title: Tablet splitting of a narrow therapeutic index drug: a case with levothyroxine sodium.
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.
authors.affiliation: 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.
authors.forename: Rakhi B
authors.initials: RB
authors.lastname: Shah
authors.forename: Jarrod S
authors.initials: JS
authors.lastname: Collier
authors.forename: Vilayat A
authors.initials: VA
authors.lastname: Sayeed
authors.forename: Arthur
authors.initials: A
authors.lastname: Bryant
authors.forename: Muhammad J
authors.initials: MJ
authors.lastname: Habib
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
mesh_terms: D004339:Drug Compounding / Q000379:methods*; D004355:Drug Stability; D011786:Quality Control; D015203:Reproducibility of Results; D013607:Tablets / Q000737:chemistry*; D013974:Thyroxine / Q000737:chemistry*
chemical_list: D013607:Tablets; D013974:Thyroxine