Adjusting the melting point of an Active Pharmaceutical Ingredient (API) via cocrystal formation enables processing of high melting drugs via combined hot melt and materials extrusion (HME and ME)

Abstract

One of the biggest challenges for the application of materials extrusion (ME) technology in the pharmaceutical sector is the lack of ready-to-use polymeric materials (filaments) of pharmaceutical quality. To overcome this challenge materials extrusion can be combined with the Hot Melt Extrusion (HME) process enabling the production of filaments using pharmaceutically approved polymers with incorporated drugs. This manuscript presents a step by step approach for the formulation of additively manufactured tablets containing a high melting point API (hydrochlorothiazide, HCT, T m = 266-268 °C) with two pharmaceutically approved polymers (polyvinyl alcohol, PVA and hydroxypropyl methylcellulose acetate succinate, HPMCAS) of different technological and pharmaceutical properties via combined HME and ME processing. The thermal properties of a model drug were adapted to the processing window of both HME and ME by obtaining a hydrochlorothiazide: nicotinamide cocrystal (HCT:NIC) with a lower melting point (T m = 173.3 °C) than the starting material. Two plasticizers were used - triethyl citrate (TEC) for HPMCAS and sorbitol (SOR) for PVA. Blends containing 10-50 wt. % of plasticizer were prepared using the fusion method and thoroughly analysed using PXRD, DSC, and FTIR enabling the selection of formulations for further HME processing. Placebo filaments with 10-30 wt. % of plasticizer were obtained and their mechanical properties and ME processability were assessed to select a polymer blend with desirable process parameters. Finally, the filaments containing 20 wt. % of plasticizer with HCT or the HCT:NIC cocrystal were produced and processed using ME to form tablets. The phase of the drug (crystalline or amorphous), mechanical properties of filaments and tablets as well as the drug content in the obtained materials were assessed using PXRD, DSC, and FTIR followed by materials imaging with polarising microscopy and SEM. The cocrystal formation not only enabled to modify the melting point of the drug to match the temperature of both processes but also improved the mechanical properties of the filaments which is important for ME processing. In the case of PVA based formulations the cocrystal turned amorphous upon HME processing forming flexible and printable filaments. In contrast, the drug embedded in HPMCAS based filaments formed crystals that affected the mechanical properties of the extrudates. The mechanical properties of the obtained tablets and the release profile of the drug from the AM tablets were enhanced as compared to the materials obtained using conventional methods, i.e. tableting and encapsulation. • High melting drugs can be incorporated into pharmaceutically approved polymers in the form of cocrystals via combined HME and ME processing, • Modification of physicochemical properties of the API via cocrystal formation enables successful processing of high melting point APIs into elastic filaments, • Low miscibility of the drug with polymers and the presence of crystalline drug in the filaments may result in brittle materials difficult to process via ME, • Openwork 3D tablet structure and cocrystal formation substantially improve drug dissolution.