Development of fixed-dose combination with dual-release properties using double-melt extrusion technology

The aim of this study was to develop an innovative fixed-dose combination (FDC) containing the sustained release of acetaminophen (AAP) and solubilized ibuprofen (IBF) using double-melt extrusion (DME) technology. The hot-melt extrusion (HME)-based formulation of AAP was screened by seven types of polymers (Polyvinyl alcohol, polyvinylpyrrolidone (Kollidon 30), polyvinyl acetate-polyvinylpyrrolidone mixture (Kollidon SR), hydroxypropyl cellulose (Klucel™ LF, Klucel™ HF), ethylcellulose (Aqualon™ N7, Aqualon™ N100). Poloxamer, polyethyleneglycol (PEG), and (meth)acrylate copolymers (Eudragit E PO, Eudragit E 100) were screened to optimize the IBF composition of the final DME formulations. Based on the transition temperature of the polymers, single-melt extrudates (SME) with AAP and Klucel™ LF were processed into pellets in a core, and the AAP SME pellets were covered with second extrudates of IBF and Eudragit E PO to achieve the final DME formulations. TGA, PXRD, and FT-IR analyses were employed to determine the physicochemical characteristics of the formulations containing APIs. These analyses were to evaluate the potential impact of the HME manufacturing process on the crystalline state of each API and to assess their stability when subjected to the temperatures involved in HME processing. Reference products, raw APIs, physical mixtures, and HME-based formulations were analyzed using a pH-shift dissolution method to compare the drug release behavior. Structural analysis of drug distribution was also performed using confocal laser scanning microscopy (CLSM) with different fluorescent dyes. As the DME extrudates were manufactured in a two-stage process, the green color for coumarin-6 (for AAP) added in the first HME process could easily be distinguished from rhodamine B (for IBF) that was added in the second HME. Furthermore, the dissolution rate of IBF in DME increased 6.7 times compared to the Raw API. Additionally, the AAP in DME formulation constantly released a 65.2% drug for 2 h without any fluctuations or interruptions. Consequently, these findings suggested that different drugs in one dosage form could be combined to achieve sustained release as well as immediate release with solubilizing effects using DME technology. [Display omitted]