The aim of this study was to evaluate the suitability of Raman spectroscopy as a Process Analytical Technology (PAT) tool for the in-line determination of the active pharmaceutical ingredient (API) concentration and the polymer-drug solid state during a pharmaceutical hot-melt extrusion process. For in-line API quantification, different metoprolol tartrate (MPT) -Eudragit ® RL PO mixtures, containing 10, 20, 30, and 40% MPT respectively, were extruded and monitored in-line in the die using Raman spectroscopy. A PLS model, regressing the MPT concentrations versus the in-line collected Raman spectra, was developed and validated, allowing real-time API concentration determination. The correlation between the predicted and real MPT concentrations of the validation samples is acceptable (R²=0.997) The predictive performance of the calibration model is rated by the root mean square error of prediction (RMSEP), which is 0.59%. Two different polymer-drug mixtures were prepared to evaluate the suitability of Raman spectroscopy for in-line polymer-drug solid state characterization. Mixture 1 contained 90% Eudragit ® RS PO and 10% MPT, and was extruded at 140°C, hence producing a solid solution. Mixture 2 contained 60% Eudragit ® RS PO and 40% MPT, and was extruded at 105°C, prod ucing a solid dispersion. The Raman spectra collected during these extrusion processes provided two main observations. First, the MPT Raman peaks in the solid solution broadened compared to the corresponding solid dispersion peaks, indicating the presence of amorphous MPT. Secondly, peak shifts appeared in the spectra of the solid dispersion and solid solution compared to the physical mixtures, suggesting interactions between Eudragit ® RS PO and MPT, most likely hydrogen bonds. These shifts were larger in the spectra of the solid solution. DSC analysis confirmed these Raman solid state observations and the interactions seen in the spectra. Raman spectroscopy is a potential PAT-tool for in-line determination of the API-concentration and the polymer-drug solid state during pharmaceutical hot-melt extrusion.

The aim of this study was to develop a multilayer (core/coat) dosage form via coextrusion, the core providing sustained drug release and the coat immediate drug release. In this study polymers were selected which can be combined in a co-extruded dosage form.Several thermoplastic polymers were hot-melt extruded and evaluated for processability and macroscopic properties (surface smoothness, die swell). Metoprolol tartrate (MPT) and hydrochlorothiazide (HCT) were incorporated as sustained and immediate release model drugs, respectively. Based on the polymer screening experiments a combination of polycaprolactone (core) and polyethylene oxide (coat) was selected for co-extrusion trials, taking into account their drug release profiles and extrusion temperature (70°C). This combination (containing 10% HCT in the coat and 45% MPT in the core) was successfully co-extruded (diameter core: 3mm / thickness coat: 0.5mm). Adhesion between the two polymer layers was good. HCT release from the coat was complete within 30 minutes, while MPT release was sustained over 24h (55, 70, 85 and 100% after 4, 8, 12 and 24h, respectively). DSC, XRD and Raman spectroscopy revealed that MPT remained crystalline during extrusion, whereas HCT was dissolved in the polyethylene oxide matrix. The in vivo study revealed no significant differences between the experimental formulation and the reference formulation (Zok-Zid ® tablet). Fixed-dose combination mini-tablets with good in vitro and in vivo performance were successfully developed by means of co-extrusion, using a combination of polycaprolactone and polyethylene oxide.

The aim was to evaluate near-infrared spectroscopy for the in-line determination of the drug concentration, the polymer-drug solid-state behaviour and molecular interactions during hot-melt extrusion.Kollidon ® SR was extruded with varying metoprolol tartrate (MPT) concentrations (20, 30, and 40%) and monitored using NIR spectroscopy. A PLS model allowed drug concentration determination. The correlation between predicted and real MPT concentrations was good (R²=0.97). The predictive performance of the model was evaluated by the root mean square error of prediction, which was 1.54%. Kollidon®SR with 40% MPT was extruded at 105°C and 135°C to evaluate NIR spectroscopy for in-line polymer-drug solid state characterization.NIR spectra indicated the presence of amorphous MPT and hydrogen bonds between drug and polymer in the extrudates. More amorphous MPT and interactions could be found in the extrudates produced at 135°C than at 105°C. Raman spectroscopy, DSC and ATR FT-IR were used to confirm the NIR observations. Due to the instability of the formulation, only in-line Raman spectroscopy was an adequate confirmation tool. NIR spectroscopy is a potential PAT-tool for the in-line determination of API-concentration and for the polymer-drug solid state behaviour monitoring during pharmaceutical hot-melt extrusion.

Objectives Co-extrusion implies the simultaneous hot-melt extrusion of two or more materials through the same die, creating a multi-layered extrudate. It is an innovative continuous production technology that offers numerous advantages over traditional pharmaceutical processing techniques. This review provides an overview of the co-extrusion equipment, material requirements and medical and pharmaceutical applications. Key findings The co-extrusion equipment needed for pharmaceutical production has been summarized. Because the geometrical design of the die dictates the shape of the final product, different die types have been discussed. As one of the major challenges at the moment is shaping the final product in a continuous way, an overview of downstream solutions for processing co-extrudates into drug products is provided. Layer adhesion, extrusion temperature and viscosity matching are pointed out as most important requirements for material selection. Examples of medical and pharmaceutical applications are presented and some recent findings considering the production of oral drug delivery systems have been summarized. Summary Co-extrusion provides great potential for the continuous production of fixed-dose combination products which are gaining importance in pharmaceutical industry. There are still some barriers to the implementation of co-extrusion in the pharmaceutical industry. The optimization of downstream processing remains a point of attention.

No abstract