powder X-ray Diffraction (PXRD) Evaluation of Levothyroxine Sodium Tablets under Ambient, Accelerated, and Stressed Conditions. Pharmaceuticals 2024);17(1):42. https://doi.org/10.3390/ph17010042.
8. Palem CR, Dudhipala NR, Goda S, B. Pokharkar V. Development and Optimization of Atorvastatin Calcium-Cyclodextrin Inclusion Complexed Orally-Disintegrating Tablets with Enhanced Pharmacokinetic and Pharmaco-dynamic Profile. International Journal of Pharmaceutical Sciences and Nanotechnology (IJPSN) 2016;9(2):3170-8. https://doi.org/10.37285/ijpsn.2016.9.2.3.
9. Palem CR, Gannu R, Yamsani SK, Yamsani VV, Yamsani MR. Development of bioadhesive buccal tablets for felodipine and pioglitazone in combined dosage form: in vitro, ex vivo, and in vivo characterization. Drug Deliv 2011;18(5):344-52. https://doi.org/10.3109/10717544.2011.557786.
10. Ledeți I, Romanescu M, Cîrcioban D, Ledeți A, Vlase G, Vlase T, Suciu O, Murariu M, Olariu S, Matusz P, Buda V, Piciu D. Stability and Compatibility Studies of Levothyroxine Sodium in Solid Binary Systems-Instrumental Screening. Pharmaceutics 2020; 12(1):58. https://doi.org/10.3390/pharmaceutics12010058.
11. Sachmechi I, Lucas KJ, Stonesifer LD, Ansley JF, Sack P, Celi FS, Scarsi C, Lanzi G, Wartofsky L, Burman KD. Efficacy of Levothyroxine Sodium Soft Gelatin Capsules in Thyroidectomized Patients Taking Proton Pump Inhibitors: An Open-Label Study. Thyroid 2023; 33(12):1414-1422. https://doi.org/10.1089/thy.2023.0382.
12. Palem CR , Rao YM, Doodipala N, Reddy S. Pharmaceutical development and clinical pharmacokinetic evaluation of gastroretentive floating matrix tablets of levofloxacin. Int J Pharm Sci Nanotech 2011; 4 (3): 1461-1467. https://doi.org/10.37285/ijpsn.2011.4.3.4.
13. Palem CR, Kumar BS, Gannu R, Yamsani VV, Repka MA, Yamsani MR. Role of cyclodextrin complexation in felodipine-sustained release matrix tablets intended for oral transmucosal delivery: in vitro and ex vivo characterization. Pharm Dev Technol 2012;17(3):321-32. https://doi.org/10.3109/10837450.2010.535829.
14. Cole ET, Cadé D, Benameur H. Challenges and opportunities in the encapsulation of liquid and semi-solid formulations into capsules for oral administration. Adv Drug Deliv Rev 2008;60(6):747-56. https://doi.org/10.1016/j.addr.2007.09.009.
15. Nazzal S, Khan MA. Controlled release of a self-emulsifying formulation from a tablet dosage form: stability assessment and optimization of some processing parameters. Int J Pharm 2006;315(1-2):110-21. https://doi.org/10.1016/j.ijpharm.2006.02.019.
16. Kommuru TR, Gurley B, Khan MA, Reddy IK. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment. Int J Pharm 2001;212(2):233-46. https://doi.org/10.1016/s0378-5173(00)00614-1.
17. Chinna Reddy P, Dudhipala NR. Goda S, Pokharkar VB. Development and optimization of Atorvastatin calcium-cyclodextrin inclusion complexed oral disintegrating tablets for enhancement of solubility, dissolution, pharmacokinetic Int J Pharm Sci Nanotech 2016; 9 (2): 1-11. https://doi.org/10.37285/ijpsn.2016.9.2.3.
18. Shayeda, Gannu R, Palem CR, Rao YM. Development of novel bioadhesive buccal formulation of diltiazem: in vitro and in vivo characterization, PDA journal of pharmaceutical science and technology 2009; 63 (5): 401-408.
19. Palem CR, Dudhipala N, Battu SK, Goda S, Repka MA, Yamsani MR. Combined dosage form of pioglitazone and felodipine as mucoadhesive pellets via hot melt extrusion for improved buccal delivery with application of quality by design approach. Journal of Drug Delivery Science and Technology 2015;30(A): 209-219. https://doi.org/10.1016/j.jddst.2015.10.017.
20. Rowe RC, Sheskey PJ, Quinn ME. Handbook of pharmaceutical excipients (6th edition). Pharmaceutical Press 2009;506-509.
21. Jannin V, Cuppok Y, Marchaud D. Approaches for the development of solid and semi-solid lipid-based formulations for oral administration. Journal of Pharmaceutical Sciences 2014;103(9): 2929–2944. https://doi.org/10.1002/jps.24091.
22. Jones BE. Hard capsules: Their origin, development and use in drug delivery. Pharmaceutical Technology Europe 2004;16(11):20-31.
23. Palem CR, Battu SK, Maddineni S,Gannu R, Repka MA, Rao YM. Oral transmucosal delivery of domperidone from immediate release films produced via hot-melt extrusion technology. Pharmaceutical development and technology 2013; 18 (1): 186-195. https://doi.org/10.3109/10837450.2012.693505.
24. Hennessey J V. Bioequivalence of levothyroxine sodium: The challenges and the science. Thyroid 2013;23(11): 1249–1256. https://doi.org/10.1089/thy.2013.0092.
Published
Abstract Display: 28 
PDF Downloads: 14 PDF Downloads: 3 How to Cite
Issue
Section
Copyright (c) 2026 Chinna Reddy Palem, Prashant Noolu , Praveen Rao Balguri , Varun Chilukoti , Dasarath Gurram , Nishanth Kumar Nagamalli , Sridhar Gumudevelli
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
How to Cite
.