Investigating the effects of formulation and manufacturing routes on the tensile strength and disintegration time of tablets containing an HPMC AS-based spray dried powder

Abstract

Amorphous solid dispersions (ASD) are an effective strategy to enhance the solubility of poorly water-soluble drugs. Hot melt extrusion and spray drying are the primary manufacturing techniques applied to produce ASDs. Albeit the increased interest in ASDs over the past decade, the formulation of ASD-based tablets is not yet exhaustively explored. This study investigates the impact of formulation and manufacturing routes on the tensile strength and disintegration time of tablets containing an HPMC AS-based spray dried powder. Utilizing a spray dried placebo as a surrogate, a design of experiment approach was employed to assess the effects of polymer amount, filler, disintegrant type and quantity, glidant, and tablet manufacturing route on tablet properties. Results indicated that tablets produced via direct compression exhibited the highest tensile strength, particularly when formulated with a low amount of polymer and microcrystalline cellulose as filler. Tablets containing mannitol as filler showed the shortest disintegration time. Moreover, mannitol-based tablets demonstrated the best balance between adequate tensile strength and rapid disintegration. Among the disintegrants tested, croscarmellose sodium presented a higher probability of meeting the established specification for disintegration time, compared to crospovidone. Validation of the models for tensile strength and disintegration time proved their ability to effectively identify runs with the highest likelihood of meeting the pre-determined specifications. Finally, recommendations are given for an optimized development of tablets containing HPMC-AS based spray dried powders.

Introduction

Aqueous solubility is one of the main factors influencing bioavailability, as it determines the fraction of active pharmaceutical ingredient (API) available for absorption in the gastro-intestinal tract (Llompart et al., 2024). With the increasing use of high throughput and combinatorial screening tools in the drug discovery, a growing number of new molecular entities exhibit poor water solubility, categorizing them as class II or class IV compounds in the biopharmaceutical classification system (BCS) (Amidon et al., 1995, Lipinski et al., 2012). Formulating poorly water-soluble APIs as amorphous solid dispersions (ASDs) has proven to be an effective strategy to enhance both their water-solubility and bioavailability (Van den Mooter, 2012, Vasconcelos et al., 2007). In ASDs, the API is stabilized in its amorphous form by a polymer carrier, thereby enhancing the API solubility and bioavailability as no energy is required to break the crystal lattice structure (Singh and Van den Mooter, 2016, Van den Mooter, 2012). Moreover, ASD formulations enable the creation and maintenance of drug supersaturation in the gastrointestinal tract by the “spring and parachute” effect: the drug initially dissolves with the soluble polymer matrix, creating a supersaturated solution (“spring”) which is then maintained in this supersaturated state by preventing recrystallization and drug precipitation (“parachute”). Formulation attributes such as API loading in the ASD and polymer selection are key aspects to achieving an adequate “spring and parachute” effect (Baghel et al., 2016, Liu et al., 2016).

Hot melt extrusion and spray drying are among the primary manufacturing techniques used to produce ASDs, accounting for nearly 90 % of the ASD-based marketed products (Moseson et al., 2024). Spray drying is particularly suitable with thermolabile APIs and is relatively easy to scale-up (Bhujbal et al., 2021). Among the polymers employed to stabilize spray-dried powders (SDP), cellulosic-based polymers, such as hydroxypropyl methylcellulose acetate-succinate (HPMC AS), are most commonly used (Friesen et al., 2008). Of the commercial ASDs products on the market, 75 % are formulated as tablets (Démuth et al., 2015, Liu, 2000, Moseson et al., 2024, Saha et al., 2023). It is also important to note that a significant portion of the ASD typically consists of the polymer. API loadings up to 30–40 % can often be achieved without inducing immediate recrystallization (Van den Mooter, 2012).

Although the interest in and knowledge about ASDs has grown tremendously over the last decade, the formulation of tablets containing ASDs is not yet exhaustively explored (Démuth et al., 2015). In addition to the ASD, tablets contain excipients with various functions. Fillers/binders increase the bulk of the tablet, while also compensating for potential deficiencies in ASD properties, such as poor cohesiveness, inadequate flowability, and weak compaction properties. Disintegrants promote tablet disintegration when in contact with a liquid, and glidants are used to enhance flowability by reducing the interparticle friction, surface charge, and cohesion (Awad et al., 2021). Moreover, the concentration of each of these components in the tablet formulation can influence the overall tablet properties. Lastly, ASD properties not only impact the formulation selection, but also the choice of the tablet manufacturing route (Leane et al., 2015, Leane et al., 2024). For example, spray dried powders, which are often characterized by a small particle size (Davis et al., 2018, Schönfeld et al., 2021) and low bulk density (Ekdahl et al., 2019) depending on the spray drying manufacturing process (Vehring, 2008), may benefit from a granulation step to improve tablet manufacturability. Dry granulation, which avoids the use of liquid binders, reduces the risk of ASD recrystallization due to plasticization and higher molecular mobility, making it a good candidate for ASD tablet production (Démuth et al., 2015). However, mechanical and thermal stresses during granulation can still trigger recrystallization by increasing molecular mobility and inducing nucleation within the ASD, particularly in cases of high drug-loaded ASDs (Leane et al., 2013, Sinclair et al., 2011, Singh and Van den Mooter, 2016). Furthermore, dry granulation is associated with a loss of tabletability in granulated plastic materials, reducing their capacity to be compacted into strong tablets. This phenomenon has primarily been attributed to granule size enlargement and granule hardening (Sun & Kleinebudde, 2016). Granule size enlargement reduces tablet strength by decreasing the available bonding area during tableting (Sun & Himmelspach, 2006), while granule hardening is associated with a higher resistance towards densification (Patel et al., 2011). Nevertheless, direct compression remains the most straightforward method to produce tablets, as feeding, blending, and tableting are the only process steps (Dhondt et al., 2022). This simplicity makes it attractive from an industrial and economic perspective, although it is more sensitive to the properties of raw materials used.

Although various studies have investigated formulation and downstream process aspects independently, to our knowledge, no prior evaluation has comprehensively assessed their combined effects. Yu and Hoag (2024) evaluated the impact of four commonly used fillers (microcrystalline cellulose, lactose anhydrous, pre-gelatinized starch, and mannitol) on the tableting behavior, dissolution, and physical stability of tablets containing itraconazole-HPMC AS spray dried powders at two different API drug loadings (20 % and 80 % w/w). Dry granulation was used to increase the particle size and flow of the SDP. Their results showed that microcrystalline cellulose provided the best performance in terms of tablet tensile strength, while lactose anhydrous and mannitol yielded tablets with the highest dissolution rate and poorest physical stability. Zhang et al. (2021) assessed the effect of polymer type (HPMC, HPMC AS, and polyvinylpyrrolidone vinyl acetate (PVP VA64)), ASD concentration in the tablet, and API loading in the ASD (20 %, 40 %, 60 %, and 80 % w/w) on tablet disintegration and drug release of GNE A. The SDPs, fillers, and a portion of the disintegrant were dry granulated together with magnesium stearate, followed by blending with the disintegrant and lubricant. The excipient composition remained constant across formulations, except for the filler concentration, which was adjusted to compensate for varying ASD levels in the tablets. The results showed that the disintegration time recorded during dissolution increased as a function of the polymer concentration in the tablet (either due to higher ASD concentrations in the tablet or a lower API loading in the ASD). This effect was more pronounced for hydrophilic polymers, such as PVP VA and HPMC, whereas the effect of API loading in the ASD was less pronounced for tablets containing HPMC AS-based SDPs. However, tablet tensile strength was not evaluated in this study. Sauer et al. (Sauer et al., 2021) compared two binder/disintegrant combinations in tablets manufactured by dry granulation, each containing 75 % w/w of nifedipine-HPMC AS spray dried powder (with an API loading of 66 % w/w in the SDP). Their results demonstrated that the combination of microcrystalline cellulose and low‐substituted hydroxypropyl cellulose (L-HPC) yielded tablets with superior tensile strength − indicating reduced tabletability loss − and a longer disintegration time compared to the formulation using microcrystalline cellulose and croscarmellose sodium.

This study aims to increase the understanding of how formulation and tablet manufacturing routes affect the properties of tablets containing an HPMC AS-based SDP. A systematic investigation using a design of experiment (DoE) approach was conducted to evaluate the effects of various factors on tablet tensile strength and disintegration time. A spray dried placebo HPMC AS powder served as surrogate for active SDPs. The factors examined included the concentration of polymer and disintegrant, as well as the types of filler, disintegrant, and glidant used. Additionally, a comparison between direct compression and dry granulation was performed. Finally, design spaces were generated to predict the formulations and manufacturing routes with the highest probability of complying with the predefined specifications for both tablet tensile strength and disintegration time.

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Materials

The spray dried placebo powder was prepared in-house starting from AQOAT® HPMC AS LG (Shin-Etsu, Japan).

Tatiana Marcozzi, Martin Otava, Sune Klint Andersen, Chris Vervaet, Valérie Vanhoorne, Investigating the effects of formulation and manufacturing routes on the tensile strength and disintegration time of tablets containing an HPMC AS-based spray dried powder, International Journal of Pharmaceutics, 2025, 126314, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.126314.

Read also our introduction article on Disintegrants here: