3D printed scaffolds as delivery devices for nanocrystals: A proof of concept loading Atorvastatin with enhanced properties for sublingual route of administration


Increasing the solubility of drugs is a recurrent objective of pharmaceutical research, and one of the most widespread strategies today is the formulation of nanocrystals (NCs). Beyond the many advantages of formulating NCs, their incorporation into solid dosage forms remains a challenge that limits their use. In this work, we set out to load Atorvastatin NCs (ATV-NCs) in a delivery device by combining 3D scaffolds with an “in situ” loading method such as freeze-drying. When comparing two infill patterns for the scaffolds at two different percentages, the one with the highest NCs load was chosen (Gyroid 20 % infill pattern, 13.8 ± 0.5 mg). Colloidal stability studies of NCs suggest instability in acidic media, and therefore, the system is postulated for use as a sublingual device, potentially bypassing stomach and hepatic first-pass effects. An ad hoc dissolution device was developed to mimic the release of actives. The nanometric size and properties acquired in the process were maintained, mainly in the dissolution rate and speed, achieving 100 % dissolution of the content in 180 s. Based on these results, the proof of concept represents an innovative approach to converting NCs suspensions into solid dosage forms.


The oral route of drug administration is often preferred initially due to its patient-friendly nature, but it poses challenges when dealing with poorly soluble drugs. Around 40 % of drugs on the market and roughly 75–90 % of those in the main development pipelines are classified, according to the Biopharmaceutical Classification System (BCS), as Class II (Lipinski, 2000). This classification entails low aqueous solubility and high permeability, often resulting in low, variable, and bioavailability dependent on factors such as concomitant administration with food (Sahoo et al., 2021).

Nanocrystals (NCs) are stabilized drug particles ranging in size from 10 to 1000 nm (Müller et al., 2011). Reducing the size of a particle down to the nanoscale involves three associated factors: Enhanced Dissolution Rate, linked to the increased surface area of the drug exposed to the solvent, as described by the Noyes-Whitney equation (Noyes & Whitney, 1897); Increased Saturation Solubility, result from the augmented curvature and dissolution pressure of the drug from the NCs. This leads to a greater availability of dissolved active molecules for absorption through physiological barriers and subsequent distribution in the body (Mauludin et al., 2009). Greater Adhesiveness since drug nanoparticles (NPs) can interact more effectively with physiological barriers due to their enlarged surface area and increased contact points (Müller et al., 2011). NCs are generally prepared using two main techniques: bottom-up and top-down. While bottom-up approaches involve the precipitation of NCs from drug solutions, top-down approaches rely on the application of large amounts of energy to fragment the drug, which is commonly suspended in aqueous solutions containing different ionic (electrostatic) or steric stabilizers (Rabinow, 2004).

Beyond the advantages of nanometrization and the method employed, this technology is currently limited mainly due to pharmaco-technical problems. The drying process is recognized as a step commonly perceived as crucial to stabilize NCs and prevent the deterioration inherent to liquid nanosuspensions, including phenomena such as Ostwald ripening, particle aggregation and sedimentation (Bhakay et al., 2018). Using techniques such as freeze-drying or spray-drying allows the elimination of solvents, giving rise to solid entities that retain their stability and re-dispersibility. However, once successful drying is achieved, NCs powders exhibit very poor fluidity, which makes their processing difficult for industrial machines. In addition, applying traditional procedures, such as compaction or compression, uses high external forces that cause collisions between the NCs, which generates their aggregation or caking, causing a substantial increase in their particle size. The irreversible aggregation by external forces is related to the proportion of nanoparticles in the tablet: the higher the proportion of NCs in the powder mixture to be compressed, the higher the probability that NCs will meet each other and undesired aggregation will occur (Junghanns & Müller, 2008). In other words, NCs are challenging to formulate into tablets, and, at the same time, tablets can only carry a low proportion of NCs. For example, Rapamune® tablets have Sirolimus NCs, but the amount of drug in the tablet is only about 1 %. Alternative methods, such as fluidized bed granulation, have been explored but often result in low loading capacities, around 1 %. Incorporating NCs into solid oral dosage forms necessitates techniques that avoid flow control issues and high pressures and facilitate NCs redispersion without significant size increases.

Recently, 3D printing technology has emerged as a viable alternative to compression for producing solid dosage forms. These pharmaceutical forms, known in the literature as “printlets” or printed tablets, are obtained from layer-by-layer deposition of the materials without applying pressure or powder flow control (in most techniques), being an ideal method for loading NCs. There are successful attempts to use NCs in solid forms in oral or sublingual “printlets” or buccal films (Germini and Peltonen, 2021, Lopez-Vidal et al., 2023, Real et al., 2023), but industrial scale-up is often complicated and ends up being beneficial only for the conditions tested in research work i.e. a production mediated by a specific printer and a particular ink, which allows obtaining small batches of a solid dosage form.

In this work, the advantages offered by 3D printing are used to develop and evaluate an innovative approach to convert NCs suspensions into solid dosage forms. Firstly, we used Fused Deposition Modeling (FDM) to print an insoluble matrix that serves as a support (scaffold). The suspended NCs obtained by wet milling, a top-down method widely used today (Malamatari et al., 2018), were immersed onto these supports and freeze-drying was used, not only as a drying method (necessary for the stability of NCs) but also as a loading method. This simplified technique would allow a solid pharmaceutical form to be obtained directly from the nanosuspension, avoiding postprocessing steps and maintaining the advantages of 3D printing relative to the dose customization.

We used Calcium Atorvastatin (ATV) as a model drug for this work. This drug of proven efficacy and wide use presents several biopharmaceutical problems: first, ATV is a Biopharmaceutics Classification System class II drug with low solubility in aqueous solution and high permeability (Löbenberg & Amidon, 2000). Its pH-dependent solubility (is insoluble in aqueous solution of pH 4 and below, and it is very slightly soluble in water and pH 7.4 phosphate buffer) (Kim et al., 2008), rapid elimination in the intestine and first-pass hepatic metabolism result in a low absolute and systemic bioavailability. Furthermore, the use of ATV may cause hepatotoxicity or other diseases, such as myopathies or rhabdomyolysis, with different degrees of incidence, which limits its clinical efficacy (Law & Rudnicka, 2006). Thus, the primary challenge lies in creating a dosage form that enhances drug solubility, boosts bioavailability, and mitigates adverse reactions (Kurakula et al., 2015, Rossetti et al., 2023).

Moreover, ATV is unstable in acid mediums and its commercial tablets are always coated. Considering these considerations, it was decided to use the technique described above to obtain sublingual dosage forms. This route produces a rapid onset of action compared to conventional tablet and capsule formulations. The absorbed drug bypasses first-pass hepatic metabolism, resulting in a fast effect that can reduce the required dose.

Scaffolds were manufactured using polylactic acid (PLA) filaments, one of today’s most popular FDM printing filaments. It is a thermoplastic synthetic polymer that is biocompatible (does not cause rejection), biodegradable (disposed of naturally), immunologically inert (does not cause allergies), non-toxic and resorbable (Estupiñan et al., 2011). Using this material and the ability of 3D printing for the design of unconventional geometries, a “release device” containing NCs within an insoluble cavity-based matrix was designed to serve as a support (scaffold) during the freeze-drying process. The result is an NCs-loaded device that the patient would place under his tongue and, after the time required for release, remove and discard it (Fig. 1).

This work describes in depth the development of the device, which includes the analysis of different design alternatives, the characterization of the NCs used, and the evaluation of the final dosage form.

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ATV was acquired from Novalquim Lab (Rosario, Argentina), Maltodextrin (MTX) was acquired from Nicco (Córdoba, Argentina) and Polysorbate 80 (T80) was kindly provided by Rumapel (Bs.As, Argentina). Zirmil® Yttria-stabilized zirconia beads of 0.1 mm (Saint-Gobain ZirPro, Kölh, Germany) were used as milling agents. The water for all the experiments was ultrapure Milli- Q® water (Millipore, Massachusetts, United States).

Bruno Andrés Barrientos, Daniel Andrés Real, Alan Rossetti, Franco E. Ambrosioni, Daniel Alberto Allemandi, Santiago Daniel Palma, Juan Pablo Real, 3D printed scaffolds as delivery devices for nanocrystals: A proof of concept loading Atorvastatin with enhanced properties for sublingual route of administration, International Journal of Pharmaceutics, Volume 661, 2024, 124396, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124396.

Read also our introduction article on 3D Printing here:

3D Printing
3D Printing
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