DEVELOPMENT OF FDM 3D-PRINTED AND INJECTION MOLDED TABLETS FOR POORLY WATER-SOLUBLE DRUGS WITH RAPID DRUG RELEASE AND REDUCED PROCESSING TEMPERATURE BY APPLYING A NOVEL ACID-BASE SUPERSOLUBILIZATION (ABS) PRINCIPLE
Date of Award
Fused deposition modeling (FDM) 3D printing has emerged as the most suitable 3D printing technology to develop personalized and on-demand medications. However, the technology faces challenges, such as slow and incomplete drug release, lack of drug-polymer miscibility for poorly water-soluble drugs, limited availability of polymers with acceptable physicochemical properties, and printability. In the present investigation, these issues were addressed using a novel physicochemical principle called acid-base supersolubilization, where a weakly basic drug, haloperidol, interacted with non-salt forming weak acids, glutaric acid or malic acid, and was mixed with polymers by HME to prepare filaments for 3D printing. Haloperidol, having pH-dependent solubility, was used as the model drug, and glutaric acid and malic acid were selected as supersolubilizing agents. The formulations containing either haloperidol-glutaric acid 1:2 molar mixture or haloperidol-malic acid mixture (1:1 and 1:2 molar ratios) along with Kollidon® VA64 or its mixture with Affinisol HPMC 15cP as polymeric carriers. They were extruded into filaments and printed into tablets. The aqueous solubility of haloperidol increased from <2.5 µg/mL at pH>8 to over 300 mg/ml in the presence of weak acid. Moreover solid dispersions of ternary drug-polymer-acid mixtures were stable with as high as 50% drug load due to the formation of a co-amorphous system of drug-acid. The formation of the co-amorphous system decreased extrusion and printing temperatures as low as 115 °C and 100 °C, respectively, and the filament printability was maintained up to 30% drug load. Moreover, complete and pH-independent drug release was achieved within 60 minutes. The ductility and toughness of drug-loaded filaments were limitations of FDM 3D printing of high drug-loaded extrudates, and to overcome them, injection molding was tried as an alternative tableting approach. Haloperidol-Kollidon® VA64-acid mixtures could be successfully molded into tablets at as high as 40% drug load. Although somewhat slower than the 3D-printed tablets, complete and pH-independent drug release was obtained. The application of the ABS principle in the present investigation to increase drug release, enhance drug-polymer miscibility, improve the printability of filaments, and reduce processing temperature may represent a breakthrough in the development of FDM 3D-printed tablets.
Patel, Nirali Girishchandra, "DEVELOPMENT OF FDM 3D-PRINTED AND INJECTION MOLDED TABLETS FOR POORLY WATER-SOLUBLE DRUGS WITH RAPID DRUG RELEASE AND REDUCED PROCESSING TEMPERATURE BY APPLYING A NOVEL ACID-BASE SUPERSOLUBILIZATION (ABS) PRINCIPLE" (2022). Theses and Dissertations. 566.