Tableting: Industry Perspectives on Sticking During Tablet Compression

Nearly every company that manufactures tablets has had to deal with a sticking problem during compression. Despite the problem’s ubiquitous nature, cross-functional collaborations to discuss sticking across the pharmaceutical industry have either been very limited or absent altogether. To address this gap and facilitate precompetitive dialogue on this important topic, in 2016 the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) formed a Compression Sticking Working Group (CSWG) to provide a venue for members to discuss the topic of tablet sticking and, in doing so, create awareness of research that has already been conducted and identify directions for future studies. 

The CSWG initially set out with two primary goals: 1) To review published literature to determine the current state of the art with respect to tablet sticking; and 2) To survey tablet manufacturers to identify trends and potentially create opportunities for collaboration. The first goal was achieved through the publication of a comprehensive literature review that provides a summary of recent advancements related to the field¹. The second goal was accomplished through a survey of IQ Consortium member companies, the results of which are summarized in this article, which is intended to provide insight into the problem and highlight opportunities for future advancement. 

About the survey 

The survey consisted of 30 questions and focused on five themes related to sticking: 

1. Prevalence and occurrence 
2. Predictive tools and modeling 
3. Drug substance properties 
4. Formulation properties 
5. Process and equipment 

The survey was open to all IQ Consortium member companies. For member companies with multiple R&D facilities, each facility could submit a response. The group received twelve responses from eleven different companies including: AbbVie, Amgen, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Merck and Company, Merck KGaA, Pfizer, and Vertex. All responses were anonymized by the IQ secretariat, and the aggregated results were provided to the CSWG for analysis. 

The survey contained a combination of multiple-choice, open/free-field, rank-order, and scale-based questions. For example, “On a scale of 1 to 5, score each option on its effectiveness to mitigate sticking.” To compare the options within a given scale-based question, the results were normalized to account for the number of responses (not every question received twelve responses), and the options were ranked based on their final, normalized values. 

A Brief Note on Terminology 

When referring to material adherence to compression tool faces, tableting professionals often use terminology inconsistently or interchangeably, which may lead to confusion. To avoid such confusion, the survey used the word “sticking” as a comprehensive term for any unwanted material adherence to the compression tool face, including “picking” and “filming,” unless stated otherwise. The same is true for this article.

Survey Results and Discussion 

Prevalence and occurrence

It is well known that tablet sticking can result in costly manufacturing yield losses due to unacceptable tablet imperfections in addition to expensive downtime because the tablet press operator must stop the process to clean the sticking material from the tooling. However, public information regarding how often sticking occurs and when organizations first encounter the problem is very limited. To provide insights into this knowledge gap, the initial subset of survey questions focused on general issues related to sticking frequency and occurrence. 

Figure 1 shows a graphical representation of the responses to the question, “What percentage of new chemical entities (NCEs) in your experience has shown some degree of sticking during drug product development and/or commercial manufacturing?” Just under half of the respondents (5/12) reported observing sticking on at least 25 percent of NCEs, indicating a relatively high occurrence of the problem. When sticking does occur, the respondents usually observe it during either Phase 1 or Phase 2 development (10/12 responses, or 83 percent) rather than in Phase 3 development (2/12 responses, or 17 percent). 

Based on a traditional clinical trial paradigm, where registration directed studies are conducted in Phase 3, this may suggest that formulation changes are still possible in the majority of cases. This is good news for companies, because changing the formulation was ranked as the most effective strategy for mitigating sticking, followed by changing drug substance properties, changing manufacturing process parameters (such as lubrication blending time or compression force), changing compression tooling/design, and changing the manufacturing process (from direct compression to wet granulation, for example), respectively. 

Scale-up of the manufacturing process is often anecdotally perceived as the most probable time when a sticking issue may present. The premise of this perception is grounded on two primary factors: 1) An increase in tableting speed upon scale-up^{2, 3}; and 2) A potential change in lubricant distribution in the final blend attributable to changing the blending scale⁴. Figure 2 shows that half of the respondents (6/12) indicated that sticking first appeared during scale-up (either from lab to pilot or from pilot to clinical) while the other half indicated that sticking first appeared during lab-scale development, presumably while the formulation was still being optimized. These responses support the notion that, while sticking commonly appears during scale-up, it can present at any stage of development. Moreover, heightened awareness of the issue may facilitate earlier detection of the problem prior to scale-up. 

Predictive tools and modeling

One of the most frustrating aspects of tablet sticking for pharmaceutical scientists and engineers is that it can appear at any stage of a product’s lifecycle, from early development through commercial manufacturing. This finding illustrates the point that models currently available are not capable of reliably predicting the underlying risk factors that lead to sticking. As a result, it is not surprising that 11 of the 12 respondents (92 percent) replied that there is a need for more effective tools/methods to predict sticking. 

Perhaps more importantly, ten of the 12 respondents (83 percent) indicated that their company was actively engaged in research and development of more effective tools/methods to predict sticking. In today’s resource- and cost-constrained environment, the fact that companies are willing to invest resources to understand and prevent tablet sticking speaks volumes about the headaches it can cause. 

The top five methods companies have used to assess sticking risk are listed in Table 1. Visual observation of tablets and/or compression tooling was easily the most common method with 11 of the 12 respondents (92 percent) stating that it was very common at their company. Unfortunately, a shared theme among the top five methods was that they all represent a relatively low level of fundamental understanding of tablet sticking, because they are all reactive in nature rather than predictive. 

This finding was also reflected in the open field responses in which there was overall dissatisfaction with the “reliability and representativeness of the prediction” from current tools/methods. When asked, “If your company could devote more time and resources, which aspects would you study to understand sticking during tablet compression?” the top answer was, “measurement tools and predictive ability.” Collectively, these results highlight the need for more development in this area. 

Drug substance properties

Drug substance attributes are often thought to be the primary culprit when sticking is encountered; therefore, it may be tempting to try to assign blame based only on drug substance physicochemical properties. Table 2 shows a rank-ordered list of the top six drug substance properties respondents perceive to have the greatest impact on sticking. While these factors may be useful for providing directionality in a sticking risk assessment on a case-by-case basis, they are nearly always inadequate by themselves to predict sticking. Moreover, the selection of drug substance properties is often entirely out of the formulator/engineer’s control (for example, milling of the drug substance based on biopharmaceutical performance). 

This underscores the fact that tablet sticking is a complex, multifactorial problem involving not only drug substance properties, but also formulation properties, manufacturing equipment, and processing conditions. As an illustrative example of the multifactorial nature of the problem, it is worth noting that nearly half of the respondents (5/11) replied that co-processing the drug substance with excipients as part of the final drug substance manufacturing process has reduced the risk of sticking. Several write-in examples of this approach were provided, including milling with silicon dioxide, co-processing with solvent and binder, and spray drying. 

Formulation properties

As previously described, respondents ranked changing the formulation as the most effective means for eliminating sticking, which is likely due to the fact that there are multiple different levers formulators can pull. Figure 3 shows the relative rank order of formulation strategies that had the biggest impact on eliminating sticking. Not surprisingly, respondents rated changing the drug load and lubricant concentration as the most effective. 

Under some circumstances, however, changing the drug load enough to reduce sticking risk may not be practical. For example, maximizing the drug load for high-dose formulations is desirable to maintain a smaller overall tablet size for swallowability. As a result, optimizing the lubricant concentration and selecting the correct lubricant and grade for the formulation may be the primary formulation mechanisms to eliminate sticking. Respondents ranked magnesium stearate as the most effective lubricant, followed by sodium stearyl fumarate, glyceryl behenate, stearic acid, and leucine, respectively. 

Respondents ranked removal of a formulation component as the third most effective strategy for eliminating sticking, and it is worth noting that five responses mentioned the removal of mannitol. This is consistent with published information, which states that mannitol often requires higher lubricant concentrations than other excipients⁵. Interestingly, respondents noted both removal and addition of silicon dioxide to help mitigate sticking, confirming that glidants and lubricants can interact and alter each other’s functionality⁶. 

Other formulation components respondents recognized as having an ability to prevent sticking were smaller particle-size grades of dry binders (such as smaller grades of microcrystalline cellulose), sodium lauryl sulfate, and polyethylene glycol (PEG). Moreover, one respondent reported that anything that helps to improve compaction strength is also useful to prevent sticking. 

Process and equipment

Depending on the phase of development, changes to the drug substance properties or formulation may not be possible based on regulatory considerations. In this situation, the few remaining options include adjusting the process parameters, equipment design, or environmental processing conditions. The manufacturing process being used will determine how many options are available to help reduce sticking. For example, a direct-compression process will have fewer processing levers to pull than a wet-granulation process. Unsurprisingly, respondents ranked direct compression as the platform that is most prone to sticking, followed by dry granulation, hot-melt extrusion, fluid- bed granulation, twin-screw granulation, and highshear wet granulation, respectively. 

If the manufacturing platform has already been locked, then the formulator/engineer will have little recourse but to work with the processing parameters and equipment available for that process. Table 3 lists the processing parameters and equipment changes respondents ranked as most effective for eliminating sticking. Interestingly, the top three perceived changes that help mitigate sticking all apply to direct compression, despite the fact that direct compression was ranked as the platform most prone to sticking. This finding may reflect the industry’s desire to pursue direct-compression tableting when technically feasible due to its simplicity and cost effectiveness compared to granulation-based tableting. 

It is also noteworthy that respondents ranked compression tooling changes as the most effective process/equipment- related change, but the vast majority of the expertise in this area lies outside the pharmaceutical industry, in the tooling manufacturing industry. This highlights the need for pharmaceutical companies to have a good working relationship with their tooling supplier. 

Other process-related survey questions concerned the use of external lubrication and the impact of environmental conditions on sticking. As Figure 4 shows, four of the 12 respondents (33 percent) have successfully used external lubrication to mitigate a sticking problem. Additionally, half of the respondents (5/10) confirmed that environmental conditions have impacted sticking, with the majority of those (4/5, or 80 percent) responding that moisture (relative humidity) was more important than temperature. 

Conclusions 

These survey results provide valuable insights into the prevalence of sticking in the pharmaceutical industry and the most effective mitigation strategies currently being used by tablet developers and manufacturers. The results provide a useful resource for novice practitioners who are still learning current industry practices as well as experienced personnel who wish to benchmark their practices against those of other companies. 

Moreover, the results have helped to identify the most important areas for future development in this field. Overwhelmingly, the respondents confirmed that there is a significant unmet need to establish predictive and robust models that can be used to identify sticking risks early in product development prior to transfer to the manufacturing site, when there are more prevention options available. 

Establishing such models would represent a step change in the industry’s understanding of the underlying phenomenon of sticking from the current state, where most methods are reactive in nature rather than predictive. We hope is that publishing these survey results will promote additional awareness of this important topic, encourage further dialogue among industry and academia, and potentially even initiate new research opportunities to advance the science of tablet sticking. 

References 

1. Sayantan Chattoraj, Patrick Daugherity, Todd McDermott, Angela Olsofsky, Wyatt J. Roth, and Mike Tobyn, “Sticking and picking in pharmaceutical tablet compression: An IQ Consortium review,” Journal of Pharmaceutical Sciences, Vol. 107, No. 9, pages 2,267-2,282. 

2. K. Kakimi, T. Niwa, and K. Danjo, “Influence of compression pressure and velocity on tablet sticking,” Chemical and Pharmaceutical Bulletin, Vol. 58, No. 12, pages 1,565-1,568. 

3. Changquan Calvin Sun, “Dependence of ejection force on tableting speed—A compaction simulation study,” Powder Technology, Vol. 279, pages 123-126.

4. J. Kushner and F. Moore, “Scale-up model describing the impact of lubrication on tablet tensile strength,” International Journal of Pharmaceutics, Vol. 399, pages 19-30. 

5. Paul J. Sheskey, Walter G. Cook, and Colin G. Cable, Handbook of Pharmaceutical Excipients, 8th edition, Pharmaceutical Press, 2017. 

6. K. Pingali, R. Mendez, D. Lewis, B. Michniak- Kohn, A. Cuitino, and F. Muzzio, “Mixing order of glidant and lubricant—Influence on powder and tablet properties,” International Journal of Pharmaceutics, Vol. 409, pages 269-277. 

Sayantan Chattoraj is a senior scientific investigator in drug product design and development at GlaxoSmithKline, Patrick Daugherity is a principal scientist in drug product design at Pfizer, Todd McDermott is director of process engineering sciences at AbbVie, Angela Olsofsky is a senior associate scientist in drug product technologies at Amgen, Wyatt J. Roth is a senior research scientist in small molecule design and development at Eli Lilly, and Mike Tobyn is a research fellow at Bristol-Myers Squibb. 

The IQ Consortium is a technically- focused organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators, and the broader R&D community. (https://iqconsortium.org/) Please address any correspondence regarding this article to Wyatt Roth at roth_wyatt_james@lilly.com.