Whole vs. Half Tablets – A Case with Diazepam Tablets
Abstract
Background: Tablet splitting is commonly used in clinical practice as a way to attain a desired drug dose and/or reducing its side effects, particularly among paediatricians and psychiatrists. However, uneven tablet scoring can lead to significant fluctuations of the administered doses, where subpotency or superpotency of drugs might harm the patients. The aim of this study was to evaluate the influence of tablet splitting on dose uniformity of diazepam by the utilization of Ph. Eur. 9.0 and FDA recommendations.
Methods: Mass variation of whole and half tablets in parallel with the determination of their content uniformity were determined according to the pharmacopoeial methods. The weight loss after tablet splitting was assessed by employing FDA guidelines. We also investigated if tablet splitting influenced in vitro dissolution properties of diazepam tablets.
Results: Diazepam whole tablets fulfilled the pharmacopoeial requirements in regard to the all investigated properties. The weight uniformity of scored diazepam tablets ranged from 63.80% to 122.55% label claim. The losses of mass after splitting diazepam tablets were 5.71%. Despite the average content of diazepam in half tablets was found to be 104.24% label claim, the requirements of Ph. Eur. were not fulfilled. Diazepam content in half tablets ranged from 0.76 mg to 1.21 mg, thus, patients might receive doses that varied by as much as 45%. However, after weight adjustment, diazepam content in each of the tested half tablets in the range of 85-115% of the average drug content meeting the Ph. Eur. criteria. Dissolution profiles of whole and half tablets were found to be similar, following Hixson-Crowell kinetic model.
Conclusion: According to the results, splitting of diazepam tablets greatly influenced the drug content in the obtained parts, i.e. the dose accuracy was fully dependent of the ability to score the tablet into exactly equal halves.
Key words: tablet splitting, diazepam, tablet scoring, half tablets, dose adjustment
References
Hill SW, Varker AS, Karlage K, Myrdal PB. Analysis of drug content and weight uniformity for half-tablets of 6 commonly split medications. J Manag Care Pharm 2009;15(3):253-61.
Jacques ER, Alexandridis P. Tablet Scoring: Current Practice, Fundamentals, and Knowledge Gaps. Applied Sciences 2019;9(15):3066.
Vranic E, Uzunovic A. Influence of tablet splitting on content uniformity of lisinopril/hydrochlorthiazide tablets. Bosn J Basic Med Sci 2007;7(4):328-34.
Watson C, Webb EA, Kerr S, Davies JH, Stirling H, Batchelor H. How close is the dose? Manipulation of 10mg hydrocortisone tablets to provide appropriate doses to children. Int J Pharm 2018;545(1-2):57-63.
Elliott I, Mayxay M, Yeuichaixong S, Lee SJ, Newton PN. The practice and clinical implications of tablet splitting in international health. Trop Med Int Health 2014;19(7):754-60.
C Andersson Å, Lindemalm S, Eksborg S. Dividing the Tablets for Children – Good or Bad? Pharmaceutical Methods 2016;7(1):23-27.
van Reuler AVR, van Diemen JJK, Harmsze AM, Fuijkschot WW, Thijs A. Subdivision of aspirin tablets? Use your hands: a study on aspirin tablet subdivision using four different methods. Journal of Pharmacy Practice and Research 2018;48(1):44-48.
Helmy SA. Tablet Splitting: Is It Worthwhile? Analysis of Drug Content and Weight Uniformity for Half Tablets of 16 Commonly Used Medications in the Outpatient Setting. Journal of Managed Care & Specialty Pharmacy 2015;21(1):76-88.
Shah RB, Collier JS, Sayeed VA, Bryant A, Habib MJ, Khan MA. Tablet splitting of a narrow therapeutic index drug: a case with levothyroxine sodium. AAPS PharmSciTech 2010;11(3):1359-67.
European Pharmacopoeia 4th edition, Council of Europe, Strasbourg, 2002.
Guidance for Industry - Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation. Food and Drug Administation, Center for Drug Evaluation and Research (CDER), U.S. Department of Health and Human Services, 2013.
Abed KK, Hussein AA, Ghareeb MM, Abdulrasool AA. Formulation and optimization of orodispersible tablets of diazepam. AAPS PharmSciTech 2010;11(1):356-61.
Martindale: The complete drug reference. Pharmaceutical Press, London, 2017.
Martindale: The complete drug reference. Pharmaceutical Press, London; 2009.
British National Formulary for Children (BNFC) 2014-2015, BMJ Group & Pharmaceutical Press, The Royal Pharmaceutical Society of Great Britain, 2014.
European Pharmacopoeia 9th edition, Council of Europe, Strasbourg, 2016.
United States Pharmacopoeia 42 - National Formulary 37. Rockville, United States Pharmacopoeial Convention, 2019.
British Pharmacopoeia, Her Majesty’s Stationery Office, London, 2012.
Moore JW, H. H. Flanner. Mathematical Comparison of Dissolution Profiles. Pharm Technol 1996;20(6):64-74.
Guidance for Industry - Dissolution Testing of Immediate Release Solid Oral Dosage Forms. Food and Drug Administation, Center for Drug Evaluation and Research (CDER), U.S. Department of Health and Human Services, 1997.
Ciavarella AB, Khan MA, Gupta A, Faustino PJ. Dose Uniformity of Scored and Unscored Tablets: Application of the FDA Tablet Scoring Guidance for Industry. PDA J Pharm Sci Technol 2016;70(6):523-32.
Paarakh MP, Jose PA, Setty CM, Christoper GVP. Release Kinetics – Concepts and Applications. International Journal of Pharmacy Research & Technology 2018;8(1):12-20.
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