When transitioning from batch to CDC, not all excipients used in batch processes can be directly applied in CT, particularly when dealing with excipients that have poor flow properties. Feeding of these materials can be negatively impacted by external factors, such as mechanical vibrations. Additionally, the Loss in Weight (LiW) feeding systems often struggle to maintain consistent and accurate feeding at low feed rates for such materials, which impairs the manufacturing process. Moreover, each excipient in the formulation is fed through an independent LiW feeder, and when working with formulations containing multiple ingredients, this can lead to a high number of feeders to manage. Furthermore, many excipients used in CT lack additional benefits like enhanced solubility and permeability, which can limit the formulation’s overall in vivo performance.
This study explores novel alternative excipients that meet the necessary requirements for CDC processes, specifically ensuring consistent feeding, without compromising the ability of each material to fulfill its intended function within the formulation. To achieve this, different excipients were tested and grouped based on their role in the formulation, namely lubricants, fillers, disintegrants, and glidants. These materials were selected based on their: (i) material properties, such as higher bulk density (BD) and particle size (PS), which enhance feeding performance; (ii) ability to combine multiple roles in a single excipient, through the use of co-processed materials that incorporate fillers, disintegrants, and/or lubricants, reducing the number of feeders needed and improving the feeding performance by increasing the target feeding flow rate; and (iii) functional properties, such as the use of protein-based materials with the potential to enhance drug bioavailability.
Based on their role in the formulation, various tests were conducted to evaluate the potential of the novel excipients as lubricants, fillers, disintegrants, and/or glidants. All these excipients were characterized by yield locus and wall yield locus (Ring Shear Tester, RST-XS.s), BD (graduated cylinder), TD (SOTAX, Tapped Density tester) and PS (Sympatec Laser Diffraction Analyzer). Their feeding performance was assessed using a LiW feeder (GEA) in standalone mode, and the flow rate relative standard deviation (RSD%) was determined. Subsequently, blends containing these materials were prepared and characterized by yield locus and wall yield locus (Ring Shear Tester, RST-XS.s), BD (graduated cylinder) and TD (SOTAX, Tapped Density tester). The blends were compressed into tablets using: (1) a benchtop compaction simulator (Nano Styl’One) to evaluate their Compressibility, Tabletability and Compactibility (CTC) profiles and to determine the ejection force; and/or (2) a lab-scale rotary tablet press (Riva Piccola) to determine the tablet weight RSD and identify the appearance of tablet defects. Additionally, the tablets’ friability and disintegration were also assessed using a friability tester (Erweka) and disintegrator tester (SOTAX), respectively. The results obtained for each excipient were compared with standard materials used in batch tableting, namely Magnesium Stearate (MgSt) and Sodium Stearyl Fumarate (SSF) for lubricants, Cab-o-sil(R) for glidants, Ac-Di-Sol for disintegrants, and cellulose, mannitol and lactose for fillers.
The success criteria for lubricants were: (i) improved feeding performance compared to traditional lubricants; (ii) ability to reduce the ejection force required to eject the tablet from the die cavity; (iii) no significant impact on the tablet’s CTC profile; and (iv) shear cell results comparable to traditional excipients. For glidants, in addition to a suitable LiW feeding performance, good blend flowability and tablet weight uniformity comparable to commonly used glidants were the defined criteria. Finally, for super fillers that combine multiple roles in formulation and/or have potential as functional excipients, the criteria included LiW feeding performance, processability and good blend flowability behavior compared to standard fillers, as well as the absence of tablets defects and/or an appropriate disintegration and lubrication.
Novel proprietary materials were tested in the scope of this work as lubricants for CT and compared with MgSt and SSF. The results demonstrated: (i) better feeding performance, as indicated by lower flow rate %RSD (around 2%); (ii) comparable ejection force results (~1.5 MPa) when present in 3% w/w in the formulation; (iii) no impact on blend processability or tablet friability; and (iv) similar flowability results using 3% w/w. These benefits highlight that these novel lubricants could address some of the inherent challenges posed by traditional lubricants in CT, while maintaining tablet quality integrity and consistency.
The potential of commercially available glidants, such as Syloid(R) and Cab-o-sil(R), as well as other materials aimed at improving the flow properties, was tested. The results indicated difficulties in feeding these materials using the current LiW feeders, since they typically make up only 1% w/w of the formulation, resulting in a low throughput of 0.2 kg/h for a line flow rate of 20 kg/h. For some materials such as Cab-o-sil(R), the feeding proved to be impossible whereas for others such as Syloid(R) a high flow rate RSD% around 8% was obtained, which exceeds the manufacturer’s recommended limits (below 5%) and therefore, is not ideal. Additionally, during Piccola runs, tablet weight RSD values as high as 6% were observed, comparable to blends without any glidant (approximately 7%), further hampering their use in CT processes. One promising strategy for improving the feeding of glidants was combining fillers with these materials, as this increased the required feeder throughput. This approach led to improved feeding performance, as demonstrated by a reduction in the flow rate RSD%. Ultimately, engineering solutions could also be envisioned to enhance the feeding of challenging materials, such as glidants, at low feed rates.
The potential of protein-based excipients as fillers was evaluated, and the results demonstrated: (i) feeding performance similar to lactose, with an RSD% below 2%; (ii) comparable CTC performance and friability results; (iii) shear cell results that were similar to or slightly better than lactose (FFC at 1000Pa of 10, compared to 5 for lactose); and (iv) no visible tablet defects. The primary advantage of using these materials is their ability to provide excellent tablet mechanical properties while simultaneously offering the benefits of protein inclusion, such as enhanced drug solubility and improved permeation.
Super excipients, which combine multiple roles in a single material, offer several advantages, such as reducing process complexity by decreasing the number of required feeders. This, in turn, helps in all the stages from the product development to commercial, including a faster and straightforward development in the laboratory and simplified Design of Experiments (DoEs) during the process validation. The tested materials demonstrated unique advantages, including higher BD, TD, and larger PS, which enabled efficient feeding without compromising the process performance. Specifically, these materials: (i) maintained good flow properties, as demonstrated by flowability testing; (ii) exhibited similar mechanical properties, as shown by comparing the CTC profiles with the ones of commonly used fillers; (iii) displayed appropriate friability and disintegration values; and (iv) showed no visible tablet defects.
In conclusion, this study demonstrates the potential of novel alternative excipients for CDC, by focusing on their feeding performance, processability, flowability, functionality, and ability to fulfill multiple roles in formulation. The materials tested showed promising results in enhancing the overall process efficiency without compromising the integrity or functionality of the tablets. Furthermore, a straightforward strategy to screen different materials for CT based on their role in the formulation, namely as lubricants, glidants, fillers, and/or disintegrants, was developed in a laboratory setting. This approach not only simplifies the selection process of excipients for CT but also provides a pathway for optimizing formulations in a more efficient and systematic manner. Integrating these materials into the formulation process allows pharmaceutical manufacturers to improve the feeding step in CT process, while also tapping into the potential benefits of functional excipients that could enhance bioavailability and therapeutic outcomes.