Assessment of potential risks at the pharmaceutical development stage of minitablets

The production of mini tablets (MTs) differs significantly from the production of regular-sized tablets and involves certain risks. The article analyzes scientific publications on the topic of MTs development and production, and based on the data obtained, assesses the risks associated with it.

The aim: To conduct a risk assessment during the pharmaceutical development of MTs.

Materials and methods. The research materials were based on the ICHQ8 guidelines for pharmaceutical development and ICHQ9 guidelines for quality risk management, State Pharmacopoeia of the Russian Federation XV edition, scientific publications on the pharmaceutical development and production of MTs. The study was conducted using the PHA (preliminary hazard analysis) method. The following were considered as critical quality attributes (CQAs) of MTs: disintegration, dissolution, uniformity of dosage units, uniformity of mass, crushing strength, and friability. Hazards were identified using the Ishikawa diagram method. Risk analysis was performed based on data from scientific publications on the development and production of MTs. Articles were searched for between 1990 and 2024 in the ScienceDirect, PubMed, Google Scholar, and elibrary.ru databases. Based on the information presented in these articles and using a logical method, the probability of occurrence and severity (consequences) of the risks were determined. Risk assessment was carried out using a risk matrix.

Results. Among the parameters of the MTs production process, the compression and mixing stages pose a danger. The compression is associated with a high risk for the following CQAs: dissolution, uniformity of dosage units, uniformity of mass, and crushing strength. Mixing is critical to ensuring dosage uniformity. Parameters of the active pharmaceutical ingredient (API), such as particle size and shape, significantly affect dissolution. In addition, the compressibility and flowability of the API are risk factors for ensuring the uniformity of dosage and MTs mass. The choice of excipients (EPs) is of great importance in the development of MTs. The type and content of the filler are of the greatest risk to the studied MTs. An irrational choice of disintegrant and anti-friction EPs can lead to impaired disintegration and dissolution of MTs.

Conclusion. As a result of the risk assessment, hazards were identified, and key risks associated with the pharmaceutical development of MTs were analyzed and evaluated. Particular attention was paid to the main groups of hazards — the influence of the properties of API, EPs, and production process parameters on MTs CQAs. It was found that during the development of MTs, the shape and size of the API particles, the compressibility and flowability of the powder mixture, the type and content of the filler and disintegrant, as well as such technological process parameters as pressing and mixing, pose a particular risk.

1. Gore R, Chugh PK, Tripathi CD, Lhamo Y, Gautam S. Pediatric Off-Label and Unlicensed Drug Use and Its Implications. Curr Clin Pharmacol. 2017;12(1):18-25. DOI: 10.2174/1574884712666170317161935

2. Ahmed H, VanderPluym C. Medical management of pediatric heart failure. Cardiovasc Diagn Ther. 2021;11(1):323-335. DOI: 10.21037/cdt-20-358

3. Malkawi WA, AlRafayah E, AlHazabreh M, AbuLaila S, Al-Ghananeem AM. Formulation Challenges and Strategies to Develop Pediatric Dosage Forms. Children (Basel). 2022;9(4):488. DOI: 10.3390/children9040488

4. Meruva S, Singaraju AB, Vinjamuri BP, Ternik R, Stagner WC. Current State of Minitablet Product Design: A Review. J Pharm Sci. 2024;113(5):1123-1154. DOI: 10.1016/j.xphs.2024.02.016

5. Egorova SN, Kondakov SE, Gordeev VV, Belezky SO, Hayatov AR, Ikhalaynen ES. Recent problems of children pharmaceutical dosage formulation in Russian Federation. Vestnik of the Smolensk State Medical Academy. 2019;4;220–228. EDN: FLQJCB

6. Zuccari G, Alfei S, Marimpietri D, Iurilli V, Barabino P, Marchitto L. Mini-Tablets: A Valid Strategy to Combine Efficacy and Safety in Pediatrics. Pharmaceuticals (Basel). 2022;15(1):108. DOI: 10.3390/ph15010108

7. Comoglu T, Dilek Ozyilmaz E. Orally disintegrating tablets and orally disintegrating mini tablets - novel dosage forms for pediatric use. Pharm Dev Technol. 2019;24(7):902-914. DOI: 10.1080/10837450.2019.1615090

8. Lennartz P, Mielck JB. Minitabletting: improving the compactability of paracetamol powder mixtures. International Journal of Pharmaceutics. 1998;173(1–2):75–85. DOI: 10.1016/S0378-5173(98)00206-3

9. Naman S, Madhavi N, Singh B, Madan J, Baldi A. Implementing risk-based quality by design for development and optimization of flavored oral disintegrating mini tablets. Journal of Drug Delivery Science and Technology. 2021;66:102799. DOI: 10.1016/j.jddst.2021.102799

10. Priyanka P, Kumar K, Teotia D. A comprehensive review on pharmaceutical mini tablets. J. Drug Delivery Ther. 2018;8(6):382-90. DOI: 10.22270/jddt.v8i6.2060

11. Klingmann V, Seitz A, Meissner T, Breitkreutz J, Moeltner A, Bosse HM. Acceptability of Uncoated Mini-Tablets in Neonates--A Randomized Controlled Trial. J Pediatr. 2015;167(4):893-896.e2. DOI: 10.1016/j.jpeds.2015.07.010

12. Klingmann V, Spomer N, Lerch C, Stoltenberg I, Frömke C, Bosse HM, Breitkreutz J, Meissner T. Favorable acceptance of mini-tablets compared with syrup: a randomized controlled trial in infants and preschool children. J Pediatr. 2013;163(6):1728-1732.e1. DOI: 10.1016/j.jpeds.2013.07.014

13. Charoo NA, Ali AA. Quality risk management in pharmaceutical development. Drug Dev Ind Pharm. 2013;39(7):947-60. DOI: 10.3109/03639045.2012.699065

14. Charoo NA, Shamsher AA, Zidan AS, Rahman Z. Quality by design approach for formulation development: a case study of dispersible tablets. Int J Pharm. 2012;423(2):167-78. DOI: 10.1016/j.ijpharm.2011.12.024

15. Fedorova AV, Krylova IY, Bezukladova EYu. Using graphical models in risk analysis. Economic vector. 1(32):109-115. DOI 10.36807/2411-7269-2023-1-32-109-115

16. Rausand M, Haugen S. Causal and Frequency Analysis. In book: Risk assessment: Theory, Methods, and Applications (2nd edition). John Wiley & Sons Ltd. 2020:339–400. DOI: 10.1002/9781119377351.ch11

17. Baker N. Quality Risk Management (QRM). In book: Pharmaceutical quality by design: a practical approach (eds Schlindwein W.S. and Gibson M.). John Wiley & Sons Ltd. 2018:11–47. DOI: 10.1002/9781118895238.ch2

18. Alalaiwe A, Alsenaidy MA, Almalki ZS, Fayed MH. Development and Optimization of Sildenafil Orodispersible Mini-Tablets (ODMTs) for Treatment of Pediatric Pulmonary Hypertension Using Response Surface Methodology. Pharmaceutics. 2023;15(3):923. DOI: 10.3390/pharmaceutics15030923

19. Stoltenberg I, Breitkreutz J. Orally disintegrating mini-tablets (ODMTs)--a novel solid oral dosage form for paediatric use. Eur J Pharm Biopharm. 2011;78(3):462-9. DOI: 10.1016/j.ejpb.2011.02.005

20. Khan D, Kirby D, Bryson S, Shah M, Mohammed AR. Development of an Age-Appropriate Mini Orally Disintegrating Carvedilol Tablet with Paediatric Biopharmaceutical Considerations. Pharmaceutics. 2021;13(6):831. DOI: 10.3390/pharmaceutics13060831

21. Lura A, Breitkreutz J. Manufacturing of mini-tablets. Focus and impact of the tooling systems. Journal of Drug Delivery Science and Technology. 2022;72:103357. DOI: 10.1016/j.jddst.2022.103357

22. Mitra B, Thool P, Meruva S, Aycinena JA, Li J, Patel J, Patel K, Agarwal A, Karki S, Bowen W. Decoding the small size challenges of mini-tablets for enhanced dose flexibility and micro-dosing. Int J Pharm. 2020;574:118905. DOI: 10.1016/j.ijpharm.2019.118905

23. Page S, Rode T, Breitkreutz J, Wagner-Hattler L. Minitablets current use and future opportunities - An APV course on manufacturing, packaging, characterization and use of minitablets. Eur J Pharm Biopharm. 2024;199:114294. DOI: 10.1016/j.ejpb.2024.114294

24. Cho CH, Kim JY, Park ES. Utilization of a compaction simulator to formulate mini-tablets containing high dose of acyclovir. Journal of Drug Delivery Science and Technology. 2021;64:102602. DOI: 10.1016/j.jddst.2021.102602 Corrigendum: Journal of Drug Delivery Science and Technology. 2021;66:102820. DOI: 10.1016/j.jddst.2021.102820

25. Hellberg E, Westberg A, Appelblad P, Mattsson S. Evaluation of dissolution techniques for orally disintegrating mini-tablets. Journal of Drug Delivery Science and Technology. 2021;61:102191. DOI: 10.1016/j.jddst.2020.102191

26. Warnken Z, Trementozzi A, Martins PP, Parekh J, Koleng JJ, Smyth HDC, Brunaugh A. Development of low-cost, weight-adjustable clofazimine mini-tablets for treatment of tuberculosis in pediatrics. Eur J Pharm Sci. 2023;187:106470. DOI: 10.1016/j.ejps.2023.106470

27. Sabbatini B, Romano Perinelli D, Filippo Palmieri G, Cespi M, Bonacucina G. Sodium lauryl sulfate as lubricant in tablets formulations: Is it worth? Int J Pharm. 2023;643:123265. DOI: 10.1016/j.ijpharm.2023.123265