Effect of microcrystalline cellulose properties on the stability of moisture-sensitive formulations

Abstract

The stability of moisture-sensitive active pharmaceutical ingredients (APIs) in solid dosage forms is a key determinant of product quality and shelf-life, with excipient selection strongly influencing degradation pathways. In an excipient compatibility screening (70°C/75%RH, 12 days), microcrystalline cellulose (MCC) induced higher degradation of acetylsalicylic acid (ASA, model API) than other excipients and was selected for further investigation. Two MCC grades, distinguished by measured initial moisture contents (5.18% vs. 1.36%), were examined to determine the effect of MCC type and excipient ratio on API stability. Six tablet prototypes were analyzed using the Accelerated Predictive Stability (ASAP) approach under varying temperature and humidity conditions. Higher MCC content resulted in increased instability of the API with mobile water content >4.0%wt, while tablet prototypes with lower MCC content showed improved stability and reduced mobile water content (≤2.0%wt). Arrhenius-based modelling (R² ≥ 0.9, Q² ≥ 0.7) confirmed humidity as a dominant driver of degradation, with MCC grades having a secondary effect. Predictions showed that high-MCC prototypes exhibited low probabilities of meeting assay specifications (e.g., 58–79% at 40°C/75%RH, 6 months), whereas low-MCC formulations were associated with 98% of probability to meet assay specifications. Model predictions were confirmed by real-time stability studies at 25°C/60%RH and 40°C/75%RH over six months, with measured and predicted degradation differing less than 1%. Overall, the API:MCC ratio was the primary determinant of stability, governing water uptake and availability. These results highlight the importance of excipient optimization and demonstrate the value of predictive stability modelling for formulation development.

Introduction

Stability of active pharmaceutical ingredients (APIs) in solid dosage forms is a critical attribute for product quality and safety during the drug product’s lifecycle. In the formulation of stable drug products, moisture-induced degradation remains one of the most significant challenges, particularly for APIs susceptible to hydrolysis, such as acetylsalicylic acid (ASA) with its well-known hydrolytic degradation to acetic and salicylic acid [[1], [2], [3], [4]].

Water present in a formulation, originated from excipients or absorbed from the environment, can accelerate API degradation pathways and reduce shelf-life [5]. While this relationship is well established, the extent to which excipient properties and ratios quantitatively influence shelf-life reduction remains insufficiently understood. Based on this, the selection of suitable excipients, especially those with hygroscopic properties or high initial water content, is important in the development of robust pharmaceutical products [6]. While some excipients may act as internal desiccants due to their water retention capacity, others can increase the availability of reactive water [7]. One example is microcrystalline cellulose (MCC), known for its excellent compressibility properties and frequently used as filler or binder [8,9]. Importantly, MCC is widely used in solid dosage forms, including formulations containing moisture-sensitive APIs such as ASA, making it a practically relevant example for investigation. MCC has a high capacity to absorb and retain large amounts of water due to its high internal porosity and large surface, which is why Fielden et al. previously described it as molecular sponge [10].

In addition to MCC, other commonly used excipients such as pregelatinized starch (PGS) or lactose types (e.g. lactose monohydrate and spray-dried lactose) can also influence the moisture within solid dosage forms. The ability of starch to bind and redistribute water, as well as differences in moisture absorption and crystallization behavior of lactose, can affect water activity and mobility within the tablet matrix [[11], [12], [13]].

These differences highlight that not only the presence of water, but its availability and distribution within the formulation are critical for API stability. Therefore, the physicochemical properties of the excipients, such as crystallinity, grade or particle size, can influence the water uptake, tablet properties and drug stability. The impact of excipient selection on the stability of moisture-sensitive APIs, was previously investigated: early work demonstrated the destabilizing effect of different excipients, including MCC, on ASA tablets under humid conditions [10,14]. Other studies investigated the influence of different MCC crystallinities and grades on ASA stability and tablet quality [[15], [16], [17], [18], [19]].

However, these studies mainly focused on individual factors (e.g., crystallinity) or limited formulation systems and did not systematically evaluate the combined effects of MCC grade, excipient ratio, and resulting water content. More recent work emphasized the importance of moisture and water activity evaluation for API stability [20,21], further underlining the need of a differentiated approach for excipient selection during formulation development. Despite advances in analytical techniques and stability testing, most published studies have focused on single excipient systems or limited stress conditions. A systematic and quantitative evaluation under accelerated and real-time storage conditions linking excipient properties, water content, and API degradation across multiple formulations is still lacking.

To address this gap, the present study aims to systematically investigate the influence of excipient properties on moisture-driven API degradation and to establish quantitative relationships across multiple formulations. In particular, focusing on the effect of MCC grade and API:MCC ratio on the stability of a moisture-sensitive API (i.e., ASA) in relation to water content. ASA was selected as the model API because it has already been widely researched, with a well-known degradation pathway, allowing the focus to be placed on excipient effects rather than uncertainties related to the API. The objective was pursued using an integrated approach incorporating accelerated predictive stability (APS) modelling (i.e., ASAP). The Accelerated Stability Assessment Program (ASAP), based on a humidity-corrected Arrhenius equation and isoconversion approach [[22], [23], [24]], enables rapid prediction of degradation kinetics and provides a practical means to evaluate formulation stability within a significantly reduced timeframe compared to conventional studies [[25], [26], [27]].

This type of study demonstrates how stability assessment could potentially be reduced from years or months to weeks and provides early insights into the robustness of formulations [[28], [29], [30], [31]]. By integrating experimental data with predictive modelling and validating outcomes against real-time stability data, this study seeks to quantitatively link excipient-driven water content to API degradation, thereby providing a rational, data-driven basis for excipient selection in formulation development.

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Materials

ASA (USP grade, Sigma-Aldrich®, USA) was used as a moisture-sensitive model API. Pregelantinized Starch (PGS, Prejel PA5 PH, DFE Pharma, Germany), lactose monohydrate (LacM, SuperTab® 30 GR, DFE Pharma), spray-dried lactose (LacSD, SuperTab® 11SD, DFE Pharma, Germany), mannitol (Man, Pearlitol® 100 SD, Roquette, France) and two MCC grades, Pharmacel® 102 (PH102, moisture content <5%, measured moisture content = 5.18% DFE Pharma, Germany) and Pharmacel® 112 (PH112, moisture content <1.5%).

Janina Steeger, Carsten Gittel, Chris Vervaet, Valérie Vanhoorne, Ghamdan Beshr, Effect of microcrystalline cellulose properties on the stability of moisture-sensitive formulations, Journal of Drug Delivery Science and Technology, Volume 124, 2026, 108651, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2026.108651.

Read also our introduction article on Mannitol here: