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Tablet Splitting of a Narrow Therapeutic Index Drug: A Case with Levothyroxine Sodium

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Abstract

Levothyroxine is a narrow therapeutic index, and to avoid adverse effect associated with under or excessive dosage, the dose response is carefully titrated. The tablets are marketed with a score providing an option to split. However, there are no systematic studies evaluating the effect of splitting on dose accuracy, and current study was undertaken to evaluate effects of splitting and potential causes for uniformity failures by measuring assay and content uniformity in whole and split tablets. Stability was evaluated by assaying drug for a period of 8 weeks. Effect of formulation factors on splittability was evaluated by a systematic investigation of formulation factors by preparing levothyroxine tablets in house by varying the type of excipients (binder, diluent, disintegrant, glidant) or by varying the processing factors (granulating liquid, mixing type, compression pressure). The tablets were analyzed using novel analytical tool such as near infrared chemical imaging to visualize the distribution of levothyroxine. Assay was not significantly different for whole versus split tablets irrespective of method of splitting (hand or splitter), and splitting also had no measurable impact on the stability. Split tablets either by hand or splitter showed higher rate of content uniformity failures as compared to whole tablets. Tablet splitter produced more fragmentation and, hence, more content uniformity and friability failures. Chemical imaging data revealed that the distribution of levothyroxine was heterogeneous and was dependent on type of binder and the process used in the manufacture of tablets. Splitting such tablets could prove detrimental if sub- or super-potency becomes an issue.

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References

  1. Carr-Lopez M, Mallett M, Morse T. The tablet splitting: barrier to compliance or cost-saving instrument? Am J Health-Syst Pharm. 1995;53:2707–8.

    Google Scholar 

  2. Fawell NG, Cookson TL, Scranton SS. Relationship between tablet splitting and compliance, drug acquisition cost, and patient acceptance. Am J Health-Syst Pharm. 1999;56:2542–5.

    CAS  PubMed  Google Scholar 

  3. Boggie DT, Delattre ML, Schaefer MG, Morreale AP, Plowman BK. Accuracy of splitting unscored valdecoxib tablets. Am J Health-Syst Pharm. 2004;61:1482–3.

    PubMed  Google Scholar 

  4. Cohen C, Cohen S. Potential savings from splitting newer antidepressant medications. CNS Drugs. 2002;16:353–8.

    Article  PubMed  Google Scholar 

  5. Parra D, Beckey NP, Raval HS, Schnacky KR, Calabrese V, Coakley RW, et al. Effect of splitting simvastatin tablets for control of low-density lipoprotein cholesterol. Am J Cardiol. 2005;95:1481–3.

    Article  CAS  PubMed  Google Scholar 

  6. Stafford RS, Radley DC. The potential of pill splitting to achieve cost savings. Am J managed Care. 2002;8:706–12.

    Google Scholar 

  7. Rosenberg JM, Nathan JP, Plakogiannis F. Weight variability of pharmacistdispensed split tablets. J Am Pharm Assoc. 2002;42:200–5.

    Article  Google Scholar 

  8. Teng J, Song CK, Willliams RL, Polli JE. Lack of medication dose uniformity in commonly split tablets. J Am Pharm Assoc. 2002;42:195–9.

    Article  Google Scholar 

  9. Stimpel M, Kuffer B, Groth H, Vetter W. Breaking tablets in half. Lancet. 1984;1:1299.

    Article  CAS  PubMed  Google Scholar 

  10. Gupta P, Gupta K. Broken tablets: does the sum of the parts equal the whole? Am J Hosp Pharm. 1988;45:1498.

    CAS  PubMed  Google Scholar 

  11. Sedrati M, Arnaud P, Fontan JE, Brion F. Splitting tablets in half. Am J Hosp Pharm. 1994;51:548–52.

    CAS  PubMed  Google Scholar 

  12. McDevitt JT, Gurst AH, Chen Y. Accuracy of tablet splitting. Pharmacotherapy. 1998;18:193–7.

    CAS  PubMed  Google Scholar 

  13. Peek BT, Al-Achi A, Coombs SJ. Accuracy of tablet splitting by elderly patients. Research letter JAMA. 2002;288:451–2.

    Article  Google Scholar 

  14. Shopper’s guide to prescription drugs number 1: pill splitting. Consumer Reports Best Buy Drugs. 2006. http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/money-saving-guides/english/PillSplitting-FINAL.pdf. Accessed 25 Mar 2010.

  15. AllThyroid.org. Thyroid patient advocacy group warns thyroid patients of potential problems with thyroid drug resulting from FDA approval of generic versions. http://www.allthyroid.org/news/latest/04_07_13_patientadvocacy.html.

  16. Frueh L. Interchangeability of critical dose drugs: Clinical perspective. Available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM209319.pdf. Accessed Aug 2010.

  17. Post A, Warren R. Sodium levothyroxine. In: Florey K, editor. Analytical Profiles of Drug Substances. New York: Academic; 1976. p. 226–81.

    Google Scholar 

  18. 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 

  19. 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 

  20. 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 

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

    CAS  PubMed  Google Scholar 

  22. Jarrod C, 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.

    Article  Google Scholar 

  23. USP. USP announces a revised monograph for levothyroxine sodium tablets. http://www.usp.org/USPNF/notices/iraLevothyroxine.html. Accessed March 25, 2010.

  24. 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 

  25. Jarrod C, Shah RB, Bryant AR, Habib MJ, Khan MA, Faustino P. Development and application of a validated HPLC method for the analysis of dissolution samples of levothyroxine sodium drug products. J Pharm Biomed Anal. 2010 (in press).

  26. Sales MM. Tablet splitting: topics in Patients safety. TIPS NCPS VA National Center for Patients Safety. 2006;6:1–5.

    Google Scholar 

  27. van Santen E, Barends DM, Frijlink HW. Breaking of scored tablets: a review. Eur J Pharm Biopharm. 2002;53:139–45.

    Article  PubMed  Google Scholar 

  28. Muller BW, Kublik H. Dosiergenauigkeit bei Tabletten mit Bruchrille? Dtsch Apoth Ztg. 1993;133:15–7.

    Google Scholar 

  29. Gupta P, Gupta K. Broken tablets: does the sum of the parts equal the whole? Am J Hosp Pharm. 1998;45:1498.

    Google Scholar 

  30. McNeil Consumer & Specialty Pharmaceuticals. Study raises concerns about tablet splitting. http://www.scienceblog.com/community/older/2004/10/200410126.shtml. Accessed March 25, 2010.

  31. Anonymous. Note on the general method. 2.9. Test for the subdivision of tablets, Pharmeuropa. 2000;12:300.

  32. Green G, Berg C, Polli J, Berends DM. Pharmacopeial standards for the subdivision characteristics of scored tablets. USP Pharmacopeial Forum. 2009;35(6):1598–611.

    Google Scholar 

  33. Kirsch JD, Drennen JK. Nondestructive tablet hardness testing by near-infrared spectroscopy: a new and robust spectral best-fit algorithm. J Pharm Biomed Anal. 1999;19:351–62.

    Article  CAS  PubMed  Google Scholar 

  34. Shah RB, Tawakkul MA, Khan MA. Process analytical technology: chemometric analysis of Raman and near Infra-red spectroscopic data for predicting physical properties of extended release matrix tablets. J Pharm Sci. 2007;96:1356–65.

    Article  CAS  PubMed  Google Scholar 

  35. Ito A, Dobashi Y, Sugihara M. The relationship between dividing properties of scored tablets and dynamic characteristics of various mixed powders. Chem Pharm Bull. 1993;41:590–4.

    CAS  Google Scholar 

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Acknowledgements

The study was partially funded as a critical path project and also by the Office of Generic Drugs, FDA. Authors also wish to thank Christopher Ellison and Abhay Gupta for their technical help.

DISCLAIMER

The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any agency determination or policy.

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Authors and Affiliations

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

    Rakhi B. Shah, Jarrod S. Collier, Arthur Bryant & Mansoor A. Khan

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

    Jarrod S. Collier & Muhammad J. Habib

  3. Division of Chemistry III, Office of Generic Drugs, OPS, CDER, FDA, Silver Spring, Maryland, USA

    Vilayat A. Sayeed

Authors
  1. Rakhi B. Shah
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  2. Jarrod S. Collier
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  3. Vilayat A. Sayeed
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  4. Arthur Bryant
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  5. Muhammad J. Habib
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  6. Mansoor A. Khan
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Corresponding author

Correspondence to Mansoor A. Khan.

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Shah, R.B., Collier, J.S., Sayeed, V.A. et al. Tablet Splitting of a Narrow Therapeutic Index Drug: A Case with Levothyroxine Sodium. AAPS PharmSciTech 11, 1359–1367 (2010). https://doi.org/10.1208/s12249-010-9515-8

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  • DOI: https://doi.org/10.1208/s12249-010-9515-8

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