Joanna Szafraniec

3D printed orodispersible films with Aripiprazole

Three dimensional printing technology is gaining in importance because of its increasing availability and wide applications. One of the three dimensional printing techniques is Fused Deposition Modelling (FDM) which works on the basis of hot melt extrusion-well known in the pharmaceutical technology. Combination of fused deposition modelling with preparation of the orodispersible film with poorly water soluble substance such as aripiprazole seems to be extra advantageous in terms of dissolution rate. 3D printed as well as casted films were compared in terms of physicochemical and mechanical properties. Moreover, drug-free films were prepared to evaluate the impact of the extrusion process and aripiprazole presence on the film properties. X-ray diffractometry and thermal analyses confirmed transition of aripiprazole into amorphous state during film preparation using 3D printing technique. Amorphization of the aripiprazole and porous structure of printed film led to increased dissolution rate in comparison to casted films, which, however have slightly better mechanical properties due to their continuous structure. It can be concluded that fused deposition modelling is suitable technique and polyvinyl alcohol is applicable polymer for orodispersible films preparation.

Molecular Dynamics, Recrystallization Behavior, and Water Solubility of the Amorphous Anticancer Agent Bicalutamide and Its Polyvinylpyrrolidone Mixtures

In this paper, we investigated the molecular mobility and physical stability of amorphous bicalutamide, a poorly water-soluble drug widely used in prostate cancer treatment. Our broadband dielectric spectroscopy measurements and differential scanning calorimetry studies revealed that amorphous BIC is a moderately fragile material with a strong tendency to recrystallize from the amorphous state. However, mixing the drug with polymer polyvinylpyrrolidone results in a substantial improvement of physical stability attributed to the antiplasticizing effect governed by the polymer additive. Furthermore, IR study demonstrated the existence of specific interactions between the drug and excipient. We found out that preparation of bicalutamide-polyvinylpyrrolidone mixture in a 2-1 weight ratio completely hinder material recrystallization. Moreover, we determined the time-scale of structural relaxation in the glassy state for investigated materials. Because molecular mobility is considered an important factor governing crystallization behavior, such information was used to approximate the long-term physical stability of an amorphous drug and drug-polymer systems upon their storage at room temperature. Moreover, we found that such systems have distinctly higher water solubility and dissolution rate in comparison to the pure amorphous form, indicating the genuine formulation potential of the proposed approach.

Enhanced dissolution of solid dispersions containing bicalutamide subjected to mechanical stress

&NA; The anticancer drug bicalutamide was co‐milled with either Macrogol 6000 or Poloxamer 407, and the physicochemical parameters that drive the phase transition of binary systems and influence the dissolution modification of bicalutamide were studied. Milled binary systems with reduced particle size were assessed by scanning electron microscopy and laser diffraction measurements. The results of thermal analysis supported by X‐ray diffractometry confirmed the reduction of the crystallinity of bicalutamide co‐milled with Macrogol 6000. Infrared spectroscopy was used to determine the molecular structure of the samples and indicated weak interactions between drug and polymer molecules. Two mechanisms were identified and were involved in up to 11‐fold enhanced dissolution. The first one was based on improved wettability due to a decreased contact angle in samples containing Macrogol 6000. The second one relied on the solubilization of bicalutamide within nanoaggregates formed by Poloxamer 407 that resulted from its surface activity. This finding was confirmed with fluorescence spectroscopy, dynamic light scattering and cryogenic transmission electron microscopy assays. Given the dissolution rate‐limited absorption combined with the reduced bioavailability of bicalutamide as a BCS class II drug, the assessment of the mechanisms driving the increase in drug dissolution is of particular importance in drug development.

Polymeric nanocapsules templated on liquid cores as efficient photoreactors

Polymeric nanocapsules templated on liquid cores were obtained without stabilization by low molecular weight surfactants and applied as photochemical reactors. Toluene cores of the capsules were stabilized by novel graft amphiphilic polyelectrolyte poly(allylamine hydrochloride)-graft-poly(vinylnaphthalene) (PAH-graft-PVN) that was synthesized via nitroxide-mediated radical polymerization. Self-aggregation of the photoactive copolymer consisting of a solvophilic backbone and solvophobic side chains in water as a selective solvent leads to formation of intermolecular aggregates in which hydrophobic perylene fluorophore can be solubilized. However, at the water/toluene interface the macromolecules partially uncoil and polymeric chains are able to stabilize emulsion droplets by anchoring the hydrophobic arms in them. Formation of such capsules was followed using dynamic light scattering and electron microscopies. The obtained capsules showed long term stability. Importantly, energy transfer between the polymeric naphthalene moieties and incorporated perylene chromophores was realized much more efficiently in the core–shell capsules than in the copolymer aggregates. This can be explained in terms of the less packed but still confined environment of the nanocapsules. Such an assembly favors migration and transfer of excitation energy, which is otherwise dissipated in naphthalene excimers and aggregates that dominate in the copolymer aggregates formed in an aqueous environment. The obtained nanocapsules were shown to serve as both stable nanocontainers and efficient nanoreactors for photooxidation of perylene as an exemplary reaction. The reaction photosensitized by the polymeric naphthalene chromophores proceeded at least 3 times faster in the capsules than in the aggregates, disregarding the pH of the medium. Such properties make these novel capsules promising for numerous applications concerning photosensitized reactions that may be carried out in an aqueous medium and benefit from the confinement effect.

Molecular Disorder of Bicalutamide—Amorphous Solid Dispersions Obtained by Solvent Methods

The effect of solvent removal techniques on phase transition, physical stability and dissolution of bicalutamide from solid dispersions containing polyvinylpyrrolidone (PVP) as a carrier was investigated. A spray dryer and a rotavapor were applied to obtain binary systems containing either 50% or 66% of the drug. Applied techniques led to the formation of amorphous solid dispersions as confirmed by X-ray powder diffractometry and differential scanning calorimetry. Moreover, solid–solid transition from polymorphic form I to form II was observed for bicalutamide spray dried without a carrier. The presence of intermolecular interactions between the drug and polymer molecules, which provides the stabilization of molecularly disordered bicalutamide, was analyzed using infrared spectroscopy. Spectral changes within the region characteristic for amide vibrations suggested that the amide form of crystalline bicalutamide was replaced by a less stable imidic one, characteristic of an amorphous drug. Applied processes also resulted in changes of particle geometry and size as confirmed by scanning electron microscopy and laser diffraction measurements, however they did not affect the dissolution significantly as confirmed by intrinsic dissolution study. The enhancement of apparent solubility and dissolution were assigned mostly to the loss of molecular arrangement by drug molecules. Performed statistical analysis indicated that the presence of PVP reduces the mean dissolution time and improve the dissolution efficiency. Although the dissolution was equally affected by both applied methods of solid dispersion manufacturing, spray drying provides better control of particle size and morphology as well as a lower tendency for recrystallization of amorphous solid dispersions.

3D printing of tablets containing amorphous aripiprazole by filaments co-extrusion

Graphical abstract Figure. No caption available. ABSTRACT Three‐dimensional printing is one of the fastest developing technology within pharmaceutical field. With many advantages this method can be found as a new dosage form manufacturing technique, however low printing efficiency stays as one of the major limitations. Therefore, the preparation of filaments as a feedstock and printing of the final dosage forms in pharmacies may by the direction of development for this method. Thus, simple dosage and dissolution profile modification seems to be essential. This can be done in simple way by addition drug‐free filament during printing process. In this work the influence of dual co‐extrusion process on the properties of 3D‐printed tablets with aripiprazole was evaluated. A ZMorph® 3D printer equipped with DualPro extruder was employed to produce tablets made from Kollicoat® IR aripiprazole‐loaded filament and commercially available PLA filament used to modify the release profile. Optical and polarized light microscopy were utilized to evaluate structure of printed objects and X‐ray diffraction studies were performed to determine crystallinity of aripiprazole within filament and tablets. Fast dissolution of aripiprazole resulted from its amorphization while prolonged drug release was a result of co‐extrusion with PLA filament. Importantly, the drug remained crystalline within the filament and phase transition into disordered system appeared during printing of tablets. Given the high stability of crystalline materials such feature is especially beneficial for long‐term storage of feedstock filament.