Search Results (43)

Background/Objectives: This study evaluates the efficacy of twin screw melt granulation (TSMG), and hot-melt extrusion (HME) techniques in enhancing the solubility and dissolution of simvastatin (SIM), a poorly water-soluble drug with low bioavailability. Additionally, the study explores the impact of binary polymer blends on the drug’s miscibility, solubility, and in vitro release profile. Methods: SIM was processed with various polymeric combinations at a 30% w/w drug load, and a 1:1 ratio of binary polymer blends, including Soluplus^® (SOP), Kollidon^® K12 (K12), Kollidon^® VA64 (KVA), and Kollicoat^® IR (KIR). The solid dispersions were characterized using modulated differential scanning calorimetry (M-DSC), powder X-ray diffraction (PXRD), and Fourier-transform infrared spectroscopy (FTIR). Dissolution studies compared the developed formulations against a marketed product. Results: The SIM-SOP/KIR blend showed the highest solubility (34 µg/mL), achieving an approximately 5.5-fold enhancement over the pure drug. Dissolution studies showed that SIM-SOP/KIR formulations had significantly higher release profiles than the physical mixture (PM) and pure drug (p < 0.01). Additionally, their release was similar to a marketed formulation, with 100% drug release within 30 min. In contrast, the SIM-K12/KIR formulation exhibited strong miscibility, but limited solubility and slower release rates, suggesting that high miscibility does not necessarily correlate with improved solubility. Conclusions: This study demonstrates the effectiveness of TSMG, and HME as effective continuous manufacturing technologies for improving the therapeutic efficacy of poorly water-soluble drugs. It also emphasizes the complexity of polymer–drug interactions and the necessity of carefully selecting compatible polymers to optimize the quality and performance of pharmaceutical formulations. Full article

Background/Objectives: Amorphization of an active pharmaceutical ingredient (API) can improve its dissolution and enhance bioavailability. Avoiding solvents for drug amorphization is beneficial due to environmental issues and potential solvent residues in the final product. Methods: Dry amorphization using a twin-screw extruder is presented in this paper. A blend of mesoporous silica particles and crystalline itraconazole was processed using a pharma-grade laboratory scale twin-screw extruder. The influence of different screw configurations and process parameters was tested. Particle size and shape are compared in scanning electron microscopy (SEM) images. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) are used to determine the residual amount of crystalline itraconazole in the final product. Results: An optimized screw configuration for the process was found which leads to more than 90% amorphous API when processed at room temperature. Full amorphization was reached at 70 °C. The specific mechanic energy (SME) introduced into the material during twin-screw processing is crucial for the dry amorphization. The higher the SME, the lower the residual amount of crystalline API. Two months after processing, however, recrystallization was observed by XRD. Conclusions: Dry processing using a twin-screw extruder is continuous, free of solvents and can be performed at low temperatures. This study proves the concept of twin-screw processing with mesoporous silica for dry amorphization of itraconazole. Full article

Background: Precise continuous feeding of active pharmaceutical ingredients (APIs) and excipients is crucial in a continuous powder-to-tablet manufacturing setup, as any inconsistency can affect the final tablet quality. Method: This study investigated the impact of various materials on the performance of a continuous twin-screw loss-in-weight (LIW) feeder. The materials tested included spray-dried lactose, anhydrous lactose, granulated lactose, microcrystalline cellulose (MCC), an MCC–lactose preblend (50%:50% w/w ratio), and a co-processed excipient (lactose–lactitol at a 95%:5% w/w ratio). The feeding performance of these excipients was systematically assessed, focusing on powder densification and screw layering within the LIW feeder. Results: The results demonstrated densification for the spray-dried lactose and preblend. Densification was more pronounced during the initial feeding cycles for spray-dried lactose, but decreased gradually over time. In contrast, the densification remained relatively constant throughout the feeding process for the preblend. Notably, minor screw layering was observed for both spray-dried lactose and anhydrous lactose, with the extent of this issue reducing over time for the spray-dried lactose. Interestingly, granulated lactose grades did not show screw layering, making them preferable for blending with APIs prone to severe screw layering. The LIW feeder control system successfully managed powder densification and minor screw layering, maintaining the mass flow rate at the set point for all investigated materials. Conclusions: These findings inform the selection of optimal excipients, appropriate tooling for LIW feeders, and the enhancement of control strategies to shorten startup times. By addressing these factors, the precision and reliability of continuous feeding processes can be improved. Full article

Binder selection is a crucial step in continuous twin-screw wet granulation (TSWG), as the material experiences a much shorter residence time (2–40 s) in the granulator barrel compared to batch-wise granulation processes. Polyvinyl alcohol (PVA) 4-88 was identified as an effective binder during TSWG, but the potential of other PVA grades—differing in polymerization and hydrolysis degree—has not yet been studied. Therefore, the aim of the current study was to evaluate the potential of different PVA grades as a binder during TSWG. The breakage and drying behavior during the fluidized bed drying of drug-loaded granules containing the PVA grades was also studied. Three PVA grades (4-88, 18-88, and 40-88) were characterized and their attributes were compared to previously investigated binders by Vandevivere et al. through principal component analysis. Three binder clusters could be distinguished according to their attributes, whereby each cluster contained a PVA grade and a previously investigated binder. PVA 4-88 was the most effective binder of the PVA grades for both a good water-soluble and water-insoluble formulation. This could be attributed to its high total surface energy, low viscosity, good wettability of hydrophilic and hydrophobic surfaces, and good wettability by water of the binder. Compared to the previously investigated binders, all PVA grades were more effective in the water-insoluble formulation, as they yielded strong granules (friability below 30%) at lower L/S-ratios. This was linked to the high dispersive surface energy of the high-energy sites on the surface of PVA grades and their low surface tension. During fluidized bed drying, PVA grades proved suitable binders, as the acetaminophen (APAP) granules were dried within a short time due to the low L/S-ratio, at which high-quality granules could be produced. In addition, no attrition occurred, and strong tablets were obtained. Based on this study, PVA could be the preferred binder during twin screw granulation due to its high binder effectiveness at a low L/S-ratio, allowing efficient downstream processing. However, process robustness must be controlled by the included excipients, as PVA grades are operating in a narrow L/S-ratio range. Full article

Twin-screw granulation has emerged as a key process in powder processing industries and in the pharmaceutical sector to produce granules with controlled properties. This comprehensive review provides an overview of the simulation techniques and approaches that have been employed in the study of twin-screw granulation processes. This review discusses the major aspects of the twin-screw granulation process which include the fundamental principles of twin-screw granulation, equipment design, process parameters, and simulation methodologies. It highlights the importance of operating conditions and formulation designs in powder flow dynamics, mixing behaviour, and particle interactions within the twin-screw granulator for enhancing product quality and process efficiency. Simulation techniques such as the population balance model (PBM), computational fluid dynamics (CFD), the discrete element method (DEM), process modelling software (PMS), and other coupled techniques are critically discussed with a focus on simulating twin-screw granulation processes. This paper examines the challenges and limitations associated with each simulation approach and provides insights into future research directions. Overall, this article serves as a valuable resource for researchers who intend to develop their understanding of twin-screw granulation and provides insights into the various techniques and approaches available for simulating the twin-screw granulation process. Full article

Twin-screw granulation (TSG) is an emerging continuous wet granulation technique that has not been widely applied in the industry due to a poor mechanistic understanding of the process. This study focuses on improving this mechanistic understanding by analyzing the effects of the mixing dynamics on the granule quality attributes (PSD, content uniformity, and microstructure). Mixing is an important dynamic process that simultaneously occurs along with the granulation rate mechanisms during the wet granulation process. An improved mechanistic understanding was achieved by identifying and quantifying the physically relevant intermediate parameters that affect the mixing dynamics in TSG, and then their effects on the granule attributes were analyzed by investigating their effects on the granulation rate mechanisms. The fill level, granule liquid saturation, extent of nucleation, and powder wettability were found to be the key physically relevant intermediate parameters that affect the mixing inside the twin-screw granulator. An improved geometrical model for the fill level was developed and validated against existing experimental data. Finally, a process map was developed to depict the effects of mixing on the temporal and spatial evolution of the materials inside the twin-screw granulator. This process map illustrates the mechanism of nucleation and the growth of the granules based on the fundamental material properties of the primary powders (solubility and wettability), liquid binders (viscosity), and mixing dynamics present in the system. Furthermore, it was shown that the process map can be used to predict the granule product quality based on the granule growth mechanism. Full article

Hydroxypropyl methylcellulose (HPMC) is a preferred hydrophilic matrix former for controlled release formulations produced through continuous twin-screw wet granulation. However, a non-homogeneous API distribution over sieve fractions with underdosing in the fines fraction (<150 µm) was previously reported. This could result in content uniformity issues during downstream processing. Therefore, the current study investigated the root cause of the non-homogeneous theophylline distribution. The effect of process parameters (L/S-ratio and screw configuration) and formulation parameters (matrix former and filler type) on content uniformity was studied. Next, the influence of the formulation parameters on tableting and dissolution behavior was investigated. Altering the L/S-ratio or using a more aggressive screw configuration did not result in a homogeneous API distribution over the granule sieve fractions. Using microcrystalline cellulose (MCC) as filler improved the API distribution due to its similar behavior as HPMC. As excluding HPMC or including a hydrophobic matrix former (Kollidon SR) yielded granules with a homogeneous API distribution, HPMC was identified as the root cause of the non-homogeneous API distribution. This was linked to its fast hydration and swelling (irrespective of the HPMC grade) upon addition of the granulation liquid. Full article

The pharmaceutical industry is in the midst of a transition from traditional batch processes to continuous manufacturing. However, the challenges in making this transition vary depending on the selected manufacturing process. Compared with other oral solid dosage processes, wet granulation has been challenging to move towards continuous processing since traditional equipment has been predominantly strictly batch, instead of readily adapted to material flow such as dry granulation or tablet compression, and there have been few equipment options for continuous granule drying. Recently, pilot and commercial scale equipment combining a twin-screw wet granulator and a novel horizontal vibratory fluid-bed dryer have been developed. This study describes the process space of that equipment and compares the granules produced with batch high-shear and fluid-bed wet granulation processes. The results of this evaluation demonstrate that the equipment works across a range of formulations, effectively granulates and dries, and produces granules of similar or improved quality to batch wet granulation and drying. Full article

The current research aims to improve the solubility of the poorly soluble drug, i.e., ibuprofen, by developing self-emulsifying drug delivery systems (SEDDS) utilizing a twin screw melt granulation (TSMG) approach. Gelucire^® 44/14, Gelucire^® 48/16, and Transcutol^® HP were screened as suitable excipients for developing the SEDDS formulations. Initially, liquid SEDDS (L-SEDDS) were developed with oil concentrations between 20–50% w/w and surfactant to co-surfactant ratios of 2:1, 4:1, 6:1. The stable formulations of L-SEDDS were transformed into solid SEDDS (S-SEDDS) using a suitable adsorbent carrier and compressed into tablets (T-SEDDS). The S-SEDDS has improved flow, drug release profiles, and permeability compared to pure drugs. The existence of the drug in an amorphous state was confirmed by differential scanning calorimetry (DSC) and powder X-ray diffraction analysis (PXRD). The formulations with 20% w/w and 30% w/w of oil concentration and a 4:1 ratio of surfactant to co-surfactant have resulted in a stable homogeneous emulsion with a globule size of 14.67 ± 0.23 nm and 18.54 ± 0.55 nm. The compressed tablets were found stable after six months of storage at accelerated and long-term conditions. This shows the suitability of the TSMG approach as a single-step continuous manufacturing process for developing S-SEDDS formulations. Full article

Melt granulation for improving material handling by modifying particle size distribution offers significant advantages compared to the standard methods of dry and wet granulation in dust reduction, obviating a subsequent drying step. Furthermore, current research in pharmaceutical technology aims for continuous methods, as these have an enhanced potential to reduce product quality fluctuations. Concerning both aspects, the use of a planetary roller granulator is consequential. The process control with these machines benefits from the enhanced ratio of heated surface to processed volume, compared to the usually-applied twin-screw systems. This is related to the unique concept of planetary spindles flowing around a central spindle in a roller cylinder. Herein, the movement pattern defines the transport characteristics, which determine the energy input and overall processing conditions. The aim of this study is to investigate the residence time distribution in planetary roller melt granulation (PRMG) as an indicator for the material transport. By altering feed rate and rotation speed, the fill level in the granulator is adjusted, which directly affects the average transport velocity and mixing volume. The two-compartment model was utilized to reflect these coherences, as the model parameters symbolize the sub-processes of axial material transport and mixing. Full article

The continuous twin-screw wet granulation (TSWG) process was investigated and optimized with prediction-oriented I-optimal designs. The I-optimal designs can not only obtain a precise estimation of the parameters that describe the effect of five input process parameters, including the screw speed, liquid-to-solid (L/S) ratio, TSWG feed rate, and numbers of the 30° and 60° mixing elements, on the granule quality in a TSWG process, but it can also provide a prediction of the response to determine the optimum operating conditions. Based on the constraints of the desired granule properties, a design space for the TSWG was determined, and the ranges of the operating parameters were defined. An acceptable degree of prediction was confirmed through validation experiments, demonstrating the reliability and effectiveness of using the I-optimal design method to study the TSWG process. The I-optimal design method can accelerate the screening and optimization of the TSWG process. Full article

Twin-screw wet granulation (TSWG) is a method of continuous pharmaceutical manufacturing and a potential alternative method to batch granulation processes. It has attracted more and more interest nowadays due to its high efficiency, robustness, and applications. To improve both the product quality and process efficiency, the process understanding is critical. This article reviews the recent work in process understanding and optimization for TSWG. Various aspects of the progress in TSWG like process model construction, process monitoring method development, and the strategy of process control for TSWG have been thoroughly analyzed and discussed. The process modeling technique including the empirical model, the mechanistic model, and the hybrid model in the TSWG process are presented to increase the knowledge of the granulation process, and the influence of process parameters involved in granulation process on granule properties by experimental study are highlighted. The study analyzed several process monitoring tools and the associated technologies used to monitor granule attributes. In addition, control strategies based on process analytical technology (PAT) are presented as a reference to enhance product quality and ensure the applicability and capability of continuous manufacturing (CM) processes. Furthermore, this article aims to review the current research progress in an effort to make recommendations for further research in process understanding and development of TSWG. Full article

Continuous manufacturing is becoming the new technological standard in the pharmaceutical industry. In this work, a twin-screw processor was employed for the continuous production of liquisolid tablets containing either simethicone or a combination of simethicone with loperamide hydrochloride. Both active ingredients present major technological challenges, as simethicone is a liquid, oily substance, and loperamide hydrochloride was used in a very small amount (0.27% w/w). Despite these difficulties, the use of porous tribasic calcium phosphate as a carrier and the adjustment of the settings of the twin-screw processor enabled the optimization of the characteristics of the liquid-loaded powders and made it possible to efficiently produce liquisolid tablets with advantages in physical and functional properties. The application of chemical imaging by means of Raman spectroscopy allowed for the visualization of differences in the distribution of individual components of the formulations. This proved to be a very effective tool for identifying the optimum technology to produce a drug product. Full article

In the last decade, twin-screw wet granulation became an essential technology for continuous pharmaceutical tablet production. Consequently, interest in (semi-)continuous fluidized bed drying systems as a subsequent processing unit has grown. In parallel, it has become pivotal to fully understand and control manufacturing processes in line with in the quality-by-design paradigm. Formulation-generic prediction models would enormously facilitate digitally enhanced process development and require dedicated experimental data collection and process knowledge. To obtain this knowledge, three experimental campaigns were performed in this work. Firstly, an investigation into the effect of dryer process settings on drying behavior is presented. Secondly, the effect of active pharmaceutical ingredient properties on drying was assessed by producing granules of similar particle size and porosity and evaluating their drying and breakage behavior. Finally, additional experiments with varying active pharmaceutical ingredients and drug load were conducted to increase the genericity of the data set. This knowledge can be used in mathematical process modelling. Full article

This paper investigates new approaches for the blending and plastification of ceramic powder with a binder to form fused deposition of ceramic (FDC) feedstock. The fabrication of highly filled ceramic filaments was accomplished using the granulation by agitation technique, followed by twin-screw extruder homogenization and single-screw extruder filament extrusion. The feedstocks are based on alumina (Al₂O₃) powders, which were prepared with an industrial binder through three different routes: wet granulation, melt granulation and melt granulation with a suspension. After printing cubic samples and tensile test specimens on a commercial fused deposition modelling (FDM) printer, the properties of the resulting green-body and sintered parts were investigated. The green-body mechanical values are compared with results from commercially available filaments. Mixing the binder with the alumina powder and surfactant in a suspension produces the lowest viscosity and the best elongation at break. Full article