Tailor-Made Doses of Pharmaceuticals by Tunable Modular Design: A Case Study on Tapering Antidepressant Medication.

An abrupt cessation of antidepressant medication can be challenging due to the appearance of withdrawal symptoms. A slow hyperbolic tapering of an antidepressant, such as citalopram hydrobromide (CHB), can mitigate the withdrawal syndrome. However, there are no viable dosage forms on the market to implement the tapering scheme. A solution using a tunable modular design (TMD) approach to produce flexible and accurate doses of CHB is proposed. This design consists of two parts: 1) a module with a fixed amount of preloaded CHB in a freeze-dried polymer matrix, and 2) fine-tuning the CHB dose by inkjet printing. A noncontact food-grade printer, used for the first time for printing pharmaceuticals, is modified to allow for accurate printing of the highly concentrated CHB ink on the porous CHB-free or CHB-preloaded modules. The produced modules with submilligram precision are bench-marked with commercially available CHB tablets that are manually divided. The TMD covers the entire range of doses needed for the tapering (0.5-23.8 mg). The greatest variance is 13% and 88% when comparing the TMD and self-tapering, respectively. Self-tapering is proven inaccurate and showcases the need for the TMD to make available accurate and personalized doses to wean off treatment with CHB.

Neonatal intestinal mucus barrier changes in response to maturity, inflammation, and sodium decanoate supplementation.

The integrity of the intestinal mucus barrier is crucial for human health, as it serves as the body's first line of defense against pathogens. However, postnatal development of the mucus barrier and interactions between maturity and its ability to adapt to external challenges in neonatal infants remain unclear. In this study, we unveil a distinct developmental trajectory of the mucus barrier in preterm piglets, leading to enhanced mucus microstructure and reduced mucus diffusivity compared to term piglets. Notably, we found that necrotizing enterocolitis (NEC) is associated with increased mucus diffusivity of our large pathogen model compound, establishing a direct link between the NEC condition and the mucus barrier. Furthermore, we observed that addition of sodium decanoate had varying effects on mucus diffusivity depending on maturity and health state of the piglets. These findings demonstrate that regulatory mechanisms governing the neonatal mucosal barrier are highly complex and are influenced by age, maturity, and health conditions. Therefore, our results highlight the need for specific therapeutic strategies tailored to each neonatal period to ensure optimal gut health.

Co-administration of Intravenous Drugs: Rapidly Troubleshooting the Solid Form Composition of a Precipitate in a Multi-drug Mixture Using On-Site Raman Spectroscopy.

Intravenous drugs are often co-administrated in the same intravenous catheter line due to which compatibility issues, such as complex precipitation processes in the catheter line, may occur. A well-known example that led to several neonatal deaths is the precipitation due to co-administration of ceftriaxone- and calcium-containing solutions. The current study is exploring the applicability of Raman spectroscopy for testing intravenous drug compatibility in hospital settings. The precipitation of ceftriaxone calcium was used as a model system and explored in several multi-drug mixtures containing both structurally similar and clinically relevant drugs for co-infusion. Equal molar concentrations of solutions containing ceftriaxone and calcium chloride dihydrate were mixed with solutions of cefotaxime, ampicillin, paracetamol, and metoclopramide. The precipitate formed was collected as an "unknown" material, dried, and analyzed. Several solid-state analytical methods, including X-ray powder diffraction, Raman spectroscopy, and thermogravimetric analysis, were used to characterize the precipitate. Raman microscopy was used to investigate the identity of single sub-visual particles precipitated from a mixture of ceftriaxone, cefotaxime, and calcium chloride. X-ray powder diffraction suggested that the precipitate was partially crystalline; however, the identity of the solid form of the precipitate could not be confirmed with this standard method. Raman spectroscopy combined with multi-variate analyses (principal component analysis and soft independent modelling class analogy) enabled the correct detection and identification of the precipitate as ceftriaxone calcium. Raman microscopy enabled the identification of ceftriaxone calcium single particles of sub-visual size (around 25 µm), which is in the size range that may occlude capillaries. This study indicates that Raman spectroscopy is a promising approach for supporting clinical decisions and especially for compatibility assessments of drug infusions in hospital settings.

Methodological Considerations in Development of UV Imaging for Characterization of Intra-Tumoral Injectables Using cAMP as a Model Substance.

A UV imaging release-testing setup comprising an agarose gel as a model for tumorous tissue was developed. The setup was optimized with respect to agarose concentration (0.5% (w/v)), injection procedure, and temperature control. A repeatable injection protocol was established allowing injection into cavities with well-defined geometries. The effective resolution of the SDi2 UV imaging system is 30-80 µm. The linear range of the imaging system is less than that of typical spectrophotometers. Consequently, non-linear cAMP calibration curves were applied for quantification at 280 nm. The degree of deviation from Beer's law was affected by the background absorbance of the gel matrix. MATLAB scripts provided hitherto missing flexibility with respect to definition and utilization of quantification zones, contour lines facilitating visualization, and automated, continuous data analysis. Various release patterns were observed for an aqueous solution and in situ forming Pluronic F127 hydrogel and PLGA implants containing cAMP as a model for STING ligands. The UV imaging and MATLAB data analysis setup constituted a significant technical development in terms of visualizing behavior for injectable formulations intended for intra-tumoral delivery, and, thereby, a step toward establishment of a bio-predictive in vitro release-testing method.

Data-Enriched Edible Pharmaceuticals (DEEP) with Bespoke Design, Dose and Drug Release.

Data-enriched edible pharmaceuticals (DEEP) is an approach to obtain personalized medicine, in terms of flexible and precise drug doses, while at the same time containing data, embedded in quick response (QR) codes at a single dosage unit level. The aim of this study was to fabricate DEEP with a patient-tailored dose, modify drug release and design to meet patients' preferences. It also aimed to investigate physical stability in terms of the readability of QR code patterns of DEEP during storage. Cannabinoids, namely, cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), were used as the model active pharmaceutical ingredients (APIs). Three different substrates and two colorants for the ink were tested for their suitability to fabricate DEEP by desktop inkjet printing. Flexible doses and customizable designs of DEEP were obtained by manipulating the digital design of the QR code, particularly, by exploring different pattern types, embedded images and the physical size of the QR code pattern. Modification of the release of both APIs from DEEP was achieved by applying a hydroxypropyl cellulose (HPC) polymer coating. The appearance and readability of uncoated and polymer-coated DEEP did not change on storage in cold and dry conditions; however, the HPC polymer layer was insufficient in preserving the readability of the QR code pattern in the extreme storage condition (40 °C and 75% relative humidity). To sum up, the DEEP concept provides opportunities for the personalization of medicines, considering also patients' preferences.

Measurement of hydrogen peroxide vapor in powders with potassium titanium oxide oxalate loaded cellulose pellets as probes.

An image-based method for determining H2O2 vapor pressures in powder systems was developed based on cellulose pellets loaded with potassium titanium oxide oxalate (PTO Pellets) as probe particles. Solid titanyl salts change color after exposure to hydrogen peroxide vapor and the quantitative response of PTO pellets to H2O2 has been established by comparing reactions with H2O2 in liquid and solid states. Analysis of pictures of the color changes of PTO Pellets mixed into powders can be used to monitor the presence of ppm levels of H2O2 vapor inside powder systems such as bleach containing dry detergent powders.•H2O2 vapor quantification in dry systems with titanyl loaded cellulose particles.•Simple fabrication of H2O2 probe particles.•High sensitivity with LOD 0.190 ppm H2O2 .

Data-enriched edible pharmaceuticals (DEEP) of medical cannabis by inkjet printing.

Medical cannabis has shown to be effective in various diseases that have not successfully been treated with other marketed drug products. However, the dose of cannabis is highly individual and additionally, medical cannabis is prone to misuse. To combat these challenges, the concept of data-enriched edible pharmaceuticals (DEEP) is introduced. Quick Response (QR) code patterns containing lipophilic cannabinoids, i.e., cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), were printed using a desktop inkjet printer. This allows for simultaneously printing an individual dose and encapsulating information relevant to the end-users and other stakeholders in a single dosage unit, which is readable by a standard smartphone. Different doses of CBD and THC were incorporated in the DEEP by printing various (1-10) layers of the cannabinoid-containing ink on porous substrates, i.e., solid foams, prepared by solvent casting and subsequent freeze-drying. The printed DEEP were still readable after 8 weeks of storage in dry and cold conditions. This approach of 'in-drug labeling' instead of 'drug package labeling' provides a new possibility for developing a more efficient supply chain of pharmaceuticals and safer medication schemes by increasing the traceability of drug products at a single dosage unit level.

Formulation of co-amorphous systems from naproxen and naproxen sodium and in situ monitoring of physicochemical state changes during dissolution testing by Raman spectroscopy.

Co-amorphous systems comprising low-molecular weight drugs and co-formers constitute an interesting approach to optimize pharmaceutical performance of drugs with low aqueous solubility. Within the different types of co-amorphous systems, the combination of a drug with its own salt may be an attractive formulation option due the absence of any inactive co-formers. The aim of this study was to investigate the possibility of forming a co-amorphous system from naproxen (NAP) and its sodium salt (NAP(Na)). Ball milling of NAP and NAP(Na) at equal molar ratio resulted in the formation of a co-amorphous system whilst NAP and NAP(Na) alone were crystalline following both, ball milling and melt quenching. Infrared spectroscopy and physical stability testing revealed that intermolecular interactions were able to maintain the ball milled NAP-NAP(Na) system amorphous for 2 months at 40 °C. Surprisingly, the dissolution rate of co-amorphous NAP-NAP(Na) was only intermediate between those of crystalline NAP and crystalline NAP(Na). In situ Raman spectroscopic measurements indicated an initial phase separation of the co-amorphous form to NAP and NAP(Na) followed by dissociation of sodium from NAP(Na) and crystallization to NAP. These findings contribute to the design of co-amorphous formulations with the combination of a drug and its own salt.

In silico design and 3D printing of microfluidic chips for the preparation of size-controllable siRNA nanocomplexes.

Small interfering RNA (siRNA) is regarded as one of the most powerful tools for the treatment of various diseases by downregulating the expression of aberrant proteins. Delivery vehicle is often necessary for getting siRNA into the cells. Nanocomplex using polyamidoamine (PAMAM) is regarded a promising approach for the delivery of siRNA. The size of siRNA nanocomplexes is a critical attribute in order to achieve high gene silencing efficiency in vivo. Microfluidics provides advantages in the preparation of siRNA nanocomplexes due to better reproducibility and a potential for more robust process control. The mixing efficiency of siRNA and PAMAM is different in microfluidics systems with different geometries, therefore, resulting in nanocomplexes with varying size attributes. In this study, hydrodynamic flow focusing microfluidic chips with different channel designs, i.e. diameters/widths, channel shapes (cylindrical/rectangular) and inter-channel spacings were optimized in silico and rapidly prototyped using 3D printing and finally, used for production of siRNA nanocomplexes. The fluid mixing inside the microfluidic chips was simulated using the finite element method (FEM) with the single-phase laminar flow interface in connection with the transport of diluted species interface. The digital design and optimization of microfluidic chips showed consistency with experimental results. It was concluded that the size of siRNA nanocomplexes can be controlled by adjusting the channel geometry of the microfluidic chips and the simulation with FEM could be used to facilitate the design and optimization of microfluidic chips in order to produce nanocomplexes with desirable attributes.

Exploring the Complexity of Processing-Induced Dehydration during Hot Melt Extrusion Using In-Line Raman Spectroscopy.

The specific aim in this study was to understand the effect of critical process parameters on the solid form composition of model drug compounds during hot melt extrusion using in-line Raman spectroscopy combined with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) modeling for semi-quantitative kinetic profiling. It was observed that the hydrate and anhydrate solid forms of two model drugs in the melts of nitrofurantoin (NF):polyethylene oxide (PEO) and piroxicam (PRX):PEO could be resolved from a MCR-ALS model without an external calibration dataset. Based on this model, the influence of two critical process parameters (shear and temperature) on the solid form composition could be evaluated in a real-time mode and the kinetics of complex transformation pathways could be explored. Additionally, the dehydration pathways of NF monohydrate and PRX monohydrate in molten PEO could be derived. It can be concluded that dehydration of both hydrates in PEO occurs via competing mechanisms-a solution-mediated transformation pathway and a solid-solid transformation, and that the balance between these mechanisms is determined by the combined effect of both temperature and shear. Another important observation was that the water released from these hydrate compounds has a detectable effect on the rheological characteristics of this mixture.

Medication Tracking: Design and Fabrication of a Dry Powder Inhaler with Integrated Acoustic Element by 3D Printing.

PURPOSE: Asthma is a prevalent lung disorder that cause heavy burdens globally. Inhalation medicaments can relieve symptoms, improve lung function and, thus, the quality of life. However, it is well-documented that patients often do not get the prescribed dose out of an inhaler and the deposition of drug is suboptimal, due to incorrect handling of the device and wrong inhalation technique. This study aims to design and fabricate an acoustic dry powder inhaler (ADPI) for monitoring inhalation flow and related drug administration in order to evaluate whether the patient receives the complete dose out of the inhaler. METHODS: The devices were fabricated using 3D printing and the impact of the acoustic element geometry and printing resolution on the acoustic signal was investigated. Commercial Foradil (formoterol fumarate) capsules were used to validate the availability of the ADPI for medication dose tracking. The acoustic signal was analysed with Partial-Least-Squares (PLS) regression. RESULTS: Indicate that specific acoustic signals could be generated at different air flow rates using a passive acoustic element with specific design features. This acoustic signal could be correlated with the PLS model to the air flow rate. A more distinct sound spectra could be acquired at higher printing resolution. The sound spectra from the ADPI with no capsule, a full capsule and an empty capsule are different which could be used for medication tracking. CONCLUSIONS: This study shows that it is possible to evaluate the medication quality of inhaled medicaments by monitoring the acoustic signal generated during the inhalation process.

Cryptopharmaceuticals: Increasing the Safety of Medication by a Blockchain of Pharmaceutical Products.

The future health-care system will contain an ever expanding number of digital elements. The data stored both at a centralized health-care level and at a local, patient level (e.g., on a smartphone) will be core elements when deciding treatment strategies in a health-care scenario with Internet of things-based elements. The current way of manufacturing pharmaceutical products and related existing logistic solutions is not ready for such a revolution. One of the key challenges is cybersecurity and related robust public key infrastructure solution. This work introduces one element of a potential solution at a prototype level: the concept of cryptopharmaceuticals where pharmaceutical products are connected in a patient-specific blockchain of individual dosage units. This technology is based on the concept where each produced dosage unit has a unique information-rich pattern. A proof-of-concept smartphone application was applied to demonstrate the visualization of this blockchain at different levels. This includes the manufacturing of the individualized dosage unit, the patient view for his/her personal blockchain, and integration of these products into a health Internet of things system. This unbreakable blockchain of personal medication history will provide means to avoid counterfeit products and to enable innovative logistic solutions.

Roadmap to 3D-Printed Oral Pharmaceutical Dosage Forms: Feedstock Filament Properties and Characterization for Fused Deposition Modeling.

Application of additive manufacturing techniques (3D printing) for mass-customized products has boomed in the recent years. In pharmaceutical industry and research, the interest has grown particularly with the future scenario of more personalized medicinal products. Understanding a broad range of material properties and process behavior of the drug-excipient combinations is necessary for successful 3D printing of dosage forms. This commentary reviews recent 3D-printing studies by fused deposition modeling (FDM) technique in pharmaceutical sciences, extending into the fields of polymer processing and rapid prototyping, where more in-depth studies on the feedstock material properties, modeling, and simulation of the FDM process have been performed. A case study of a model oral dosage form from custom-prepared indomethacin-polycaprolactone feedstock filament was used as an example in the pharmaceutical context. The printability was assessed in the different process steps: preparation of customized filaments for FDM, filament feeding, deposition, and solidification. These were linked with the rheological, thermal, and mechanical properties and their characterization, relevant for understanding the printability of drug products by FDM.

Transforming nanomedicine manufacturing toward Quality by Design and microfluidics.

Nanopharmaceuticals aim at translating the unique features of nano-scale materials into therapeutic products and consequently their development relies critically on the progression in manufacturing technology to allow scalable processes complying with process economy and quality assurance. The relatively high failure rate in translational nanopharmaceutical research and development, with respect to new products on the market, is at least partly due to immature bottom-up manufacturing development and resulting sub-optimal control of quality attributes in nanopharmaceuticals. Recently, quality-oriented manufacturing of pharmaceuticals has undergone an unprecedented change toward process and product development interaction. In this context, Quality by Design (QbD) aims to integrate product and process development resulting in an increased number of product applications to regulatory agencies and stronger proprietary defense strategies of process-based products. Although QbD can be applied to essentially any production approach, microfluidic production offers particular opportunities for QbD-based manufacturing of nanopharmaceuticals. Microfluidics provides unique design flexibility, process control and parameter predictability, and also offers ample opportunities for modular production setups, allowing process feedback for continuously operating production and process control. The present review aims at outlining emerging opportunities in the synergistic implementation of QbD strategies and microfluidic production in contemporary development and manufacturing of nanopharmaceuticals. In doing so, aspects of design and development, but also technology management, are reviewed, as is the strategic role of these tools for aligning nanopharmaceutical innovation, development, and advanced industrialization in the broader pharmaceutical field.

Characterisation of pore structures of pharmaceutical tablets: A review.

Traditionally, the development of a new solid dosage form is formulation-driven and less focus is put on the design of a specific microstructure for the drug delivery system. However, the compaction process particularly impacts the microstructure, or more precisely, the pore architecture in a pharmaceutical tablet. Besides the formulation, the pore structure is a major contributor to the overall performance of oral solid dosage forms as it directly affects the liquid uptake rate, which is the very first step of the dissolution process. In future, additive manufacturing is a potential game changer to design the inner structures and realise a tailor-made pore structure. In pharmaceutical development the pore structure is most commonly only described by the total porosity of the tablet matrix. Yet it is of great importance to consider other parameters to fully resolve the interplay between microstructure and dosage form performance. Specifically, tortuosity, connectivity, as well as pore shape, size and orientation all impact the flow paths and play an important role in describing the fluid flow in a pharmaceutical tablet. This review presents the key properties of the pore structures in solid dosage forms and it discusses how to measure these properties. In particular, the principles, advantages and limitations of helium pycnometry, mercury porosimetry, terahertz time-domain spectroscopy, nuclear magnetic resonance and X-ray computed microtomography are discussed.

Additive manufacturing of prototype elements with process interfaces for continuously operating manufacturing lines.

Rapid prototyping based on in silico design and 3D printing enables fast customization of complex geometries to multiple needs. This study utilizes, additive manufacturing for rapid prototyping of elements for continuously operating mixing geometries including interfaces with process analytical technology (PAT) tools, to show that 3D printing can be used for prototyping of both parts of production line and PAT interfacing solution. An additional setup was designed for measuring the dynamic calibration samples for a semi-quantitative near infrared (NIR) spectroscopic model. The powder was filled in a small calibration chamber and in-line NIR spectra of calibration samples were collected from moving material while mimicking the powder flow dynamics in a typical continuous mixer. This dynamic powder mixing system was compared with a static powder calibration model where the NIR probe was placed at different positions on a static sample. Principal component analysis (PCA) revealed that the 3D printed device with dynamic measurement of the NIR spectra had more potential for quantitative analysis. With the prototype continuous mixer, two differently placed process interfaces for NIR spectroscopic monitoring of the powder mixing were evaluated. With this approach, the importance of positioning the process analytical tools to assess the blend uniformity could be demonstrated. It was also observed that with the longer mixing geometry, a better mixing result was achieved due to a larger hold up volume and increased residence time.

Analysis of 3D Prints by X-ray Computed Microtomography and Terahertz Pulsed Imaging.

PURPOSE: A 3D printer was used to realise compartmental dosage forms containing multiple active pharmaceutical ingredient (API) formulations. This work demonstrates the microstructural characterisation of 3D printed solid dosage forms using X-ray computed microtomography (XµCT) and terahertz pulsed imaging (TPI). METHODS: Printing was performed with either polyvinyl alcohol (PVA) or polylactic acid (PLA). The structures were examined by XµCT and TPI. Liquid self-nanoemulsifying drug delivery system (SNEDDS) formulations containing saquinavir and halofantrine were incorporated into the 3D printed compartmentalised structures and in vitro drug release determined. RESULTS: A clear difference in terms of pore structure between PVA and PLA prints was observed by extracting the porosity (5.5% for PVA and 0.2% for PLA prints), pore length and pore volume from the XµCT data. The print resolution and accuracy was characterised by XµCT and TPI on the basis of the computer-aided design (CAD) models of the dosage form (compartmentalised PVA structures were 7.5 ± 0.75% larger than designed; n = 3). CONCLUSIONS: The 3D printer can reproduce specific structures very accurately, whereas the 3D prints can deviate from the designed model. The microstructural information extracted by XµCT and TPI will assist to gain a better understanding about the performance of 3D printed dosage forms.

Near-infrared chemical imaging (NIR-CI) of 3D printed pharmaceuticals.

Hot-melt extrusion and 3D printing are enabling manufacturing approaches for patient-centred medicinal products. Hot-melt extrusion is a flexible and continuously operating technique which is a crucial part of a typical processing cycle of printed medicines. In this work we use hot-melt extrusion for manufacturing of medicinal films containing indomethacin (IND) and polycaprolactone (PCL), extruded strands with nitrofurantoin monohydrate (NFMH) and poly (ethylene oxide) (PEO), and feedstocks for 3D printed dosage forms with nitrofurantoin anhydrate (NFAH), hydroxyapatite (HA) and poly (lactic acid) (PLA). These feedstocks were printed into a prototype solid dosage form using a desktop 3D printer. These model formulations were characterized using near-infrared chemical imaging (NIR-CI) and, more specifically, the image analytical data were analysed using multivariate curve resolution-alternating least squares (MCR-ALS). The MCR-ALS algorithm predicted the spatial distribution of IND and PCL in the films with reasonable accuracy. In the extruded strands both the chemical mapping of the components in the formulation as well as the solid form of the active compound could be visualized. Based on the image information the total nitrofurantoin and PEO contents could be estimated., The dehydration of NFMH to NFAH, a process-induced solid form change, could be visualized as well. It was observed that the level of dehydration increased with increasing processing time (recirculation during the mixing phase of molten PEO and nitrofurantoin). Similar results were achieved in the 3D printed solid dosage forms produced from the extruded feedstocks. The results presented in this work clearly demonstrate that NIR-CI in combination with MCR-ALS can be used for chemical mapping of both active compound and excipients, as well as for visualization of solid form variation in the final product. The suggested NIR-CI approach is a promising process control tool for characterization of innovative patient-centred medicinal products.

Physical Stability of Freeze-Dried Isomalt Diastereomer Mixtures.

PURPOSE: Isomalt is a sugar alcohol used as an excipient in commercially available solid oral dosage forms. The potential of isomalt as a novel freeze-drying excipient was studied in order to increase knowledge of the behavior of isomalt when it is freeze-dried. METHODS: Isomalt was freeze-dried in four different diastereomer compositions and its physical stability was investigated with differential scanning calorimetry, Fourier-transform infrared and Raman spectroscopy, X-ray powder diffraction, Karl-Fischer titration and thermogravimetric analysis in order to verify the solid state form of isomalt after freeze-drying and observe any changes occurring during storage in three different relative humidity conditions. RESULTS: Isomalt was successfully transformed into the amorphous form with freeze-drying and three diastereomer combinations remained stable as amorphous during storage; one of the diastereomer compositions showed signs of physical instability when stored in the highest relative humidity condition. The four different crystalline diastereomer mixtures showed specific identifiable solid state properties. CONCLUSIONS: Isomalt was shown to be a suitable excipient for freeze-drying. Preferably a mixture of the diastereomers should be used, as the mixture containing only one of the isomers showed physical instability. A mixture containing a 1:1 ratio of the two diastereomers showed the best physical stability in the amorphous form.

Oscillatory Shear Rheology in Examining the Drug-Polymer Interactions Relevant in Hot Melt Extrusion.

The flow properties of drug-polymer mixtures have a significant influence on their processability when using techniques such as hot melt extrusion (HME). Suitable extrusion temperature and screw speed to be used in laboratory scale HME were evaluated for mixtures containing 30% of paracetamol (PRC), ibuprofen (IBU), or indomethacin (IND), and 70% of polyethylene oxide, by using small amplitude oscillatory shear rheology. The initial evaluation of the drug:polyethylene oxide solubility was estimated by differential scanning calorimetry of the physical mixtures containing a wide range of weight fractions of the drug substances. Consecutively, the mixtures were extruded, and the maximum plasticizing weight fraction of each drug was determined by means of rheological measurements. IBU was found to have an efficient plasticizing functionality, decreasing the viscosity of the mixtures even above its apparent saturation solubility, whereas IND and PRC initially lowered the viscosity of the mixture slightly but increased it significantly with increasing drug load. The main reason for the enhanced plasticization effect seems to be the lower melting temperature of IBU, which is closer to the used HME temperature, compared to PRC and IND. This study highlights the importance of rheological investigation in understanding the drug-polymer interactions in melt processing.