How do polymer composition and infill density of 3D printed oral forms influence the dissolution rate of a BCSII molecule ?

INTRODUCTION
In recent years, the use of three-dimensional (3D) printing for drug manufacturing has considerably increased in the pharmaceutical field. The modification of the drug release profile by the elaboration of complex geometries is a reason why 3D printing and, more specifically, Fused Deposition Modeling (FDM) appears as a promising tool. Nowadays, many active pharmaceutical ingredients (API) are classified in the Biopharmaceutics Classification System class II (BCS II) since they are poorly soluble. Elaboration of new solid oral forms by HME and FDM can be a solution to increase the dissolution rate of these BCSII API by the amorphisation of the drugs and the modification of the geometry of the printed forms. Therefore, the goal of this work is to enhance the solubility and the dissolution rate of poorly soluble drugs by the use of hot-melt extrusion (HME) coupled with 3D printing.
MATERIALS AND METHODS
Materials: Itraconazole (ITZ), a BCS II API, was chosen as the model
drug. Four formulations containing 25% of ITZ and different proportions of Affinisol® 15LV (hydroxypropylmethylcellulose) and Kollidon® VA 64 (vinylpyrrolidone-vinyl acetate copolymer) were elaborated
thanks to previous studies. Methods: - HME and FDM 3D Printing : HME process (Pharma 11, ThermoFisher Scientific®, Waltham, MA, USA) was performed on the four formulations to produce three batches of filaments. For each formulation except formulation 4, which was not printable, printed forms with infill densities of 20%, 50% and 80% and thickness of 5.8 mm, 4.4 mm and 3.4 mm, respectively, were printed (Prusa® i3MK3 3D printer, Prusa Research, Prague, Czech Republic). Tablet thickness were modified to keep a constant drug load of 100 mg in each form since a comparison is made with Sporanox®, the correspondent commercialized drug in Belgium. - Differential Scanning Calorimetry (DSC): Printed forms were analyzed in triplicates by DSC (Mettler- Toledo, Schwerzenbach, Suisse) every four weeks to determine the physical state of ITZ. - High Performance Liquid Chromatography (HPLC): The amount of ITZ in filaments and printed forms was evaluated in triplicates every four weeks by a validated HPLC method (Agilent® 1100, Santa Clara, USA). - Dissolution Test: Dissolution studies were performed on the printed forms, in triplicates, using the USPII paddle method in a Sotax® AT7 apparatus (Allschwil, Switzerland) in HCl 0.1 M medium during 6 h at 50 rpm and 37 °C. - Computerized Tomography (CT)-Scan: Printed forms were scanned with a Skyscan 1172/G (Bruker®, Billerica, Massachusetts, United States). Reconstructions and segmentations were performed on NRecon software (v. 1.7.3.1) to obtain the 3D rendering before measuring surface areas and volumes.
RESULTS AND DISCUSSION
Drug Amorphisation: The absence of a melting point at 167 °C in the thermograms of the three printed forms indicates that ITZ is in an amorphous form. In addition, the three formulations of printed forms allowed ITZ to be maintained in an amorphous forms during the 9 months of storage.
Drug Concentration: ITZ yields ranged from 95% to 105% indicating that no degradation occurred during the HME and 3D printing thermal processes and that ITZ is uniformly distributed throughout the filaments and printed forms. Furthermore, no degradation of ITZ occurred during the 9 months of storage. Drug Dissolution: First of all, the solubility and the drug release rate were
improved in all the printed forms produced compared to ITZ in a crystalline form. The influence of polymer composition and infill density of the printed forms on the dissolution rate of ITZ were studied. One graph example is illustrated for each factor, but same observations can be made for the other
printed forms. - Influence of the Polymer Composition: In formulation 3, which contains a greater proportion of Kollidon VA64 (45%) than formulation 1 (0%) the amount of ITZ in solution after 2 hours of dissolution test is the
lowest. However, formulation 2, which contains a proportion of 22,5% of Kollidon VA64 gives the best solubility profile to ITZ overall. In fact, the variation of the interactions between the components depending on the proportions of polymers can influence the dissolution profile of the drug. Several techniques like Fourier Transform Infrared (FTIR) Microscopy and Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) were used to analyse the affinity between the components as well as the distribution of the components within the printed forms. Results show that ITZ is distributed differentially within the two polymers depending on the ratio of both polymers in the formulations. - Influence of the Infill Density: According to the literature, the drug dissolution mainly depends on the surface area/volume ratio of the printed forms, which were measured using CT-scan (Dr Erwan Plougonven, Pr Angélique Léonard, PEPs, University of
Liege). Printed forms with 20% and 50% infill densities dissolves faster than printed forms with 80% infill density, because their surface/volume ratio is greater. However, dissolution rate also depends on the penetration of water through the printed form which is easier when the infill density is lower, explaining why tablet with 20% infill density dissolve the fastest. - Comparison with Sporanox®: A solubility profile similar to the one of Sporanox®, which also contains amorphous ITZ, is obtained with the printed form of formulation 2 with an 20% infill density.
CONCLUSION
Thanks to the association of Affinisol®15 LV and Kollidon®VA64 with ITZ, printed forms with different infill densities were successfully printed and the drug release rate was improved. Both polymer composition and infill density
of printed forms influence the dissolution rate of the BCS II drug they contain. The interactions between the components change depending on the proportions of polymers used in the formulations and can influence the dissolution profile of the drug. Therefore, it is important to keep this in mind when formulating solid oral forms by HME and FDM and to study closely the affinity between the components as well as the distribution of the components within the printed forms. In addition, for the first three formulations, the lower the infill density of the printed form is, the higher the porosity and the faster the dissolution rate are. The printed forms from the
formulation 2 with an infill density of 20% even have a solubility profile similar to that of Sporanox® which is highly encouraging for future experiments.