Particle-based investigation of excipients stability: the effect of storage conditions on moisture content and swelling

Abstract

Moisture sensitivity poses a challenge in formulating oral dosage forms, particularly when considering disintegrants’ swelling due to prior moisture exposure, impacting performance and physical stability. This study utilises dynamic vapour sorption to simulate real-world storage scenarios, investigating the equilibrium moisture content and dynamics of eight commonly used excipients in oral solid dosage forms. A model was developed to determine the kinetic rate constant of moisture sorption and desorption for different storage conditions. Dynamic vapour sorption tests revealed that excipients with higher moisture-binding capacities showed slower equilibration to the target relative humidity (RH). Elevated temperatures accelerated the moisture sorption/desorption process for all excipients, reducing the equilibrated moisture content for most, except mannitol and lactose. Particle imaging over a 14-day accelerated storage period quantified swelling, indicating approximately 6% increase in particle diameter for croscarmellose sodium (CCS) and sodium starch glycolate (SSG), and a lesser 2.7% for microcrystalline cellulose (MCC), predominantly caused by the humidity. All excipients reached their swelling peak within the first day of storage, with permanent particle size enlargement for CCS and SSG, whereas MCC displayed a partial reversibility post-storage. Enhancing our understanding of excipients’ stability and interaction with moisture and the resulting particle swelling contributes to the rational design of oral solid dosage formulations and promotes a better understanding of their long-term physical stability.

Introduction

Excipients are essential components incorporated into pharmaceutical formulations for various purposes, ranging from facilitating manufacturing processes and sustaining product stability to enhancing bioavailability, as well as improving patient acceptability and compliance.1 Although excipients are considered pharmacologically inactive, they are far from inert within a formulation. Instead, they play an active role in the physical aspects of the dosage form as they make up a significant majority of the final formulation. It has become widely recognised that the performance of a dosage form is closely linked to the physical and chemical properties of all its ingredients.2,3 Consequently, excipient properties affect various quality attributes of the drug product, including drug release, friability, tensile strength, appearance, and stability. Among these attributes, stability stands out as a particularly crucial aspect for a drug product to be released to the market.4

Advances in particle-based investigation methods have improved our understanding of excipient properties. Techniques like high resolution imaging and single crystal X-ray diffraction enable accurate particle characterisation such as size, surface area, morphology, crystal structure, and presence of polymorphs which are vital to the overall physical, chemical and biological behaviour of pharmaceutical products.5 These particle-based techniques combined with bulk-based methods like dynamic vapour sorption (DVS) allow detailed analysis of individual particles and their interactions with each other and with environmental factors to enhance formulation stability and reduce development costs. As the pharmaceutical industry prioritises efficiency, particle characterisation data are attracting a great attention across development, manufacturing, and quality control processes. Both the API and excipient particle characteristics can influence the stability and efficacy of the drug product, making thorough particle assessment essential. This shift has been influenced by Quality by Design (QbD) principles, which encourage using a data- and risk-based approach to optimize product development leading to more robust pharmaceutical formulations.

Throughout the drug development process, stability testing of pharmacological compounds and drug products is a standard procedure used to investigate the causes or mechanisms of product instability.6 The majority of studies on drug stability have focused on the chemical stability of the drug substance, which can cause a loss in potency. However, it is also crucial to evaluate the physical stability of drugs and excipients within the dosage form to ensure their effectiveness. This includes assessing changes in organoleptic properties, water content, solid-state, tensile strength, disintegration, and dissolution rate, all of which are influenced by the intrinsic physicochemical properties of the individual components such as their particle size, morphology, moisture content, and polymorphic form.7,8 The monographs of each excipient in the pharmacopeia provide “particular tests” that must be followed to indicate their quality and functionality. Additionally, excipient manufacturers and researchers have explored various material properties that can impact tablet performance and stability.9 Numerous factors may influence these properties; however, temperature and water, whether liquid or gaseous as moisture, are considered the primary reactants affecting tablet performance.10

Water plays a crucial role in various stages of pharmaceutical product manufacturing, directly contributing as a component in processes like wet granulation or coating. Environmental moisture during packaging, transportation, storage, and usage also indirectly affects drug product attributes.6 Moisture is adsorbed in the form of monolayers or multilayers, or it may exist as condensed water on the surface. The presence of moisture will not only change the pharmaceutical and mechanical properties of the final product but may also pose a risk of physicochemical instability ultimately affecting the effectiveness of the drug as well.11 The interaction of moisture with different materials is connected to the chemical affinity of their particles, their physical properties such as particle size, specific surface area, and porosity, and on the ambient relative humidity (RH) and temperature of the environment.12–14 Consequently, every element in a formulation possesses a distinct affinity for moisture, so it is crucial to understand their specific interactions with moisture concerning their behaviour at various RH levels and the resulting influence on the performance of the product. In a study conducted by Dalton and Hancock (1997), notable variations in formulations’ water sorption tendencies were observed, primarily due to the considerable differences in how the excipients absorbed water.15 Starch and cellulose excipients, commonly used in oral solid dosage forms, are particularly affected by the hydrogen bonding between water and solid molecules.16

To characterise water associated with these excipients, moisture sorption isotherms are established, which illustrate the relationship between RH and water activity under a constant temperature by establishing a correlation between equilibrium moisture content (EMC) and RH at a fixed temperature. This offers valuable insights into materials’ equilibrium moisture levels and their moisture retention capacities under certain temperature and humidity conditions. Hysteresis, observed with starch and cellulose-based excipients, occurs during desorption where some water molecules remain within the powder and cannot be dissociated at the same equilibrium RH level, attributed to the particles swelling and changes in the conformational structure. This alters the accessibility of binding sites for water molecules and leads to incomplete removal of water molecules during desorption.16–18 As a result, the moisture affinity of a material can be influenced by its prior exposure to moisture or its history of moisture exposure.4 Analysing sorption isotherms can uncover information about water interactions with particles and understand water adsorption and desorption extents under different RH levels. This is of practical importance as it can directly affect drug product performance and stability.

Among the excipients significantly affected by water sorption are disintegrants. The swelling of their particles when they come in contact with a physiological fluid is essential to disrupt interparticulate bonds within the tablet, thereby enhancing tablet disintegration, promoting dissolution, and facilitating drug release.19,20 Common disintegrants include sodium starch glycolate (SSG), croscarmellose sodium (CCS), low-substituted hydroxypropyl cellulose (L-HPC), and crospovidone (XPVP). In addition to disintegrants, other excipients such as microcrystalline cellulose (MCC), typically used as a diluent, filler, or binder, can also experience swelling, thereby also playing a role in the tablet swelling process.21 The swelling of these particles primarily relies on two key factors: the water diffusion coefficient (D) and the maximum absorption ratio (Qmax), which is the ratio of the mass of hydrated particles to dry particles. While Qmax can be experimentally measured through straightforward weighing methods, determining the value of D directly is often more challenging.22 These excipients are considered inert in the dry tablets, but they should cause the tablet matrix to swell and disintegrate rapidly in the patient, accelerating the dissolution of the drug particles. Any prior exposure of these agents to moisture or liquid will impact their moisture affinity and physical properties, potentially leading to a loss of disintegrant power due to the possibility of “pre-activation” of the disintegrant swelling and influencing the performance and stability of the dosage form.23,24

Considerable research efforts have been directed toward quantifying the swelling behaviour of particles in response to liquid water. Soundaranathan et al. (2020) used an optical microscope paired with a custom flow cell and utilising single particle swelling model to quantify the swelling characteristics of different disintegrants (SSG, CCS, and L-HPC) along with five grades of MCC.25 They showed that the swelling behaviour varied among the different excipients, with CCS having the highest diffusion coefficient and SSG having the highest maximum absorption ratio. Zhao and Augsburger (2005) utilised laser diffraction to quantify the intrinsic swelling of disintegrants in a suspension, finding that SSG exhibited a superior swelling capacity compared to CCS.26 Rojas et al. (2012) assessed the swelling value and water uptake ability of SSG, CCS, and MCC powder in simulated gastric and intestinal fluid, revealing that SSG had the highest water uptake ability and swelling value, followed by CCS and MCC.27

Investigations into the behaviour of excipients in response to humidity have predominantly concentrated on the impact of water at or near its saturation point. To the best of the authors’ knowledge, none of these studies have explored the swelling of particles induced by moisture in the gaseous phase during storage. It is noteworthy that the variations in water absorption observed below 96% RH may not align with findings at 99.98% RH.28 This limits the relevance of research outcomes derived from fully saturated conditions for stability studies at lower RH levels. Furthermore, there is also a gap in the literature regarding how moisture affects the particle size of these swelling excipients where the bulk of research efforts have been given to exploring the effects of storage conditions on the tablets containing these excipients.24,29–33

The primary objective of this study is to thoroughly investigate the impact of storage conditions, both moisture and temperature variations, on the intrinsic properties of eight commonly used excipients in oral solid dosage forms. Specifically, this study focuses on the moisture content and moisture sorption kinetics in a manner that reflects the dynamic simulation of moisture sorption in practice, using dynamic vapour sorption (DVS) paired with a mathematical model. The temporal effect of sorbed moisture on the particle size distribution of potential swelling excipients MCC, CCS, and SSG, is also discussed.

Download the full article as PDF here Particle-based investigation of excipients stability: the effect of storage conditions on moisture content and swelling

or read it here

Materials

A full list of excipients studied is detailed in Table 1, including CCS, XPVP, L-HPC, and SSG as disintegrants, as well as MCC, mannitol, lactose, and DCPA as fillers.

Table 1 Materials used, their suppliers and abbreviations used in this study

Isra Ibrahim, Mark Carroll, Anas Almudahka, James Mann, Alexander Abbott, Fredrik Winge, Adrian Davis, Bart Hens, Ibrahim Khadrab and Daniel Markl, Particle-based investigation of excipients stability: the effect of storage conditions on moisture content and swelling, Received 6th September 2024,^Accepted 8th January 2025, DOI: 10.1039/d4pm00259h, RSC Pharm., 2025, Advance Article