Nitrogen plasma modification boosts up the hemocompatibility of new PVDF-carbon nanohorns composite materials with potential cardiological and circulatory system implants application.

To design new material for blood-related applications one needs to consider various factors such as cytotoxicity, platelet adhesion, or anti-thrombogenic properties. The aim of this work is the design of new, highly effective materials possessing high blood compatibility. To do this, the new composites based on the poly(vinylidene fluoride) (PVDF) support covered with a single-walled carbon nanohorns (CNHs) layer were prepared. The PVDF-CNHs composites were subsequently used for the first time in the hemocompatibility studies. To raise the hemocompatibility a new, never applied before for CNHs, plasma-surface modifications in air, nitrogen and ammonia were implemented. This relatively cheap, facile and easy method allows generating the new hybrid materials with high effectiveness and significant differences in surface properties (water contact angle, surface ζ-potential, and surface functional groups composition). Changing those properties made it possible to select the most promising samples for blood-related applications. This was done in a fully controlled way by applying Taguchi's "orthogonal array" procedure. It is shown for the first time that nitrogen plasma treatment of new surfaces is the best tool for hemocompatibility rise and leads to very low blood platelet adhesion, no cytotoxicity, and excellent performance in thromboelastometry and hemolysis tests. We propose a possible mechanism explaining this behavior. The optimisation results are coherent with biological characterisation and are supported with Hansen Solubility Parameters. New surfaces can find potential applications in cardiological and circulatory system implants as well as other blood-related biomaterials.

Five-Stage Approach for a Systematic Screening and Development of Etravirine Amorphous Solid Dispersions by Hot-Melt Extrusion.

The aim of this study was to develop a fast, effective, and material sparing screening method to design amorphous solid dispersions (ASDs) of etravirine to drive more effectively the development process, leading to improved bioavailability (BA) and stability. A systematic step-by-step approach was followed by combining theoretical calculations with high-throughput screening (HTS) and software-assisted multivariate statistical analysis. The thermodynamic miscibility and interaction of the drug in several polymers were predicted using Hansen solubility parameters (δ). The selected polymers were evaluated by HTS, using solvent evaporation. Binary compositions were evaluated by their solubilization capacity and physical stability over 2 months. JMP 14.0 was used for multivariate statistical analysis using principal components analysis. Extrusion was performed in Thermo Scientific HAAKE MiniLab II, and extrudates were characterized by assay, related substances, dissolution, and physical state (polarized light microscopy (PLM), Raman spectroscopy, and X-ray powder diffraction (XRPD)). A short stability study was performed where milled extrudates were exposed to 25 °C/60%RH and 40 °C/75%RH for 3 months. Through thermodynamic predictions, five main polymers were selected. The HTS enabled the evaluation of 42 formulations for solubilization capacity and physical stability. The three most promising compositions were selected for hot-melt extrusion (HME) tests. In general, a good correlation was found among the results of theoretical predictions, HTS, and HME. Poly(vinylpyrrolidone) (PVP)-based formulations were shown to be easily extrudable, with low degradation and complete amorphicity, whereas in Soluplus, the drug was not miscible, leading to a high crystalline content. The drug release rate was improved more than two times with PVP, and the manufactured ASD was demonstrated to be stable physically and chemically. A fast and effective screening technique to develop stable ASDs for a poorly soluble drug was successfully developed as applied to etravirine. The given method is easy to use, requires a low amount of drug, and is fairly accurate in predicting the amorphization of the drug when formulated. The success of HME formulation development of etravirine was undoubtedly enhanced with this high-throughput tool, which led to the identification of extrudates with improved biopharmaceutical properties. The structural characterization performed by PLM, XRPD, and Raman spectroscopy demonstrated that the HME prototype was essentially amorphous. The unexpected stability at 40 °C/75%RH was correlated with the presence of molecular interaction characterized by Raman spectroscopy.

Engineering of pharmaceutical cocrystals in an excipient matrix: Spray drying versus hot melt extrusion.

The comparison of spray drying versus hot melt extrusion (HME) in order to formulate amorphous solid dispersions has been widely studied. However, to the best of our knowledge, the use of both techniques to form cocrystals within a carrier excipient has not previously been compared. The combination of ibuprofen (IBU) and isonicotinamide (INA) in a 1:1 M ratio was used as a model cocrystal. A range of pharmaceutical excipients was selected for processing - mannitol, xylitol, Soluplus and PVP K15. The ratio of cocrystal components to excipient was altered to assess the ratios at which cocrystal formation occurs during spray drying and HME. Hansen Solubility Parameter (HSP) and the difference in HSP between the cocrystal and excipient (ΔHSP) was employed as a tool to predict cocrystal formation. During spray drying, when the difference in HSP between the cocrystal and the excipient was large, as in the case of mannitol (ΔHSP of 18.3 MPa0.5), a large amount of excipient (up to 50%) could be incorporated without altering the integrity of the cocrystal, whereas for Soluplus and PVP K15, where the ΔHSP was 2.1 and 1.6 MPa0.5 respectively, the IBU:INA cocrystal alone was only formed at a very low weight ratio of excipient, i.e. cocrystal:excipient 90:10. Remarkably different results were obtained in HME. In the case of Soluplus and PVP K15, a mixture of cocrystal with single components (IBU and INA) was obtained even when only 10% excipient was included. In conclusion, in order to reduce the number of unit operations required to produce a final pharmaceutical product, spray drying showed higher feasibility over HME to produce cocrystals within a carrier excipient.

Continuous production of itraconazole-based solid dispersions by hot melt extrusion: Preformulation, optimization and design space determination.

The purpose of this work was to increase the solubility and the dissolution rate of itraconazole, which was chosen as the model drug, by obtaining an amorphous solid dispersion by hot melt extrusion. Therefore, an initial preformulation study was conducted using differential scanning calorimetry, thermogravimetric analysis and Hansen's solubility parameters in order to find polymers which would have the ability to form amorphous solid dispersions with itraconazole. Afterwards, the four polymers namely Kollidon® VA64, Kollidon® 12PF, Affinisol® HPMC and Soluplus®, that met the set criteria were used in hot melt extrusion along with 25wt.% of itraconazole. Differential scanning confirmed that all four polymers were able to amorphize itraconazole. A stability study was then conducted in order to see which polymer would keep itraconazole amorphous as long as possible. Soluplus® was chosen and, the formulation was fine-tuned by adding some excipients (AcDiSol®, sodium bicarbonate and poloxamer) during the hot melt extrusion process in order to increase the release rate of itraconazole. In parallel, the range limits of the hot melt extrusion process parameters were determined. A design of experiment was performed within the previously defined ranges in order to optimize simultaneously the formulation and the process parameters. The optimal formulation was the one containing 2.5wt.% of AcDiSol® produced at 155°C and 100rpm. When tested with a biphasic dissolution test, more than 80% of itraconazole was released in the organic phase after 8h. Moreover, this formulation showed the desired thermoformability value. From these results, the design space around the optimum was determined. It corresponds to the limits within which the process would give the optimized product. It was observed that a temperature between 155 and 170°C allowed a high flexibility on the screw speed, from about 75 to 130rpm.

Poly(N-vinylimidazole/ethylene glycol dimethacrylate) for the purification and isolation of phenolic acids.

In this study we report the novel polymeric resin poly(N-vinyl imidazole/ethylene glycol dimethacrylate) for the purification and isolation of phenolic acids. The monomer to crosslinker ratio and the porogen composition were optimized for isolating phenolic acids diluted in acetonitrile at normal phase chromatography conditions, first. Acetonitrile serves as polar, aprotic solvent, dissolving phenolic acids but not interrupting interactions with the stationary phase due to the approved Hansen solubility parameters. The optimized resin demonstrated high loading capacities and adsorption abilities particularly for phenolic acids in both, acetonitrile and aqueous solutions. The adsorption behavior of aqueous standards can be attributed to ion exchange effects due to electrostatic interactions between protonated imidazole residues and deprotonated phenolic acids. Furthermore, adsorption experiments and subsequent curve fittings provide information of maximum loading capacities of single standards according to the Langmuir adsorption model. Recovery studies of the optimized polymer in the normal-phase and ion-exchange mode illustrate the powerful isolation properties for phenolic acids and are comparable or even better than typical, commercially available solid phase extraction materials. In order to prove the applicability, a highly complex extract of rosemary leaves was purified by poly(N-vinyl imidazole/ethylene glycol dimethacrylate) and the isolated compounds were identified using UHPLC-qTOF-MS.

The influence of drug physical state on the dissolution enhancement of solid dispersions prepared via hot-melt extrusion: a case study using olanzapine.

In this study, we examine the relationship between the physical structure and dissolution behavior of olanzapine (OLZ) prepared via hot-melt extrusion in three polymers [polyvinylpyrrolidone (PVP) K30, polyvinylpyrrolidone-co-vinyl acetate (PVPVA) 6:4, and Soluplus® (SLP)]. In particular, we examine whether full amorphicity is necessary to achieve a favorable dissolution profile. Drug­polymer miscibility was estimated using melting point depression and Hansen solubility parameters. Solid dispersions were characterized using differential scanning calorimetry, X-ray powder diffraction, and scanning electron microscopy. All the polymers were found to be miscible with OLZ in a decreasing order of PVP>PVPVA>SLP. At a lower extrusion temperature (160°C), PVP generated fully amorphous dispersions with OLZ, whereas the formulations with PVPVA and SLP contained 14%-16% crystalline OLZ. Increasing the extrusion temperature to 180°C allowed the preparation of fully amorphous systems with PVPVA and SLP. Despite these differences, the dissolution rates of these preparations were comparable, with PVP showing a lower release rate despite being fully amorphous. These findings suggested that, at least in the particular case of OLZ, the absence of crystalline material may not be critical to the dissolution performance. We suggest alternative key factors determining dissolution, particularly the dissolution behavior of the polymers themselves.

Preparation of carbamazepine-Soluplus solid dispersions by hot-melt extrusion, and prediction of drug-polymer miscibility by thermodynamic model fitting.

Hot-melt extrusion (HME) is a dust- and solvent-free continuous process enabling the preparation of a variety of solid dosage forms containing solid dispersions of poorly soluble drugs into thermoplastic polymers. Miscibility of drug and polymer is a prerequisite for stable solid dispersion formation. The present study investigates the feasibility of forming solid dispersions of carbamazepine (CBZ) into polyethyleneglycol-polyvinyl caprolactam-polyvinyl acetate grafted copolymer (Soluplus) by hot-melt extrusion. Physicochemical properties of the raw materials, extrudates, co-melted products, and corresponding physical mixtures were characterized by thermo-gravimetric analysis (TGA), differential scanning calorimetry (DSC), attenuated total reflectance infrared (ATR-FTIR) spectroscopy and hot stage microscopy (HSM), while miscibility of CBZ and Soluplus was estimated on the basis of the Flory-Huggins theory, Hansen solubility parameters, and solid-liquid equilibrium equation. It was found that hot-melt extrusion of carbamazepine and Soluplus is feasible on a single-screw hot-melt extruder without the addition of plasticizers. DSC analysis and FTIR spectroscopy revealed that a molecular dispersion is formed when the content of CBZ does not exceed ∼5% w/w while higher CBZ content results in a microcrystalline dispersion of CBZ form III crystals, with the molecularly dispersed percentage increasing with extrusion temperature, at the risk of inducing transformation to the undesirable form I of CBZ. Thermodynamic modeling elucidated potential limitations and temperature dependence of solubility/dispersibility of carbamazepine in Soluplus hot-melt extrudates. The results obtained by thermodynamic models are in agreement with the findings of the HME processing, encouraging therefore their further application in the HME process development.