Impact of disintegrants on the structure and disintegration of hydroxypropyl methylcellulose-based amorphous solid dispersion tablets

Abstract

Amorphous solid dispersion (ASD) is a widely adopted strategy to enhance the solubility of poorly water-soluble drugs. However, disintegration delay after storage poses a significant challenge to formulation performance. This study investigates the influence of disintegrant characteristics on disintegration behavior of hydroxypropyl methylcellulose (HPMC)-based ASD tablets containing griseofulvin (GRF). Two disintegrants, croscarmellose sodium (CCS) and crospovidone (CPV), were evaluated for their effects on the physical structure and disintegration performance of HPMC-based ASDs tablets under accelerated storage conditions (40°C/75% relative humidity). Dynamic viscoelastic measurements, hardness testing and disintegration testing revealed that disintegrant type markedly affected HPMC structural reorganization after storage. Tablets with CCS exhibited plasticization and a temporary loosening of the structure initially. Over time, water retention by CCS facilitated the rearrangement of HPMC chains, leading to prolonged disintegration times. Conversely, CPV maintained a loose network structure due to its high wicking ability, which prevented significant structural changes and preserved the disintegration performance. Tablets without disintegrants showed significant disintegration delay, highlighting the critical role of disintegrant selection in ensuring effective drug absorption through rapid disintegration. These findings underscore the importance of understanding the disintegrant mechanisms for optimizing ASD formulations for improved bioavailability.

Introduction

Currently, most candidate compounds for drugs exhibit poor solubility characteristics.1 After oral administration, drugs such as tablets and capsules undergo disintegration, followed by their dissolution and subsequent absorption through the gastrointestinal (GI) tract. Therefore, the solubility of a drug directly affects its ability to exert a pharmacological effect. However, improving drug solubility is a major challenge in pharmaceutical development.2,3

Several technologies exist to improve the solubility of drugs. Among these, amorphous solid dispersion (ASD) is one of the most commonly used ones.4 ASD constitutes a solid system in which the drug is molecularly dispersed in an amorphous form within an inert and water-soluble polymer carrier. ASD offers a practical approach for improving the solubility of poorly water-soluble compounds. Furthermore, ASD generates a supersaturated state during the dissolution of the compound, in which the amorphous form of the compound dissolves at a concentration temporarily exceeding its equilibrium solubility. This state can enhance its absorption, improving its oral bioavailability.5 Because of the higher energy state of the amorphous form, a compound can initially reach a concentration above its equilibrium solubility, which gradually decreases over time toward the equilibrium solubility. This is mainly caused by the inability to maintain the supersaturated state due to crystallization. Therefore, extending the duration during which the drug remains supersaturated is a critical factor in the formulation design, which is influenced by the preparation method for the amorphous form and the type of polymer carrier.6,7

Water-soluble polymers such as hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) are commonly used as carriers in ASDs, which are typically prepared by melt extrusion or solvent evaporation methods.8,9 These polymers preserve the amorphous state of the compound during manufacture and storage as well as maintain the supersaturated state following the dissolution in the gastrointestinal (GI) tract, facilitating efficient absorption of the compound.10,11 However, while ASD can improve the solubility of poorly water-soluble compounds, it does not always enhance the absorption.12 For example, in the case of ASDs containing cellulose-based polymers such as HPMC or hydroxypropyl cellulose (HPC), the gelation induced by contact with water prevents the water penetration and delays tablet disintegration.13,14 Furthermore, praziquantel tablets have been reported to display slower disintegration, resulting in lower bioavailability.15 Therefore, improving the solubility and dissolvability of a drug is essential to enhance its absorption.

Based on these studies, rapid disintegration is crucial for achieving immediate drug release from solid formulations containing ASDs after oral administration. However, polymers used as excipients may undergo gelation upon contact with water, leading to delayed tablet disintegration. Generally, oral solid dosage forms include a disintegrant to ensure rapid disintegration and dissolution of the drug in the GI tract. Several mechanisms of disintegration exist depending on the type of disintegrants.16 Selection of an appropriate disintegrant is important to achieve rapid tablet disintegration and maintain a supersaturated state of the drug.17 In formulation development, design of experiments is a useful approach for evaluating the formulation components and their concentrations. In ASD formulations, in addition to the type of disintegrant, differences in the grade of the same material, such as particle size and viscosity, have been reported to affect gel formation.18,19 Therefore, the selection of an appropriate disintegrant is a critical factor in designing ASD formulations.

Disintegrants can be broadly classified into two types based on their mechanisms. The first one is the wicking-type, which promotes disintegration by drawing water into the tablet and weakening the bonding between particles. The second one is swelling-type, which swells upon exposure to water and induces disintegration through an increase in volume.16 Although the mechanisms underlying these disintegrants have been extensively studied, most studies have focused on swelling or wicking individually. These disintegrants have complex mechanisms of action, with both swelling and wicking activities working in parallel rather than independently. Particularly in oral solid dosage forms, upon exposure to moisture, the disintegrant undergoes a coordinated process of swelling and wicking, which influence each other and promote rapid disintegration of the tablet.16 Therefore, exploring the complex mechanisms where multiple functions co-occur is crucial for ensuring that the disintegrants perform as expected.

Delayed disintegration is caused by the gelation of the polymer carriers used in ASDs. This is most likely influenced by the mechanism of action of different disintegrants, but the details remain unclear. Therefore, understanding how disintegrants influence the delay in disintegration due to the gelation of the polymer carriers will significantly aid in enhancing the supersaturated solubility of ASD formulations. Kondo et al. performed a comprehensive analysis by quantitatively evaluating the functionality of disintegrants and the differences in disintegration performance between wicking and swelling-type disintegrants using viscoelastic measurements.20

In this study, we investigated the effects of two disintegrants with different mechanisms of action on ASDs. We used HPMC as a carrier, as it is known to undergo gelation, assuming the disintegration of solid dispersible tablets. To evaluate the function of the disintegrants, we designed tablets containing different types of disintegrants and assessed their hardness and disintegration time under accelerated storage conditions. The selected disintegrants were croscarmellose sodium (CCS), which exhibits disintegration by swelling in three dimensions, and crospovidone (CPV), which disintegrates through swelling in the direction of recovery from compression during tableting as well as by wicking.21,22 These two disintegrants were selected to identify the most effective disintegration mechanism against the gelation by HPMC. Using a tablet without any disintegrant as a control, three types of tablets were evaluated in this study.

Next, to investigate the changes arising from the combination of ASD and disintegrants, dynamic viscoelastic measurements were performed on wetted mixtures prepared by adding water to the ASD components and their physical mixtures with disintegrants. These measurements were used to evaluate the gelation behavior of the HPMC. Furthermore, the physical mixtures were subjected to dynamic viscoelastic analysis after storage under accelerated conditions to assess changes over time. Finally, the three types of tablets were evaluated by dynamic viscoelastic measurements before and after accelerated storage to elucidate the relationship between the storage-induced modifications in the physical properties and the disintegration time.

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Materials

HPMC (TC-5 E, Shin-Etsu Chemical Co., Ltd., Tokyo, Japan) was used as the polymeric carrier for the ASD. Griseofulvin (GRF; Tokyo Chemical Industry Co., Ltd., Tokyo, Japan) was used as the model drug. CCS (KICCOLATE ND-2HS, Nichirin Chemical Industries, Hyogo, Japan) and CPV (Kollidon CL, BASF Japan Ltd., Tokyo, Japan) were employed as disintegrants.

The excipients used for tablet compression included microcrystalline cellulose (MCC; PH-102, Asahi Kasei Corp., Tokyo, Japan), lactose monohydrate

Natsuki Takahashi, Miho Inoue, Takayuki Terukina, Hiromu Kondo, Impact of disintegrants on the structure and disintegration of hydroxypropyl methylcellulose-based amorphous solid dispersion tablets, Journal of Pharmaceutical Sciences, 2026, 104194, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2026.104194.

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