Phase Solubility Diagrams Research Articles

Mono-Dendronized β-Cyclodextrin Derivatives as Multitasking Containers for Curcumin. Impacting Its Solubility, Loading, and Tautomeric Form.

In this study, three mono-dendronized β-cyclodextrin (βCD) derivatives (βCD-1G, βCD-2G, and βCD-3G) were used as multitasking containers of curcumin (CUR) to influence its aqueous solubility and tautomerism, both of which are related to its biological activity. We evaluated the relevant physicochemical properties of these containers associated with their potential hosting capacity. All mono-dendronized derivatives exhibited enhanced solubility in different solvents, including water, in comparison with native βCD. Gas-phase geometry optimizations by density functional theory (DFT) confirmed that none of the dendrons blocked the passage of CUR into the βCD cavity, and depending on the generation, different preorganization scenarios were promoted before complexation. Phase solubility diagrams showed that all the dendronized containers have superior performance for solubilizing CUR compared to native βCD. We proved that coprecipitation is most efficient than lyophilization for forming inclusion complexes (ICs) with dendronized containers. Even though βCD-3G with the largest 3G dendron exhibited the highest CUR loading, the complexation of CUR with βCD-2G provided the supramolecular system that contains CUR preferentially in its diketo tautomer, which is known for its antioxidant activity.

Novel treatment for refractory rheumatoid arthritis with total glucosides of paeony and nobiletin codelivered in a self-nanoemulsifying drug delivery system.

Patients with refractory rheumatoid arthritis (RA) remain a substantial clinical problem, while the overexpression of P-glycoprotein (P-gp) on their lymphocytes may contribute to resistance to anti-rheumatic drugs. This study aims to develop a novel treatment for refractory RA consisting of the combination of total glucosides of paeony (TGPs) and the P-gp inhibitor nobiletin (N), which are codelivered in a self-nanoemulsifying drug delivery system (SNEDDS). Based on the solubility, compatibility, and pseudoternary phase diagram tests, a nano-SNEDDS formulation composed of capryol 90-cremophor EL35-tcranscutol HP (CET) to codeliver TGP and N was developed, and this formulation increased the bioavailability of TGP by 435.04% (indicated with paeoniflorin). A modified adjuvant-induced arthritis (AIA) rat model was verified for the overexpression of P-gp in lymphocytes and resistance to methotrexate (MTX) treatment at the reported anti-inflammatory dosage. CET formulation not only increased the solubility and permeability of TGP but also inhibited the function and expression of P-gp, leading to enhanced bioavailability and intracellular concentration in the lymphocytes of AIA rats and consequently boosting the anti-arthritic effects of TGP. Moreover, TGP and N coloaded CET reduced the expression of P-gp in AIA rats partly by inhibiting the phosphorylated AKT and HIF-1α pathways. In summary, TGP-N coloaded SNEDDS is a novel and effective treatment for refractory RA.

Host-guest inclusion systems of two bioactive natural products derivantives and three polyamine-modified β-cyclodextrins: Preparation, characterization, biological activity

Two bioactive natural products derivatives including hydroxycamptothecin (HCPT) and etoposide (EPEG), which are one of the most common classes of first-line anticancer drugs used for the treatment of cancer. Of note, their application is still limited by poor water solubility and bioavailability. Therefore, it is very important to develop a new means to solve these shortcomings. In this work, the molecular binding behavior of three polyamine-modified β-cyclodextrins (H1-3) with HCPT and EPEG was investigated. The six novel H1-3/HCPT (EPEG) inclusion complexes were prepared and characterized by Fourier transform infrared spectrometry (FTIR), 2D nuclear magnetic resonance (2D ROESY), 1H nuclear magnetic resonance (NMR), X-ray powder diffraction (XRD) and scanning electron microscopy (SEM). The phase solubility diagrams indicated that the stability constants (K1:1) of host H1-3 to the free drugs decrease sequentially as follows: H3>H2>H1. After forming inclusion complexes with H1-3, the water solubility of HCPT (EPEG) were obviously increased from the initial value of 0.0011 mg/mL (0.373 mg/mL) to 0.90 mg/mL (32.55 mg/mL), 2.01 mg/mL (38.73 mg/mL), and 2.39 mg/mL (47.42 mg/mL), enhanced by 84.9–225.5 times compared with the free drug, respectively. The in vitro release tests confirmed that the cumulative release of drug from H1-3/EPEG (HCPT) complexes was significantly higher than that from free drug solution in 50 h. The cytotoxicity assay showed that the H1/HCPT exhibited higher cytotoxicity towards MCF-7 cell in comparison to the free drug HCPT. Meanwhile, the toxicity of HCPT is obviously reduced after the formation of H2/HCPT. Apoptosis experiments revealed that the percentage of apoptotic cells was increased by H3/HCPT (65.80%), which close to increasing by free drugs HCPT (74.00%) when the concentrations of H3/HCPT and HCPT reached to a certain level (5.0 μg/mL). The satisfactory water solubility, high activity, and low toxicity of H1-3/HCPT (EPEG) inclusion complexes contributes to research with new applications of the HCPT and EPEG as anticancer drug formulations.

Preparation, characterization, dissolution, and permeation of flibanserin − 2-HP-β-cyclodextrin inclusion complexes

Flibanserin (FLB), an antiserotonin drug, is used to treat women with hypoactive sexual appetite disorder. FLB shows low bioavailability (~33%) probably due to its low water solubility. The current study investigated the impact of hydroxypropyl-β-cyclodextrin (HP-β-CD) and sodium lauryl sulfate (SLS) on the dissolution and permeation of FLB. HP-β-CD–FLB inclusion complexes were prepared using physical mixing and kneading at 1:1 and 1:2 M ratios and characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffractometry. The dissolution and permeation of the complexes through a cellophane membrane were performed in, 0.1, 0.3 and 0.5% SLS in phosphate buffer (pH 6.8).Derived from the slope of the linear phase solubility diagram, the apparent stability constant (K1:1) was 372.54 M−1. Kneading changed the crystalline form of FLB to an amorphous appearance characterized by minimal crystalline peaks, indicating successful inclusion complex formation. In addition, the HP-β-CD–FLB inclusion complexes showed twofold increased dissolution efficiency at 6 h. The cumulative FLB amount permeated at 6 h increased from 14.1% to 21.88% and 34.56% in the presence of 0.1% and 0.3% of SLS, respectively. However, increasing SLS to 0.5% did not show an increase in FLB permeation. Therefore, the HP-β-CD–FLB inclusion complex has an improved dissolution rate compared to FLB alone. The presence of SLS in the dissolution medium increases the dissolution rate of pure FLB and its complex with HP-β-CD. kneaded 1:1 complex was formulated bioadhesive buccal tablets and showed enhanced drug release.

In Vitro Microbiological and Drug Release of Silver/Ibuprofen Loaded Wound Dressing Designed for the Treatment of Chronically Infected Painful Wounds.

This study consisted of developing a dressing loaded with silver (Ag) and ibuprofen (IBU) that provides a dual therapy, antibacterial and antalgic, intended for infected painful wounds. Therefore, non-woven polyethyleneterephtalate (PET) textiles nonwovens were pre-treated by cyclodextrin crosslinked with citric acid by a pad/dry/cure process. Then, textiles were impregnated in silver solution followed by a thermal treatment and were then coated by Layer-by-Layer (L-b-L) deposition of a polyelectrolyte multilayer (PEM) system consisting of anionic water-soluble poly(betacyclodextrin citrate) (PCD) and cationic chitosan. Finally, ibuprofen lysinate (IBU-L) was loaded on the PEM coating. We demonstrated the complexation of IBU with native βCD and PCD by phase solubility diagram and 1H NMR. PEM system allowed complete IBU-L release in 6 h in PBS pH 7.4 batch (USP IV). On the other hand, microbiological tests demonstrated that loaded silver induced bacterial reduction of 4 Log10 against S. aureus and E. coli and tests revealed that ibuprofen lysinate loading did not interfere with the antibacterial properties of the dressing.

Inclusion complexation of the anticancer drug pomalidomide with cyclodextrins: fast dissolution and improved solubility

Pomalidomide (POM), a potent anticancer thalidomide analogue was characterized in terms of cyclodextrin complexation to improve its aqueous solubility and maintain its anti-angiogenic activity. The most promising cyclodextrin derivatives were selected by phase-solubility studies. From the investigated nine cyclodextrins – differing in cavity size, nature of substituents, degree of substitution and charge – the highest solubility increase was observed with sulfobutylether-β-cyclodextrin (SBE-β-CD). The inclusion complexation between POM and SBE-β-CD was further characterized with a wide variety of state-of-the-art analytical techniques, such as nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), circular dichroism spectroscopy, fluorescence spectroscopy as well as X-ray powder diffraction method (XRD). Job plot titration by NMR and the AL-type phase-solubility diagram indicated 1:1 stoichiometry in a liquid state. Complementary analytical methods were employed for the determination of the stability constant of the complex; the advantages and disadvantages of the different approaches are also discussed. Inclusion complex formation was also assessed by molecular modelling study. Solid state complexation in a 1:1 M ratio was carried out by lyophilization and investigated by IR and XRD. The complex exhibited fast-dissolution with immediate release of POM, when compared to the pure drug at acidic and neutral pH. Kinetic analysis of POM release from lyophilized complex shows that Korsmeyer-Peppas and Weibull model described the best the dissolution kinetics. The cytotoxicity of the complex was tested against the LP-1 human myeloma cell line which revealed that supramolecular interactions did not significantly affect the anti-cancer activity of the drug. Overall, our results suggest that the inclusion complexation of POM with SBE-β-CD could be a promising approach for developing more effective POM formulations with increased solubility.

Studying the Complex Formation of Sulfonatocalix[4]naphthalene and Meloxicam towards Enhancing Its Solubility and Dissolution Performance.

The interaction between meloxicam and sulfonatocalix[4]naphthalene was investigated to improve the meloxicam solubility and its dissolution performance. Solubility behavior was investigated in distilled water (DW) and at different pH conditions. Besides, solid systems were prepared in a 1:1 molar ratio using coevaporate, kneading, and simple physical mixture techniques. Further, they were characterized by PXRD, FT-IR, DCS, and TGA. In vitro dissolution rate for coevaporate, kneaded, and physical mixture powders were also investigated. Solubility study revealed that meloxicam solubility significantly increased about 23.99 folds at phosphate buffer of pH 7.4 in the presence of sulfonatocalix[4]naphthalene. The solubility phase diagram was classified as AL type, indicating the formation of 1:1 stoichiometric inclusion complex. PXRD, FT-IR, DCS, and TGA pointed out the formation of an inclusion complex between meloxicam and sulfonatocalix[4]naphthalene solid powders prepared using coevaporate technique. In addition, in vitro meloxicam dissolution studies revealed an improvement of the drug dissolution rate. Furthermore, a significantly higher drug release (p ≤ 0.05) and a complete dissolution was achieved during the first 10 min compared with the other solid powders and commercial meloxicam product. The coevaporate product has the highest increasing dissolution fold and RDR10 in the investigated media, with average values ranging from 5.4–65.28 folds and 7.3–90.7, respectively. In conclusion, sulfonatocalix[4]naphthalene is a promising host carrier for enhancing the solubility and dissolution performance of meloxicam with an anticipated enhanced bioavailability and fast action for acute and chronic pain disorders.

Використання полімерних композиційних матеріалів для підвищення біодоступності гесперидина

Purpose. Investigation of the influence of the composition of polymeric solubilizers on the phase solubilization in water of the model active pharmaceutical ingredient of flavonoid nature hesperidin.Methods. Hesperidin was chosen as a model substance of characteristic chemical structure. Pharmaceutically acceptable high molecular weight polymers based on polyvinylpyrrolidone (PVP) with a molecular weight of from 2500 to 58000 D were used for research; cetylpyridinium chloride; β-cyclodextrin. Phase solubilization of hesperidin was investigated by the method of Higuchi and Connors. The concentration of hesperidin was determined spectrophotometrically by absorption at 284 nm. The phase solubility diagram was constructed as the dependence of the concentration of hesperidin in solution on the concentration of the polymer. The obtained phase solubility profiles of hesperidin were compared with standard curves. For different compositions at the experiment temperature of 37 ± 0.5 °C, the stability constant and the dissociation constant of intermolecular complexes were calculated.Scientific novelty. The influence of the composition of polymer solubilizers on the phase solubilization in water of the model API of flavonoid nature of hesperidin was established. Practical significance. The optimal composition of the polymer composite material with hesperidin in the form of a solid dispersed system to maximize the solubility of flavonoids in water is substantiated. Results. The influence of the composition of polymer solubilizers on the phase solubilization in water of the model API of flavonoid nature of hesperidin was investigated. Based on the results of graphical analysis of the obtained data, it was concluded that the solubility of hesperidin increases with increasing number of polymers with different molecular weights and surfactants. The increase in solubility depends on the composition. When adding several polymers or a combination of a polymer with a surfactant, the solubility increases significantly more than when adding one compound. It is shown that the maximum value of solubility increase is observed in the system with polymer C and K surfactant - 42.7 times. It was found that the stability constants of polymeric composite materials of hesperidin based on polyvinylpyrrolidones are in the range from 161.87 to 219.88 M-1, which indicates favorable conditions for the formation of complexes.

Improved water solubility of quercetin by preparing complexation with cyclodextrins in binary solvent

The antioxidant capacity of polyphenols have been widely used in food and pharmaceutical industries. Quercetin (Quer) is a polyphenolic flavonoid that shows several biological effects such as antioxidant, antitumor, antibacterial and antiproliferative effects both in-vitro and in-vivo. However, the solubility of quercetin in water is poor. Thus, it is essential to improve solubility of quercetin in pharmaceuticals by making its complexation with other compounds. In this study, the synthesis of the 2-hydroxypropyl-β-cyclodextrin complex with quercetin (Quer-HPβCD) in the form of nanoparticles in water-ethanol solvents has been carried out. The results showed that the obtained yield of (Quer-HPβCD) complexation in binary solvent was greater than that in pure water. The highest Y value was 80% in a binary solvent with 20% v/v of ethanol. The composition, morphology, structural and thermodynamic properties of the nanoparticles Quer-HPβCD have been determined. This study demonstrated that using mixed water- ethanol solvent and lyophilization technique was able to produce quercetin nanoparticles with significantly smaller particle size. The nanoparticles have a spherical shape with an average size of about 40-60 nm. The results of the phase solubility diagram showed that in water the solubility of quercetin increased and linearly depended on the concentration of host’s molecule while Quer and HP-βCD obtained a 1:1 stoichiometric complex. The stability constant of (Quer-HPβCD) complex was found to be logK = 2.56. The Gibbs energy change of the complexation reaction was found to be -14.60 kJ/mol.

Bergenin-isonicotinamide (1:1) cocrystal with enhanced solubility and investigation of its solubility behavior

Bergenin (BER) is a bioactive compound used for the treatment of chronic bronchitis in China. However, its low solubility and permeation limits its oral bioavailability. In this study, a new BER: isonicotinamide (ISN) cocrystal (1: 1, molar ratio) was reported for the first time. BER-ISN shows better solubility and intrinsic dissolution rates (IDRs) in aqueous medias such as water, buffer solutions with pH = 1.2, 4.5, and 6.8 in comparison to BER monohydrate. For instance, the solubilities of BER-ISN and BER monohydrate in water were 3.72 ± 0.22 and 1.42 ± 0.006 mg/mL, respectively, showing 2.62 times improvement. IDRs of BER-ISN and BER monohydrate were 29.90 ± 0.04 and 18.64 ± 0.27 mg/min/cm2, respectively, which was consistent with the solubility results. To explain the solubility behavior, phase solubility diagrams of BER monohydrate, ISN and BER-ISN in three pure organic solvents (ethanol, isopropanol and ethyl acetate) were performed according to the solubility product (Ksp) and complexes formation (K11) theory. The predicted solubilities are consistent with experimental solubilities considering complexation effects. The Hildebrand solubility parameter (HSP) calculations support the results. Thus, BER-ISN cocrystal (1: 1) with improved solubility is a good candidate for further formulation development.

Phase solubility diagrams and energy surface calculations support the solubility enhancement with low hygroscopicity of Bergenin: 4-Aminobenzamide (1: 1) cocrystal

Herein, we reported a new bergenin: 4-aminobenzamide (BGN-4AM) cocrystal with significantly enhanced solubility and low hygroscopicity probed from two aspects such as phase solubility diagrams and theoretical calculations. Compared with anhydrous BGN, BGN-4AM solubilities in water and different buffer solutions (pH = 1.2, 4.5, 6.8) increase significantly. It is noted that BGN-4AM solubility in pH = 6.8 buffer solution presents 32.7 times higher than anhydrous BGN. Interestingly, BGN-4AM (0.31 ± 0.07%) showcases lower hygroscopicity than anhydrous BGN (9.31 ± 0.16%). The predicted and experimental solubilities agree with each other when considering solubility product (Ksp) and solution binding constant (K11) in phase solubility diagrams, indicating the solution complexes formation occurs. Further crystal surface-water interactions and Bravais, Friedel, Donnay-Harker (BFDH) analyses based on Density Functional Theory with dispersion correction (DFT-d) methods support the enhanced solubility. The water probe demonstrates an average interaction energy of −6.48 kcal/mol on the 002 plane of BGN-4AM, and only −5.47 kcal/mol on the 011 plane of BGN monohydrate. The lower lattice energy of BGN-4AM guarantees its lower hygroscopicity than BGN monohydrate. BGN-4AM with enhanced solubility and low hygroscopicity can be a potential candidate for further formulation development.

Phase solubility investigation and theoretical calculations on drug-drug cocrystals of carbamazepine with Emodin, Paeonol

Carbamazepine (CBZ), a Biopharmaceutics Classification System (BCS) class II drug, is widely-used as a first line antiepileptic drug. Numbers of cocrystals have reported to regulate its poor solubility. However, the solubility behaviors are rarely discussed on theoretical calculations and phase solubility diagrams. In this study, two new drug-drug cocrystals (DDC) of CBZ with emodin (EMO, 1: 1) and paeonol (PAE, 1: 1) as conformers, which offer the advantages of synergetic therapy and patient compliance are reported for the first time. The solubilities in water and in pH = 1.2, 6.8 buffer solutions, demonstrating that the rank order is as follows: CBZ-PAE > CBZ > CBZ-EMO. CBZ-PAE presents the biggest solubility at 0.563 ± 0.003 mmoL/L of in water among all the investigated samples. The solubilities of all the starting materials and cocrystals in six pure organic solvents such as methanol, ethanol, 2-propanol, acetone, acetonitrile, ethyl acetate were investigated to discuss the phase solubility diagrams. The results indicate that experimental solubilities are consistent with the theoretical solubilities on consideration of solubility product (Ksp) and solution binding constant (K11) together. The enthalpy differences between cocrystal and its coformer are calculated through the Perdew-Burke-Ernzerhof (PBE) functional with the projector augmented wave (PAW) pseudopotentials. CBZ-EMO presents the lowest enthalpy (−0.38 kcal/mol) with a highly unfavorable solvation energy (2.42 kcal/mol), resulting in unfavorable in an aqueous environment. Overall, the phase solubility diagrams and theoretical calculations support the solubility regulations on DDCs of CBZ.

Development and Characterization of a Tacrolimus/Hydroxypropyl-β-Cyclodextrin Eye Drop.

Uveitis is a vision inflammatory disorder with a high prevalence in developing countries. Currently, marketed treatments remain limited and reformulation is usually performed to obtain a tacrolimus eye drop as a therapeutic alternative in corticosteroid-refractory eye disease. The aim of this work was to develop a mucoadhesive, non-toxic and stable topical ophthalmic formulation that can be safely prepared in hospital pharmacy departments. Four different ophthalmic formulations were prepared based on the tacrolimus/hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complexes’ formation. Phase solubility diagrams, Nuclear Magnetic Resonance (NMR) and molecular modeling studies showed the formation of 1:1 and 1:2 tacrolimus/HPβCD inclusion complexes, being possible to obtain a 0.02% (w/v) tacrolimus concentration by using 40% (w/v) HPβCD aqueous solutions. Formulations also showed good ophthalmic properties in terms of pH, osmolality and safety. Stability studies proved these formulations to be stable for at least 3 months in refrigeration. Ex vivo bioadhesion and in vivo ocular permanence showed good mucoadhesive properties with higher ocular permanence compared to the reference pharmacy compounding used in clinical settings (t1/2 of 86.2 min for the eyedrop elaborated with 40% (w/v) HPβCD and Liquifilm® versus 46.3 min for the reference formulation). Thus, these novel eye drops present high potential as a safe alternative for uveitis treatment, as well as a versatile composition to include new drugs intended for topical ophthalmic administration.

Solubility enhancement of mefenamic acid by inclusion complex with β-cyclodextrin: in silico modelling, formulation, characterisation, and in vitro studies

The aim of this study was to prepare and characterise inclusion complexes of a low water-soluble drug, mefenamic acid (MA), with β-cyclodextrin (β-CD). First, the phase solubility diagram of MA in β-CD was drawn from 0 to 21 × 10−3 M of β-CD concentration. A job’s plot experiment was used to determine the stoichiometry of the MA:β-CD complex (2:1). The stability of this complex was confirmed by molecular modelling simulation. Three methods, namely solvent co-evaporation (CE), kneading (KN), and physical mixture (PM), were used to prepare the (2:1) MA:β-CD complexes. All complexes were fully characterised. The drug dissolution tests were established in simulated liquid gastric and the MA water solubility at pH 1.2 from complexes was significantly improved. The mechanism of MA released from the β-CD complexes was illustrated through a mathematical treatment. Finally, two in vitro experiments confirmed the interest to use a (2:1) MA:β-CD complex.

Insights to the phase solubility diagrams of flurbiprofen with inclusion complex

Insights to the phase solubility diagrams of flurbiprofen with inclusion complex

Molecular dynamics simulations and theoretical calculations of cyclodextrin-polydatin inclusion complexes

In our previous work, the PD/γ-cyclodextrin complex was discovered to have higher calculated Kc and Gibbs free energy (ΔG0) values by the phase-solubility diagram method, and molecular dynamics (MD) simulations were carried out to investigate the structure and dynamics of the 1:1 inclusion complexes formed by β- and γ-cyclodextrins (CD) with PD in water. The simulation results indicated that γ-CD provides the most stable inclusion complex of among all PD-CD complexes in this study. Similar to the MD results, the thermodynamics of the selected inclusion complex structure was calculated by semi-empirical (PM3) and DFT (B3LYP/6-31G) methods. The statistical thermodynamics calculations also suggested that orientation b (including in CD's cavity from the wide side) of the PD/γ-CD inclusion complex is a favourable binding mode and in good agreement with the experimental and MD data. Most importantly, the simulation results of present study are in good agreement with the experimental data.

Thermodynamic parameters and mitochondrial effects of supramolecular complexes of quercetin with β-cyclodextrins

The aim of the present study was to evaluate the thermodynamic parameters of the formation of supramolecular complexes of the flavonoid quercetin, a plant polyphenol with high therapeutic activity, and the molecular containers, β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD), as well as to assess the effects of quercetin and the quercetin - HPβСD complex on the functional activity of isolated rat liver mitochondria. The formation of the complex (stoichiometry 1:1) resulted in a marked elevation of quercetin water solubility: more than 5-fold in the case of 16 mM βCD (the association constant was equal to 300±45 М−1 as determined by the method of phase solubility diagram), and more than 50-fold in the case of 16 mM HPβCD (the association constant was equal to 3275±450 М−1), which reflects increased bioavailability of quercetin. In comparison, the association constant of the polyphenol sesamin - HPβСD complex formation (stoichiometry 1:1 and 1:2) was 2500 ± 350 М−1, and the solubility of sesamin in the complex increased more than 60-fold in the case of 10 mM HPβСD. The inclusion complex formation was spontaneous and exothermic, and both the enthalpic and entropic effects competed during complexation of polyphenol molecules with HPβCD, but the enthalpic factor was dominating in the bounding process in the case of quercetin and the entropic factor – in the case of sesamin. Quercetin and the quercetin - HPβCD complex considerably inhibited the respiratory activity of mitochondria, and uncoupled the oxidation and phosphorylation reactions, whereas quercetin alone, and not the complex, enhanced the mitochondria susceptibility to Ca2+-induced mitochondrial permeability transition (MPT). The complex quercetin - HPβCD (10–50 μM) was much more effective in preventing mitochondrial reduced glutathione depletion and α-ketoglutarate dehydrogenase impairment during mitochondria exposure to hypochlorous acid in comparison with the quercetin water solution due to enhanced availability of mitochondria matrix components to the antioxidant (quercetin). The decrease of quercetin lipophilicity after the complexation with HPβCD attenuated the effects on mitochondrial respiration and changed the direction of the effect on the MPT process owing to the quercetin redistribution between water and lipid phases.

Improvement of Pharmaceutical Properties of Zerumbone, a Multifunctional Compound, Using Cyclodextrin Derivatives.

Zerumbone is a multifunctional compound which shows various biological activities, such as antitumor activity, anti-inflammatory activity, antiulcer activity, etc. However, to use Zerumbone as functional foods or medicines, its pharmaceutical properties such as solubility should be improved. In the present study, we prepared its inclusion complexes with various cyclodextrin (CyD) derivatives, and evaluated their solubility, release profile of the drug and cytotoxic activity. Among 11 CyDs, sulfobutylether (SBE)-β-CyD showed the highest solubilizing effect for Zerumbone. Phase solubility diagrams of SBE-β-CyD/Zerumbone in 10% methanol solution showed AL type, and the stability constant was 756 M-1. SBE-β-CyD also formed the solid complex with Zerumbone by kneading for 90 min. Importantly, the dissolution rate of Zerumbone was improved by complexation with SBE-β- and hydroxypropyl (HP)-β-CyDs, and its supersaturation was maintained for several hours. The solubilizing effects by SBE-β-CyD was greater than that of HP-β-CyD. Moreover, SBE-β-CyD/Zerumbone complex also retained the cytotoxic activity of Zerumbone. These results suggest that CyDs, especially SBE-β-CyD, were useful to improve the solubility of Zerumbone.

Ultrasonic-assisted efficient synthesis of inclusion complexes of salsalate drug and β-cyclodextrin derivatives for potent biomedical applications

The inclusion complexes of the salsalate drug (SLT) with β-cyclodextrin derivatives (β-CDs); namely, β-cyclodextrin (β-CD), hydroxypropyl-β-cyclodextrin (HPβ-CD), and sulfobutylether-β-cyclodextrin (SBEβ-CD) are synthesized using the ultrasound process. The enhanced aqueous solubility of SLT is demonstrated by phase solubility diagram and optical spectroscopy, showing the inclusion complexation of β-CDs and SLT with a 1:1 stoichiometry. The β-CDs:SLT inclusion complexes exhibit potent bacterial activity against Staphylococcus aureus and Escherichia coli and reduce the cytotoxic effects of SLT on MCF-7 cells. The β-CDs:SLT complexes display further important activity for the inhibition of α-amylase and α-glucosidase, indicating their antidiabetic capability. The designed and synthesized inclusion complexes of SLT with β-CDs are widely expected to have potential applications in the preparation of novel pharmaceutical formulations containing SLT.

Phase diagrams and thermochemical modeling of salt lake brine systems. IV. Thermodynamic framework and program implementation for multicomponent systems

This paper is part of a series of studies on the development of a multi-temperature thermodynamically consistent model for salt lake brine systems. The objective of this study is to extend the binary thermodynamic models published in our previous studies to multicomponent systems. A revised general Pitzer–Simonson–Clegg (PSC) gE,∗ equation for multicomponent system is proposed without limitation on the number of components. From the gE,∗ equation, mathematical expressions of the activity coefficient of each component as well as the excess enthalpy and excess heat capacity of the aqueous phase are derived. Based on the multicomponent PSC equations and the CALPHAD-type thermodynamic framework, a generic command-line based program, named ISLEC, was developed for the thermodynamic modeling of aqueous system. The performance of the model and program were tested using three case studies based on typical systems. In the first case study, a temperature-dependent model for a six-component system of Li+-Na+-K+-Mg2+-Ca2+-Cl--H2O was developed based our previous published binary models and the regressed mixing parameters developed in this study. The model well represents the phase equilibrium and activity properties of all 10 sub-ternary systems well over a wide temperature range. These ternary models are generally valid from the lowest eutectic temperature to approximately 373.15 K. For most of the studied ternary systems, the original PSC model is valid for solubility isotherm and phase diagram modeling. However, for the LiCl + KCl + H2O and KCl + CaCl 2+ H2O ternary systems, the revised PSC equations are advantageous in describing the solid-liquid phase equilibria, especially at elevated temperatures. Using the parameters determined in binary and ternary systems, the Li+-Na+-K+-Mg2+-Ca2+-Cl--H2O model system reproduces the phase diagrams of its 10 sub-quaternary and two of its sub-quinary systems (LiCl + NaCl + KCl + MgCl2+H2O and NaCl + KCl + MgCl2+CaCl2+H2O) generally well at various temperatures. However, the reliability of our model predictions of the thermal properties of multicomponent aqueous mixture cannot be assured, and the differences from experimental data are usually large. Thus, the thermal data generated from our model should be used with caution for multicomponent systems. The evaporation and cooling crystallization processes of Dead Sea brine, which is a six-component Li+–Na+–K+–Mg2+-Ca2+-Cl--H2O system, were simulated to test the ISLEC program. The results demonstrate the satisfactory performance of the ISLEC program for solving multiphase equilibria in systems containing at least six components. In the second case study, the PSC equations were applied to model the solubility isotherms in a neutral-solute-containing system: H3BO3+NaCl + H2O. The results are excellent, but additional H3BO3-containing systems should be studied for further validation. In the last case study, mass and energy balance simulations were performed for the process of KCl production using sylvinite as the raw material, thus revealing the applications of ISLEC for process design and simulation.