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. Tablet Splitting of a Narrow Therapeutic Index Drug: A Case with Levothyroxine Sodium | AAPS PharmSciTech | Springer Nature Link Skip to main content Advertisement Tablet Splitting of a Narrow Therapeutic Index Drug: A Case with Levothyroxine Sodium Research Article Published: 26 August 2010 Volume 11 , pages 1359–1367 ( 2010 ) Cite this article Save article View saved research AAPS PharmSciTech Aims and scope Submit manuscript 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. 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. This is a preview of subscription content, log in via an institution to check access. Dosage compensation Drug Delivery Pharmaceutics Pharmacology Pharmacokinetics Pharming Thyroid Hormone Function and Disorders References 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 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 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 Cohen C, Cohen S. Google Scholar 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 Muller BW, Kublik H. Dosiergenauigkeit bei Tabletten mit Bruchrille? Dtsch Apoth Ztg. 1993;133:15–7. Google Scholar Gupta P, Gupta K. Broken tablets: does the sum of the parts equal the whole? Am J Hosp Pharm. 1998;45:1498. Google Scholar McNeil Consumer & Specialty Pharmaceuticals. Study raises concerns about tablet splitting. http://www.scienceblog.com/community/older/2004/10/200410126.shtml . Accessed March 25, 2010. Anonymous. Note on the general method. 2.9. Test for the subdivision of tablets, Pharmeuropa. 2000;12:300. 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 Download references 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. 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 Download citation Received : 06 June 2010 Accepted : 12 August 2010 Published : 26 August 2010 Issue date : September 2010 DOI : https://doi.org/10.1208/s12249-010-9515-8 Share this article Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy shareable link to clipboard Provided by the Springer Nature SharedIt content-sharing initiative Key words content uniformity hand splitting levothyroxine sodium narrow therapeutic index

<h4>Objective</h4>Tablet splitting is frequently performed to facilitate correct dosing, but the practice and implications in low-income settings have rarely been discussed.<h4>Methods</h4>We selected eight drugs, with narrow therapeutic indices or critical dosages, frequently divided in the Lao PDR (Laos). These were split, by common techniques used in Laos, by four nurses and four laypersons. The mean percentage deviation from the theoretical expected weight and weight loss of divided tablets/capsules were recorded.<h4>Results</h4>Five of eight study drugs failed, on splitting, to meet European Pharmacopoeia recommendations for tablet weight deviation from the expected weight of tablet/capsule halves with 10% deviating by more than 25%. There was a significant difference in splitting accuracy between nurses and laypersons (P = 0.027). Coated and unscored tablets were less accurately split than uncoated (P = 0.03 and 0.0019 for each half) and scored (0.0001 for both halves) tablets.<h4>Conclusion</h4>These findings have potential clinical implications on treatment outcome and the development of antimicrobial resistance. Investment by drug companies in a wider range of dosage units, particularly for narrow therapeutic index and critical dosage medicines, is strongly recommended. Methods We selected eight drugs, with narrow therapeutic indices or critical dosages, frequently divided in the Lao PDR (Laos). These were split, by common techniques used in Laos, by four nurses and four Coated and unscored tablets were less accurately split than uncoated ( P = 0.03 and 0.0019 for each half) and scored (0.0001 for both halves) tablets. Conclusion These findings have potential clinical implications on treatment outcome and the development of antimicrobial resistance. Investment by drug companies in a wider range of dosage units, particularly for narrow therapeutic index and critical dosage medicines, is strongly recommended. Drug costs per unit of active pharmaceutical ingredient (API) frequently decrease with increasing dose or flat charges may exist, independently of dose. Tablet splitting can therefore have an economic incentive, benefitting both the individual patient and the healthcare provider. Estimates of cost saving for splitting statins from innovative pharmaceutical companies are as high as 40–50% ( Fawell et al . 1999 ; Duncan et al . 2002 ; Gee et al . 2002 ). This cost saving is, however, limited to relatively few drugs. Finally, a more pragmatic reason for tablet splitting is to aid swallowing. If one tablet falls outside this range, it must fall within 75–125% of the expected mass/content. Although a homogeneous distribution of active drug is generally assumed in unscored tablets, some variation is expected and US Food and Drug Administration (FDA) bioequivalence standards permit variance of ±20%. The FDA, American Medical Society and American Pharmacists Association advise against splitting modified or sustained release, co-formulated, unscored, film-coated, friable or dose-critical tablets ( American Pharmacists Association 2003 ). The accuracy of tablet splitting is influenced by tablet size, shape, hardness, splitting method and human ability. Small, round or unusual-shaped tablets give rise to the greatest deviations and harder tablets are most likely to fragment or powder, leading to drug loss ( McDevitt et al . 1998 ; Polli et al . 2003 ). Dividing tablets into quarters results in even greater ranges of weight differences ( Biron et al . 1999 ; Kayumba 2006 ). Tablets with score lines, especially if deep, tend to split more uniformly ( Gupta & Gupta 1988 ; Kayumba 2006 ). Hand-split tablets were less uniform than those split by razor, and knife splitting was less accurate than a tablet splitter ( Teng et al . 2002 ; Cook et al . 2003 ). These are the two major groups responsible for tablet splitting in Laos (pharmacists are less frequently involved). Study drugs Eight medicines frequently split in Laos, with narrow therapeutic indices or critical dosages, were selected (Table 1 and Table S1). Participants were requested to divide all drugs into halves with the exception of phenobarbitone, where one set was divided into halves and another into thirds, as is commonly required in paediatrics. For each study drug, 80 tablets (160 for phenobarbitone) were purchased from a local pharmacy, of the same dose, manufacturer and lot number per medicine. There was a significantly greater deviation from theoretical weight and weight loss for unscored (chloroquine and phenobarbitone) tablets than scored tablets ( P = 0.0001 for both half weights and weight loss). A similar result was seen for coated (chloroquine and atenolol) versus uncoated tablets ( P = 0.030 and 0.0019 for each half). Weight loss was also significantly higher for coated tablets ( P = 0.0001). Significant differences were seen between the different methods used to divide the tablets or capsules for both weight deviation from theoretical weight and weight loss (all P ≤ 0.0001). No specific recommendations were provided by the manufacturers of any of the study drugs, scored or unscored, specifically advising on whether tablet or capsule splitting could be performed. The uniformity of distribution of API in the study drugs was also not recorded. Scored tablets facilitate splitting, and the importance of manufacturing quality assurance standards for API distribution in whole tablets has recently been highlighted ( Anonymous 2014 ). In the absence of explicit documentation by the manufacturer allowing splitting of unscored or coated tablets, we recommend education of healthcare staff and patients against dividing these tablets. Investment by drug companies in the production of a wider range of dosage units or tablets better designed for splitting and better product information on the suitability of tablets for splitting, particularly for narrow therapeutic or critical dosage drugs, is strongly recommended.

The authors investigated the weight variation of split scored and unscored tablets of several dosages of three costly psychotropic drugs, using weight variation criteria based on the United States Pharmacopoeia 26 (USP) Content Uniformity of Dosage Units. Whole tablets of Paxil 20 and 40 mg, Risperdal 2 and 4 mg, and Zoloft 100 mg that had been split with a widely available device by pharmacy technicians in a managed care pharmacy were evaluated. Each half tablet weight was recorded using a digital electronic balance. Weight variability was determined by comparing actual half tablet weight to the theoretical half tablet weight and calculating the relative standard deviation. Results showed that weight variability occurred in half tablets of unscored tablets of Paxil 40 mg, Risperdal 2 and 4 mg, and scored tablets of Zoloft 100 mg. Half tablets of scored Paxil 20 mg tablets did not show weight variability, resulting in uniform half tablet dosages. The authors concluded that tablet splitting does not generally produce uniform and equal half tablet doses, and that split tablets should be evaluated using weight variation criteria before tablet splitting programs are initiated.

<h4>Aim</h4>To explore the challenges and risks associated with the manipulation of solid oral dosage forms in paediatric healthcare. To compile recommendations to support the safety, efficacy and patient outcomes in paediatric patients.<h4>Methods</h4>A narrative review was conducted based on literature searches in PubMed, Scopus and Web of Science (2000-2024), including regulatory guidelines and clinical case reports. Selection focused on studies involving oral drug manipulation in children, particularly dose extraction, dispersing tablets, and administration via enteral tubes.<h4>Results</h4>Between 15%-37% of paediatric oral drug administrations require manipulation due to lack of age-appropriate formulations. Common manipulations include tablet splitting, crushing or dispersing, often resulting in dose inaccuracies, variable solubility and inconsistent pharmacokinetics. Risks are elevated in children using enteral feeding tubes or when manipulating poorly soluble drugs. Studies show manipulation can lead to dosing errors with potential harm.<h4>Conclusion</h4>Oral drug manipulation in paediatrics is widespread but often unsupported by evidence. Safer practices require improved access to licensed formulations, better training and clinical support tools. Pharmacy compounding, personalised manufacturing and technologies like 3D printing may reduce risks. Regulatory alignment and interdisciplinary collaboration are critical to improving drug safety and outcomes for paediatric patients.

Objective To assess the practices and dose uniformity of tablet splitting at selected public hospitals in Northwest Ethiopia. Methods A hybrid study method was employed to see the overall practices of tablet splitting. A prospective cross-sectional study was conducted to explore the practices of tablet splitting by administering structured questionnaires to patients and pharmacy professionals. Experimental data on dose and content uniformity of split tablets were obtained from the results of drugs split by study subjects. The content uniformity assay was performed using UV/Vis spectrophotometry. Results A total of 241 patients and 82 pharmacy professionals participated in the cross-sectional study. The majority of patient participants (51.3%) faced problems while splitting their tablet medications and this had a significant association with the education level of the patients (χ2 = 60.5; p = 0.001). Enteric-coated formulations were dispensed to be split, despite the precaution given by the manufacturers against splitting or crushing these products. Splitting of enteric-coated products accounts for 11% of the total drugs that were dispensed to be taken after a split. The mean of weight variation test for the half tablets does not meet the specifications set in pharmacopoeias when splitting was done by patients. The unscored haloperidol tablets were hard to split and resulted in a significant weight variation of half-tablets than the scored furosemide tablets. Moreover, the weight of 4 out of 20 fragments that were split by patients deviated at least by 15%. Conclusions This finding showed that the tablet-splitting practices are poor and do not meet the specifications set by pharmacopoeias. Splitting by patients resulted in significantly higher dose variation and weight loss of fragments than splitting by pharmacists.

The splitting of scored tablets provides many advantages. One benefit is to achieve dose flexibility to account for the huge interindividual differences in dose requirements for instance in paediatric and geriatric patients, which are often not covered by the available strengths in the market. Moreover, large-sized tablets can easier be swallowed if broken before swallowing and medication costs can often be reduced by splitting brands with higher strength. But not all tablets, mostly unscored tablets, are suitable for splitting. Splitting of extended release formulations can result in an overdose by uncontrolled release of the active component and degradation of the compound can occur if an enteric coating is destroyed by the splitting process. Whether tablets are suitable for splitting depends on the properties of the active component (e.g. light sensitivity), the galenics, the shape of the tablet, and the shape of the scoreline. Moreover, not all patients are informed, able, or willing to split tablets and the majority of the elderly population is not capable to break tablets. When split tablets are prescribed it is therefore important to view the shape of the tablet, to assess the patients ability and willingness to break tablets, to properly inform the patient about the appropriate way of splitting, and if necessary to suggest (and instruct) the use of a tablet splitting device.

Tablet scoring is a controversial but common practice used to adjust doses, facilitate drug intake, or lower the cost of drug treatment, especially in children and the elderly. The risks of tablet scoring are mainly related to inaccuracies in the resulting dose and stability problems. The aim of this article is to provide an overview of worldwide guidelines regarding tablet scoring. We found that regulatory health agencies in Mercosur countries as well as other South American countries do not have published standards addressing tablet splitting. Among the surveyed health agencies, the Food and Drug Administration (FDA) in the United States is the only one to present standards, ranging from splitting instructions to regulation of the manufacturing process. The concept of functional scoring implemented by the FDA has introduced some level of guarantee as to the ability of tablets to be split. In conclusion, technical and scientific bases are still insufficient to guide health rules on this subject, making the decision on scoring, in certain situations, random and highly risky to public health. The need for more detailed regulation is vital to ensure the safety of tablet medications.