(685d) Personalising Dosage Forms By 3D Printing and Computer Simulation

Personalising
Dosage Forms By 3D Printing and Computer Simulation

The emphasis on personalized (precision)
medicine in recent years together with new discoveries in diagnostics and
pharmacogenomics have led to increased research and development of novel
formulation methods and optimized dosage forms. Amongst the most promising newly
employed techniques is 3D printing of tablets or films, most notably Fused
Deposition Modelling 3D printing (FDM), since it offers the possibility to
produce dosage forms with complex structures and defined drug contents, adjusted
to the specific needs of each individual patient (potentially also containing
multiple drugs with varying release profiles). The tablet geometry and internal
structure (which affects the drug release kinetics) is determined by 3D
drawings, produced by computer-aided design.

In the presented work, mathematical simulation was
employed to adjust these tablet structures to achieve desired dissolution
profiles of the produced tablets. The composition of biocompatible drug‑loaded
filaments, which were produced by hot-melt extrusion and then used as the feed
material for the FDM 3D printer, was optimized to achieve reproducible printing
with good resolution. Relevant properties of the filaments, such as mechanical
stability, dynamic viscosity and composition homogeneity were analyzed and the observed trends were used to determine the
ideal composition of the excipients for the filaments. Furthermore, drug
structure was analyzed using XRPD and DSC.

In the first step, a parametric series of structural
motifs (tablets with varying internal infill) was printed and dissolved in
controlled conditions, while the concentration of the released drug in time was
analyzed using HPLC. This allowed to generate a library of drug release
profiles, corresponding to each structural motif. Simultaneously, the release
profiles were also produced computationally, which allowed for evaluation of
the effectivity of the mathematical model and for its subsequent optimization. Next,
the combination of these motifs whose superposition provides the closest
approximation of a required drug release profile was found by a linear
combination of pre-calculated release profiles. To prove the feasibility of
this concept, the combined motifs (tablets, containing two different regions
with different infill ratios) were printed and the computational method was
able to predict their dissolution behavior with a good accuracy.

The employed computational method is based on
the 3D numerical solution of drug diffusion in a boundary layer surrounding the
tablet, coupled with erosion of the tablet structure encoded by the phase
volume function. While the method proved to be able to predict dissolution of
complex tablet structures, slight tablet swelling during the dissolution was
also observed and is believed to have an impact on the process, therefore new
simulation modifications are being tested to take into
account this phenomenon and make the methodology universally applicable
for a wider range of drugs.

In the next stage of the work, the methodology
was applied for more complex systems - tablets containing two different
materials (each with a different active substance) were printed, the layout of
the materials and their infill ratio was again varied to achieve different
dissolution profiles and the computational method was further adjusted to be
able to predict release profiles of both of the active
substances. Lastly, the method was employed to determine, how such a tablet should
be designed in order to achieve a desired drug release
profile.

Fig. 1 – 3D
drawings of cylindrical tablets with a single infill
density that serve as templates for the FDM 3D printing (left). Detail of the
FDM print-head used in this work (middle). Photo and microscopic image of a
printed tablet with infill density of 40%.

Fig. 2 – The dissolution of tablets, containing
two regions with different infill density – the lines represent computationally
obtained data, while the symbols show the experimentally obtained dissolution (left).
Photo of a composite (“pie“)tablet, consisting from ¼
of a region with an infill density of 70% and from ¾ of a region with an infill
density of 30%.

Reference:

Novak M, Boleslavska T, Grof
Z, Wanek A, Zadrazil A,
Beranek J, et al. Virtual Prototyping and Parametric Design of 3D-Printed
Tablets Based on the Solution of Inverse Problem. AAPS PharmSciTech.
2018.