Abstract
In the last decades, tremendous improvements have been made in enhancing the bioavailability of poorly soluble active pharmaceutical ingredients (APIs). Lately, their customisation potential has become a reality through filament-based 3D-printing (3DP). Highly loaded oral amorphous solid dispersions (ASDs) are of particular interest, since they drastically reduce the pill burden. However, such systems are limited by their high tendency of API recrystallisation, compromising the API solubility and the mechanical properties of filaments fabricated for 3DP. The following work closes this gap by developing compact 3DP tablets containing an ASD system of 70 % itraconazole in hydroxypropyl methylcellulose acetate succinate (HPMCAS). The processability via HME and 3DP processes was thoroughly investigated by considering filament properties such as solid-state, rheology and mechanical behaviour. Even after six months of storage, the ASD did not show recrystallisation and maintained a zero-order drug release for variable 3DP infill patterns, demonstrating the potential of this approach for on-demand processing at the point-of-care. A strong differentiation in release kinetics was found for different infills that can be used for further improvement of the product to allow tailored release rates. This work provides a strong basis for successful personalisation of highly loaded ASDs via 3DP.
Introduction
Over the past decades, the amorphous solid dispersion (ASD) strategy has been extensively researched to formulate solubility- and dissolution-limited drugs into oral dosage forms. One of the benefits of ASDs is their straightforward translation to the clinic: an early choice of drug-load and polymer carrier has a low chance of reformulation in the following development phases [1]. Today, more than 20 ASD pharmaceutical products have been approved by the U.S. Food and Drug Administration (FDA) [2] using water-soluble polymers of established profiles for oral administration [1]. Moreover, ASD manufacturing technologies such as hot melt extrusion (HME) and spray drying are well-studied processes, with the former being easily up-scalable and usable as a continuous manufacturing process [[3], [4], [5], [6]].
The oral solid dosage form market is increasing in complexity and demands personalisation. Advances in pharmacogenomics and bioinformatics revealed that drugs exhibit variability in patient response according to gender, lifestyle, genetics and environment [[7], [8], [9]]. These variabilities can significantly impact the outcome of the treatment. Relevant examples are psychiatric and neurological treatments which tend to have variability in patient response and demand dose adaptations due to severity, comorbidities and psychosocial effects [[8], [9], [10]].
An enabling technology that allows ASD personalisation is the coupling of HME and material extrusion 3D-printing (3DP), also known as fused deposition modelling (FDM). This technique involves melting an extruded ASD filament through a heated nozzle to form a structure layer by layer via selective deposition of the filament. FDM is the most widely used 3DP technology due to its safety, accessibility, affordability, and ease-of-use [11]. Its versatility allows printing tablets, polypills, capsules, films, gastroretentive, and pressure-controlled oral delivery systems, which in most cases comply with pharmacopeial specifications [[12], [13], [14]]. Due to its inherent dose flexibility, the production of tailored doses via 3DP for animal and human populations in preclinical and clinical settings could greatly accelerate the approval of newly discovered drugs [[15], [16], [17]].
Similar to conventional oral dosage forms, maximising the drug loading is critical for formulating 3D-printed ASDs. At least 50 % of the 20 FDA-approved ASDs have a dose strength higher than 100 mg and some of them, such as Lynparza (Olaparib) require a dose as high as 800 mg per day [18]. Only one commercial ASD, Zelboraf® (Vemurafenib in HPMCAS), employs a drug loading above 70 % [19]. Higher drug loadings can expand the dose range and accommodate higher doses and extended-release formulations without increasing solid volume [1,20]. In this way, the therapeutic levels of poorly soluble drugs can be achieved in higher concentrations, over longer durations and at lower administration frequencies.
Various formulation strategies to increase drug loading include the application of polymer combinations, polymeric salts, in situ thermal crosslinking, incorporation of surfactants, utilization of mesoporous silicas, and implementation of surface nanocoating techniques [21]. To our knowledge, only a handful of 3DP FDM studies have explored drug loadings above 50 %. Most studies were based on BCS class I drugs and required the use of plasticisers. The only reported investigation on a BCS class II drug reported poor dispensability and no available release data [15,[22], [23], [24], [25]].
Increasing the drug loading for BCS class II drugs is still a challenge due to solid state and dissolution limitations to increase bioavailability. A rational selection starts by first inspecting the solid-state stability. Adequate drug-polymer intermolecular interactions, a high glass transition, appropriate viscosity, molecular weight, low hygroscopicity as well as acceptable glass forming ability and recrystallisation kinetics are favourable [26]. Once physical stability has been established, further considerations should be given to the dissolution mechanism of the ASD. At low drug loadings, the ability of an ASD to undergo liquid-liquid phase separation (LLPS) can improve the bioavailability of poorly soluble drugs by the formation of discrete drug-rich colloids, which act as a drug reservoir during GI permeation [27,28]. However, above a certain drug loading reported as the limit of congruency (LoC), the phenomenon of amorphous-amorphous phase separation (AAPS) predominates over LLPS, forming a continuous and interconnected drug-rich layer at the surface of the ASD with release kinetics similar to that of the pure amorphous drug [29]. These phenomena seem to be specific to drug-polymer-water interactions and remain under investigation.
Controlled release polymers may benefit from highly loaded ASDs due to their capacity to control the rate of supersaturation, resulting in bioavailability improvement via a broader maximum kinetic solubility profile with lower chance to recrystallise [30]. Certain types of polymethacrylate copolymers (Eudragit®) as well as hydroxypropyl methylcellulose acetate succinate (HPMCAS) are capable of stabilizing high drug loadings in the solid state. Eudragit® relies on its high glass transition to immobilize drug molecules, while HPMCAS’s amphiphilic structure enables hydrophobic drug interactions and hydrophilic aqueous-phase interactions, making it a potent recrystallisation inhibitor in both solid state and during dissolution [31,32]. In summary, the possibilities to increase the drug loading in ASDs remain limited and specific to each drug-polymer combination.
In this study, a challenging but robust formulation composed of 70 % itraconazole (ITZ) as a BSC Class II compound in HPMCAS-LMP, was successfully developed and formulated into compact oral tablets with tailored release rates. A testing framework comprising rheology, mechanics, solid state and drug release properties was developed to characterise the highly drug loaded filaments and 3DP dosage forms. The high drug loading was found to not only facilitate melt plasticization but also contribute to shape integrity, mechanical robustness, and the thermoplastic properties required for successful HME and FDM 3D-printing. A rational design of the ASD was employed to maximise the drug-loading by simultaneously delivering efficient processability via 3DP. The presented approach can be applied to develop tailored high-loaded ASD systems.
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Materials
Itraconazole (ITZ) was purchased from Shenzhen Nexconn Pharmatechs Ltd. (China) and hypromellose acetate succinate Shin-Etsu AQOAT® AS-LMP (LMP) was kindly donated by Shin-Etsu Chemical Co., Ltd. (Japan). The ITZ commercial oral dosage form Sporanox® with a dose strength of 100 mg was purchased at a local pharmacy. Sporanox® was used as a control formulation and is an immediate release capsule containing spray layered ITZ-HPMC ASD on inert sugar cores [27].
Carolina Alva, Elisa Goetzinger, Josip Matić, Aygün Doğan, Eyke Slama, Sarah Heupl, Thomas Rillmann, Susanna Abrahmsén-Alami, Jonathan Booth, Sharareh Salar-Behzadi, Martin Spoerk, Tailoring the release of highly loaded amorphous solid dispersions via additive manufacturing, Journal of Controlled Release, Volume 382, 2025, 113723, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2025.113723.
Read also our introduction article on 3D Printing here:
