Considering the demographic changes of society and the connected increase in multimorbid patients, new individualized therapies must be developed including the combination of highly dosed formulations in a single dosage form to improve patient compliance. To produce dosage forms with individual doses and release profiles, new production processes are necessary. As a promising tool for the production of individualized solid dosage forms, additive manufacturing techniques have emerged in pharmaceutical research in the past two decades [1
]. With these techniques, three-dimensional objects are made without molds or tools by successive build-up of layers of source materials [3
]. Depending on the source material, different physical principals are applicable, like powder-bed binding via laser sintering or binder fluid, extrusion freeforming, and stereo lithography [3
]. All named techniques are also applicable for the production of solid dosage forms [2
]. The first and only approved additively manufactured pharmaceutical. Spritam®
, is produced by the ZipDose®
technology where a powder bed of levetiracetam is selectively bound with a binder fluid to generate an ultra-rapidly disintegrating tablet [4
]. However, as there are only few different doses approved and only one dissolution profile is available, Spritam®
does not utilize all advantages of additive manufacturing to produce individual dosage forms on demand. Another technique, selective laser sintering, was used to produce orally disintegrating [5
] or modified-release tablets [6
]. Extrusion-based techniques include the selective deposition of hydrogels loaded with active pharmaceutical ingredients (API) [7
] which after drying, were tested with up to five different drugs with each having a different excipient to obtain different release profiles [9
]. Furthermore, fused layer modeling (FLM), where a polymer-API formulation is selectively deposited via a hot nozzle, also represents extrusion-based technologies and is currently the fastest evolving technique in pharmaceutical research [1
Few approaches use direct melt extrusion of polymer-API powder blends [10
]. However, most FLM machines use polymer wires, so-called filaments, as source material [1
]. The first applications of FLM in pharmaceutics soaked commercially available polyvinyl alcohol filaments in API solutions to additively produce dosage forms [12
]. More recent works use mostly hot melt extrusion (HME) to produce API-loaded filaments [1
]. In general, HME of polymer-API blends is an advantageous process to improve solubility of BCS type-II and -IV APIs by intensively compounding the materials to gain solid dispersions and solutions [14
]. For more soluble APIs, the compounding in polymeric excipients can be used to achieve modified and control release kinetics. To gain lower viscosities and therefore lower process temperatures in HME, plasticizers are frequently used [15
]. However, it has to be considered that every substance in the process can have a plasticizing, viscosity decreasing, or even viscosity increasing effect. For example, absorbed water may plasticize polymers and alter the melting process [16
], but can also cause polymer degradation [17
] and physical instability of preliminary stable solid solutions [18
]. Amorphous, molecularly dispersed APIs also have a plasticizing effect [19
]. On the contrary, dispersely mixed APIs increase viscosity [21
]. To produce filaments suitable for FLM machines adequate process parameters for HME and formulation are crucial. Thus, adequate mechanical stability, a consistent diameter, and a homogeneous API distribution are required [23
]. There are different excipients of pharmaceutical grade that can be used as matrix polymer or plasticizer [24
]. Depending on the excipient used, different release kinetics can be adjusted. It is also possible to mix different polymeric excipients to gain better applicability to FLM [24
For the production of API-loaded filaments, different machinery was applied. For example, filaments were produced by the extrusion of powder blends with a single-screw extruder [23
] with marginal shear and melt mixing or with a self-constructed ram-extruder [27
] without any melt mixing. However, in most cases a co-rotating twin-screw extruder is applied [28
] to obtain well-compounded, homogeneous filaments.
Different API-loaded filaments were, as mentioned before, successfully used in FLM to produce immediate [27
] and controlled [23
] release solid dosage forms. This includes first approaches with two formulations using a dual FLM machine to obtain delayed release and dosage forms with API combinations [32
]. However, in most cases the used formulations include low API loads [23
]; only few use API loads higher than 40 wt.% [31
Especially for polypill applications, it is necessary to use source materials with high API loads to limit the dosage form size whilst increasing the maximum dose for each API. There are only few approaches to systematically investigate the influence of highly disperse API load on filament and additively produced dosage form properties. Therefore, the aim of the present work is to investigate the introduction of theophylline as model drug at different concentrations into different polymer matrices via HME. The obtained filaments and additively produced dosage forms were methodically characterized concerning parameters crucial over the whole process chain such as mechanical properties, content and mass uniformity, and drug release.
For individualization approaches of pharmaceuticals, combining different APIs into one dosage form by 3D-printing, a high API load in the respective intermediate products is needed. This makes the thorough evaluation of highly loaded filaments inevitable. However, by increasing disperse API content, properties of filaments for 3D-printing may be altered, modulating the performance along the process chain. Therefore, particle-induced effects on printability and product properties must be elucidated to finally enable the prediction of overall process performance based on formulation and API particle properties.
In general, particles inside the polymer matrix proved to particularly alter the mechanical properties of both filaments and 3D prints. The systematic adaption of specific FLM parameters can attenuate several challenges such as layer adhesion to a certain extent. However, as the influence of size and shape of particles and their behavior during multiple heating, such as in filament extrusion and FLM itself, and their interplay with dissolved API molecules in the melt are not fully understood, further investigations are required.
Additionally, higher API content can cause instabilities in the 3D-printing process, making prediction of dosage form mass and therefore content uniformity more challenging. For tested HPMC formulations, the release profile of geometries with low surface-area-to-volume ratio is independent of the API content, facilitating an independent adjustment of the dose-and-release profile as well as the application of highly loaded polymer formulations in polypill applications.
To conclude, all experimental data demonstrate the significance of the impact of the API load over the whole process chain of 3D-printing of tablets. This knowledge must be extended further to derive models that should be taken into consideration during product development of individualized medicines.