(M0930-11-65) Optimization of a Mini-Tablet Compression Process

Purpose: Mini-tablets serve as a pediatric dosage form due to advantages in addressing unique needs of children. Their small size facilitates ease of administration, allows simplified swallowing and reduces risk of choking. Mini-tablets are a valuable alternative to syrup for children 6 months–6 years of age and are more acceptable compared with liquid formulation. [1] Due to the small size (2–3 mm [2]) the manufacturing process also poses challenges like achieving uniformity of dose strength, wear of compression tooling and intactness of the tablet cores. Additionally, core tablet formulation leaves limited space for other ingredients than the API, due to overall size. This technical abstract delves into optimization of mini-tablet compression process and its unique challenges.

Methods: Final blend for compression of mini-tablets was manufactured in a direct blend approach containing API, Cellulose (Avicel^® PH-102, Dupont), Mannitol (Pearlitol^® 100 SD, Roquette), Croscarmellose-Sodium (Ac-Di-Sol^® SD-711) and Sodium Stearyl Fumarate (PRUV^®, JRS). The API is a micronized sulfate salt with a drug-load of approximately 12%. Final blend was manufactured in a blend-mill-blend approach in a scale of approx. 20 kg, using a PM-400 free fall blender, a MC 400 blending container (both L.B. Bohle, Germany) and a Comil conical-mill with a 991 μm sieve (Quadro Engineering, Canada). The lubricant (Sodium Stearyl Fumarate) was sieved through a 250 μm hand sieve. Compression was performed on a Korsch XL 200 rotary tablet press (Korsch AG, Berlin) with 20 punch stations. Multi-tip tooling bears 14 separate pins in EU-D die format and was manufactured by Natoli Engineering Company, Inc. USA. Tooling is made from M340 steel which should prevent sticking issues during compression. Resulting biconvex round tablets have a diameter of 2.30 mm, a cup depth of 0.26 mm, overall weight of 10 mg and a thickness of 1.9 mm. Since the standard tablet scraper was feasible for such small tablets, a 3D-printed prototype was developed together with the manufacturer. This 3D-printed prototype was further improved and finally manufactured out of stainless steel, to enable usage in GMP-production. Mini-tablets were tested for uniformity of mass, thickness and hardness based on European Pharmacopoeia methods. Visual appearance was checked after each test run.

Results: Problem

Description: During the first manufacturing campaign with the 2.3 mm multi-tip tooling, using the standard tablet scraper, severe issues during the tablet compression occurred. Manufactured tablet cores were trapped in a gap between die table and tablet scraper. In addition, ejected cores were not guided away from the rotor into the chute and continued to collide with newly ejected cores. Consequently, tablets broke during ongoing rotation of the tablet press and were not properly discharged from the press. Solution/Technological development: The gap between tablet scraper and die table was reduced resulting in a reduction of observed defects. However, tablets were still “caught” in front of the tablet scraper and not able to leave the rotating die table. This was mainly caused by the small size and low tablet weight. It was concluded that the tablets need to be actively forced into the direction of the discharge chute. Guidance of the tablets with compressed air and a slightly different scraper angle was anticipated. A 3D-printed prototype was developed together with the manufacturer. This prototype was tested and modified during subsequent compression trials. By adaption of compressed air pressure and overall angle of the tablet scraper, previously observed defects were completely eliminated. After successful proof of the concept, the tablet scraper was manufactured out of stainless steel to comply with GMP-standards.

Conclusion: It was possible to overcome the physical challenges of a mini-tablet compression process, which is driven by the overall size of this dosage form. Severe defects with an effect on the dosage uniformity were noticed and needed to be addressed. After a technical investigation, the tablet scraper was identified as main root cause. A prototype was developed, 3D-printed and tested successfully. After further improvement, this prototype is successfully used as a standard equipment for several GMP manufacturing campaigns.

References: 1. 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 Dec;163(6):1728-1732.e1. doi: 10.1016/j.jpeds.2013.07.014. Epub 2013 Aug 22. PMID: 23972645.
2. P. Lennartz, J.B. Mielck, Minitabletting: improving the compactability of paracetamol powder mixtures, International Journal of Pharmaceutics, Volume 173, Issues 1–2, 1998, pages 75-85, ISSN 0378-5173


Figure 1: Mini-Tablet punch tips 2.3 mm diameter


Figure 2: A) Defective Mini-Tablets manufactured with standard scraper, B) 3D-printed scraper prototype


Table 1: Comparison of different tablet scrapers & adjustments