Three-dimensional printing of ramipril tablets by fused deposition modeling

Abstract

Introduction. Arterial hypertension is one of the main risk factors for the development of cardiovascular diseases. Drug treatment of arterial hypertension is associated with a number of difficulties: often requires combination therapy, also a possible change in either dosages or drugs during treatment during the patient's life. Three-dimensional printing allows to create individual medicines on-demand.Aim. Study suitability of Kollidon® VA 64 as a matrix-polymer for the preparation of immediate release ramipril printing tablets.Materials and methods. Substance: ramipril; excipients: Kollidon® VA 64, Kollidon® CL-F, Soluplus®, PEG 1500, sodium carbonate anhydrous, Poloxamer 188, sodium stearyl fumarate, mannitol; reagents: hydrochloric acid, acetonitrile for ultra-HPLC, sodium octanesulfonate for HPLC, orthophosphoric acid 85 %, sodium perchlorate analytical grade, triethylamine, standard: ramipril USP (№1598303). Ramipril filaments were prepared by hot melt extrusion on the extruder Haake™ miniCTW (Thermo Fisher Scientific). The tablets were printed on a hand-made 3D printer. The printlets were studied for friability and hardness. Uniformity and quantitative determination of ramipril and impurities in tablets and filaments were determined by high performance liquid chromatography on a Shimadzu Prominence LC liquid chromatograph. Stability of ramipril was studied on a DSC 3+ Mettler Toledo by differential scanning calorimetry. Also, the stability of ramipril was determined by the Raman spectroscopy on an analytical system ORTES-785TRS-2700.Results and discussion. Ramipril filaments with a diameter of 1.75 mm were obtained by melt extrusion at a temperature of 105 °C. They were homogeneous in quantitative content of the active substance. From the resulting filaments, tablets were printed in five configurations with three filling densities: 30 %, 50 % and 100 %. Degradation of ramipril in filaments and tablets is not observed. The melting point of the selected mixture is lower than the melting point of matrix-polymer. It makes possible to lower the processing temperature. Tablets with 100 % filling provide an immediate release of ramipril.Conclusion. Kollidon® VA 64 is suitable as a matrix-polymer for the development of immediate release ramipril printlets. Kollidon® VA 64 provides the necessary physical and processing properties of the filament required for FDM printing.

Keywords

• hot melt extrusion
• filament
• fused deposition modeling
• three-dimension printing
• additive manufacturing
• personalized medicine
• printlets
• ramipril