Concordance of vacuum compression molding with spray drying in screening of amorphous solid dispersions of itraconazole.

Spray drying is a well-established method for screening spray dried dispersions (SDDs) but is material consuming, and the amorphous solid dispersions (ASDs) formed have low bulk density. Vacuum Compression Molding (VCM) is a potential method to avoid these limitations. This study focuses on VCM to screen ASDs containing itraconazole and L, M, or H polymer grades of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and compares their morphology, amorphous stability, and dissolution performance with spray drying. Results indicate that VCM ASDs were comparable to SDDs. Both VCM ASDs and spray drying SDDs with HPMCAS-L and HPMCAS-M had improved dissolution profiles, while HPMCAS-H did not. Dynamic light scattering findings agreed with dissolution profiles, indicating that L and M grades produced monodisperse, smaller colloids, whereas H grade formed larger, polydisperse colloids. Capsules containing ASDs from VCM disintegrated and dissolved in the media; however, SDD capsules formed agglomerates and failed to disintegrate completely. Findings indicate that the VCM ASDs are comparable to SDDs in terms of dissolution performance and amorphous stability. VCM may be utilized in early ASD formulation development to select drug-polymer pairs for subsequent development.

Vacuum Compression Molding as a Screening Tool to Investigate Carrier Suitability for Hot-Melt Extrusion Formulations.

Hot-melt extrusion (HME) is the most preferred and effective method for manufacturing amorphous solid dispersions at production scale, but it consumes large amounts of samples when used for formulation development. Herein, we show a novel approach to screen the polymers by overcoming the disadvantage of conventional HME screening by using a minimum quantity of active pharmaceutical ingredient (API). Vacuum Compression Molding (VCM) is a fusion-based method to form solid specimens starting from powders. This study aimed to investigate the processability of VCM for the creation of amorphous formulations and to compare its results with HME-processed formulations. Mixtures of indomethacin (IND) with drug carriers (Parteck® MXP, Soluplus®, Kollidon® VA 64, Eudragit® EPO) were processed using VCM and extrusion technology. Thermal characterization was performed using differential scanning calorimetry, and the solid-state was analyzed via X-ray powder diffraction. Dissolution studies in the simulated gastric fluid were performed to evaluate the drug release. Both technologies showed similar results proving the effectiveness of VCM as a screening tool for HME-based formulations.

A novel tool to standardize rheology testing of molten polymers for pharmaceutical applications.

Melt rheology provides information about material properties that are of great importance for equipment design and simulations, especially for novel pharmaceutical manufacturing operations, including extrusion, injection molding or 3d printing. To that end, homogeneous samples must be prepared, most commonly via compression or injection molding, both of which require costly equipment and might not be applicable for shear- and heat-sensitive pharmaceutical materials. Our study introduces a novel vacuum compression molding (VCM) tool for simple preparation of thermoplastic specimens using standard laboratory equipment: a hot plate and a vacuum source. Sticking is eliminated by applying polytetrafluoroethylene (PTFE) coated separation foils. The evacuation of the tool leads to compression of the sample chamber, which is cost-efficient compared to conventional methods, such as compression molding or injection molding that require special equipment. In addition, this compact design reduces the preparation time and the heat load. The VCM tool was used to prepare samples for a rheological study of three pharmaceutical polymers (Soluplus(®), Eudragit(®)E, EVA Rowalit(®) 300-1/28). The prepared samples were without any air inclusions or voids, and the measurements had a high reproducibility. All relative standard deviations were below 3%. The obtained data were fitted to the Carreau-Yasuda model and time-temperature superposition was applied.

In-line implementation of an image-based particle size measurement tool to monitor hot-melt extruded pellets.

This work focuses on the implementation and application of an in-line particle measurement tool to monitor particle properties of hot-melt extruded pellets. A novel image analysis system (Eyecon) is used to analyze pellets with a size of approximately 1mm. The method is based on photometric stereo imaging, which is achieved by three different-colored light sources arranged circularly around the lens. Several implementations, whereby the product stream was led through the optical sampling volume, have been tested. The advantages and disadvantages of each implementation are discussed and evaluated. The most suitable implementation was applied to an extrusion run with constant throughput and different cutting frequencies resulting in different pellet sizes. A particle size distribution comparison between the image analysis system and an off-line reference particle analysis (QICPIC) showed good agreement although only a small fraction of the particles were analyzed in-line. Additionally, some illustrative examples for process development are given. With this approach the capability of hot-die face pelletizing to manufacture nearly-spherical pellets with a narrow size distribution is proven.

Inline monitoring and a PAT strategy for pharmaceutical hot melt extrusion.

Implementation of continuous manufacturing in the pharmaceutical industry requires tight process control. This study focuses on a PAT strategy for hot melt extrusion of vegetable calcium stearate (CaSt) as matrix carrier and paracetamol as active pharmaceutical ingredient (API). The extrusion was monitored using in-line near-infrared (NIR) spectroscopy. A NIR probe was located in the section between the extrusion screws and the die, using a novel design of the die channel. A chemometric model was developed based on premixes at defined concentrations and was implemented in SIPAT for real time API concentration monitoring. Subsequently, step experiments were performed for different API concentrations, screw speeds and screw designs. The predicted API concentration was in good agreement with the pre-set concentrations. The transition from one API plateau to another was a smooth curve due to the mixing behaviour of the extruder. The accuracy of the model was confirmed via offline HPLC analysis. The screw design was determined as the main influential factor on content uniformity (CU). Additionally the influence of multiple feeders had a significant impact on CU. The results demonstrate that in-line NIR measurements is a powerful tool for process development (e.g., mixing characterization), monitoring and further control strategies.