Subdivision of modified-release Tablets: state-of-the-art and Future Perspectives

Abstract

Tablet splitting is a practice disseminated among health professionals for dose adjustments, swallowing facilitation or even treatment cost reduction. Nevertheless, tablets not designed for this purpose cause imprecise dosage and stability loss with important therapeutic repercussions. Novel technologies of modified drug release tablets have come to market including new materials and innovative production processes, for example, polymeric matrix, orodispersible, 3D printing, MUPs, etc. The heterogeneity and complexity of these tablets go well beyond a traditional gastroresistant coating tablet, making orientations on the practice of tablet subdivision difficult. This editorial aims to provide a critical and up-to-date evaluation of this scenario based on the most recent studies involving the subdivision of modified-release tablets.

Keywords:

• dose variation
• modified-release tablets
• multilayer tablets
• multiple-unit particulate system
• orally disintegrating tablets
• stability
• sustained-release tablets
• tablets subdivision
• therapy personalization

The tablet subdivision issue

Amidst the technological advances of the 21st century and the beginning of the fourth industrial revolution, tablets; a dosage form launched in the distant year of 1834, are still the most widely used drug administration vehicles, and the natural choice of any industrial development [1]. Despite appearing to have stood still in time, behind the archaic shape, tablets may embody the latest available technology from billions of dollars of investments. Drug products such as Viekira XR^®; one of the most expensive medications in the world, used to treat hepatitis, Spritam^®; a tablet produced by 3D printing and Rybelsus^®; the first oral tablet containing a peptide to treat diabetes, are some examples of tablets that incorporate sophisticated drug-delivery mechanisms [2–4].

Even in the face of such advances, an old problem within the large-scale pharmaceutical industry, has never been satisfactorily solved, the need for therapeutic individualization [5]. Variations in race, ethnicity, age and disease progression among others, require dose adjustments that are incompatible with industrial tablet production, which leads to a practice as old as the invention of tablets; tablet subdivision [6]. Several studies, conducted mostly with immediate-release tablets, revealed that these products may present poor splitting behavior with dose variations as high as 40%, and even for narrow therapeutic window drugs such as sertraline [7–10].

In the case of modified-release tablets, traditionally, the only restriction imposed on the subdivision procedure is not to divide enteric-release tablets, in which a polymeric film rupture would inevitably lead to the mistaken release of its contents into the gastric environment, utterly compromising its effectiveness. Similarly, tablets containing OROS^® technology, whose drug release kinetics depend on the integrity of the semi-permeable coating that surrounds the tablet, follow the same restriction. In other cases, tablet subdivision has been encouraged and is commonly recommended by manufacturers. Recent studies conducted by our research group and others, however, identify previously ignored problems arising from this practice [11–15]. The scenario becomes even more complicated with the advancement of drug-release technologies employing new materials and processes.

How the tablet subdivision could affect different technologies

For sustained-release matrix tablets with no functional coating, it is assumed that their subdivision will be without undue damage to the mechanisms of drug release control, yet these tablets are often scored. Nevertheless, studies conducted with different types of matrices have demonstrated that in the case of tablets that preserve their shape for a longer period of time along with the dissolution (such as inert and lipid matrices), the drug diffusion mechanism is decisively influenced by the surface area of the dosage form [16,17]. Hence, the cross-section of the tablet caused by the subdivision gives rise to a new surface, leading to dissolution rate variations of up to 20%, an unacceptable range for a narrow therapeutic window drug such as clomipramine tablets [15].

Contrary to what one might suppose, the problem of breaking modified-release tablets goes beyond the influence on the dissolution profile, for example, other peripheral issues of the dosage form may compromise different aspects of tablet quality and need to be studied case by case. An example is tablets comprising a multiple-unit particulate system, in which the tablet subdivision does not lead to direct changes in the dissolution profile, as the granules originated after the tablet disintegration would rule such an event. Still, studies have demonstrated that a multiple-unit particulate system subdivision may lead to drug content variations of up to 10% in tablet halves, as a consequence of failures in tablet uniformity, putting doubt in the safety of splitting this class of tablets [11,12].

Another class of modified-release tablets that have become quite popular over the years are orally disintegrating tablets (ODTs), which are designed for instantaneous disintegration in the oral cavity, improving therapeutic drug efficiency due to a pregastric absorption. Also, the easy swallowing of these tablets makes them the first choice for patients with dysphagia. As ODTs are widely indicated in pediatrics and geriatrics, their use often require dose adjustments and the consequent need for subdivision. Our research group has recently evaluated the subdivision behavior of several commercial ODTs [13]. This study demonstrated that upon subdivision, the presence of highly hygroscopic components in ODTs causes a rapid water absorption when each tablet half is exposed to ambient humidity, followed by clear signs of hydrolysis, even for a short period of time. Thus, the subdivision of ODTs is recommended, but the half left should be discarded, even when the next uptake is required in a short-time interval [13].

Also, multilayer tablets already account for an essential share of the modified-release tablet market. Several advantages of multilayer tablets, such as the possibility of combining incompatible active ingredients and different release profiles in the same dosage form, quickly popularized them. Layer adhesion for multilayer tablets is done by progressive compaction processes [18]. There are no studies on the subdivision behavior for this class of tablet, but layer separation could potentially be accentuated by a split process, as a predisposition to lamination and capping has been reported [18]. Moreover, differences in composition between the layers can make a homogeneous division process difficult. The stability of the tablet halves also seems to be a relevant issue, as moisture absorption, facilitated by opening the primary package and sectioning the tablet, can lead to a late layer separation process. Studies need to be conducted to clarify the best course of action for this technology.

In such a complex scenario, some technologies may provide tablets that are better suited for subdivision. Hot-melt extrusion is a recent technology that has been increasingly utilized in the production of modified-release tablets. Dozens of tablets on the market that are already produced in polymeric matrices based on this, have remarkably adapted to the continuous industrial-scale production technology [2]. A study conducted with tablets obtained using different polymers by hot-melt extrusion demonstrated that when ideal processing conditions are selected (heat treatments with plastic effects on these matrices), more uniform and resistant internal structures are created with excellent response to subdivision. When the right processing conditions are selected, these tablets can have better splitting behavior than traditional powder matrix tablets, with the complete elimination of any crumbling mass loss due to subdivision [14].

Conclusion

Despite all of the technological advances, tablet subdivisions will still be part of the clinical practice, at least in the near future. Although, the most recent studies point to new obstacles in the subdivision of modified-release tablets, none of these studies presented insurmountable impediments that make this practice unfeasible. Quite the opposite, studies demonstrate that it is possible to optimize formulation and production conditions through strategies such as the use of quality-by-design tools, to achieve more appropriate results with tablet subdivision [19,20].

Thus, the issue with the subdivision of modified-release tablets is more complex than one might suppose and requires more research, especially for the new release-drug devices coming to the market. The concern with this issue must be part of the formulation design in the early stages of its development. In this sense, a greater regulatory effort needs to be made to push manufacturers to conceive drug products that can be safely subdivided.

Particularly in the case of modified-release tablets, it is necessary to ensure, on the one hand, that the splitting of the pharmaceutical unit does not change the mechanism of drug-release control, and on the other, that the tablets have the physical and mechanical characteristics necessary to undergo the subdivision process.

Financial & competing interests disclosure

The authors acknowledge the financial support of CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil) and FAPDF (Fundação de Apoio à Pesquisa do Distrito Federal, Brazil). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.