Mini-tablet use continues to grow as an accepted option for small-volume, high-value products, especially for specific patient populations. Mini-tablet applications, as either single- or multi-tablet units, allow for fixed-dose combinations and dose titrations1. Because of their small size (typically less than 3.0 millimeters in diameter), mini-tablets also offer an approach for populations that have difficulty swallowing traditional tablets and capsules, such as pediatric and geriatric patients or patients suffering from dysphagia.
This article describes a study that was designed to demonstrate experimental design, equipment feasibility, lactose-based excipient performance, and critical material attributes within a typical mini-tablet manufacturing operation. Example formulations were chosen to investigate compaction and release performance, as well as the impact of particle size using two different active pharmaceutical ingredients (APIs) and three functional excipients. Each formulation consisted of a powder blend comprising 10 percent API, 89 percent excipient, and 1 percent lubricant.
Materials and methods
The materials used in the study are listed in Table 1. Vitamin B2 (riboflavin) and vitamin C (ascorbic acid) were chosen as the APIs for handling and functionality reasons. Table 2 shows the laser-diffraction particle- size-analysis data for the APIs.
The excipients examined included spray-dried lactose (FlowLac 100), and two lactose-based, co-processed excipients (CPEs) (CombiLac and RetaLac). The d50 values for the three excipients were comparable and ranged between 120 and 160 microns. Magnesium stearate, at 1 percent, was used as a lubricant.
Blends were prepared using an IMA CyLab bin blender, and mixing quality was monitored by a VIAVI MicroNIR PAT-W probe. For each formulation, 90 revolutions were used to incorporate the API and 30 revolutions were used for final lubrication. This was believed to be sufficient as supported by moving block standard deviation. Compaction was performed using an 8-station IMA Prexima 80 rotary tablet press. The mini-tablet diameter was 2.5 millimeters, and the shape was round with a flat face.
XIMA software was used for data acquisition. The tablet press operated at a constant rotational speed of 20 rpm and applied compression forces between 5 and 20 kilonewntons. The angle of repose for each powder blend was determined according to compendial methods (Ph. Eur. 2.9.16), and the average tablet breaking force was evaluated using an Erweka TBH 425TD hardness tester with ten compacts.
The mini-tablet manufacturing process followed a typical direct compression (DC) scheme: excipient and API blending followed by lubrication and compaction. Vitamin B2 mini-tablet dissolution testing was performed according to Ph. Eur. 2.9.3 using an Agilent 1260 Infinity Quaternary LC spectrophotometer at 445 nanometers. Tests were performed in triplicate.
Results and discussion
The mini-tablets’ compression- breaking force profiles were assessed, as shown in Figure 1. Results showed that mini-tablets made using the finer, more plastically deforming vitamin B2 withstood approximately twice the absolute breaking force as mini-tablets made using the coarser, more brittle vitamin C. At 10 kilonewtons compaction force, the vitamin B2 compensated for performance variations in the three excipients, while mini-tablets made with the coarser, more brittle vitamin C demonstrated greater differences in binder compaction behavior. Of the excipients, the RetaLac performed better than the spray-dried FlowLac 100 and the CombiLac. This may be attributable to RetaLac’s composition having the highest level of plastically deforming materials, dominated by hypromellose. Additionally, load-time profiles showed a shift to greater plasticity by maintaining an increased curve symmetry, especially when using RetaLac.
The impact of flowability on tablet weight variation was monitored, and material characteristics such as particle size and size distribution and API morphology were critical. The blends demonstrating the best flowability resulted in the lowest tablet mass relative standard deviation (RSD). Research by Rumondor et al. found a similar trend for α-lactose monohydrate-based mixtures2. Nevertheless, the results showed that ratio and absolute values for angle of repose versus tablet mass RSD were also material specific. At a 39-degree angle of repose, vitamin C blends showed higher tablet mass RSD values (3 to 4 percent) compared to vitamin B2 (1 to 2 percent). The flowability change “sensitivity” was also found to be different for the two example formulations as indicated by the overall regression line inclinations shown in Figure 2. Tablet mass RSD increased more than 4 times faster when compacting the vitamin B2 blend.
The results showed that the vitamin B2 sustained drug release when using RetaLac as an excipient was independent from mini-tablet breaking force between 28 and 48 newtons, which is in full agreement with typical tablets with 80 percent release between 4 and 5 hours3. In comparison, FlowLac 100 showed immediate-release performance, with 80 percent release after 15 minutes.
Subsequently, a limited stability study has been conducted for RetaLac- and FlowLac 100-based formulations, monitoring tablet dimensions and breaking forces. The goal was to evaluate possible elastic recovery impact on final tablet dimensions and/or storage-induced changes in tablet breaking force pertaining to API release. For that reason, tablet diameter, thickness, and breaking force changes were investigated at 7 and 28 days after compaction at 25°C and 60 percent relative humidity (RH) using mini-tablets compacted at 10 kilonewtons compaction force. Overall dimensional changes were small and did not exceed 7 percent for RetaLac and 1 percent for FlowLac 100 when the tablet diameter was measured after one month. At 4 weeks, tablet thickness had increased by 2 percent for both formulations. Breaking force differed by approximately 28 percent for the FlowLac and 18 percent for the RetaLac.
Conclusions
This study compared the lactose- based CPEs, CombiLac and RetaLac, to spray-dried lactose, FlowLac 100, in mini-tablet manufacturing unit operations using an 8-station Prexima 80 rotary tablet press. All materials performed within expected ranges with respect to compactibility, tablet mass uniformity, and vitamin B2 API release.
The study confirmed that blend flowability was critical for tablet weight uniformity. Compression-breaking force profiles showed an indirect correlation between API particle size and compaction behavior for the vitamin B2 and C systems. Retesting the mini-tablets after 1 month at 25°C and 60 percent RH showed no significant changes in tablet diameter or thickness, but breaking force variations were slightly larger. These study results clearly demonstrate design and equipment feasibility and material performance.
References
1. N. Passerini, C. Funaro, G. Mondelli, G. Calogéra, B. Albertini, A. Fiorino, L. Rodriguez, 49th AFI Symposium (2009).
2. A. C. F. Rumondor, D. Harris, F. Flanagan, V. Biyvala, M. A. Johnson, D. Zhang, S. Patel; A. Pharm. Rev., (2016).
3. J. A. Zeleznik, C. Nowak, F. K. Penz ; AAPS, (2014).
Federica Giatti is process development technologist, R&D laboratory, and Caterina Funaro is process laboratory manager at IMA Active, a manufacturer of solid dose processing equipment (978 537 8534, www.ima.it). Vera Fichtner is senior project manager, R&D, and Franz Penz is head of application technology at Meggle, which supplies excipients to the pharmaceutical industry (845 289 0264, www.meggle-pharma.com).