Development of immediate release 3D-printed dosage forms for a poorly water-soluble drug by fused deposition modeling: Study of morphology, solid state and dissolution.

3D-printing technologies such as Fused Deposition Modeling (FDM) bring a unique opportunity for personalized and flexible near-patient production of pharmaceuticals, potentially improving safety and efficacy for some medications. However, FDM-printed tablets often exhibit tendency for slow dissolution due to polymer erosion-based dissolution mechanisms. Development of immediate release (IR) 3D-printed dosage with poorly water-soluble compounds is even more challenging but necessary to ensure wide applicability of the technology within pharmaceutical development portfolios. In this work, process and morphology were considered to achieve IR of BCS class IV compound lumefantrine as model active pharmaceutical ingredient (API) using basic butylated methacrylate copolymer (Eudragit EPO) as matrix former, as well as hydrophilic plasticizer xylitol and pore former maltodextrin. Grid-designed tablets with size acceptable for children from 6 years old and varying programmed infill density were successfully 3D-printed with 5% lumefantrine while higher drug load led to increased brittleness which is incompatible with 3D-printing. Lumefantrine assay was 92 to 97.5% of theoretical content depending on drug load and process parameters. 3D-printed tablets with 65% infill density met rapid release criteria, while 80% and 100% showed slower dissolution. Structural characteristics of 3D-printed tablets with non-continuous surface such as accessible porosity and specific surface area by weight and by volume were quantified by a non-destructive automated µCT-based methodology and were found to correlate with dissolution rate. Increase in accessible porosity, total surface area, specific surface area and decrease in relative density were statistically significant critical factors for modification of lumefantrine dissolution rate. Crystallinity in manufactured tablets and filaments was explored by highly sensitive Raman mapping technique. Lumefantrine was present in the fully amorphous state in the tablets exhibiting adequate stability for on-site manufacturing. The study demonstrates feasibility of immediate release FDM-3D-printed tablets with BCS class IV API and illustrates the correlation of FDM design parameters with morphological and dissolution characteristics of manufactured tablets.

An Indirect Synthetic Approach toward Conformationally Constrained 20-Membered Unclosed Cryptands via Late-Stage Installation of Intraannular Substituents.

A new protocol for PTC-mediated O-alkylation of the intraannular position of 20-membered unclosed cryptands (UCs) is reported. In contrast to the classical, "direct" strategy, which requires functionalization of the lariat arm at the beginning of synthesis, this "indirect" approach enables the late-stage introduction of various benzylic substituents after an unfavorable macrocyclization step (11 examples, yields up to 98%). Notably, this method permits preparation of, previously inaccessible, crowded UCs bearing 1-acetylpyrene substituent and dimer joined by p-xylene linker.

Photochromic Torsional Switch (PTS): a light-driven actuator for the dynamic tuning of π-conjugation extension.

Here we present a molecular architecture that can reversibly change the geometric conformation of its π-system backbone via irradiation with two different wavelengths. The proposed 'molecular actuator' consists of a photoswitchable azobenzene orthogonally connected to a π-conjugated bithiophene by both direct and aliphatic linker-assisted bonding. Upon exposure to 350 nm light, the trans azobenzene moiety isomerizes to its cis form, causing the bithiophene to assume a semiplanar anti conformation (extended π-conjugation). Exposure to 254 nm light promotes the isomerization of the azobenzene unit back to its initial extended trans conformation, thus forcing the bithiophene fragment to twist out of coplanarity (restricted π-conjugation). The molecular conformation of the bithiophene was characterized using steady-state UV-vis and nuclear magnetic resonance spectroscopy, as well as ab initio computations. The proposed molecular design could be envisaged as a π-conjugation modulator, which has potential to be incorporated into extended linear π-systems, i.e. via the terminal α-thiophene positions, and used to tune their optical and electronic properties.

Self-organizing surface-initiated polymerization, templated self-sorting and templated stack exchange: synthetic methods to build complex systems.

In nature, spectacular function is achieved by highly sophisticated supramolecular architectures. Little is known what we would obtain if we could create complexity with similar precision, because the synthetic methods to do so are not available. This account summarizes recent approaches conceived to improve on this situation. With self-organizing surface-initiated polymerization (SOSIP), charge-transporting stacks can be grown directly on solid substrates with molecular-level precision. The extension to templated self-sorting (SOSIP-TSS) offers a supramolecular approach to multicomponent architectures. A solid theoretical framework for the transcription of information by templated self-sorting has been introduced, intrinsic templation efficiencies up to 97% have been achieved, and the existence of self-repair has been shown. The extension to templated stack exchange (SOSIP-TSE) offers the complementary covalent approach. Compatibility of this robust method with the creation of double-channel architectures with antiparallel two-component gradients has been demonstrated.

Creation of chiral thixotropic gels through a crown-ammonium interaction and their application to a memory-erasing recycle system.

A unique class of oligothiophene-based organogelator bearing two crown ethers at both ends was synthesized. This compound could gelatinize several organic solvents, forming one-dimensional fibrous aggregates. From the observation of circular dichroism, it was confirmed that the helical handedness of the fibrous assembly is controllable by the chirality of 1,2-bisammonium guests, thus suggesting that one guest molecule bridges two gelator molecules through the crown-ammonium interaction. Interestingly, we have found that such chirality is created by thermal gelation, whereas it disappears by thixotropic gelation. The new finding implies that the present organogel system is applicable as a reversible switching memory device, featuring memory creation by a heat mode and memory erasing by a mechanical mode.

Study of host-guest interactions in benzodiazacoronands by means of solid state NMR spectroscopy, X-ray diffraction and quantum mechanical computations.

In this work we present solid state data for five host-guest complexes formed by N-(4,19-dioxo-2,8,15,21-tetraoxa-5,18-diazatricyclohexacosa-1(25),9(14),10,12,22(26),23-hexaen-26-yl)-benzamide (1) belonging to the group of benzodiazacoronands, achiral compounds for which chiral crystals were found (J. Kalisiak and J. Jurczak, Cryst. Growth Des., 2006, 6, 20). The X-ray structure was resolved for four of them. It was found that 1 crystallizes in P2(1)/c, P1 and P2(1)/n achiral space groups. Differentiation of molecular packing and the presence of guest molecules within the crystal lattice were analyzed with solid state NMR. An attempt was made to correlate changes in (13)C δ(ii) and (15)N δ(ii) chemical shift tensor values, obtained from analysis of spinning sidebands of 1D and 2D (2D PASS) NMR spectra, with changes in the strength of hydrogen bonding. Quantum mechanical DFT GIAO calculations of NMR shielding parameters carried out on structures with coordinates taken from XRD were employed for signals assignment and verification of structural constraints.

New strategy for controlling the oligothiophene aggregation mode utilizing the gel-to-sol phase transition induced by crown-alkali metal interactions.

A new functional low molecular-weight gelator (LMWG) based on crown-appended quaterthiophene was synthesized and investigated as a new alkali metal cation responsive material with enhanced fluorescence emission upon gel-to-sol phase transition.