Impact of disintegrants on rheological properties and printability in SSE 3D printing of immediate-release formulations

Abstract

This study investigates the effects of disintegrants sodium starch glycolate (SSG) and crospovidone (CP) on the printability, rheological properties, and disintegration time of agar and hydroxypropyl methylcellulose (HPMC)-based formulations designed for semi-solid extrusion. Printability was assessed by measuring the dimensional accuracy of manually extruded filaments. Rheological analysis was performed using oscillatory measurements. Principal component analysis (PCA) and Spearman correlation analysis identified three key components (phase angle, critical strain, and elastic modulus) that explained the total variance in the rheological dataset. A 2 x 3 $^{2}$ factorial design was employed to evaluate the impact of CP, SSG, and HPMC on these rheological parameters, as well as on printability and disintegration time. Results indicated that formulations containing HPMC and SSG generally exhibited better printability. Formulations containing CP achieved satisfactory printability only when SSG or HPMC was included. The optimal printability and rheological properties were achieved with formulations containing 5 % CP and 10 % SSG. Linear regression models correlated geometric volumes of the model and pycnometric volumes of printed objects, with validation showing that predicted masses were within a 95 % confidence interval of measured values for various shapes. All formulations demonstrated immediate-release properties, confirming the successful fabrication of personalised immediate-release dosage forms using semi-solid extrusion technology.

Introduction

Oral solid dosage forms are the most commonly used form of drug administration. These forms include tablets, capsules, and powders, which offer advantages such as ease of administration, precise dosing, stability, and cost-effectiveness in manufacturing and packaging (Awad et al., 2021, Sohail Arshad et al., 2021). Immediate-release (IR) dosage forms, a type of oral solid dosage form, are particularly favoured due to their rapid dissolution and quick absorption into the bloodstream, leading to prompt therapeutic effects. This swift onset of action makes IR dosage forms suitable for medications that require rapid relief, such as analgesics, antipyretics, and certain cardiovascular drugs (Funk et al., 2022, Steffens and Wagner, 2021, Schick et al., 2020). Furthermore, dispersible tablets (a form of IR dosage form) can be dissolved in water, enhancing the ease of administration for patients who have difficulty swallowing traditional tablets, including children, the elderly, and those with dysphagia (Panraksa et al., 2022, Baral et al., 2021).

However, the current procedure for producing such tablets involves direct compression, where excipients and the active pharmaceutical ingredient (API) are blended before tabletting. This method relies extensively on the flowability and compressibility of the excipients to achieve tablets of uniform weight, ensuring precise drug dosing (Trisopon et al., 2020, Trisopon et al., 2021). Furthermore, variations in particle sizes between the API and the excipients can cause uneven distribution within the blend. This non-uniform distribution may impact the consistency and efficacy of the final dosage units, highlighting the need for meticulous control over formulation and blending processes. As such, complicated downstream processes such as granulation, blending, compression, and coating are usually carried out (Wilkins et al., 2024, Kokott et al., 2021, Wang et al., 2022). Despite these additional steps, achieving adequate homogeneity is not always guaranteed. For instance, the blending must be meticulously monitored to prevent segregation of the powder mixture, where this segregation can lead to inconsistent drug content in the final tablets, impacting their efficacy and safety (Bowler et al., 2020, Stranzinger et al., 2021, Rosas et al., 2023).

In contrast, 3D printing (3DP), also known as additive manufacturing, offers a flexible and efficient method for producing immediate-release (IR) dosage forms through layer-by-layer deposition directly from digital designs. Unlike traditional manufacturing processes, 3DP eliminates many intermediate steps, providing precise control over drug release properties. This approach facilitates rapid prototyping, customization, on-demand manufacturing, and the creation of complex dosage forms (Wang et al., 2022, Liang et al., 2019, Zhang et al., 2018, Abdella et al., 2024). Several 3DP techniques are used to fabricate IR dosage forms, including inkjet printing, stereolithography, selective laser sintering, fused deposition modeling, direct powder extrusion, and semi-solid extrusion (SSE) (Xue et al., 2023, Deon et al., 2022). Among these, SSE has attracted significant attention due to its simplicity and ability to create unique solid dosage forms, such as chewable and gummy tablets (Herrada-Manchón et al., 2020, Tagami et al., 2021). Additionally, SSE does not require high heat, minimizing the risk of drug degradation and allowing for a broader range of excipients (El Aita et al., 2020).

Moreover, in the context of in vitro drug release or dissolution of these IR dosage forms, excipients play a critical role in facilitating the disintegration of the matrix upon contact with water. This disintegration leads to the fragmentation of the tablet into smaller particles, which is essential for the rapid release of the active pharmaceutical ingredient (API). The disintegration process is often enhanced by the inclusion of disintegrants, which can be either natural or chemically modified (superdisintegrants). Examples of natural disintegrants include starch- and cellulose-based excipients, while commonly used synthetic disintegrants include crospovidone, sodium starch glycolate, and sodium croscarmellose (Funk et al., 2022, Steffens and Wagner, 2021). These disintegrants, particularly superdisintegrants, enhance the disintegration rate, which is vital for the immediate-release properties of the tablet. Although they are widely used, disintegrants and superdisintegrants exhibit different behaviors due to variations in their physicochemical properties and disintegration mechanisms (Berardi et al., 2022, Zarmpi et al., 2017, Berardi et al., 2021). Such differences can introduce challenges related to printability and rheological properties, which are critical for the success of SSE 3DP. Although higher concentrations of disintegrants in SSE 3D printing have been reported compared to traditional tabletting methods (Patel et al., 2021, Roche et al., 2023), research on how disintegrants impact the rheology and printability of SSE formulations remains limited.

In light of this research gap, this study investigates the impact of two widely used pharmaceutical superdisintegrants—crospovidone (CP) and sodium starch glycolate (SSG)—on the disintegration time, rheological properties, and printability of IR formulations intended for SSE 3D printing. This work also aims demonstrate that the incorporation of disintegrant in the formulation would not only accelerate the rate of disintegration, but also enhance the immediate-release properties. To test this hypothesis, we used a previously developed formulation by Aina et al. (2024c), consisting of 3% agar (A), 2% hydroxypropyl methylcellulose (HPMC or H), 10% sucrose (S), and 2 % caffeine (C), was used as a basis. Specifically, it was postulated that formulations with rheological properties similar to those of this previously optimised formulation would also exhibit optimal printability. A factorial design was employed, considering the mass fractions of HPMC (at 2 levels), CP (at 3 levels), and SSG (at 3 levels). By investigating how CP and SSG influence these key factors, this study aims to contribute to the advancement of fast-disintegrating dosage forms produced using SSE.

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Materials

Agar (Molecular weight, MW = 372.3 g/mol), anhydrous caffeine (C8H10N4O2, MW = 194.19 g/mol), and pulverised sucrose (C12H22O11, MW = 342.3 g/mol) were purchased from Cooper’s Laboratory, France. Methocel® K4M (HPMC, USP 2208 grade, 4000 cp, MW = 2.1 × 10⁵ g/mol, 8.1% hydroxypropyl and 22% methoxy substituted) was a gift from Colorcon Ltd, France. Free samples of Crospovidone and Sodium Starch Glycolate were obtained from JRS Pharma, Germany. Ultrapure water for sample preparation was obtained from a Purelab® water purification system (VWR, France), with a resistance of 18 MΩ cm. All solutions were filtered through a 0.45μm membrane filter (Merck, France) prior to use.

Morenikeji Aina, Darya Kuznyetsova, Fabien Baillon, Romain Sescousse, Noelia M. Sanchez-Ballester, Sylvie Begu, Ian Soulairol, Martial Sauceau, Impact of disintegrants on rheological properties and printability in SSE 3D printing of immediate-release formulations, European Journal of Pharmaceutical Sciences, 2025, 107017, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2025.107017.