Rheological characterization of molten polymer-drug dispersions as a predictive tool for pharmaceutical hot-melt extrusion processability

The aim of this study was to investigate (i) the influence of drug solid-state (crystalline or dissolved in the polymer matrix) on the melt viscosity and (ii) the influence of the drug concentration, temperature and shear rate on polymer crystallization using rheological tests. Poly (ethylene oxide) (PEO) (100.000 g/mol) and physical mixtures (PM) containing 10-20-30-40% (w/w) ketoprofen or 10% (w/w) theophylline in PEO were rheologically characterized. Rheological tests were performed (frequency and temperature sweeps in oscillatory shear as well as shear-induced crystallization experiments) to obtain a thorough understanding of the flow behaviour and crystallization of PEO-drug dispersions. Theophylline did not dissolve in PEO as the complex viscosity (eta*) of the drug-polymer mixture increased as compared to that of neat PEO. In contrast, ketoprofen dissolved in PEO and acted as a plasticizer, decreasing eta*. Acting as a nucleating agent, theophylline induced the crystallization of PEO upon cooling from the melt. On the other hand, ketoprofen inhibited crystallization upon cooling. Moreover, higher concentrations of ketoprofen in the drug-polymer mixture increasingly inhibited polymer crystallization. However, shear-induced crystallization was observed for all tested mixtures containing ketoprofen. The obtained rheological results are relevant for understanding and predicting HME processability (e.g., barrel temperature selection) and downstream processing such as injection moulding (e.g., mold temperature selection)

The impact of the injection mold temperature upon polymer crystallization and resulting drug release from immediate and sustained release tablets

It was the aim of this study to elucidate the impact of the injection mold temperature upon the polymer crystallinity, its microstructure and the resulting drug release from immediate and sustained release tablets containing semi-crystalline polymers. The immediate release formulation contained 20% (w/w) ketoprofen (KETO) in poly (ethylene oxide) (PEO) and the sustained release formulation contained 20-40% (w/w) metoprolol tartrate (MPT) in polycaprolactone (PCL). Physical mixtures of drug-polymer were characterized via isothermal crystallization experiments using DSC and rheological measurements to elucidate the impact of the drug solid-state upon the crystallization kinetics. Tablets were prepared using various thermal histories (extrusion barrel temperature and injection mold temperatures). Polymer crystallinity and microstructure in the tablets was characterized via DSC and polarized optical microscopy. The polymer microstructure was altered by the various applied thermal histories. The differences in PEO crystallinity induced by the various mold temperatures did not affect the KETO dissolution from the tablets. On the other hand, MPT (20-40% w/w) dissolution from the PCL matrix when extruded at 80 degrees C and injection molded at 25 and 35 degrees C was significantly different due to the changes in the polymer microstructure. More perfect polymer crystals are obtained with higher mold temperatures, decreasing the drug diffusion rate through the PCL matrix. The results presented in this study imply that the injection mold temperature should be carefully controlled for sustained release formulations containing hydrophobic semi-crystalline polymers

Assessment and prediction of tablet properties using transmission and backscattering Raman spectroscopy and transmission NIR spectroscopy

This study investigated whether Raman and Near Infrared (NIR) spectroscopy could predict tablet properties. Granules were produced on a continuous line by varying granulation parameters. Tableting process parameters were adjusted to obtain uniform tablet weight and thickness. Spectra were collected offline and tablet properties determined with traditional analyzing methods. Partial Least Squares (PLS) regression was used to correlate spectral information to tablet properties, but predictive models couldn't be established. Principal component analysis (PCA) was effectively used to distinguish theophylline concentrations and hydration levels and multiple linear regression (MLR) analysis allowed insight on how granulation parameters affect granule and tablet properties

Bioleaching of metals from secondary materials using glycolipid biosurfactants

With the global demand for economically important metals increasing, compounded by the depletion of readily accessible ores, secondary resources and low-grade ores are being targeted to meet growing demands. Novel technologies developed within biobased industries, such as microbial biosurfactants, could be implemented to improve the sustainability of traditional hydrometallurgy techniques. This study investigates newly developed microbial biosurfactants (acidic- and bolaform glycolipids) for the leaching of metals (particularly Cu and Zn) from a suite of mine tailings, metallurgical sludges and automotive shredder residues. Generally, acidic sophorolipids were the most performant, and optimal Cu leaching was observed from a fayalite slag (27%) and a copper sulfide mine tailing (53%). Further investigation of the leached fayalite material showed that leaching was occurring from small metallic Cu droplets in this material via a corrosion-based mechanism, and/or from Cu-Pb sulfides, selective against dominant Fe-silicate matrices. This study highlights that acidic sophorolipid microbial biosurfactants have the potential to leach Cu and Zn from low-grade secondary materials. It also provides important fundamental insights into biosurfactant-metal and mineral interactions that are currently unexplored. Together, the convergence of leaching and mining industries with bio-industries can improve material recovery and will positively impact the bio- and circular economies and the environment.The authors thank Bio Base Europe Pilot plant for supplying the biosurfactants that enabled the execution of the leaching experiments. We also thank Joachim Neri, Karel Folens, Nina Ricci Nicomel and Melgü Kizilmese for their assistance during ICP-analyses

A continuous manufacturing concept for a pharmaceutical oral suspension

The aim of this study was to investigate the applicability of an innovative continuous manufacturing system for semi-solid and liquid pharmaceutical formulations. A commercially available pharmaceutical oral suspension was selected as model formulation. Premixes of the raw materials were dosed via peristaltic pumps to the mixing compartment, which consists of two consecutive mixing units. An experimental design was used to study the influence of several process parameters (throughput, mixing speed in mixing unit 1 and mixing speed in mixing unit 2) on the quality attributes of the oral suspension. The pH, density, active pharmaceutical ingredient (API) concentration, sedimentation after 30 days (expressed by the sedimentation volume) and rheological characteristic (yield stress) of the suspension were determined. No significant influence of the process parameters on the pH, density and API concentration was observed. The throughput and mixing speed in mixing unit 1 had a significant impact on both the sedimentation volume and yield stress, and were therefore critical to acquire physical stable suspensions. Furthermore, the yield stress measured one day after production was predictive for the occurrence of sedimentation in the suspensions after 30 days. When selecting the optimal process settings, the continuously manufactured suspension had a similar product quality as the original batch-processed suspension and even possessed a higher yield stress. This study demonstrated that the investigated innovative continuous manufacturing technology is suitable for the manufacturing of a commercially available pharmaceutical suspension and that the product quality can be optimized by adjusting the process parameters

Assessment of volumetric scale-up law for processing of a sustained release formulation on co-rotating hot-melt extruders

In this research, the volumetric scale-up law was assessed for its applicability to scale-up from a laboratory-scale extruder (11 mm diameter) to a pilot-scale extruder (16 mm diameter) with geometric similarity using low feed rates (0.1-0.26 kg/h at lab-scale). A sustained release formulation was extruded on both scales using scaled feed rates according to the volumetric scale-up law. The specific mechanical energies, drug solid-state, drug dissolution and the residence time distribution responses (i.e. axial mixing degree, mean residence time, width of distribution) were compared between both scales. The results showed that the difference in mean residence time between both scale extruders reduced with higher throughput and thus fill level. Overall, the specific mechanical energies (SME) were comparable between scales when using the volumetric scale-up law (i.e. applying scaling factor q = 3) and were exactly matching with a scaling factor of q = 2.6. Furthermore, plug flow conditions at lab-scale should be avoided before scaling up to obtain similar SMEs. The same degree of axial mixing (represented by the Peclet number) was demonstrated at a scaling factor of q = 2. If drug solid-state is a critical quality attribute (CQA), focus should be on the screw speed and cooling capacity of the larger scale extruder. The drug dissolution showed similarity between scales and was independent of drug solid-state for this formulation, indicating that successful scale-up was possible