This study reports, for the first time, the formation of four new multicomponent solid forms of norfloxacin (NOR) with p-aminobenzoic acid (PABA). Among them, the ethanol-assisted grinding product (NPL) and the heat-treated salt (NPH) exhibited a remarkable sevenfold increase in solubility compared to commercial NOR. These materials were prepared by mechanochemical and slurry methods and characterized by thermal analysis, X-ray diffraction, and spectroscopic techniques. Mechanochemistry proved to be a sustainable approach, avoiding large amounts of solvent. Furthermore, conditions for the reproducible scale-up production of NPH with high purity were successfully established. These findings highlight the potential of solid-state modulation with PABA to significantly improve the pharmaceutical performance of NOR and provide viable routes for industrial applications.

The development of CO2-based polymers integrating photo-responsiveness, synthetic versatility and processability remains an important challenge in polymer chemistry. Herein, a modular strategy was developed for multifunctional CO2-derived photosensitive polycarbonates. Catalytic copolymerisation of CO2 and 1,2-epoxy-4-vinylcyclohexene using tetrapyrrolic macrocyclic metal complexes (Cr porphyrin or Al phthalocyanine) as dual-function catalysts and embedded photosensitisers afforded polycarbonates with high carbonate incorporation (95-99%) and preserved photophysical features. Pendant vinyl groups enabled post-polymerisation modification, through an unprecedented Rh-catalysed hydroformylation introducing formyl groups with remarkable chemo- and regioselectivity, while bromination with Br2 provided an additional functionalisation route. Comprehensive structural, spectroscopic and thermal characterisation confirmed the robustness and tunability of the materials. Notably, the Al-phthalocyanine-based polycarbonates retained key photophysical properties of the photosensitiser (phi F up to 0.46, phi Delta up to 0.21). To overcome polymer brittleness, an ethyl cellulose-based biocomposite film incorporating the formyl-functionalised polycarbonate was prepared, leading to improved flexibility and thermal stability. The formyl-functionalised polymer and the corresponding biocomposite film exhibited strong photo-antibacterial activity, completely eradicating Staphylococcus aureus (>= 7-log CFU reduction) under red light (660 nm, 49 J cm-2), highlighting the potential of CO2-derived photosensitive polycarbonates for light-responsive environmental applications.

Sustainable CO 2 -derived photosensitive polycarbonates are synthesised using tetrapyrrolic macrocycles as catalysts/photosensitisers. Post-polymer functionalisation and biocomposite fabrication enable tunable, processable photoactive materials.

This work significantly expands the understanding of the solid-form landscape of iguratimod, a nonsteroidal anti-inflammatory disease-modifying antirheumatic drug (DMARD) used to treat rheumatoid arthritis, with promising potential for other therapeutic applications. Comprehensive solid-form screening by melt cooling, grinding, and crystallization from solutions, complemented by mechanochemical exploration of cocrystals and coamorphous phases, revealed rich solid-form diversity. Nicotinamide, sulfasalazine, and folic acid were selected as pharmaceutically relevant coformers, while picolinamide, isonicotinamide, and benzamide were employed to provide molecular-level insight into the recognition phenomena. Three polymorphs (I, II, and III, the latter reported for the first time) were identified, and conditions for their preparation were established. Crystallization from solutions predominantly yielded form II, and two new solvates, with methanol and acetonitrile, were discovered. Equimolar cocrystals of iguratimod with benzamide, picolinamide, and nicotinamide were obtained, with the nicotinamide cocrystal being the first structurally resolved iguratimod cocrystal reported to date. In contrast, attempts to form a cocrystal with isonicotinamide failed, underscoring the specificity of molecular recognition in this system. Neat grinding produced amorphous iguratimod and multicomponent amorphous phases with nicotinamide, sulfasalazine, and folic acid, showing enhanced kinetic stability over that of the pure amorphous drug. This highlights multicomponent amorphous phases as promising routes to stabilize amorphous drugs.

Amide-amide, acid-amide, and acid-pyridine synthons are among the most effective hydrogen-bonded building blocks in multicomponent drug systems. In this work, a conformationally flexible compound with prolific polymorphism was chosen as a carboxylic acid model drug, combined with three pyridinecarboxamide positional isomers as co-formers-picolinamide, nicotinamide, and isonicotinamide. Quench-cooling molten mixtures with different molar ratios produced binary coamorphous systems. Their thermal stability was dependent on the heating rate, relaxing to equimolar cocrystals with picolinamide and isonicotinamide, also obtained by mechanochemistry. Contrarily, both methods could only produce physical mixtures with nicotinamide. Thermal analysis and X-ray diffraction were used to characterize the crystalline phases. Furthermore, the molecular dynamics of the pure compounds and binary phases were studied by dielectric spectroscopy, while the main intermolecular interactions were investigated by FTIR-ATR and computational methods based on DFT calculations-molecular electrostatic potential, NBO, and IGM-delta g analyses. The acid hydroxyl group was the strongest hydrogen bond donor, and the amide carbonyl group was the best acceptor. However, the synthon competition outcome was found to depend on the pyridinecarboxamide isomer, with picolinamide having a more different behavior because of electronic and steric effects. Experimental and computational results suggest an acid-amide synthon in the nateglinide-picolinamide cocrystal, which was fully confirmed by single-crystal X-ray diffraction.

In this work, the solid-form landscape of probucol is investigated by crystallization from solutions in various solvents (methanol, ethanol, acetonitrile, and dichloromethane), under different experimental conditions. A total of four polymorphs were obtained from ethanol, changing the experimental conditions (FI to FIV), which were characterized by thermal analysis, infrared spectroscopy, and powder and single-crystal X-ray diffraction. Form I is the stable polymorph at least for T >= -15 degrees C. FIII and FIV, identified in this work for the first time, could only be obtained after long induction times (weeks or months) at subambient conditions. A comparison of the crystal structures of the polymorphs shows that the molecular flexibility and hindrance of the hydroxyl groups are relevant in the diversity of solid forms of probucol. FI (and FIV), FII, and FIII are conformational polymorphs: bent conformations (central chain dihedral angles) for FI, FIII, and FIV and a straighter conformation in FII, which has a high degree of void volume. Three solvates were obtained by crystallizations from methanol, acetonitrile, and dichloromethane, with low induction times, which are more stable than FI. These solvates (crystal structures solved in this work) are almost isostructural to FII, with the solvent molecules located in FII voids.

In this work, binary mixtures of valsartan and menthol (MENT), thymol (THY) and catechol (CAT) were investigated using thermal analysis, complemented by powder X-ray diffraction and infrared spectroscopy. Eutectic forming systems were obtained for samples prepared by neat mechanochemistry using crystalline valsartan (VALc), whose thermal behavior deviates considerably from the ideal prediction. For VALc-CAT, the eutectic temperature is about 40 degrees C lower than predicted by Schroeder-van Laar equation, although the eutectic mixture is not liquid under ambient conditions. After cooling from the melt, the samples give rise to amorphous phases. Attending to their glass transition temperature, mixtures were selected (xVAL = 0.3 for VAL-MENT and VAL-THY, xVAL = 0.5 for VAL-CAT) that are liquid under ambient conditions (Low Transition Temperature Mixtures, LTTM) or at physiological temperature. Amorphous phases were also obtained for the same composition, for VAL-MENT and VAL-THY by neat grinding using amorphous valsartan (VALa). The release profiles of valsartan through a cellulose dialysis membrane into a pH 6.8 phosphate buffer at 37 degrees C were evaluated for VALMENT and VAL-THY (xVAL = 0.3) that are liquid at room temperature and VAL-CAT (xVAL= 0.5) that is liquid at physiological temperature) and compared with that of pure VALa.

The global rise of multidrug-resistant (MDR) bacteria highlights the urgent need for alternative strategies to prevent their spread, particularly in healthcare environments. Here, we report the synthesis and evaluation of a novel mono-cationic meso-imidazolyl porphyrin (3) and its integration into biodegradable poly(lactic acid) (PLA) films, resulting in potentially effective, reusable, and broad-spectrum photodynamic antibacterial surfaces. The porphyrin was prepared using a mixed aldehyde condensation followed by microwave-assisted methylation, reducing reaction time to just 1 minute with near-quantitative yield. PLA films containing porphyrin 3 (+PLA-3) were successfully prepared and fully characterized, showing exceptional photostability and minimal leaching in aqueous environments, even under prolonged light exposure. Notably, cationic +PLA-3 exhibited superior material stability compared to analogous PLA films incorporating tetra-cationic porphyrins, attributed to the improved amphiphilic balance of the mono-cationic photosensitizer. Antibacterial studies confirmed that cationic +PLA-3 films achieved complete photodynamic inactivation (7 log CFU reduction) of both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria under blue LED irradiation. They also demonstrated great effectiveness against clinical multidrug-resistant strains, including MRSA, E. coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae, reaching total inactivation under light doses up to 23.5 J cm-2. Reusability tests confirmed full retention of antibacterial efficacy after up to 11 irradiation cycles, totalling 258.5 J cm-2. These results position cationic +PLA-3 as a promising candidate for use in self-disinfecting surfaces with potential to reduce nosocomial infection risks and environmental impact in healthcare settings.

Polymorphism has been the subject of many studies in the last decades, including a particular type of polymorphism where the colors exhibited by the polymorphs differ. However, only relatively limited or narrow differences in color were observed in color polymorphs of the same compound. Indeed, to this date, almost all compounds known to show color polymorphism exhibit red, orange, or yellow tones, as is the case of the notable ROY molecule (5-methyl-2-[(2-nitrophenyl)-amino]-3-thiophenecarbonitrile), which is the compound with more polymorphs reported and structurally characterized hitherto. In this work, we report a new color polymorphic material derived from ROY, (2-(4-((3-cyanothiophen-2-yl)-amino)-3-nitrophenyl)-acetic acid; or ROY-CAM), synthesized for the first time by nucleophilic aromatic substitution reaction between 2-(4-fluoro-3-nitrophenyl)-acetic acid and 2-aminothiophene-3-carbonitrile, which exhibits a red (P21/n, m.p.: 184 C-degrees and theta = -4.4(degrees) and 3.0(degrees)) and a brownish-green polymorph (P1, m.p.: 190 C-degrees and theta = -66.1(degrees)). This is the first time a member of the ROY family of compounds was observed to exhibit a brownish-green polymorph and, more importantly, the first time that a molecular compound exhibits a red and a greenish polymorphs, i.e., this is the first example of an organic molecule that originates polymorphs covering such a wide range of color. The isolated molecule of ROY-CAM has 11 low-energy conformers, which were accessed by DFT calculations, with two of these conformers being identified in the observed polymorphs of the compound: in the brownish-green polymorph, the most stable conformer exists, while the red polymorph is composed of molecules assuming a conformation similar to that of the third most stable conformer. In the latter polymorph, the intramolecularly disfavored conformation assumed by the molecules is stabilized in the crystal lattice through interactions between carboxylic acid groups of neighboring molecules, resulting in dimeric units formed between pairs of the two distinct molecules that constitute the asymmetric unit of the crystal. The two identified polymorphs were characterized vibrationally (by both IR and Raman spectroscopies), and a thermal study is also presented (based on DSC, PLTM, and TGA measurements). Furthermore, the brownish-green and red colors exhibited by the polymorphs of ROY-CAM are explained based on the differences in the structures of the molecules that are present in these crystals.

Nateglinide is a prolific polymorph former. Cryo-milling and quench cooling were explored as alternatives to stabilize its co-amorphous systems with ranolazine and tryptophan, and their molecular dynamics of relaxation investigated.

In this work, multicomponent trimethoprim-based pharmaceutical solid systems were developed by mechanochemistry, using coformers from the GRAS list and other active pharmaceutical ingredients. The choice of coformers took into account their potential to increase the aqueous solubility/dissolution rate of TMP or its antibacterial activity. All the binary systems were characterized by thermal analysis, powder X-ray diffraction and infrared spectroscopy, and 3 equimolar systems with FTIR pointing to salts, and 4 eutectic mixtures were identified. The intrinsic dissolution rate of TMP in combination with nicotinic acid (a salt) and with paracetamol (eutectic mixture) were 25% and 5% higher than for pure TMP, respectively. For both Gram-positive and -negative strains, the antibacterial activity of TMP with some of the coformers was improved, since the dosage used was lower than the TMP control. A significant increase in antibacterial activity against E. coli was found for the eutectic mixture with curcumin, with the best results being obtained for the eutectic and equimolar mixtures with ciprofloxacin. Combining trimethoprim with coformers offers an interesting alternative to using trimethoprim alone: multicomponent forms with enhanced TMP dissolution rates were identified, as well as combinations showing enhanced antibacterial activity relatively to the pure drug.

The results of broadband dielectric spectroscopy and differential scanning calorimetry of the trans and cis isomers of 1,2-cyclohexanediol and 1,3-cyclohexandiol are presented. Numerical analysis of the dielectric spectra points to complex dynamics of presented compounds in isotropic liquid, ordered crystalline, and orientationally disordered (plastic) crystal phases. Two relaxation processes were found in plastic crystal phases in cis-1,2-cyclohexanediol and trans-1,3-cyclohexanediol. These processes are responsible for the a-relaxation and forming/breaking hydrogen bonds between molecules forming clusters. One relaxation process was found in crystal phases and isotropic liquid phase. Temperature dependences of mean relax-ation times are of the Arrhenius type, except for trans-1,3-cyclohexanediol compound for which the Vogel-Fulcher-Tammann dependence is fitted. The electric conductivity, fitted by Jonscher power law, is of similar order as for semiconducting materials. The electrode polarization effect is strong, especially in isotropic liquid and plastic crystal phases. CO 2022 Elsevier B.V. All rights reserved.

Cocrystals are recognized as one of the most efficient approaches to improve aqueous solubility of Biopharmaceutical Classification System, BCS, classes II and IV drugs. Cocrystal discovery and the establishment of experimental conditions suitable for scale-up purposes are some of the main challenges in cocrystal investigation. In this work, the investigation of mechanochemical synthesis of norfloxacin cocrystals with picolinic and isonicotinic acids is performed, leading to the discovery of two new cocrystals of this important BCS class IV antibiotic, which were characterized through thermal, spectral and diffractometric analysis. Norfloxacin apparent aqueous solubility using the cocrystals is also presented, with higher values being obtained for all the investigated systems when compared to the pure drug. Norfloxacin has 3 polymorphs and several solvents/hydrates, which represents a challenge for obtaining pure cocrystal forms from solvent crystallization. This challenge was successfully overcome in this work, as experimental conditions to obtain the pure cocrystals (the new ones and also norfloxacin-nicotinic acid and norfloxacin-saccharin) were established using Crystal16 equipment. This is a crucial step to envisage future scale-up procedures and therefore a valuable information for the pharmaceutical industry.

The aqueous photocatalyzed degradation of trimethoprim (TMP) and sulfamethoxazole (SMX), highly prescribed antibiotics, often found in hospital wastewaters and/or surface/ground waters in high concentrations, is described, using a 400 W medium pressure mercury lamp as irradiation source, air as oxidant and a porphyrin based photocatalyst. The new photocatalyst was prepared by encapsulation of stable meso-tetra(2,6-dichlorophenyl)porphyrin photosensitizer into acetylated lignin nanoparticles, which are derived from a bio-based cellulose industry byproduct. This is a reusable stable catalyst (after at least 7 cycles, no loss of activity or degradation/leaching, was observed) capable of promoting the nearly complete degradation of TMP and SMX antibiotics, with unprecedented total organic carbon (TOC) removal, namely 75 % and 85 %, respectively. Mechanistic studies of these reactions, using singlet oxygen and radical scavengers, followed by HPLC-MS analysis allowed the identification of only two residual TMP photoproducts.

Different methods were explored for the amorphization of ranolazine, a sparingly soluble anti-anginal drug, such as mechanochemistry, quench-cooling, and solvent evaporation from solutions. Amorphous phases, with Tg values lower than room temperature, were obtained by cryo-milling and quench-cooling. New forms of ranolazine, named II and III, were identified from the relaxation of the ranolazine amorphous phase produced by cryo-milling, which takes place within several hours after grinding. At room temperature, these metastable polymorphs relax to the lower energy polymorph I, whose crystal structure was solved in this work for the first time. A binary co-amorphous mixture of ranolazine and tryptophan was produced, with three important advantages: higher glass transition temperature, increased kinetic stability preventing relaxation of the amorphous to crystalline phases for at least two months, and improved aqueous solubility. Concomitantly, the thermal behavior of amorphous tryptophan obtained by cryo-milling was studied by DSC. Depending on experimental conditions, it was possible to observe relaxation directly to the lower energy form or by an intermediate metastable crystalline phase and the serendipitous production of the neutral form of this amino acid in the pure solid phase.

Coamorphous formation in binary systems of valsartan (Val) with 4,4′-bipyridine (Bipy) and trimethoprim (Tri) was investigated for mixtures with a mole fraction of 0.16~0.86 of valsartan and evaluated in terms of the glass transition temperature. The glass transition of the systems had a behavior outside the values predicted by the Gordon–Taylor equation, showing that Val-Bipy (hydrogen bonding between the components) had a lower deviation and Val-Tri (ionic bonding between the components) had a higher deviation. Mixtures of compositions 2:1 Val-Bipy and 1:1 Val-Tri were selected for further investigation and verified to be stable, as no crystallization was observed during subsequent heating and cooling programs. For these systems, the effective activation energy during glass transition was evaluated. Compared to pure valsartan, the system with the lower glass transition temperature (Val-Bipy) presented the highest effective activation energy, and the system with the higher glass transition temperature (Val-Tri) presented a lower effective activation energy. The results presented a good correlation between the data obtained from two different techniques to determine the fragility and effective activation energy: non-isothermal kinetic analysis by DSC and TSDC.

The concept of co-amorphous systems is introduced in an integrated laboratory experiment, designed for advanced chemistry students, using solvent-free, environmentally friendly mechanochemistry. The dual-drug naproxen-cimetidine co-amorphous system (NPX-CIM) is investigated as an example of the emergent field of medicinal mechanochemistry. Students are trained in solid-state characterization techniques including X-ray powder diffraction, Fourier-transform infrared spectroscopy, and thermal analysis by differential scanning calorimetry. This lab experiment also provides an opportunity to discuss the relevance of different solid forms of pharmaceutics, emphasizing particular properties of disordered materials. This experiment can easily fit the curriculum of any Chemistry or Pharmacy master level degree in courses dealing with instrumental analysis, solid state chemistry, or green chemistry, for classes of 6 to 18 students, in a 5-h lab session. Suggestions to adapt it to the use of a single characterization technique are provided.

A novel derivative of ROY, AcROY, was synthesized and studied in this work, where 3 different colored polymorphs were identified. The observed polymorphism of AcROY is an interesting case of packing-determined color polymorphism.