Exploring the Impact of Formulation and Tablet Shape on Tablet Integrity: A Comprehensive Investigation Using Mechanical and Imaging Techniques

Abstract

Tablets are subjected to collisions during processing and handling which can result in defects and even failed batches at commercial scale. This study investigated the influence of composition and tablet shape on the tablet integrity under simulated stressed settings. Tablet formulations with two filler combinations were compressed to different shapes and tensile strengths. Tablet integrity was characterized using tensile strength, friability, drop test, impact testing, indentation and X-ray microtomography. Pharmacopeial tests demonstrated that all tablets including the lowest tensile strength tablets had acceptable integrity. Impact testing and drop test provided stressed conditions to discriminate and rank the tablet integrity according to the composition and shape. Microtomography and indentation results revealed heterogenous density distribution with respect to tablet shape and the composition. Increasing the amount of microcrystalline cellulose was the most successful approach to address tablet integrity issues. Tablet shape also influenced the number as well as the nature of tablet defects. Application of more discriminating tests could serve as extra tools to support selection of right tablet shape and composition. This can lead to the development of a robust formulation with potential to save resource required for troubleshooting tablet defect during both clinical and commercial supply.

Highlights

Formulation and tablet shapes significantly influenced the resistance to tablets defects.

Impact testing identified tablets with weaker integrity.

MCC-DCPA formulation decreased the propensity for tablet defects.

Micro-CT and micro-indentation confirmed tablet density and hardness anisotropy.

Introduction

Powder compaction is an integral part in the pharmaceutical industry to produce most common dosage form –tablets. Despite the widespread adoption of tabletting processes, achieving high-quality and robust pharmaceutical tablets remains a significant challenge. The intricate interactions occurring during the compaction could lead to many undesirable defects. Weak tablets are susceptible to breakage during production, transportation and end use, which can result in wastage and poor yield that fails to meet required product specifications. Furthermore, aesthetically undesirable surface damage, such as chipping, can compromise dose uniformity. Hence there is a pressing need for reliable means during the development, possibly at early stages, to establish integrity targets for tablet drug products, ensuring a reduced number of defects during the production process.

The most prevalent method of characterising tablet mechanical strength in industry involves diametric compression, which is a standard test described by the USP-NF as Tablet Breaking Force <1217>. This test induces the propagation of a crack on a plane along the compression axis upon reaching the failure force, calculating the tablet’s tensile strength, which increases within the working compaction pressure range. Achieving high tablet mechanical strength involves thorough consideration of various composition and manufacturing process-related factors.2 Compressing the blend at very high pressure is not a solution to achieve tablets with high tensile strength since such tablets acquire low porosity, which can lead to major tablet defects such as lamination and capping. Additionally, high compaction pressure negatively impacts the tablet disintegration and dissolution.2 Generally, tablet tensile strength in the range of 1.5-2.5 MPa is recommended.

The mechanical strength of the tablets is also tested using the Roche friabilator, setting an upper limit of 1% for weight loss. However, this method, aims to characterise the susceptibility of tablets to attrition. During the friability testing, tablets uncontrollably roll, slide and fall onto the drum plastic base or onto each other. This results in the varied distribution of impact angles, velocities and frequencies. Moreover, the stresses experienced by tablets during processing (e.g., film-coating, packaging) and patient handling remain undefined. Consequently, the friability test lacks credibility in replicating these conditions, especially considering the current pharmacopeial threshold limit of 1% for acceptable friability.5 Furthermore, in early stages of formulation development and screening, where the drug substance is very limited, friability test becomes impractical due to the minimum requirement of 6.5 g of tablets, potentially translating to 1- 3 g of API for each prototype formulation. Consequently, predictive models have been investigated to expedite development using minimum amount of API.

Materials exhibit diverse elastomeric properties, such as brittleness and ductility. Despite having similar tensile strength, two materials may break at significantly different energies. Considering this, stress-strain responses also show time-dependent effects. When developing pharmaceutical tablets, two different fillers are often combined to achieve the right balance of plastic and brittle properties. Microcrystalline cellulose (MCC), dibasic calcium phosphate anhydrous (DCPA) and mannitol (MAN) are conventionally used as tablet diluents. While MCC offers attractive dry binding properties due to its plastic nature, DCPA and mannitol serve as brittle excipients, making them attractive to combine with MCC.

The tablet shape is a crucial factor in determining final quality of the tablet. There are two primary tablet shapes: round and non-round. Non-round shapes can vary greatly in complexity. Tablet profiles come in various options, such as flat-faced, standard biconvex, and double-radius (compound) cups. The choice of profile depends on factors like embossing requirements, coating processes, packaging, and branding. For tablets requiring extensive branding, profiles with larger surface area, such as flat shapes or shallow double-radius cups, are preferred. The double-radius design provides rounded tablet edges, which perform better in coating pans. Guidelines from tooling manufacturer, iHolland, indicate that standard biconvex round tooling can withstand punch tip forces of up to 47 kN, whereas double-radius tooling is limited to 27 kN. Therefore, formulations requiring high compression forces are better suited for standard biconvex profiles.

Highest stresses the tablets encounter are from impacts during handling, processing, packaging, and shipping. In the large industrial setups, tablets experience impact from free-fall on the stationary surfaces such as during high speed compression runs and vacuum transfer from an intermediate bulk container to a large pan coater. In contrast, during coating in a large pan, impacts occur on a moving surface. Regardless of the cause, these impacts involve a rapid transfer of energy that can result in fractures. Fractures occur when the elastic limit is exceeded or when sufficient repeated strain causes fatigue failure. Therefore, measuring the tablet’s physical integrity through impact testing in addition to measuring breaking force is important. Wilson and Potter used impact testing by dropping a weight on a tablet from different heights.8 Hare et al. evaluated the propensity of tablet defects as a function of mechanical properties using single tablet impact testing by using the model of Ghadiri and Zhang. Sabri et al. developed a new modified tablet drop test that closely mimics the condition that pharmaceutical tablets encounter during commercial manufacture. They found that increased drop height and number of drops increased the likelihood of tablet breakage. Ketterhagen et al. established tablet breakage risk profiles as a function of impact speed. Their results agreed well with the model proposed by Vogel and Peukert, which is based on a Weibull distribution where probability of breakage is related with material properties, object size, number of collisions and collision velocity.

In a recent study, Alhusban and Murgatroyd used an impact tester to simulate mechanical stresses that tablets experience in a commercial manufacturing line and used that to evaluate the resistance to defect of wide range of tablet formulations.16 Impact fracture force was identified as a test to measure the force absorbed by the material before fracturing when applying impact energy (dynamic stress). They demonstrated that impact testing significantly improved correlation with tablet defect rate in comparison to the standard pharmacopeial tablet breaking force and friability test.

The aim of the study was to investigate the influence of composition and tablet shape on the tablet integrity under simulated stressed settings. Tablet formulations with two filler combinations were compressed to different shapes and tensile strengths. Tablets were characterized using both pharmacopeial tests (breaking force and friability) and stressed conditions (drop tests and impact fracture tests). Indentation test was used to quantify the tablet hardness in different planes and X-ray microtomography was utilized to visualize the density distribution of the tablets.

Materials

Tablets were compressed using combination of two fillers. Mannitol (Pearlitol 100 SD, Roquette) –microcrystalline cellulose (Avicel PH-102, International Flavors & Fragrances) (MAN-MCC) based formulations were prepared in 7:3 proportion, and microcrystalline cellulose –dibasic calcium phosphate anhydrous (Anhydrous Emcompress, JRS Pharma) (MCC-DCPA) based formulations were prepared in 7:3 proportion.

Mayank Singhal, Joona Sorjonen, Håkan Wikström, Pratik Upadhyay, Farhan Alhusban, Dean Murphy, Luis Martin de Juan, Jarkko Ketolainen, Pirjo Tajarobi, Exploring the Impact of Formulation and Tablet Shape on Tablet Integrity: A Comprehensive Investigation Using Mechanical and Imaging Techniques, Journal of Pharmaceutical Sciences, 2025, 103832, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2025.103832.