1,720,964 research outputs found
More than “just a drop”: the enigmatic role of liquid additives in mechanochemistry
No full textWe debate the role of liquid additives in liquid-assisted mechanochemistry, highlighting how miniscule amounts of liquid profoundly and mostly inexplicably affect the mechanism and outcomes of mechanochemical reactions. A critical analysis of well-known mechanochemistry studies, along with those reporting emerging concepts (such as the competitive liquid effect and dual-function liquids) underpins the complexity and mystery surrounding mechanochemical processes and suggest where the most series gaps in our understanding of mechanochemistry lie
Esplorazione del panorama delle forme solide nelle combinazioni di farmaci antiparassitari
No full textQuesta tesi esplora strategie innovative per migliorare le proprietà fisiche e farmacologiche dei farmaci attraverso l'impiego della chimica supramolecolare e delle tecniche meccanochimiche. Questi metodi rivestono un ruolo cruciale nel superare sfide quali la bassa solubilità e biodisponibilità, problematiche che affliggono sia i farmaci già in commercio sia le nuove entità chimiche. La stretta relazione tra la forma solida di un farmaco e la sua solubilità è ben documentata, rendendo la modifica dello stato solido uno degli approcci fondamentali per ottimizzare le prestazioni farmaceutiche.
La prima sezione di questa ricerca si concentra sulla cocristallizzazione del praziquantel e della niclosamide, due farmaci antiparassitari noti per la loro spiccata tendenza a trasformarsi allo stato solido. Attraverso metodi meccanochimici, è stato ottenuto un nuovo cocristallo anidro farmaco-farmaco, la cui struttura è stata pienamente caratterizzata. Una delle scoperte più significative riguarda la stechiometria 1:3 tra praziquantel e niclosamide, una configurazione piuttosto rara negli studi di cocristallizzazione. Il nuovo cocristallo ha mostrato una migliorata attività antielmintica in vitro contro Schistosoma mansoni, superando l'efficacia dei farmaci puri e dimostrando un elevato potenziale terapeutico.
La seconda sezione amplia questo approccio, introducendo l'acido acetico per la formazione di un sistema ternario farmaco-farmaco. Attraverso tecniche meccanochimiche, è stato sintetizzato un cocrystallo solvato con stechiometria 1:1:1. Questo nuovo sistema ternario ha mostrato una significativa attività in vitro, superando non solo i singoli farmaci, ma anche la loro combinazione binaria, sottolineando il ruolo delle interazioni sinergiche nel potenziamento delle terapie antiparassitarie.
Nella terza sezione, l’attenzione si sposta sullo sviluppo di sistemi coamorfi, ottenuti combinando praziquantel, niclosamide e mebendazolo tramite tecniche di macinazione. Utilizzando una strategia di progettazione delle miscele, sono stati creati dieci sistemi amorfi multicomponente distinti. Questi sistemi si sono rivelati omogenei e altamente stabili, superando anche le aspettative teoriche. Ciò dimostra come il controllo delle interazioni non covalenti possa portare a formulazioni farmaceutiche amorfe più organizzate e resistenti, con miglioramenti in solubilità e biodisponibilità.
L'ultima parte della ricerca si concentra sulla sintesi di solvati di niclosamide, progettati per affrontare le difficoltà di solubilità legate alla sua tendenza a convertirsi in una forma monoidrata poco solubile. Sei nuovi solvati cristallini sono stati sintetizzati con successo tramite tecniche meccanochimiche e classificati in base alle loro proprietà strutturali: solvati stechiometrici, solvati non-stechiometrici/canalari e una forma intermedia. Tutti i sei solvati hanno mostrato un'eccellente stabilità meccanica, resistendo alla conversione nella forma monoidrata indesiderata, anche dopo un'esposizione prolungata all'umidità.
Nel complesso, questa tesi evidenzia il grande potenziale della chimica supramolecolare e della meccanochimica nello sviluppo di nuove formulazioni farmaceutiche allo stato solido. La creazione di cocristalli, sistemi coamorfi e solvati dimostra come queste tecniche possano migliorare sia le proprietà fisiche sia quelle biologiche dei farmaci, aprendo nuove possibilità per trattamenti più efficaci, specialmente nel campo della parassitologia.This thesis explores innovative strategies to improve the physical and pharmacological properties of drugs through supramolecular chemistry and mechanochemical techniques. These methods are critical in facing challenges such as poor solubility and bioavailability, which are common issues in both marketed drugs and new chemical entities. The relationship between a drug solid-state form and its solubility is well-established, making solid-state modification a key approach for enhancing pharmaceutical performance.
The first section of this research focuses on the cocrystallization of praziquantel and niclosamide, two antiparasitic drugs with a strong tendency for solid-state transformations. Mechanochemical methods were employed to create a novel anhydrous drug-drug cocrystal, which was fully characterized. One of the most remarkable findings was the 1:3 praziquantel-niclosamide stoichiometry, which is uncommon in cocrystallization studies. The new cocrystal demonstrated improved in vitro anthelmintic activity against Schistosoma mansoni compared to the pure drugs, highlighting its therapeutic potential.
The second section extends this approach by introducing acetic acid to form a ternary drug-drug system. Through mechanochemical methods, a 1:1:1 cocrystal solvate was synthesized. This new ternary system showed enhanced in vitro activity, outperforming both individual drugs and their binary combination.
In the third section, attention shifts to the development of coamorphous systems, combining praziquantel, niclosamide, and mebendazole using milling techniques. A mixture design strategy was applied to create ten distinct amorphous multicomponent systems. These systems exhibited enhanced stability, even beyond theoretical expectations, illustrating how controlling non-covalent interactions can lead to more organized and stable amorphous drug formulations.
The final part delves into the formation of niclosamide solvates to address the solubility challenges posed by its tendency to convert into a poorly soluble monohydrate form. Six new crystalline solvates were successfully synthesized using mechanochemistry and categorized based on their structural properties: stoichiometric solvates, non-stoichiometric/channel solvates, and an intermediate form. All six solvates showed excellent mechanical stability and resisted conversion to the undesirable monohydrate form, even after prolonged exposure to humidity.
Overall, this thesis demonstrates the transformative potential of supramolecular chemistry and mechanochemistry in the development of novel solid-state drug formulations. The successful creation of cocrystals, coamorphous systems, and solvates showcases how these techniques can enhance both the physical and biological properties of drugs, opening new possibilities for more effective treatments in areas such as parasitology
Enantiospecific crystallisation behaviour of malic acid in mechanochemical reactions with vinpocetine
Full text link: We report an intriguing example of enantioselectivity in the formation of new multicomponent crystalline solid containing vinpocetine and malic acid. Several experimental data sets confirmed that the multicomponent system presents a clear enantiospecific crystallisation behaviour both in the solid-state and in solution: only the system consisting of vinpocetine and L-malic acid produces a free-flowing solid consisting of a new crystalline form, while the experiments with D-malic acid produced an amorphous and often deliquescent material. The new vinpocetine-L-malic system crystallizes in the monoclinic space group of P21 and in a 1:1 M ratio, where the two molecules are linked through intermolecular hydrogen bonds in the asymmetric unit. The vinpocetine-DL-malic system was partially crystalline (with also traces of unreacted vinpocetine) with diffraction peaks corresponding to those of vinpocetine-L-malic acid. Solid-state NMR experiments revealed strong ionic interactions in all the three systems. However, while vinpocetine-L-malic acid system was a pure and crystalline phase, in the other two systems the presence of unreacted vinpocetine was always detected. This resulted in a significant worsening of the dissolution profile with respect to vinpocetine-L-malic pure crystalline salt, whose dissolution kinetics appeared superior
Investigation of Solid-State Forms between p-Aminosalicylic Acid and Adenine: Exploring Salts, Cocrystals and their Polymorphism
No full textThis study investigates the polymorphic behavior of multi-component adducts formed between p-aminosalicylic acid (PAS), a second-line anti-tuberculosis drug, and adenine (ADE), a hydrogen bond-rich coformer. Given a ΔpKa of 2.2 between PAS and ADE, within the salt–cocrystal uncertainty region, three distinct solid-state forms (an anhydrous and two hydrates) were synthesized via solvent-tuned liquid-assisted grinding and solution evaporation. Comprehensive characterization was performed using solid-state NMR, FT-IR and Raman spectroscopy, X-ray diffraction (SCXRD and PXRD), DSC, TGA, and in vitro dissolution tests. Results revealed significant differences in structure, hydrogen-bonding networks, and thermal properties among the forms, with PAS:ADE stoichiometries of 3:2 for the anhydrous form and 1:1 for the hydrated forms. These findings demonstrate the critical role of solvent and stoichiometry in directing adduct formation and polymorphism, offering insights for optimizing drug formulation and expanding intellectual property strategies in pharmaceutical development
3D-printed chewable gummy tablets: A new tool for oral amoxicillin administration in paediatric population
Full text linkAmoxicillin is one of the most prescribed antibiotics in the paediatric population. Currently available formulations (i.e., suspensions and tablets) suffer from limited acceptability often responsible for the therapeutic failure. In the present study it is proposed an innovative formulation for amoxicillin oral administration that could meet acceptability requirements of the paediatric population. Chewable gummy tablets were produced by the Pressure-Assisted Microsyringe 3D printing technology. As "ink" it was used a gel obtained by the co-formulation of corn starch with acacia honey. The optimized formulation, having a final dose of 200 mg per unit, resulted visually appealing. Good accuracy between the computer-aided design and final 3D-printed product was evident as well. The fabricated gummy tablets (1.07 ± 0.05 g) showed acceptable mechanical properties such as hardness (150.52 ± 5.67 N), and gumminess (68.13 ± 6.51 N) when exposed to simulated salivary fluid. Moreover, the 3D-printed gummy tablets determined the almost complete release of the drug in the gastric environment within 2 h and assured its permeation through the PermeaPad® membranes. The obtained results suggest that 3D printing is a versatile and scalable technology useful in the pharmaceutical industry to fabricate customized chewable formulations as a suitable alternative to conventional formulations for amoxicillin administration in the paediatric population
The ideal duo for salt formation: vinpocetine and tosylic acid
Full text linkTwo novel soluble salts of vinpocetine were prepared through simple and highly sustainable mechanochemical methods. Specifically, water-assisted grinding led to the formation of a crystalline, anhydrous, equimolar salt with p-toluenesulfonic acid, whereas neat grinding produced its amorphous counterpart. The structure of the crystalline salt was elucidated using single-crystal X-ray diffraction, while the ionic nature of the amorphous salt was confirmed by X-ray photoelectron spectroscopy. The large ΔpKa between p-toluenesulfonic acid and vinpocetine promotes the formation of a stable salt, with strong ionic interactions between the protonated tertiary amine of vinpocetine and the tosylate anion (as also attested by amorphous salt glass transition of about 81 °C). Both salts significantly enhance the saturation solubility of vinpocetine at 37 °C in phosphate buffer, achieving thermodynamic equilibrium in half the time compared to the pure crystalline drug. These findings highlight new opportunities for the development of vinpocetine, a compound with well-documented effects on cerebral circulation, whose broader application has so far been limited by its extremely low aqueous solubility
Structural insights into novel coamorphous systems of azithromycin with faster dissolution profile
Full text link: In this study, azithromycin, a broad-spectrum antibiotic compound used for the treatment of several bacterial infections, which is characterized by a very low water solubility, was combined with different small molecules to generate more soluble coamorphous solids. The multicomponent systems were prepared through fast precipitation from ethyl acetate solution, facilitating the formation of amorphous phases in seven azithromycin-based systems. Differential scanning calorimetry confirmed the coamorphous nature for five out of seven systems (i.e., azithromycin-2-, 3-, and 4-aminobenzoic acids, -salicylic acid, -caprylic acid), while two systems (azithromycin-methyl salicylate, -glycerol) exhibited ambiguous thermal behavior. Stability assessments revealed that the homogeneous coamorphous systems remained stable for at least 140 days at 40 °C, while pure amorphous azithromycin, recrystallized within 72 h. The most suitable coamorphous systems were further characterized using pair distribution function analysis, providing molecular-level insights into their structural organization. Notably, the azithromycin-caprylic acid system exhibited distinct molecular packing, likely attributable to the unique structural characteristics of its fatty acid-based coformer, which also led to a faster drug dissolution rate compared to the pure crystalline and amorphous azithromycin forms
Innovative bilayered buccal films: A paediatric-friendly dosage form for transmucosal azithromycin delivery
Full text linkAzithromycin (AZT) is one of the most prescribed antibiotics in children, generally administered through the oral route. However, its low aqueous solubility, poor oral bioavailability and bitter taste can affect the therapy efficacy and the children's compliance. In this study, different mucoadhesive polymers and solubilizers were explored to develop a primary layer capable of establishing a prolonged contact with the mucosa. An ethylcellulose layer was further applied to assure the drug unidirectional absorption through the buccal mucosa and limit its bitter taste in the mouth. Films were characterized for their thickness, drug content and solid state, morphology, hydration mucoadhesion and mechanical properties. In vitro drug release and permeation through the buccal mucosa as well as antimicrobial activity were also investigated. The selected compositions, based on chitosan (CS), alginate (ALG) or sodium hyaluronate (HYA) in association with Soluplus® or polyvinylpyrrolidones allowed to obtain uniform, thin and mucoadhesive films. CS films determined a quick AZT release, due to the presence of a new, more soluble form of the drug (confirmed by PXRD and FT-IR analysis) with unaltered antimicrobial properties. Conversely, HYA and ALG films showed a more sustained release. Interestingly, the presence of the backing layer, confirmed by morphological studies, hindered the drug release, thus demonstrating that films could limit AZT taste inside the mouth. Among all the formulations, HYA film was characterized by the best profile of drug permeation, allowing the retention of drug antimicrobial ability and can be proposed as a buccal delivery system for the systemic absorption of AZT
Higher-order multicomponent crystals as a strategy to decrease the IC50 parameter: the case of praziquantel, niclosamide and acetic acid
Full text linkWe successfully assembled via mechanochemistry 3 anthelmintic molecules in a single stable solid, namely praziquantel (PZQ), niclosamide (NCM), and acetic acid (AA). We obtained a cocrystal solvate with largely superior anthelmintic activity against in vitro Schistosoma mansoni adults and, notably, against Newly Transformed Schistosomula compared to pure individual drugs (i.e., PZQ and NCM) and to its binary counterparts (i.e., PZQ-NCM cocrystal and PZQ-AA monosolvate).
We also demonstrated 5 different strategies for synthesizing the ternary cocrystal not only starting from individual coformers but also by combining different building blocks (i.e. preformed binary solids). The new phase was only obtainable through mechanochemistry as comparative slurry experiments were unsuccessful. Even though the ternary solid was crystallized through all five investigated routes, a pure phase was obtained by milling the preformed praziquantel-acetic acid monosolvate and raw niclosamide in an equimolar ratio for 60 min in the presence of 160 μL of acetic acid. Acetic acid acted both as a solvate-forming molecule and a liquid additive.
The purity of this new solid phase was confirmed by SS-NMR spectrum, also suggesting the presence of one independent molecule of PZQ, one of NCM and one of AA, as confirmed by 1H NMR. The cocrystal structure was solved from the Synchrotron powder X-ray pattern and optimized via DFT calculations. Crystallizing in the triclinic P-1 space group, the solid comprises one PZQ, one NCM, and one AA molecule linked via hydrogen bonds, as demonstrated by FT-IR analyses. The solid phase exhibits small plate agglomerates, as observed through SEM analysis, a desolvation event at ∼107 °C (TGA weight loss: 9.77 %), and physical stability over 24 months at room temperature.
The drastic reduction in IC50 (0.01 μM against Newly Transformed Schistosomula and Schistosoma mansoni adults) of the new solid fully justifies the ambitious challenge of incorporating more than two components into a single crystalline phase, underscoring the pivotal role of the ternary system in enhancing bioactivity. This finding highlights the need to tackle the next challenge: identifying the most suitable oral dosage form for a cocrystal solvate, a requirement that remains unmet in the pilot studies conducted in this work
A Crystal and Particle Engineering Approach To Modulating the Properties of Polymer
Full text linkPolymer-based cocrystals represent a highly promising subclass of multicomponent solids. One interesting aspect of these materials is related to the possibility of obtaining isostructural crystals simply by changing the chain length of the polymer used. In this study, we perform an in-depth investigation of the solid-state features of several isostructural ternary polymer-based cocrystals composed of caffeine, 5-fluoroanthranilic acid, and polyethylene glycols of varying chain lengths. Thermal analyses, synchrotron powder X-ray diffraction studies, and atomic-resolution transmission electron experiments were used to investigate the solid-state features of the multicomponent solids. We observed that cocrystallization of polyethylene glycol with caffeine and 5-fluoroanthranilic acid led to a solid with a melting point at least 50 °C higher than that of the pure polymer. We also discovered that further tuning of the melting behavior can be achieved through particle engineering, whereby the crystallite size and strain are controlled by the length of the polymer chain. A better understanding of the solid-state features of such materials would allow, in the near future, the development of polymer-based cocrystals with tailored solid-state properties
- …
