Personalised 3D Printed Medicines: Optimising Material Properties for Successful Passive Diffusion Loading of Filaments for Fused Deposition Modelling of Solid Dosage Forms.

Although not readily accessible yet to many community and hospital pharmacists, fuse deposition modelling (FDM) is a 3D printing technique that can be used to create a 3D pharmaceutical dosage form by employing drug loaded filaments extruded via a nozzle, melted and deposited layer by layer. FDM requires printable filaments, which are commonly manufactured by hot melt extrusion, and identifying a suitable extrudable drug-excipient mixture can sometimes be challenging. We propose here the use of passive diffusion as an accessible loading method for filaments that can be printed using FDM technology to allow for the fabrication of oral personalised medicines in clinical settings. Utilising Hansen Solubility Parameters (HSP) and the concept of HSP distances (Ra) between drug, solvent, and filament, we have developed a facile pre-screening tool for the selection of the optimal combination that can provide a high drug loading (a high solvent-drug Ra, >10, and an intermediate solvent-filament Ra value, ~10). We have identified that other parameters such as surface roughness and stiffness also play a key role in enhancing passive diffusion of the drug into the filaments. A predictive model for drug loading was developed based on Support Vector Machine (SVM) regression and indicated a strong correlation between both Ra and filament stiffness and the diffusion capacity of a model BCS Class II drug, nifedipine (NFD), into the filaments. A drug loading, close to 3% w/w, was achieved. 3D printed tablets prepared using a PVA-derived filament (Hydrosupport, 3D Fuel) showed promising characteristics in terms of dissolution (with a sustained release over 24 h) and predicted chemical stability (>3 years at 25 °C/60% relative humidity), similar to commercially available NFD oral dosage forms. We believe FDM coupled with passive diffusion could be implemented easily in clinical settings for the manufacture of tailored personalised medicines, which can be stored over long periods of time (similar to industrially manufactured solid dosage forms).

Engineering of pharmaceutical cocrystals in an excipient matrix: Spray drying versus hot melt extrusion.

The comparison of spray drying versus hot melt extrusion (HME) in order to formulate amorphous solid dispersions has been widely studied. However, to the best of our knowledge, the use of both techniques to form cocrystals within a carrier excipient has not previously been compared. The combination of ibuprofen (IBU) and isonicotinamide (INA) in a 1:1 M ratio was used as a model cocrystal. A range of pharmaceutical excipients was selected for processing - mannitol, xylitol, Soluplus and PVP K15. The ratio of cocrystal components to excipient was altered to assess the ratios at which cocrystal formation occurs during spray drying and HME. Hansen Solubility Parameter (HSP) and the difference in HSP between the cocrystal and excipient (ΔHSP) was employed as a tool to predict cocrystal formation. During spray drying, when the difference in HSP between the cocrystal and the excipient was large, as in the case of mannitol (ΔHSP of 18.3 MPa0.5), a large amount of excipient (up to 50%) could be incorporated without altering the integrity of the cocrystal, whereas for Soluplus and PVP K15, where the ΔHSP was 2.1 and 1.6 MPa0.5 respectively, the IBU:INA cocrystal alone was only formed at a very low weight ratio of excipient, i.e. cocrystal:excipient 90:10. Remarkably different results were obtained in HME. In the case of Soluplus and PVP K15, a mixture of cocrystal with single components (IBU and INA) was obtained even when only 10% excipient was included. In conclusion, in order to reduce the number of unit operations required to produce a final pharmaceutical product, spray drying showed higher feasibility over HME to produce cocrystals within a carrier excipient.

Production of cocrystals in an excipient matrix by spray drying.

Spray drying is a well-established scale-up technique for the production of cocrystals. However, to the best of our knowledge, the effect of introducing a third component into the feed solution during the spray drying process has never been investigated. Cocrystal formation in the presence of a third component by a one-step spray drying process has the potential to reduce the number of unit operations which are required to produce a final pharmaceutical product (e.g. by eliminating blending with excipient). Sulfadimidine (SDM), a poorly water soluble active pharmaceutical ingredient (API), and 4-aminosalicylic acid (4ASA), a hydrophilic molecule, were used as model drug and coformer respectively to form cocrystals by spray drying in the presence of a third component (excipient). The solubility of the cocrystal in the excipient was measured using a thermal analysis approach. Trends in measured solubility were in agreement with those determined by calculated Hansen Solubility Parameter (HSP) values. The ratio of cocrystal components to excipient was altered and cocrystal formation at different weight ratios was assessed. Cocrystal integrity was preserved when the cocrystal components were immiscible with the excipient, based on the difference in Hansen Solubility Parameters (HSP). For immiscible systems (difference in HSP > 9.6 MPa0.5), cocrystal formation occurred even when the proportion of excipient was high (90% w/w). When the excipient was partly miscible with the cocrystal components, cocrystal formation was observed post spray drying, but crystalline API and coformer were also recovered in the processed powder. An amorphous dispersion was formed when the excipient was miscible with the cocrystal components even when the proportion of excipient used as low (10% w/w excipient). For selected spray dried cocrystal-excipient systems an improvement in tableting characteristics was observed, relative to equivalent physical mixtures.