Technical concerns on the subdivision of multilayer tabletsAbstract
Multilayer tablets are gaining popularity for combining active pharmaceutical ingredients in a single dosage unit. However, the need to personalize drug treatment frequently demands the subdivision of such dosage forms. This study aimed to evaluate the performance of commercial multilayer tablets from different geographic origins for subdivision. An analysis of morphology, dimensions, mechanical resistance, and mass measurements of the halves after subdivision by a tablet splitter was performed, as well as an analysis of the adhesion layers. The tablets failed to meet acceptable standards for mass variation (more than 10 % in over 60 % of the samples), mass loss, and friability (more than 3.0 and 1.5 % in half of the samples, respectively). Furthermore, most of the tabletshad exhibited layer separation or weakening after the subdivision, resulting in a marked decreasein fracture force to values below 10 N. Several factors, including matrix heterogeneity and high thickness, may contribute to these results. Delamination in multilayer tablets represents a significant quality issue that can compromise their therapeutic utility. Given such a scenario, the subdivision of multilayer tablets should be avoided until developers implement appropriate strategies, ensuring safe conditions for the user.
Keywords:
Multilayer tablet; Tablet subdivision; Tensile test.
INTRODUCTION
Multilayer tablets have become increasingly popular as they combine different drug delivery systems or active pharmaceutical ingredients (APIs) in a dosage unit, even if chemical incompatibility between them is present. Such tablets have strong commercial appeal, indicating that they will remain a trending topic in the pharmaceutical field in the coming years (Akhtar et al., 2020).
Some technological issues in the production of multilayer tablets that previously limited their use have recently been overcome. For example, the adaptation of tablet presses to this technology has lowered production costs, and the development of improved formulations and processes has reduced layer separation (delamination), which has always been a vulnerable aspect of these products (Bellini, Walther, Bodmeier, 2020).
The subdivision of multilayer tablets to adjust the dosage, as commonly occurs with regular tablets, remains a clinical need, especially for specific populations such as children and the elderly (van Riet-Nales et al., 2014). Despite their relevance in the pharmaceutical market, to our knowledge, there is still no study on the impact of the subdivision process on these tablets. Nevertheless, subdivision studies involving several tablets have shown that this process can impact their mechanical properties, reducing hardness and increasing friability (Teixeira et al., 2017; Bedogni et al., 2021). Multilayer tablets can be particularly sensitive to this effect, which can potentially cause the separation of their layers and compromise the treatment.
Therefore, this work aimed to evaluate the suitability of multilayer tablets for subdivision, with particular emphasis on the impact on layer adhesion. To this end, physical and morphological tests were carried out, including analysis of morphology, dimensions, mechanical resistance, and mass measurements of the halves after subdivision, as well as tensile testing of the layers using a protocol specifically designed for this purpose.
MATERIAL AND METHODS
Material
As described in Table I, twelve marked multilayer tablets from three different geographic regions (Brazil, Germany, and the USA) were selected for this study. The tests were conducted using the same tablet batch, and the tablets were subdivided into two halves using a regular tablet splitter.
Mass measurements
The mass variation in percentage was calculated by the difference in the mass of each whole tablet divided by two and its halves after subdivision. The mass loss in percentage was calculated as the difference between the mass of the whole tablet and the sum of the two halves. Twenty replicates of each sample were used for these determinations (Teixeira et al., 2017).
Friability and hardness
Friability was evaluated using ten replicates (whole tablets or halves) weighed before and after placement in a friabilimeter (Slabor, Brazil) operating at 25 rpm for 4 min. The hardness, in turn, was determined using a durometer (Stokes, USA) in quintuplicate. The variation in hardness of whole and half tablets was determined in percentage. Height and thickness were measured with a caliper (Mitutoyo, Brazil).
Morphology
A stereomicroscope (Laborana, China) connected to a smartphone camera was used to acquire imagesof the cross-section of the tablets where the cut was performed.
Tensile test
The adhesion between tablet layers was evaluated before and after the subdivision using uniaxial tensile tests on a universal testing machine (Shimadzu EZ test, Japan) equipped with a tension grip and a 5 kN load cell. First, machine-fitting supports were designed using TinkerCAD software (Autodesk, USA) to adequately accommodate whole and half tablets in the equipment and printed in PLA with a ZMorph 3D printer (model 2.0S, Poland) (Figure 1A).
(A) 3D design of the support to accommodate the tablets on the universal testing machine for the tensile test (a), a printed device containing the specimen (b), the test completed with the whole tablet (c), and the half tablet (d). (B) Fracture force results from multilayer tablets (wholes and halves). *p<0.05 and **p<0.01 (t-test).
For the assay, each printed support was attached to one side of the tablet using cyanoacrylate glue and then maintained in a desiccator with silica (UR~2 %) for 24h. This setup ensured the stability and integrity of the attachment, as the adhesion of the glue and printed supports was stronger than that of the tablet layers, preventing interference with the test results. The supports were then fixed in the grips, and a 0.5 mm min- 1 crosshead speed was vertically applied (Gonçalves et al., 2021; Paradowska-Stolarz et al., 2023). All samples were tested in sextuplicate.
The data were evaluated regarding the normal distribution, and a student t-test was used to compare wholes and halves tablets using GraphPad Prism® (USA).
RESULTS AND DISCUSSION
When evaluating the subdivision of the multilayer tablets, it was important to consider whether the resulting halves met minimum quality requirements for use. It was observed that none of the tested tablets met acceptable standards for mass variation (<10 %), mass loss (<3 %), and friability (<1.5 %). Additionally, there was a significant reduction in hardness (>30 %) and layer separation due to subdivision, as indicated by the results highlighted in red in Figure 2 (United States Food and Drug Administration, 2013; Anvisa, 2019). Although manufacturers do not recommend splitting the multilayer tablets studied, 25 % had a score line (Table I), which misleadingly suggests that they could be divided. Furthermore, in clinical practice, these tablets have been divided to adjust the dosage, often following the recommendation of health professionals (Cunha-Filho, Gelfuso, Gratieri, 2020).
Images of halves (x2) in the cross-section of the division, together with results of mass variation, mass loss, layer separation after the subdivision, friability, and variation in hardness of the halves. In green are the results that met usage requirements, and in red those that were outside acceptable limits.
The mass variation was above 10 % in more than 60 % of the samples, therefore higher than the average for regular commercial tablets (Teixeira et al., 2017; Pereira et al., 2018). Notably, the mass variation for COR/BRA and GAV/GER was 24.9 and 19.5 %, respectively. The inaccuracy in the dosage of these medications is especially critical given the potential interactions between drugs in these products. For instance, COR/BRA has four APIs: acetylsalicylic acid, which can cause bleeding in the case of underdosing and hypoprothrombinemia in overdoses; dexchlorpheniramine, which can lead to hallucinations and convulsions in overdose; phenylephrine, which can trigger liver and kidney damage in under-dosage conditions and cardiovascular and neurological complications due to overdose; and caffeine, whose overdose can cause tremors and tachycardia (Whalen, Finkel, Panavelil, 2015).
The erosion of the fragile edges resulting from tablet subdivision resulted in mass loss measurements with average values above 3 % in 41.7 % of the samples (Figure 2). In the most critical cases, such as ENG/ BRA and HCT/BRA, mass losses were 15.4 and 35.5 %, respectively. This result can be partly explained by the significant decrease in tablet hardness after subdivision (Teixeira et al., 2017); for example, ENG/ BRA experienced a 39.2 % reduction in hardness. Furthermore, 50 % of the halves presented friability above the pharmacopeial acceptable level of 1.5 %, highlighting the fragility of the fractions and their unsuitability for handling (Figure 2).
Such poor subdivision results may be related to several factors, with the homogeneity of the matrix being particularly crucial. Matrices with a continuous internal structure have been shown to favor appropriate division (Cunha-Filho, Gelfuso, Gratieri, 2020; Cunha- Filho et al., 2019). In contrast, the irregularity of the matrix structure in multilayer tablets, where each layer is formed by different granules and/or powder mixtures, may lead to more irregular division of the tablets. In fact, notable differences in particle size and matrix uniformity among the various layers are evident in the microscopy images of the tablets' cross-sections (Figure 2). Similar outcomes have been observed in the subdivision of orodispersible and matrix tablets, which have heterogeneous matrices (Cunha-Filho et al., 2019; Temer et al., 2018).
Another unfavorable aspect of the subdivision is the high thickness of the multilayer tablets, which presented average values above 6 mm, resulting in an increased sectioned area and imprecise tablet splitting. Furthermore, image analysis revealed that the layer’s distribution in the tablet may not be homogeneous, as in the cases of HCT/BRA and ADV/USA (Figure 2). Thus, the subdivision process may not necessarily result in fractions with equivalent dosages, especially in cases of multiple subdivisions.
Delamination in multilayertablets,inturn,is a critical quality deviation that can ultimately compromise their therapeutic utility (Akhtar et al., 2020). Remarkably, the mechanical stress involved in the tablet subdivision process was sufficient to cause immediate layer separation in 46.7 % of the 12 tested tablets (Figure 2). Nonetheless, the coating prevents this occurrence, likely by increasing the cohesiveness between the layers, which mitigates the effect of subdivision (Table I).
The assessment of adhesion between the layers of a multilayer tablet is not a standardized test by the pharmacopeia for tablet production. However, it is of crucial importance to ensure product quality. Thus, in light of recent proposals to perform this assay (Bellini, Walther, Bodmeier, 2020), a universal testing machine was adapted for the tensile test (Figure 1A), yielding reproducible and coherent results, i.e., tablets consistently fractured at the layer interface, presenting coefficients of variation often below 20 %. Accordingly, the force required to separate the tablet layers was measured in wholes and halves (Figure 1B). The fracture force decreased statistically in 50 % of the tablets. In fact, the adhesion force between layers in halves showed an average fracture force below 10 N, meaning that the adhesion between layers is weakened and can easily separate when the halves are handled.
The subdivision of multilayer tablets showed mass variation, mass loss, and friability exceeding the acceptable ranges. Furthermore, most of the commercial tablets tested exhibited layer separation due to the subdivision process or had weakened layer adhesion. Given this unfavorable scenario, it appears that these products were not designed for division. Therefore, the subdivision of multilayer tablets should be avoided until developers implement strategies specifically designed for this purpose, ensuring safe conditions for users.
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SOURCE OF FUNDING
This research was supported by Fundação de Apoio à Pesquisa do Distrito Federal (FAPDF, 00193-00000735/2021-10 and 00193-00000817/2021-64) and the University of Brasilia.
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Edited by
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Associated Editor:
Silvya Stuchi Maria Engler
