A comprehensive study published on January 12th in the International Journal of Pharmaceutics (DOI: 10.1016/j.ijpharm.2024.123806) has ushered in a significant stride in pharmaceutical manufacturing by shedding light on the controversial topic of multi-tip punch tooling and its impact on the quality of high drug load minitablets. The study was spearheaded by a team of researchers from the GEA-NUS Pharmaceutical Processing Research Laboratory at the National University of Singapore, including Loo Shang Jun, Lim Cheng Yee, Heng Paul Wan Sia, and Chan Lai Wah. Through their meticulous investigation, they examined the intricacies of compaction forces, dwell time, punch geometry, and lubrication levels, offering invaluable insights that promise to enhance productivity while maintaining the paramount standard of drug quality.
Minitablets, due to their petite size and potency, have gained popularity for their ease of ingestion across diverse patient demographics, including pediatric and geriatric populations. The manufacturing process, however, has remained a complex puzzle, particularly when it comes to optimizing the compaction process that plays a crucial role in determining the Critical Quality Attributes (CQAs) such as weight variation, tensile strength, and disintegration time.
The typical production of minitablets involves utilizing single-tip punches or tools with multiple die openings and multi-tip punches. Multi-tip punches, preferred for their higher productivity, function under the assumption that the overall compaction force is the product of the desired compaction force per tip and the number of tips on the punch barrel. This study, however, has controversially demonstrated that compaction forces leading to consistent CQAs are not directly proportional to the number of punch tips as previously conceived.
The team’s findings indicate that minitablets prepared with multi-tip tools exhibit greater weight variation compared to those manufactured with single-tip tools. Multi-tips also lead to longer dwell times during compaction, resulting in minitablets with higher tensile strength but, consequently, also a protracted disintegration time—a critical aspect when considering drug bioavailability and efficacy.
In a surprising twist, the researchers found that the punch face geometry’s effect was negligible in comparison. Instead, the concentration of magnesium stearate, a common lubricant in tablet formulation, emerged as a significant factor. Increasing the magnesium stearate concentration from 0.75 to 1.25%, w/w, notably reduced the weight variation for minitablets produced with multi-tip tools, while simultaneously prolonging the disintegration time—though it had no appreciable impact on tensile strength.
To counteract the disparities in dwell time and tensile strength between single-tip and multi-tip produced minitablets, the research highlighted the efficacy of adjusting compaction speed. In particular, a larger reduction in compaction speed was requisite for single-tip tools at higher compaction pressures, suggesting a potential compensatory measure for manufacturers to consider.
This study’s revelations carry profound implications for pharmaceutical production. By fine-tuning parameters such as compaction forces and speeds, pharmaceutical companies can mitigate quality issues inherent to multi-tip tooling, marking a leap forward in the scalable production of high drug load minitablets without compromising on quality.
In the conclusion of their report, the authors assert the absence of any competing financial interests or relationships that could influence the work—reaffirming the study’s objectivity and the robustness of the findings. The study’s sponsors and the research community have lauded the comprehensive investigation for its potential to revolutionize the manufacturing process of minitablets and other solid dosage forms, calling for further research to build on these groundbreaking insights.
For those within the pharmaceutical industry, the findings of this research are nuancing what is known about tablet compaction and design, advocating for a more nuanced approach that can ensure both efficiency and quality in production.
The full study can be accessed through the International Journal of Pharmaceutics with the article number 123806 and DOI 10.1016/j.ijpharm.2024.123806.
References
1. Loo Shang Jun, Lim Cheng Yee, Heng Paul Wan Sia, Chan Lai Wah (2024). Study of compaction tools and parameters on critical quality attributes of high drug load minitablets. International Journal of Pharmaceutics, 652, 123806. DOI: 10.1016/j.ijpharm.2024.123806
2. European Pharmacopoeia Commission. (2017). Uniformity of Dosage Units. In European Pharmacopoeia (9th ed.).
3. United States Pharmacopeia and National Formulary (USP 41-NF 36). (2018). <1216> Tablet Friability.
4. Shotton, E., & Ridgway, K. (2017). The role of lubricants in solid oral dose manufacturing. The Pharmaceutical Journal.
5. International Conference on Harmonisation. (2005). ICH Guideline Q8 (R2): Pharmaceutical Development.
6. Reynolds, T. D., Mitchell, S. A., & Balwinski, K. M. (2010). Effect of multi-tip tablet press tooling on tablet properties and the discrimination of formulation blends. European Journal of Pharmaceutical Sciences, 39(3-4), 224-231.
Keywords
1. Minitablets production
2. Pharmaceutical compaction
3. Multi-tip punch tooling
4. Tablet manufacturing
5. Drug quality attributes