Bridging Material Variability and Tablet Performance: Optimization of Direct Compression Using Tensile Strength–Ejection Stress Mapping

Abstract

Objectives: The current study presents a sequential strategy for the development of directly compressible powder formulations relying on Design of Experiments (DoE) and Compactibility-Ejection stress plots.

Methods: Compression analysis was used to evaluate the impact of changing the sort of microcrystalline cellulose (MCC), dicalcium phosphate (DCP), the diluent ratio, lubricant type, and the inclusion of an API from different suppliers.

Results: The effect of DCP particle size on the ejection stress was efficiently mitigated in the placebo formulations by lubrication. However, the initial differentiation between sorts was highlighted at a smaller scale when the active pharmaceutical ingredient (API) was included in the formulation. For MCC, the tensile strength was positively correlated with the level of plasticity and tabletability capacity of different sorts. The particle size was a critical attribute for the API, influencing the detachment and ejection stress values. Fine particles (d50 = 30 µm) presented increasing stress values once the compression force rose, while for coarser particles (d50 = 50 µm) these effects were limited.

Conclusions: Material-related variability must be understood to design products and processes with adequate performance. The proposed strategy enables early identification of critical material attributes, supporting rational formulation and supplier selection to ensure consistent quality during manufacturing.

Introduction

Oral drug therapy, and especially tablets as dosage forms, are preferred by patients and drug manufacturers alike. Patients value their easy administration, while the pharmaceutical industry aims for high productivity, robust technological processes, and low costs [1,2,3]. Tablet preparation involves the compression of several components, from 4 to 12, active pharmaceutical ingredients (APIs), and excipients with different functions, such as volume increase, API release modulation, and processability improvement [2,4]. Traditionally, the selection of excipients and of their ratios was done mostly empirically, based on a few experimental results and prior knowledge of the formulators [2,5]. Currently, the concept of Quality by Design (QbD) described in International Conference of Harmonization Guidelines Q8 (R2), Q9 aims to design medicines with embedded quality assurance strategies through the rigorous knowledge of the relations between their critical quality attributes, the critical material characteristics and process parameters [6,7]. Supporting the QbD approach and aiming to overcome empirical formulation practices, expert systems like SeDeM have been developed to assess powder suitability for direct compression by integrating multiple physical parameters into a unique compression index [8]. SeDeM diagrams also enabled the identification of formulation deficiencies and the rational selection of corrective excipients [9].

Among the tablet preparation methods, direct compression is always the first choice of any formulation team, due to its straightforward nature involving only two main unit operations that ensure both cost and time effectiveness [10]. Despite its evident advantages, designing directly compressed tablets is not an easy task, as it requires appropriate powder flow, compressibility, compactibility, blend homogeneity, and it was reported that less than 20% of the APIs comply [11,12]. As in direct compression APIs and excipients only go through a mixing stage before tableting, their physical properties have an important impact on the blend flowability and compression behavior [10,13]. The Manufacturing Classification System (MCS) formalizes the link between API material properties and processing route, ranking direct compression as the simplest, yet the most property-sensitive manufacturing approach, compared to granulation methods that can accommodate broader ranges of API characteristics [14]. Particle sizes and shapes were shown to impact powder flow and, consequently, particle rearrangement during compression, with better rearrangement requiring lower compression forces for polydisperse samples [15]. Analysis of commercial products confirmed that small particle sizes and high API load are associated with more complex manufacturing routes [16]. API particle size reduction was found to increase resistance against compressibility and compactibility due to changes in deformation behavior and less fragmentation tendency [5,17]. For some materials, it had a positive impact on the mechanical strength of tablets due to extended specific surface areas but displayed a negative influence on flowability [4,5]. However, particle properties cannot be separated from the deformation behavior of each of the components of a powder blend, as fragmentation occurred at low compression pressures and depended both on the initial particle size and on the predominant deformation mechanism [18]. For example, high initial particle sizes of 355–500 µm of microcrystalline cellulose (MCC), a predominantly plastic material, tended to remain large upon compression with limited fragmentation, whereas calcium hydrogen phosphate (DCP), known as a brittle solid, underwent extensive fracturing, independent of the initial particle sizes [17]. The selection of process parameters must also be well thought-out, as they can be held accountable for both processing errors and for the correction of formulation deficiencies [19,20]. The tablet microstructure is therefore a result of the interplay of material characteristics and process parameters applied in tablet manufacturing, and was shown to impact quality attributes such as disintegration and drug release [18,21]. Along with product quality, Osamura et al. considered ejection stress as a measure that relates to the preparation performance and more precisely to the ease of tablet ejection [22].

Although tablet compression abounds in research and the understanding of the phenomena has increased over time, the development of a new product imposes numerous challenges. As described above, the performance of a process and the quality of products are influenced by a large number of factors, so most of the compression studies try to eliminate particular sources of variability to better understand the influences of certain factors, working on individual APIs or excipients [5,23], sometimes of narrow size ranges [24,25], particular shapes [25] or on binary mixtures [1]. Recent advances in tabletability modeling, such as the Vreeman-Sun equation, allowed the quantitative estimation of tensile strength as a function of compaction pressure through material-related parameters. This predictive approach for binary mixtures paves the way for the digital design of tablets [26]. While such results greatly contribute to the knowledge of powder tabletability, drug development teams still need science-based and easy-to-implement strategies for the overall understanding of their real, often complex formulations.

Therefore, the current study proposes a sequential strategy based on two QbD tools, Design of Experiments (DoE) and Multivariate Data Analysis (MVDA), to design a robust powder blend formulation for direct compression. As manufacturing companies often opt for dual supply policies to overcome unexpected API or excipient shortages [27], the study aimed to evaluate the impact of various raw material sorts and the effect of alternating suppliers on the compaction behavior. An investigation that includes a large number of input variables requires many experiments; hence, an efficient procedure to obtain product-related knowledge was needed. Compaction simulation enables the evaluation of powder tableting performance in a timely manner and with little material investment [28,29,30]. It was successfully used to support scale-up strategies and predict formulation behavior under controlled compaction conditions [31]. However, several authors have shown that compaction simulators do not fully reproduce all sub-processes encountered in rotary tablet presses, such as die filling or feeding dynamics; therefore, the direct transfer of results to industrial manufacturing requires careful consideration [32,33,34]. Nonetheless, previous results showed that the careful control of the compression analysis enables good correlations between small-scale and industrial performance under specific conditions, which underpins our choice to perform in-die and out-of-die measurements in this study [35].

Working with qualitative input variables simplifies the screening procedures associated with the development of new formulations. However, once inter-sort/-supplier differences are identified for a certain formulation component, it is recommended to identify the relevant physical properties that influence the product’s performance. In this respect, multivariate methods, i.e., Principal Component Analysis (PCA), can be efficiently used to highlight similarities and differences between excipients, considering the multiple variables collected for fundamental analysis. For this directly compressible powder formulation, each excipient was systematically characterized with respect to particle size, particle shape, flowability, and compression properties in order to better understand deformation mechanisms and predict overall blend behavior.

The proposed strategy consists of three stages: an initial screening study conducted on placebo formulations, where a high number of excipient sorts were evaluated for their compaction properties. The previously screened excipients were carried on to a second optimization study meant to reveal the influence of the API sort, with known physical and compression characteristics, as an extra qualitative variable. Finally, ejection stress assessment and extended root cause analysis using multivariate tools meant to overlap the gathered information for a coherent understanding of the process and of the roles of each of the formulation components.

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Materials

Microcrystalline cellulose and dicalcium phosphate were selected as diluents of this powder blend. Five sorts of microcrystalline cellulose (Vivapur 102, Vivapur 12, Vivapur 200, Vivapur 302 JRS Pharma, Rosenberg, Germany; Sigachi 102, Hyderabad, India) and four sorts of calcium hydrogen phosphate (anhydrous: Dicafos A60, Dicafos A150, JRS Pharma, Germany; dihydrate: Dicafos D160, Budenheim, Budenheim, Germany, Emcompress DC, JRS Pharma, Rosenberg, Germany) were included in the study. Sodium stearylfumarate (JRS Pharma, Rosenberg, Germany) and magnesium stearate (Union Derivan, Barcelona, Spain) were tested as lubricants, whereas sodium croscarmellose (JRS Pharma, Rosenberg, Germany) was chosen for its disintegrant properties. For the API, three different suppliers were included in the study. The identity of the API was not divulged due to confidentiality reasons.

Casian, T.; Iurian, S.; Gâvan, A.; Negoi, O.; Marusca, D.; Marina, A.; Suciu, M.; Muntean, D.; Porfire, A.; Pop, A.L.; et al. Bridging Material Variability and Tablet Performance: Optimization of Direct Compression Using Tensile Strength–Ejection Stress Mapping. Pharmaceutics 2026, 18, 357. https://doi.org/10.3390/pharmaceutics18030357

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