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Inulin has been applied in Inulin-Eudragit RS (Inu-ERS) coatings as the component responsible for degradation by human microbiota. However, studies on how bacterial enzymes can degrade polysaccharides like inulin imbedded in water insoluble polymers like Eudragit RS are still elusive. The present work aims at elucidating the complex process of enzyme triggered biodegradation of inulin with various molecular weights in isolated films with Eudragit RS. The ratio of inulin to Eudragit RS was varied to create films with different degree of hydrophilicity. The phase behavior study revealed that blends of inulin and Eudragit RS are phase separated systems. The film permeability was studied by determination of the permeability coefficient of caffeine and the fraction of inulin that was released from the films in a buffer solution with or without inulinase was quantified. Together with the morphology characterization of the Inu-ERS films with and without incubation in the enzyme solution, these results suggest that the action of the enzyme was only limited to the fraction of inulin released in the buffer solution. Inulin fully embedded in the Eudragit RS matrix was not degraded. The permeation of the model drug caffeine occurred in the phase-separated film as a result of pores formed as a consequence of inulin release. The inulin to Eudragit RS blend ratio and the molecular weight of inulin affected the percolation threshold, the release of inulin, the morphology of the film formed thereafter and the connectivity of the formed water channels, thus influencing the drug permeation properties.

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Spray drying is one of the most commonly used manufacturing techniques for amorphous solid dispersions (ASDs). During spray drying, very fast solvent evaporation is enabled by the generation of small droplets and exposure of these droplets to a heated drying gas. This fast solvent evaporation leads to an increased viscosity that enables kinetic trapping of an active pharmaceutical ingredient (API) in a polymer matrix, which is favorable for the formulation of supersaturated, kinetically stabilized ASDs. In this work, the relation between the solvent evaporation rate and the kinetic stabilization of highly drug-loaded ASDs was investigated. Accordingly, thermal gravimetric analysis (TGA) was employed to study the evaporation kinetics of seven organic solvents and the influence of solutes, i.e., poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), fenofibrate (FNB), and naproxen (NAP), on the evaporation behavior. At 10 °C below the boiling point of the respective solvent, methanol (MeOH) had the lowest evaporation rate and dichloromethane (DCM) had the highest. PVPVA decreased the evaporation rate for all solvents, yet this effect was more pronounced for the relatively faster evaporating solvents. The APIs had opposite effects on the evaporation process: FNB increased the evaporation rate, while NAP decreased it. The latter might indicate the presence of interactions between NAP and the solvent or NAP and PVPVA, which was further investigated using Fourier transform-InfraRed (FT-IR) spectroscopy. Based on these findings, spray drying process parameters were adapted to alter the evaporation rate. Increasing the evaporation rate of MeOH and DCM enabled the kinetic stabilization of higher drug loadings of FNB, while the opposite trend was observed for ASDs of NAP. Even when higher drug loadings could be kinetically stabilized by adapting the process parameters, the improvement was limited, demonstrating that the phase behavior of these ASDs of FNB and NAP immediately after preparation was predominantly determined by the API-polymer-solvent combination rather than the process parameters applied.

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In spite of the fact that spray drying is widely applied for the formulation of amorphous solid dispersions (ASDs), the influence of the solvent on the physical properties of the ASDs is still not completely understood. Therefore, the impact of organic solvents on the kinetic stabilization of drug components in a polymer matrix prepared by either film casting or spray drying was investigated. One polymer, PVPVA 64, together with one of four poorly water soluble drugs, naproxen, indomethacin, fenofibrate or diazepam, were film casted and spray dried using either methanol, ethanol, isopropanol, acetonitrile, acetone, dichloromethane or ethyl acetate. For every combination, the highest drug loading that could be formulated as a single amorphous phase was established. The solvent determined the maximum amount of drug that could be kinetically trapped in the polymer matrix and thereby the extent of kinetic stabilization. These maximum drug loadings were compared to the thermodynamic solubilities of the drugs in the seven solvents. Generally, there was no relation between the thermodynamic solubility of a drug and its highest drug loading attained using the same solvent. Hence, the contribution of the solvent to the generation of a supersaturated state should not be underestimated.

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Spray drying and electrospraying are well-established drying processes that already have proven their value in the pharmaceutical field. However, there is currently still a lack of knowledge on the fundamentals of the particle formation process, thereby hampering fast and cost-effective particle engineering. To get a better understanding of how functional particles are formed with respect to process and formulation parameters, it is indispensable to offer a comprehensive overview of critical aspects of the droplet drying and particle formation process. This review therefore closely relates single droplet drying to pharmaceutical applications. Although excellent reviews exist of the different aspects, there is, to the best of our knowledge, no single review that describes all steps that one should consider when trying to engineer a certain type of particle morphology. The findings presented in this article have strengthened the predictive value of single droplet drying for pharmaceutical drying applications like spray drying and electrospraying. Continuous follow-up of the particle formation process in single droplet drying experiments hence allows optimization of manufacturing processes and particle engineering approaches and acceleration of process development.

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Amorphous solid dispersions (ASDs) are single-phase amorphous systems, where drug molecules are molecularly dispersed (dissolved) in a polymer matrix. The molecular dispersion of the drug molecules is responsible for their improved dissolution properties. Unambiguously establishing the phase behavior of the ASDs is of utmost importance. In this paper, we focused on the complementary nature of (modulated) differential scanning calorimetry ((m)DSC) and X-ray powder diffraction (XRPD) to elucidate the phase behavior of ASDs as demonstrated by a critical discussion of practical real-life examples observed in our research group. The ASDs were manufactured by either applying a solvent-based technique (spray drying), a heat-based technique (hot melt extrusion) or mechanochemical activation (cryo-milling). The encountered limiting factors of XRPD were the lack of sensitivity for small traces of crystallinity, the impossibility to differentiate between distinct amorphous phases and its impossibility to detect nanocrystals in a polymer matrix. In addition, the limiting factors of (m)DSC were defined as the well-described heat-induced sample alteration upon heating, the interfering of residual solvent evaporation with other thermal events and the coinciding of enthalpy recovery with melting events. In all of these cases, the application of a single analytical technique would have led to erroneous conclusions, whilst the combination of (m)DSC and XRPD elucidated the true phases of the ASD.

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In spite of the large research efforts in the past two decades, it is still difficult, if possible at all, to predict what manufacturing technology will lead to the best amorphous solid dispersions (ASDs) in terms of drug to polymer ratio ("drug loading") and physical stability. In general, ASDs can be prepared by solvent based methods, heat based methods and mechanochemical activation. In the current study, one manufacturing technique per category was selected: spray drying, hot melt extrusion and cryo-milling, respectively. These processes were compared for their capability to formulate high drug loaded ASDs. High drug loadings may allow decreasing the pill burden and/or reducing dosage size, which both increase the therapeutic compliance. A fast crystallizer, naproxen, in combination with PVP K25, PVP-VA64, HPMC and HPMC-AS was used as a model system. Clear differences in the physical structure of the ASDs were observed. Our data indicate that not only the drug loading is dependent on the manufacturing process, but also the carrier that is able to incorporate the highest drug loading. This suggests that a carrier should be selected not only as function of the API, but also as function of the manufacturing process. Overall, hot melt extrusion showed to be most suited to reach high drug loadings for these naproxen-polymer combinations. This was in agreement with our finding that heat is an important energy input for mixing.

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