Formulation of silymarin binary and ternary solid dispersions: Characterization, simulation study and cell viability assessment against lung cancer cell line.

Silymarin (SL) is a water-insoluble flavonoid used in the treatment of different diseases, but its therapeutic activity is limited due to its low solubility. So, in the present study, SL solid dispersions (SDs) were developed using different carriers like Kollidone VA64 (KL), Soluplus (SP), and Poloxamer 188 (PL) by solvent evaporation (SE), microwave irradiation (MI), and freeze-drying (FD) methods. The phase solubility and saturation solubility studies were assessed to estimate the stability constant as well as the carrier effect. The dissolution studies were performed for prepared SL-SDs (binary and ternary) to select the optimum SL-SDs. The selected SL-SDs (F5, F9) were further characterized for infrared spectroscopy (IR), nuclear magnetic resonance (NMR), differential scanning calorimeter (DSC), scanning electron microscope (SEM), and X-ray diffraction (XRD). Finally, the comparative cell viability assay (lung cancer cell line) was performed to evaluate the change in activity after the formulation of SDs. The phase solubility and solubility study results displayed marked enhancements in solubility. The dissolution study findings showed significant enhancement in drug release from ternary solid dispersions (F7-F9) > ternary physical mixture (PM3) > binary solid dispersions (F1-F6) > binary physical mixture (PM1, PM2) in comparison to free SL. A greater release was observed from ternary SDs due to the addition of PL in the formulation, which had a synergistic effect on increasing the solubility. IR and NMR spectra revealed no chemical interaction between SL, KL, and PL. DSC, XRD, and SEM all confirmed the transformation of crystalline SL into amorphous SL. The cell viability assay demonstrated significantly enhanced results from ternary solid dispersion (F9) compared to free SL. Based on the study results, it can be said that SL-SDs are an alternative way to deliver drugs orally that can improve solubility and have anti-cancer activity.

Assessing the Solubility of Baricitinib and Drug Uptake in Different Tissues Using Absorption and Fluorescence Spectroscopies.

The low water solubility of baricitinib (BCT) limits the development of new formulations for the topical delivery of the drug. The aims of this study were to assess the solubility of BCT in different solvents, including Transcutol, a biocompatible permeation enhancer that is miscible in water, to evaluate the drug uptake in human skin and porcine tissues (sclera, cornea, oral, sublingual, and vaginal), and to subsequently extract the drug from the tissues so as to determine the drug recovery using in vitro techniques. Analytical methods were developed and validated for the quantification of BCT in Transcutol using absorption and fluorescence spectroscopies, which are complementary to each other and permit the detection of the drug across a broad range of concentrations. Results show that Transcutol permits an increased drug solubility, and that BCT is able to penetrate the tissues studied. The solutions of BCT in Transcutol were stable for at least one week. Hence, Transcutol may be a suitable solvent for further development of topical formulations.

In Vivo Investigation of (2-Hydroxypropyl)-ß-cyclodextrin-Based Formulation of Spironolactone in Aqueous Solution for Paediatric Use.

Spironolactone (SPL), a potent anti-aldosterone steroidal drug used to treat several diseases in paediatric patients (e.g., hypertension, primary aldosteronism, Bartter's syndrome, and congestive heart failure), is not available in child-friendly dosage forms, and spironolactone liquids have been reported to be unpalatable. Aiming to enhance SPL solubility in aqueous solution and overcome palatability, herein, the effects of (2-hydroxypropyl)-ß-cyclodextrin (HP-ß-CyD) were thoroughly investigated on solubilisation in water and on masking the unpleasant taste of SPL in vivo. Although the complexation of SPL with HP-ß-CyD was demonstrated through phase solubility studies, Job's plot, NMR and computational docking studies, our in vivo tests did not show significant effects on taste aversion. Our findings, on the one hand, suggest that the formation of an inclusion complex of SPL with HP-ß-CyD itself is not necessarily a good indicator for an acceptable degree of palatability, whereas, on the other hand, they constitute the basis for investigating other cyclodextrin-based formulations of the poorly water-soluble steroidal drug, including solid dosage forms, such as spray-dried powders and orodispersible tablets.

Preparation and Characterization of Water-Insoluble Gardenia Blue Pigment.

Based on molecular simulations, the synthetic route of water-insoluble gardenia blue pigment was prepared by the reaction of genipin and L-Phenylalanine methyl ester hydrochloride. A highly purified pigment was obtained after extraction by chloroform and purification by silica gel column chromatography, and the value of color is up to 288. A study on the structural characteristics of the pigment was implemented with a scanning electron microscope, ultraviolet-visible spectrophotometer, Fourier transform infrared spectrometer, X-ray photoelectron spectrometer, and quatropde-time of flight mass spectrometer. The results showed that the surface of the pigment was largely smooth and spherical; The λmax was 607 nm, and the main functional groups include O-C=O, C=O, C-N, C=C, OH, and benzene ring; We detrained six different molecular weight and chemical structures of pigments and speculated the particular structures and formation mechanisms of three kinds of pigment, whose molecular weights are 690.1156, 720.1226, and 708.1246 Da, respectively. The pigment was only able to be dissolved in ethanol, methanol, acetone, ethyl acetate, and other strong polar organic solvents, but was not able to be dissolved in water, ethyl ether, petroleum ether, and other weak polar organic solvents. In terms of light and thermal stabilities, water-insoluble gardenia blue pigment is significantly better than water-soluble gardenia blue pigment (p < 0.05). When it is under direct light for 7 days or incubated at 80-120 °C for 24 h, the pigment residual rates were 74.90, 95.26, 88.27, and 87.72%, respectively.

Preparation of Soluble Complex of Curcumin for the Potential Antagonistic Effects on Human Colorectal Adenocarcinoma Cells.

This study was designed to investigate the effects of curcumin (CMN) soluble complex (SC) prepared by melt casting (HM) and hot-melt extrusion (HME) technology. Phase solubility (PS) study, in silico molecular modeling, aqueous solubility, drug release, and physicochemical investigation including a novel dyeing test was performed to obtain an optimized complex by a central composite design (CCD). The results show that the HME-SC produces better improvements towards solubility (0.852 ± 0.02), dissolution (91.87 ± 0.21% at 30 min), with an ideal stability constant (309 and 377 M-1 at 25 and 37 °C, respectively) and exhibits AL type of isotherm indicating 1:1 stoichiometry. Intermolecular hydrogen bonding involves the formation of SC, which does not undergo any chemical modification, followed by the complete conversion of the amorphous form which was identified by XRD. The in vitro cytotoxicity showed that IC50 was achieved in the SW480 (72 µM.mL-1) and Caco-2 (40 µM.mL-1) cells while that of pure CMN ranged from 146 to 116 µM/mL-1. Apoptosis studies showed that cell death is primarily due to apoptosis, with a low rate of necrosis. In vivo toxicity, confirmed by the zebrafish model, exhibited the safety of the HME-SC. In conclusion, the HME-SC potentially enhances the solubility and cytotoxicity to the treatment of colorectal cancer (CRC).

The Effect of Molecular Weight on the Solubility Properties of Biocompatible Poly(ethylene succinate) Polyester.

Poly(ethylene succinate) (PES) is one of the most promising biodegradable and biocompatible polyesters and is widely used in different biomedical applications. However, little information is available on its solubility and precipitation properties, despite that these solution behavior properties affect its applicability. In order to systematically study these effects, biodegradable and biocompatible poly(ethylene succinate) (PES) was synthesized using ethylene glycol and succinic acid monomers with an equimolar ratio. Despite the optimized reaction temperature (T = 185 °C) of the direct condensation polymerization, relatively low molecular mass values were achieved without using a catalyst, and the Mn was adjustable with the reaction time (40-100 min) in the range of ~850 and ~1300 Da. The obtained crude products were purified by precipitation from THF ("good" solvent) with excess of methanol ("bad" solvent). The solvents for PES oligomers purification were chosen according to the calculated values of solubility parameters by different approaches (Fedors, Hoy and Hoftyzer-van Krevelen). The theta-solvent composition of the PES solution was 0.3 v/v% water and 0.7 v/v% DMSO in this binary mixture. These measurements were also allowed to determine important parameters such as the coefficients A (=0.67) and B (=3.69 × 104) from the Schulz equation, or the Kη (=8.22 × 10-2) and α (=0.52) constants from the Kuhn-Mark-Houwink equation. Hopefully, the prepared PES with different molecular weights is a promising candidate for biomedical applications and the reported data and constants are useful for other researchers who work with this promising polyester.

Novel Aceclofenac Cocrystals with l-Cystine: Virtual Coformer Screening, Mechanochemical Synthesis, and Physicochemical Investigations.

AIM: Current work focuses on the improvement of the solubility and dissolution of ACF by the cocrystal approach. BACKGROUND: Aceclofenac (ACF) is one of the commonly used Nonsteroidal Anti-Inflammatory Drug (NSAID) representing a variety of therapeutic applications including management of pain, inflammation, rheumatoid arthritis, and osteoarthritis, etc. But very low solubility and dissolution rate of ACF compromise its therapeutic utility. Now a day's cocrystallization technique has emerged as a novel technique for modulation of the said problems. OBJECTIVE: The Specific objectives of this research work were mechanochemical synthesis, characterization, and performance evaluation of aceclofenac cocrystal. METHODS: ACF was screened with various pharmaceutically acceptable coformers (Selected from GRAS and EAFUS list) using MOPAC software and physical screening method to find out novel cocrystals of ACF with enhanced solubility and dissolution rate. Novel cocrystals (multi-component crystalline solid) of ACF with l-cystine were prepared by a neat grinding method and by liquid assisted grinding method. The synthesized cocrystals (ACF-l-CYS NG and ACF-l-CYS LAG) were characterized carefully by Differential Scanning Calorimetry (DSC), Infrared Spectroscopy (IR), and Powder XRay Diffraction (PXRD) to verify the formation of the cocrystals. Pharmaceutically significant properties such as powder dissolution rate, solubility, and stability of the prepared cocrystals were evaluated. RESULTS: Compared to pure ACF, the prepared cocrystals showed superior solubility and dissolution rate. The prepared cocrystals were found to be stable and non-hygroscopic under study conditions. CONCLUSION: The cocrystallization technique was successfully utilized to increase the solubility and dissolution rate of aceclofenac.

Chiral bis(mandelato)borate salts for resolution via metathesis crystallization.

Spiroborate anions have potential for crystallization or resolution and chiral bis(mandelato)borate anions can be used for the efficient resolution of a diverse range of racemic cations via diastereomeric salt formation. The syntheses, X-ray crystal structures and solubilities of three chiral bis(mandelato)borate salts, namely poly[[aqua-µ3-bis[(R)-mandelato]borato-lithium(I)] monohydrate], [Li(C16H12BO6)(H2O)]n or Li[B(R-Man)2]·H2O, (1), ammonium bis[(R)-mandelato]borate, NH4+·C16H12BO6- or NH4[B(R-Man)2], (2), and tetra-n-butylammonium bis[(R)-mandelato]borate, C16H36N+·C16H12BO6- or NBu4[B(R-Man)2], (3), are reported. They all have a BS configuration and show a reasonably well-conserved anion geometry. The main conformational variation is the orientation of the two phenyl groups, supporting the idea that [B(Man)2]- is a semi-rigid anion. The salts are differentially soluble in a range of solvents, meaning they could be useful as reagents for resolution via a metathesis crystallization approach.

6-Triazolyl-6-deoxy-ß-cyclodextrin derivatives: synthesis, cellular toxicity, and phase-solubility study.

Heptakis{6-(4-hydroxymethyl-1H-[1,2,3]triazol-1-yl)-6-deoxy}-ß-cyclodextrin (HTßCD) and heptakis{6-(4-sulfonylmethyl-1H-[1,2,3]triazol-1-yl)-6-deoxy}-ß-cyclodextrin (STßCD) were prepared using copper(I)-catalyzed azide-alkyne cycloaddition between 6-azido-6-deoxy-ß-CD and one of two alkynes, propargyl alcohol, and sodium propargyl sulfonate, respectively. The structures of HTßCD and STßCD were characterized by NMR techniques. NMR interpretations and computer modeling suggested that the limited freedom of rotation of the triazole moieties keeps HTßCD and STßCD rigid and compact. Water solubility tests of HTßCD and STßCD showed that the minimum water solubility of HTßCD and STßCD is at least 20times higher than that of ß-CD. MTT assay showed that HTßCD and STßCD did not influence the cell viability under 1mM. A phase-solubility study of prednisolone with the CD derivatives showed increased solubility of prednisolone in the presence of increasing concentrations of HTßCD and STßCD.

Determination and Quantification of Molecular Interactions in Protein Films: A Review.

Protein based films are nowadays also prepared with the aim of replacing expensive, crude oil-based polymers as environmentally friendly and renewable alternatives. The protein structure determines the ability of protein chains to form intra- and intermolecular bonds, whereas the degree of cross-linking depends on the amino acid composition and molecular weight of the protein, besides the conditions used in film preparation and processing. The functionality varies significantly depending on the type of protein and affects the resulting film quality and properties. This paper reviews the methods used in examination of molecular interactions in protein films and discusses how these intermolecular interactions can be quantified. The qualitative determination methods can be distinguished by structural analysis of solutions (electrophoretic analysis, size exclusion chromatography) and analysis of solid films (spectroscopy techniques, X-ray scattering methods). To quantify molecular interactions involved, two methods were found to be the most suitable: protein film swelling and solubility. The importance of non-covalent and covalent interactions in protein films can be investigated using different solvents. The research was focused on whey protein, whereas soy protein and wheat gluten were included as further examples of proteins.