Predicting the compressibility and compactibility profiles of pharmaceutical active ingredients for design of multi-component tablets

Abstract

Digital design of multi-component pharmaceutical tablets based on the properties of individual constituents plays a critical role in the rational design and optimisation of pharmaceutical formulations. Most active pharmaceutical ingredients (APIs) used in tablet formulations are crystalline materials with diverse mechanical properties, including elastic, plastic, brittle, or combined deformation characteristics. These properties can lead to manufacturing challenges such as capping and sticking during the tableting process, or the formation of fragile tablets, making the direct compaction and testing of pure API tablets difficult or even impossible. In this study, we present an approach to predict the compressibility and compactibility profiles of APIs that cannot be directly compacted into tablets without the support of excipients. The method is based on the assumptions of additive volume fractions and the geometric mean mixing rule applied to the compactibility models of the individual components. API compressibility and compactibility models were derived from the analysis of “out-of-die” compaction data obtained from binary powder mixtures containing 50% API and 50% microcrystalline cellulose, compressed at different compaction pressures. Five APIs with diverse mechanical properties, i.e., aspirin, carbamazepine, metronidazole, paracetamol, and theophylline, were investigated. The proposed approach successfully predicted tablet solid fractions and tensile strengths for both binary (API and filler) and ternary (API, filler and disintegrant) mixtures of the APIs. The predicted tablet solid fractions were within ± 5% of the measured values, while tensile strength predictions showed errors typically ranging from ± 20% to ± 50%, depending on the API, formulation, and compaction pressure. Overall, the approach provides a practical digital design tool for the formulation of multi-component pharmaceutical tablets based on constituent material properties.

Introduction

Pharmaceutical tablets are the most important dosage forms to deliver active pharmaceutical ingredients (APIs) to patients, which can be produced by direct compression (DC), dry granulation, wet granulation or other technologies (Leane et al., 2015). Among them, DC, compressing a powder mixture of an API and excipients into tablets without a prior granulation step, is the most preferred approach due to its simplicity, cost effectiveness and inherently continuous nature (Van Snick, 2017). To meet the required quality target product profile of DC tablets, it is required not only to select and optimise various excipients with APIs in formulations to achieve the desired pharmaceutical performance (e.g., drug’s effectiveness and safety) but also to determine the tableting process parameters, i.e., applied compaction pressure, to ensure that the resulting tablets are strong enough to withstand the subsequent processing, transport and handling by patients. Tablet tensile strength is commonly used as a measure of the mechanical strength of pharmaceutical compacts, representing the maximum tensile stress that can be tolerated by the tablet before it breaks (Fell and Newton, 1970). Predicting the tablet tensile strength as a function of the applied compaction pressure of a powder (i.e., tabletability) to screen a large space of potential API formulations can significantly reduce the experimental needs for drug product development (Reynolds et al., 2017, Bhagali, 2025).

Currently two different approaches, i.e., indirect approach (Reynolds et al., 2017) and direct approach (Bhagali, 2025), have been explored to predict the tablet tensile strength of a powder mixture. In the indirect approach, API compressibility, defined as tablet solid fraction (or porosity) versus applied compaction pressure, is firstly predicted. Several promising models have been developed to predict the compressibility of a single component tablet successfully, including Heckel equation, Kawakita equation, Percolation model, and Gurnham equation (Polak, 2024, Queiroz, 2019). The API tablet tensile strength is predicted based on its solid fraction (i.e., compactibility) by the Ryshkewitch-Duckworth equation (Wu, 2005, Wu, 2006, Patel and Bansal, 2011). For a powder mixture, the tablet solid fraction is predicted based on the API compression model with those of the excipients in the formulation through an additive mixing rule in which the volume reduction of an individual component in the mixture is the same as that of each of individual components when compacted alone (Berkenkemper et al., 2023). The tensile strength of the mixture tablet is predicted by the tensile strengths of the constituents weighted based on their volume fractions through a linear, power or harmonic mixing law (Polak, 2024). In contrast, a direct approach, an API tablet tensile strength is predicted directly as a function of compaction pressure, which was developed based on Ryshkewitch-Duckworth and Kuentz-Leuenberger equations (Vreeman and Sun, 2022, Vreeman and Sun, 2025). Similarly, the mixture tablet tensile strength is estimated from the tensile strengths of individual components weighted with their initial volume fractions by an appropriate mixing model of linear, power or harmonic (Bhagali, 2025).

Nevertheless, it is clear that the prerequisite for predicting the tensile strength profile of a pharmaceutical powder mixture based on the pure materials is to obtain the property profiles of the individual constitutes in formulations, which could be extremely difficult, in particular for APIs. The majority of APIs for tablet formulations are crystalline materials with diverse mechanistical properties, e.g., elastic, plastic, brittle or combinations (Roberts and Rowe, 1987). Many crystalline APIs show poor compressibility and/or compactibility, resulting in capping and sticking during the tableting process or fragile tablets which makes a manufacture and testing of API tablets impossible. To avoid these issues, much research has been conducted to investigate the tableting behaviour of a binary mixture containing a poorly compactable API with a well compactable excipient such as microcrystalline cellulose (MCC), aiming to develop a correction model between the API characteristics and its tabletability (Kuentz and Leuenberger, 2000, Hayashi, 2018). Although it is effective, the study needs to prepare a series of powder mixtures for DC tablets of the API and excipient at various ratios to obtain a large set of data for understanding tableting behaviours of the binary mixture (Sun, 2016). In this context, obtaining the compaction profiles of a pure API with minimal experiments is of importance, particularly in early drug development with limited API resources.

The aim of this study was to predict the compressibility and compactibility profiles of an API based on the compaction data analyses of a binary powder mixture containing 50% API and 50% microcrystalline cellulose (MCC), which was compressed at six different compaction pressures ranging from 40 and 350 MPa. Five APIs with diverse mechanical properties, including aspirin, carbamazepine, metronidazole, paracetamol, and theophylline, have been selected in the study. Among them, aspirin and theophylline exhibit good compressibility and compactibility and can be directly compressed into tablets, whereas carbamazepine, metronidazole, and paracetamol show poor compressibility and/or compactibility and, therefore, require blending with suitable excipients for tablet formation. The effectiveness of the predicted compressibility and compactibility profiles of the APIs has been evaluated to predict the tablet solid fraction and tensile strength of the binary and ternary mixtures

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Materials

In this work, five APIs were selected for model development and validation, including Aspirin (ASP, 99%, Fisher Scientific, UK), Carbamazepine (CAR, Fagron Ltd, UK), Metronidazole (MET, Acros Organics, UK), Paracetamol (PAR, Acros Organics, UK), Theophylline (THP, Merck, UK). Microcrystalline cellulose (MCC102, Avicel® – PH-102, extra pure, Thermo Scientific, Germany) and α lactose monohydrate (LAM, Sigma-Aldrich, US) were employed as a filler for binary or ternary formulation design. Crospovidone (CRO, Kollidon CL-SF, BASF, Germany) was employed as a disintegrant for ternary formulation design. All materials were used as received without being sieved prior to use.

Chuhong Cheng, Ke Wang, Walkiria Schlindwein, Carol Crean, Chuan-Yu Wu, Zhonggui He, Xiaohong Liu, Mingzhong Li, Predicting the compressibility and compactibility profiles of pharmaceutical active ingredients for design of multi-component tablets, International Journal of Pharmaceutics, 2026, 127000, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.127000.

Read also our introduction article on Microcrystalline Cellulose here: