The Effect of Compression Pressure on the First Layer Surface Roughness and Delamination of Metformin and Evogliptin Bilayer and Trilayer Tablets

Multi-layer tablets (MLTs), including bilayer or trilayer tablets, are gaining considerable attention as effective tools for fixed-dose combination (FDC) therapy, with advantages over conventional monolithic tablets [1,2]. Incompatible active ingredients can be formulated in separate layers, minimizing the contact area and providing a better physicochemical stability [3]. Moreover, MLTs can be designed to simultaneously provide immediate- and slow-release layers to provide the desired drug release profile for individual ingredients in a single-dosage form [4,5,6]. However, despite the several advantages of the MLT system, the fabrication process is complicated, with steps including die filling for the first layer, pre-compression, die filling for the second layer, main compression, unloading, and ejection [7]. This complex process occasionally causes more technical challenges compared to conventional monolithic tablets, including tablet defects such as delamination separation of individual layers at the interfaces during manufacturing, shipping, and storage [8,9].

Various physical and mechanical studies have been conducted to understand the factors that contribute to delamination or cracks in MLTs. Tablet defects are principally associated with interfacial adhesion between adjacent layers and the mechanical integrity of the solid dosage form [10]. Moreover, the difference in deformation and/or elastic recovery between the adjacent layers contributes to radial stress, causing delamination of the MLTs [11,12]. The interfacial bonding strength is reportedly significantly influenced by the compression properties of the individual layers and the process parameters, particularly the compression pressure and punch speed [12]. An appropriate compression pressure on the first layer (pre-compression) is required to flatten the first layer surface, reduce the volume of powder/granulated substances, and provide space to place the second layer [13,14]. However, the application of excess compression pressure leads to a lower interfacial roughness, which could promote MLT delamination by diminishing the intermolecular adherence between adjacent layers [15,16]. Particularly, when a plastic material (e.g., methylcellulose) is included in both layers, an increased pre-compression pressure (PRE-P) applied to the first layer causes a decline in the interfacial strength of the bilayer tablets [17]. To date, most mechanistic studies have been conducted using one or two components made of common pharmaceutical excipients, such as microcrystalline cellulose, lactose, or starch. However, the compression of one or two components does not represent actual pharmaceutical formulations, especially granules fabricated using wet or dry granulation methods, which are composed of drug substances, diluents, disintegrants, binders, and lubricants. Furthermore, to the best of our knowledge, quantitative measurements of surface roughness and its relationship with the mechanical strength of bilayer and trilayer tablets have not yet been reported to date.

Therefore, we aimed to evaluate the effect of the compression pressure on the surface roughness of first layer, the compaction force required to break the MLTs, and the interfacial strength, and their correlations in the MLT pharmaceutical product. As a model product, metformin HCl (MF) and evogliptin tartrate (EG) fixed-dose combination tablets, currently prescribed to treat type 2 diabetes mellitus, were employed [18,19,20]. MLTs are oval-shaped, convex tablets consisting of a sustained-release (SR) MF layer and an immediate-release (IR) EG layer [21]. The exact compositions of the mixtures subjected to granulation processes are listed in Table 1. In this study, the compaction force required to break MF/EG MLTs and the interfacial strength between the adjacent MF and EG layers depending on different PRE-Ps and main compression pressures (MAIN-Ps) were determined. Subsequently, the surface roughness of the first layer was quantitatively analyzed using a profilometer, and the correlation between the compaction breaking force and interfacial strength was investigated. A profilometer was used to determine commonly applied roughness parameters, and attempts have been made to correlate these values with other characteristic material parameters. Furthermore, the inter-penetration of the active ingredient of the first layer (MF) into the second layer (EG), depending on the PRE-P, was analyzed using energy dispersive spectrometer (EDS)-equipped scanning electron microscopy (SEM).