Exploring the effect of raw material properties on continuous twin-screw wet granulation manufacturability.

Twin-screw wet granulation (TSWG) stands out as a promising continuous alternative to conventional batch fluid bed- and high shear wet granulation techniques. Despite its potential, the impact of raw material properties on TSWG processability remains inadequately explored. Furthermore, the absence of supportive models for TSWG process development with new active pharmaceutical ingredients (APIs) adds to the challenge. This study tackles these gaps by introducing four partial least squares (PLS) models that approximate both the applicable liquid-to-solid (L/S) ratio range and resulting granule attributes (i.e., granule size and friability) based on initial material properties. The first two PLS models link the lowest and highest applicable L/S ratio for TSWG, respectively, with the formulation blend properties. The third and fourth PLS models predict the granule size and friability, respectively, from the starting API properties and applied L/S ratio for twin-screw wet granulation. By analysing the developed PLS models, water-related material properties (e.g., solubility, wettability, dissolution rate), as well as density and flow-related properties (e.g., flow function coefficient), were found to be impacting the TSWG processability. In addition, the applicability of the developed PLS models was evaluated by using them to propose suitable L/S ratio ranges (i.e., resulting in granules with the desired properties) for three new APIs and related formulations followed by an experimental validation thereof. Overall, this study helped to better understand the effect of raw material properties upon TSWG processability. Moreover, the developed PLS models can be used to propose suitable TSWG process settings for new APIs and hence reduce the experimental effort during process development.

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.

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.

Melt Extrusion of High-Dose Co-Amorphous Drug-Drug Combinations : Theme: Formulation and Manufacturing of Solid Dosage Forms Guest Editors: Tony Zhou and Tonglei Li.

PURPOSE: Many future drug products will be based on innovative manufacturing solutions, which will increase the need for a thorough understanding of the interplay between drug material properties and processability. In this study, hot melt extrusion of a drug-drug mixture with minimal amount of polymeric excipient was investigated. METHODS: Using indomethacin-cimetidine as a model drug-drug system, processability of physical mixtures with and without 5% (w/w) of polyethylene oxide (PEO) were studied using Differential Scanning Calorimetry (DSC) and Small Amplitude Oscillatory Shear (SAOS) rheometry. Extrudates containing a co-amorphous glass solution were produced and the solid-state composition of these was studied with DSC. RESULTS: Rheological analysis indicated that the studied systems display viscosities higher than expected for small molecule melts and addition of PEO decreased the viscosity of the melt. Extrudates of indomethacin-cimetidine alone displayed amorphous-amorphous phase separation after 4 weeks of storage, whereas no phase separation was observed during the 16 week storage of the indomethacin-cimetidine extrudates containing 5% (w/w) PEO. CONCLUSIONS: Melt extrusion of co-amorphous extrudates with low amounts of polymer was found to be a feasible manufacturing technique. Addition of 5% (w/w) polymer reduced melt viscosity and prevented phase separation.

Potential of surface-eroding poly(ethylene carbonate) for drug delivery to macrophages.

Films composed of poly(ethylene carbonate) (PEC), a biodegradable polymer, were compared with poly(lactide-co-glycolide) (PLGA) films loaded with and without the tuberculosis drug rifampicin to study the characteristics and performance of PEC as a potential carrier for controlled drug delivery to macrophages. All drug-loaded PLGA and PEC films were amorphous indicating good miscibility of the drug in the polymers, even at high drug loading (up to 50wt.%). Polymer degradation studies showed that PLGA degraded slowly via bulk erosion while PEC degraded more rapidly and near-linearly via enzyme mediated surface erosion (by cholesterol esterase). Drug release studies performed with polymer films indicated a diffusion/erosion dependent delivery behavior for PLGA while an almost zero-order drug release profile was observed from PEC due to the controlled polymer degradation process. When exposed to polymer degradation products the murine macrophage cell line J774A.1 showed less susceptibility to PEC than to PLGA. However, when seeding the macrophages on PLGA and PEC films no relevant difference in cell proliferation/growth kinetics was observed. Overall, this study emphasizes that PEC is an attractive polymer for controlled drug release and could provide superior performance to PLGA for some drug delivery applications including the treatment of macrophage infections.

Modifying release characteristics from 3D printed drug-eluting products.

This work describes an approach to modify the release of active compound from a 3D printed model drug product geometry intended for flexible dosing and precision medication. The production of novel polylactic acid and hydroxypropyl methylcellulose based feed materials containing nitrofurantoin for 3D printing purposes is demonstrated. Nitrofurantoin, Metolose® and polylactic acid were successfully co-extruded with up to 40% Metolose® content, and subsequently 3D printed into model disk geometries (ø10mm, h=2mm). Thermal analysis with differential scanning calorimetry and solid phase identification with Raman spectroscopy showed that nitrofurantoin remained in its original solid form during both hot-melt extrusion and subsequent 3D printing. Rheological measurements of the different compositions showed that the flow properties were sensitive to the amount of undissolved particles present in the formulation. Release of nitrofurantoin from the disks was dependent on Metolose® loading, with higher accumulated release observed for higher Metolose® loads. This work shows the potential of custom-made, drug loaded feed materials for 3D printing of precision drug products with tailored drug release characteristics.

Anhydrate to hydrate solid-state transformations of carbamazepine and nitrofurantoin in biorelevant media studied in situ using time-resolved synchrotron X-ray diffraction.

Transformation of the solid-state form of a drug compound in the lumen of the gastrointestinal tract may alter the drug bioavailability and in extreme cases result in patient fatalities. The solution-mediated anhydrate-to-hydrate phase transformation was examined using an in vitro model with different biorelevant media, simulated fasted and fed state intestinal fluids containing bile salt and dioleoylphosphatidylcholine (DOPC) micelles, DOPC/sodium dodecyl sulfate (SDS) mixture, bile salt solution and water. Two anhydrate compounds (carbamazepine, CBZ and nitrofurantoin, NF) with different overall transformation time into hydrate form were used as model compounds. The transformations were monitored using direct structural information from time-resolved synchrotron X-ray diffraction. The kinetics of these transformations were estimated using multivariate data analysis (principal component analysis, PCA) and compared to those for nitrofurantoin (NF). The study showed that the solution-mediated phase transformation of CBZ anhydrate was remarkably faster in the DOPC/SDS medium compared to transformation in all the other aqueous dispersion media. The conversion time for CBZ anhydrate in water was shorter than for DOPC/SDS but still faster than the conversion seen in fed and fasted state micellar media. The conversion of CBZ anhydrate to hydrate was the slowest in the solution containing bile salt alone. In contrast, the solution-mediated phase transformations of NF did only show limited kinetic dependence on the dispersion media used, indicating the complexity of the nucleation process. Furthermore, when the CBZ and NF material was compacted into tablets the transformation times were remarkably slower. Results suggest that variations in the composition of the contents of the stomach/gut may affect the recrystallization kinetics, especially when investigating compounds with relatively fast overall transformation time, such as CBZ.

Design and processing of nanogels as delivery systems for peptides and proteins.

Nanogels, cross-linked networks of >1 µm in size, are attractive drug-delivery systems, as they not only possess the potential advantages of nanoscale formulations, but also the attractive abilities of a hydrogel; high hydrophilicity, high loading capacity and the potential for biocompatibility and controlled release. The focus of this review is to provide an overview of the recent developments within the nanogel field, and how the chemical design of the nanogel polymer has been found to influence the properties of the nanogel system. Novel nanogel systems are discussed with respect to their type of cross-linkage and their suitability as therapeutic delivery systems, as well as their ability to stabilize the protein/peptide drug.