Jorge Guillermo Domínguez-Chávez

Separation of mixtures containing low-molecular-weight hydrocarbons using sustainable and less energy-intensive processes is one of the grand challenges facing the chemical sciences. In this work, we report the peculiar ability of molecular crystals containing boron-based receptors A1 assembled through dative B←N bonds between 2-(naphthalen-1-yl)naphtho[2,3-d][1,2,3]dioxaborolane and 3,6-di(pyridin-4-yl)-1,2,4,5-tetrazine (BiPyTz), to readily capture and separate small molecules of great industrial interest like benzene (Bz) and cyclohexane (Cy) via the formation of stoichiometric solvates A1·2Cy and A1·2Bz with high conversions. Sorption in mixtures Bz/Cy 1:1 (v/v) showed high selectivity (≥99%) for Bz over Cy in liquid-solid experiments and up to 96% in vapor-solid tests. The dynamics of the vapor-solid sorption process revealed a transient formation of A1·2Cy that gradually converts to the more stable A1·2Bz. Recyclability of the sorbent materials was accomplished without heating through the reversible transformation of A1·2Bz toward the unsolvated form of A1 or A1·MeCN. Receptor A1 is prone to crystallize with MeCN in various stoichiometric ratios with noncentrosymmetric conformations displaying syn orientation of the naphthylboronic fragments, whereas crystals of A1 containing Bz or Cy exhibited a more stable conformation with antiparallel disposition of the aromatic substituents and crystallographic inversion symmetry. Computational studies of adduct-adduct and solvent-adduct interaction energies in the crystals of A1·MeCN, A1·2MeCN, and A1·2Bz confirmed a favorable solid phase transformation toward the Bz solvate due to two factors: (i) the conformational adaptability of receptor A1 to optimize adduct-adduct aromatic interactions, accounting for the major contribution to the crystal stability, and (ii) a larger attachment energy of Bz over MeCN. Overall, our studies demonstrate the potential of receptor-based molecular crystalline materials containing flexible and adaptive acyclic B←N adducts to effectively separate a very challenging hydrocarbon solvent system under gentle conditions and with recycling capabilities.

Introducción. La solubilidad y la velocidad de disolución son dos factores fisicoquímicos clave en la eficacia terapéutica de un fármaco administrado por vía oral, ya que estos parámetros determinan la cantidad de fármaco disponible para su absorción. En este contexto, el desarrollo de co-amorfos farmacéuticos es una estrategia prometedora para mejorar la solubilidad y la velocidad de disolución de compuestos poco solubles en medios fisiológicos. En este sentido, la sulfasalazina se caracteriza por una elevada permeabilidad intestinal pero una baja solubilidad que resulta en una biodisponibilidad menor al 15%. Con base en lo anterior, la obtención de sistemas co-amorfos de sulfasalazina que posean mayor solubilidad y velocidad de disolución, incrementaría la cantidad de fármaco disponible para su absorción, mejorando su biodisponibilidad y su eficacia terapéutica. Objetivo: Obtener y caracterizar química y biofarmacéuticamente un co-amorfo de sulfasalazina:L-Arginina con propiedades mejoradas de solubilidad y velocidad de disolución. Metodología el co-amorfo se obtuvo mediante las técnicas de slurry y de molienda mecanoquímica en proporción 1:1 de sulfasalazina y L-Arginina. Su caracterización incluyó la difracción de rayos X para determinar su naturaleza cristalina o amorfa, espectroscopía FT-IR y microscopía Raman para analizar interacciones intermoleculares y homogeneidad. La estabilidad térmica y la presencia de solvatos o hidratos fueron evaluadas con calorimetría diferencial y termogravimetría. Además, se analizaron su estabilidad en medios fisiológicos, solubilidad y la velocidad de disolución. Resultados: Se obtuvo un co-amorfo puro con estequiometría sulfasalazina: L-Arginina:agua de 1:1:2, estable hasta 50 °C sin humedad y hasta 40 °C con 75 % de humedad relativa. Este mostró estabilidad en medios con pH 1.2, 4.5 y 6.8, y triplicó la solubilidad y la velocidad de disolución en comparación con la sulfasalazina libre. Conclusión: La obtención de un co-amorfo estable y con mejor solubilidad sugiere un potencial aumento en la biodisponibilidad de la sulfasalazina, favoreciendo su aplicación en formulaciones más eficaces. Co-amorphous of sulfasalazine:arginine with improved solubility and dissolutionrate properties for enhanced bioavailability and therapeutic efficacy Introduction: Solubility and dissolution rate are two key physicochemical factors in the therapeutic efficacy of an orally administered drug, as these parameters determine the amount of drug available for absorption. In this context, the development of pharmaceutical co-amorphoses is a promising strategy to improve both solubility and dissolution rate of poorly soluble compounds in physiological media. Sulfasalazine is characterised by high intestinal permeability but low solubility, resulting in a bioavailability of less than 15%. Based on the above, obtaining co-amorphous of sulfasalazine with higher solubility and dissolution rate would increase the amount of drug available for absorption, thereby improving its bioavailability. Objective: To obtain and characterize chemically and biopharmaceutically a sulfasalazine: L-arginine co-amorphous with improved solubility and dissolution rate properties. Methods The co-amorphous is obtained by slurry and/or mechanochemical milling in a 1:1 ratio of sulfasalazine and L- rginine. Its characterization included X-ray diffraction to determine its crystalline or amorphous nature, FT-IR spectroscopy and Raman microscopy to analyze intermolecular interactions and homogeneity. Thermal stability and the presence of solvates or hydrates were evaluated by differential calorimetry and thermogravimetry. In addition, their stability in physiological media, solubility and dissolution rate were analyzed. Results: A pure co-amorphous was obtained with a sulfasalazine:L-arginine:water stoichiometry of 1:1:2, which was stable up to 50°C without humidity and up to 40°C with 75% relative humidity. It showed stability in media with pH 1.2, 4.5 and 6.8 and tripled the solubility and dissolution rate compared to free sulfasalazine. Conclusion: Obtaining a stable co-amorph with better solubility suggests a potential increase in the bioavailability of sulfasalazine, favoring its application in more effective formulations.

Background: Curcumin appears to be well tolerated and effective for managing chronic inflammatory pain, but its poor oral bioavailability has been a hurdle in its use as a therapeutic agent. The current study was performed to characterize a novel co-amorphous compound based on curcumin/L-arginine 1:2 (CAC12). Methods: Stability, solubility and structural characterization of the CAC12 were carried out by spectrometry techniques and in vitro assays, whereas the antinociceptive and anti-inflammatory effects were evaluated by CFA or carrageenan models. The mechanism of action was determined by cytokine quantification, and pharmacokinetic parameters were obtained through UPLC-MS/MS. The co-amorphous compound was prepared by fast solvent evaporation. Powder XRD, 13C-NMR, ATR-FTIR and TGA/DSC thermal analysis showed a 1:2 stoichiometry for the CAC12. Results: CAC12 was 1000 times more soluble than curcumin, and it was stable for 1 month at 40 °C and 75% relative humidity or for 60 min in physiological medium at pH 4.5–6.8. Co-amorphous curcumin/L-arginine, but not curcumin + L-arginine, decreased carrageenan- or CFA-induced inflammation and nociception by decreasing IL-1α, IL-1β, IL-6, TNF-α, MCP-1 and CXCL1 cytokines. The bioavailability of free plasmatic curcumin increased about 22.4 times when it was given as CAC12 relative to a phytosome formulation at the equivalent dose. Conclusions: Results suggest the possible use of CAC12 to treat inflammatory pain disorders in human beings.

Background/Objective: In recent studies, it has been shown that dietary bioactive compounds can produce health benefits; however, it is not known whether an improvement in solubility can enhance their biological effects. Thus, the aim of this work was to study whether co-amorphous (CoA) naringenin or fisetin with enhanced solubility modify glucose and lipid metabolism, thermogenic capacity and gut microbiota in mice fed a high-fat, high-sucrose (HFSD) diet. Methods: Mice were fed with an HFSD with or without CoA-naringenin or CoA-fisetin for 3 months. Body weight, food intake, body composition, glucose tolerance, hepatic lipid composition and gut microbiota were assessed. Results: CoA-naringenin demonstrated significant reductions in fat-mass gain, improved cholesterol metabolism, and enhanced glucose tolerance. Mice treated with CoA-naringenin gained 45% less fat mass and exhibited improved hepatic lipid profiles, with significant reductions seen in liver triglycerides and cholesterol. Additionally, both CoA-flavonoids increased oxygen consumption (VO₂), contributing to enhanced energy expenditure and improved metabolic flexibility. Thermogenic activation, indicated by increased UCP1 and PGC-1α levels, was observed with CoA-fisetin, supporting its role in fat oxidation and adipocyte size reduction. Further, both CoA-flavonoids modulated gut microbiota, restoring diversity and promoting beneficial bacteria, such as Akkermansia muciniphila, which has been linked to improved metabolic health. Conclusions: These findings suggest that co-amorphous naringenin or fisetin offers promising applications in improving solubility, metabolic health, and thermogenesis, highlighting the potential of both as therapeutic agents against obesity and related disorders.

Background/Objective: In recent studies, it has been shown that dietary bioactive compounds can produce health benefits, however, it is not known whether an improvement in solubility can enhance their biological effects. Thus, the aim of this work was to study whether co-amorphous (CoA) of naringenin or fisetin with enhanced solubility modify glucose and lipid metabolism, thermogenic capacity and gut microbiota in mice fed a high-fat, high-sucrose (HFSD) diet. Methods: Mice were fed with a HFSD with or without CoA-naringenin or CoA-fisetin for 3 months. Body weight, food intake, body composition, glucose tolerance test, hepatic lipid composition and gut microbiota were assessed. Results: CoA-naringenin demonstrated significant reductions in fat mass gain, improved cholesterol metabolism, and enhanced glucose tolerance. Mice treated with CoA-naringenin gained 45% less fat mass and exhibited improved hepatic lipid profiles, with significant reductions in liver triglycerides and cholesterol. Additionally, both CoA-flavonoids increased oxygen consumption (VO2), contributing to enhanced energy expenditure and improved metabolic flexibility. Thermogenic activation, indicated by increased UCP1 and PGC-1α levels, was observed with CoA-naringenin, supporting its role in fat oxidation and adipocyte size reduction. Further, both CoA-flavonoids modulated gut microbiota, restoring diversity and promoting beneficial bacteria, such as Akkermansia muciniphila, linked to improved metabolic health. Conclusions: These findings suggest that co-amorphous naringenin or fisetin offer promising applications in improving solubility, metabolic health, and thermogenesis, highlighting their potential as therapeutic agents against obesity and related disorders.

Purpose: To investigate the stability and solubility of co-amorphous systems of glibenclamide (GBC) with L-arginine (L-Arg) at different pH values. Methods: Three co-amorphous solids of GBC and L-Arg were obtained by fast solvent evaporation using 2:1, 1:1 and 1:2 stoichiometries. All co-amorphous systems were characterized by XRPD, FTIR, RAMAN and NMR-solid state as well as thermal techniques such as DSC and TGA. The stability of coamorphous systems was evaluated by indicative stability and stability in relevant physiological media was measured at different pH values. Results: The chemical characterization suggest that there was no proton transference between L-Arg and GBC indicative of co-amorphous solids. Stability studies showed that all the co-amorphous solids are unstable under humid conditions and only the co-amorphous system of GBC: L-Arg 1:2 was stable in all the pH values tested. Solubility studies at different pH values showed that the co-amorphous GBC: L-Arg 1:1 and 1:2, showed increasing solubility values even at pH < 7 (0.6468 mg/mL at pH 1.2 for coamorphous GBC: L-Arg 1:2 at the first hour) where free GBC was not soluble. Conclusion: Co-amorphous systems of GBC and L-Arg, is an interesting strategy to increase the solubility of poorly-soluble drugs at acidic pH values Keywords: Co-amorphous; Glibenclamide; L-Arginine; Solubility; Stability

A cocrystal of the antihypertensive drug chlorthalidone (CTD) with caffeine (CAF) was obtained (CTD-CAF) by the slurry method, for which a 2:1 stoichiometric ratio was found by powder and single-crystal X-ray diffraction analysis. Cocrystal CTD-CAF showed a supramolecular organization in which CAF molecules are embedded in channels of a 3D network of CTD molecules. The advantage of the cocrystal in comparison to CTD is reflected in a threefold solubility increase and in the dose/solubility ratios, which diminished from near-unit values for D_0D to 0.29 for D_0CC. Furthermore, dissolution experiments under non-sink conditions showed improved performance of CTD-CAF compared with pure CTD. Subsequent studies showed that CTD-CAF cocrystals transform to CTD form I where CTD precipitation inhibition could be achieved in the presence of pre-dissolved polymer HPMC 80–120 cPs, maintaining supersaturation drug concentrations for at least 180 min. Finally, dissolution experiments under sink conditions unveiled that the CTD-CAF cocrystal induced, in pH-independent manner, faster and more complete CTD dissolution when compared to commercial tablets of CTD. Due to the stability and dissolution behavior of the novel CTD-CAF cocrystal, it could be used to develop solid dosage forms using a lower CTD dose to obtain the same therapeutic response and fewer adverse effects.

Immobilization of enzymes has many advantages for their application in biotechnological processes. In particular, the cross-linked enzyme aggregates (CLEAs) allow the production of solid biocatalysts with a high enzymatic loading and the advantage of obtaining derivatives with high stability at low cost. The purpose of this study was to produce cross-linked enzymatic aggregates (CLEAs) of LipMatCCR11, a 43 kDa recombinant solvent-tolerant thermoalkaliphilic lipase from Geobacillus thermoleovorans CCR11. LipMatCCR11-CLEAs were prepared using (NH₄)₂SO₄ (40% w/v) as precipitant agent and glutaraldehyde (40 mM) as cross-linker, at pH 9, 20 °C. A U₁₀(5⁶) uniform design was used to optimize CLEA production, varying protein concentration, ammonium sulfate %, pH, glutaraldehyde concentration, temperature, and incubation time. The synthesized CLEAs were also analyzed using scanning electron microscopy (SEM) that showed individual particles of <1 µm grouped to form a superstructure. The cross-linked aggregates showed a maximum mass activity of 7750 U/g at 40 °C and pH 8 and retained more than 20% activity at 100 °C. Greater thermostability, resistance to alkaline conditions and the presence of organic solvents, and better durability during storage were observed for LipMatCCR11-CLEAs in comparison with the soluble enzyme. LipMatCCR11-CLEAs presented good reusability by conserving 40% of their initial activity after 9 cycles of reuse.