Experimental Examination of Solubility and Lipophilicity as Pharmaceutically Relevant Points of Novel Bioactive Hybrid Compounds.

The important physicochemical properties of three novel bioactive hybrid compounds with different groups (-CH3, -F and -Cl) were studied, including kinetic and thermodynamic solubility in pharmaceutically relevant solvents (buffer solutions and 1-octanol) as well as partition coefficient in system 1-octanol/buffer pH 7.4. The aqueous solubility of these chemicals is poor and ranged from 0.67 × 10-4 to 1.98 × 10-3 mol·L-1. The compounds studied are more soluble in the buffer pH 2.0, simulating the gastrointestinal tract environment (by an order of magnitude) than in the buffer pH 7.4 modelling plasma of blood. The solubility in 1-octanol is significantly higher; that is because of the specific interactions of the compounds with the solvent. The prediction solubility behaviour of the hybrid compounds using Hansen's three-parameter approach showed acceptable results. The experimental solubility of potential drugs was successfully correlated by means of two commonly known equations: modified Apelblat and van't Hoff. The temperature dependencies of partition coefficients of new hybrids in the model system 1-octanol/buffer pH 7.4 as a surrogate lipophilicity were measured by the shake flask method. It was found that compounds demonstrated a lipophilic nature and have optimal values of partition coefficients for oral absorption. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than fluconazole. In addition, the thermodynamic aspects of dissolution and partition processes have been examined. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than the reference drug.

Solubility and Thermodynamic Data of Febuxostat in Various Mono Solvents at Different Temperatures.

This study examines the solubility and thermodynamics of febuxostat (FBX) in a variety of mono solvents, including "water, methanol (MeOH), ethanol (EtOH), isopropanol (IPA), 1-butanol (1-BuOH), 2-butanol (2-BuOH), ethylene glycol (EG), propylene glycol (PG), polyethylene glycol-400 (PEG-400), ethyl acetate (EA), Transcutol-HP (THP), and dimethyl sulfoxide (DMSO)" at 298.2−318.2 K and 101.1 kPa. The solubility of FBX was determined using a shake flask method and correlated with "van't Hoff, Buchowski-Ksiazczak λh, and Apelblat models". The overall error values for van't Hoff, Buchowski-Ksiazczak λh, and Apelblat models was recorded to be 1.60, 2.86, and 1.14%, respectively. The maximum mole fraction solubility of FBX was 3.06 × 10−2 in PEG-400 at 318.2 K, however the least one was 1.97 × 10−7 in water at 298.2 K. The FBX solubility increased with temperature and the order followed in different mono solvents was PEG-400 (3.06 × 10−2) > THP (1.70 × 10−2) > 2-BuOH (1.38 × 10−2) > 1-BuOH (1.37 × 10−2) > IPA (1.10 × 10−2) > EtOH (8.37 × 10−3) > EA (8.31 × 10−3) > DMSO (7.35 × 10−3) > MeOH (3.26 × 10−3) > PG (1.88 × 10−3) > EG (1.31 × 10−3) > water (1.14 × 10−6) at 318.2 K. Compared to the other combinations of FBX and mono solvents, FBX-PEG-400 had the strongest solute-solvent interactions. The apparent thermodynamic analysis revealed that FBX dissolution was "endothermic and entropy-driven" in all mono solvents investigated. Based on these findings, PEG-400 appears to be the optimal co-solvent for FBX solubility.

Stabilization of Hybrid Adhesives and Sealants by Thermodynamic Tuning of Molecularly Optimized Lignin Bio-Additives: Small Changes, Big Effects.

The use of lignin as a functional additive has long been a promising topic in both industry and academia, but the development of such systems is still limited by the considerable challenges posed by the incompatibility of lignin with common polymers. Herein, we designed modified silicone (MS) sealants with enhanced UV and thermal stability by incorporating molecularly engineered lignin bio-additives while establishing robust design principles to finely adjust the morphology of such blends by tailoring the molecular structures of lignin fractions. To that end, we first constructed a library of lignin fractions with various molecular weights (obtained by fractionating Kraft lignin and by using a lignin model compound) and with several chemical modifications (acetylation, butyrylation, and silylation). The lignin bio-additives were then melt-blended with MS polyethers. The experimental phase diagrams of the resulting blends were established and rationalized with a thermodynamic framework combining Hansen solubility parameters and Flory-Huggins theory, unraveling fascinating insights into the complex solubility behavior of lignin fractions and notably, for the first time, the subtle interplay between molecular weight (entropic effects) and chemical modifications (enthalpic effects). A molecularly optimized lignin additive was then selected to achieve full solubility while providing better thermal stability and UV-blocking properties to the resulting MS material. Overall, this article provides robust design principles for the elaboration of functional biomaterials with optimized morphologies based on rationally engineered lignin fractions.

Solubilization of a novel antitumor drug ribociclib in water and ten different organic solvents at different temperatures.

OBJECTIVE: This study reports new solubility and physicochemical data for ribociclib (RCB) in water and ten organic solvents including "methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA), n-butanol (n-BuOH), propylene glycol (PG), polyethylene glycol-400 (PEG-400), acetone, ethyl acetate (EA), Transcutol-HP (THP), and dimethyl sulfoxide (DMSO)" at 293.2-313.2 K and 101.1 kPa. SIGNIFICANCE: The obtained data are useful for the industrial applications of RCB. METHODS: The solubility of RCB was measured and regressed using "van't Hoff, Buchowski-Ksiazczak λh, the modified Apelblat, and Jouyban models." RESULTS: The overall deviations of <4.0% were recorded for all four models. The maximum mole fraction solubility of RCB was 2.66 × 10-2 in PEG-400 at 313.2 K, however, the lowest one was in the water. The RCB solubility increased with temperature and the order followed in the water and ten different organic solvents was PEG-400 (2.66 × 10-2) > THP (1.00 × 10-2) > PG (5.39 × 10-3) > DMSO (5.00 × 10-3) > n-BuOH (3.23 × 10-3) > acetone (3.11 × 10-3) > IPA (1.58 × 10-3) > EA (1.41 × 10-3) > EtOH (1.37 × 10-3) > MeOH (8.10 × 10-4) > water (2.38 × 10-5) at 313.2 K. The maximum solute-solvent interactions were found in RCB-PEG-400 in comparison with other combination of RCB and solvents. "Apparent thermodynamic analysis" indicated an "endothermic and entropy-driven dissolution" of RCB in water and ten organic solvents. CONCLUSIONS: Based on all these data and observations, PEG-400 can be used as the best co-solvent for RCB solubilization.

Solubility of Cinnarizine in (Transcutol + Water) Mixtures: Determination, Hansen Solubility Parameters, Correlation, and Thermodynamics.

Between 293.2 and 313.2 K and at 0.1 MPa, the solubility of the weak base, cinnarizine (CNZ) (3), in various {Transcutol-P (TP) (1) + water (2)} combinations is reported. The Hansen solubility parameters (HSP) of CNZ and various {(TP) (1) + water (2)} mixtures free of CNZ were also predicted using HSPiP software. Five distinct cosolvency-based mathematical models were used to link the experimentally determined solubility data of CNZ. The solubility of CNZ in mole fraction was increased with elevated temperature and TP mass fraction in {(TP) (1) + water (2)} combinations. The maximum solubility of CNZ in mole fraction was achieved in neat TP (5.83 × 10-2 at 313.2 K) followed by the minimum in neat water (3.91 × 10-8 at 293.2 K). The values of mean percent deviation (MPD) were estimated as 2.27%, 5.15%, 27.76%, 1.24% and 1.52% for the "Apelblat, van't Hoff, Yalkowsky-Roseman, Jouyban-Acree, and Jouyban-Acree-van't Hoff models", respectively, indicating good correlations. The HSP value of CNZ was closed with that of neat TP, suggesting the maximum solubilization of CNZ in TP compared with neat water and other aqueous mixtures of TP and water. The outcomes of the apparent thermodynamic analysis revealed that CNZ dissolution was endothermic and entropy-driven in all of the {(TP) (1) + water (2)} systems investigated. For {(TP) (1) + water (2)} mixtures, the enthalpy-driven mechanism was determined to be the driven mechanism for CNZ solvation. TP has great potential for solubilizing the weak base, CNZ, in water, as demonstrated by these results.

A rush to explore protein-ligand electrostatic interaction energy with Charger.

The mutual penetration of electron densities between two interacting molecules complicates the computation of an accurate electrostatic interaction energy based on a pseudo-atom representation of electron densities. The numerical exact potential and multipole moment (nEP/MM) method is time-consuming since it performs a 3D integration to obtain the electrostatic energy at short interaction distances. Nguyen et al. [(2018), Acta Cryst. A74, 524-536] recently reported a fully analytical computation of the electrostatic interaction energy (aEP/MM). This method performs much faster than nEP/MM (up to two orders of magnitude) and remains highly accurate. A new program library, Charger, contains an implementation of the aEP/MM method. Charger has been incorporated into the MoProViewer software. Benchmark tests on a series of small molecules containing only C, H, N and O atoms show the efficiency of Charger in terms of execution time and accuracy. Charger is also powerful in a study of electrostatic symbiosis between a protein and a ligand. It determines reliable protein-ligand interaction energies even when both contain S atoms. It easily estimates the individual contribution of every residue to the total protein-ligand electrostatic binding energy. Glutathione transferase (GST) in complex with a benzophenone ligand was studied due to the availability of both structural and thermodynamic data. The resulting analysis highlights not only the residues that stabilize the ligand but also those that hinder ligand binding from an electrostatic point of view. This offers new perspectives in the search for mutations to improve the interaction between the two partners. A proposed mutation would improve ligand binding to GST by removing an electrostatic obstacle, rather than by the traditional increase in the number of favourable contacts.

Solubilization of Trans-Resveratrol in Some Mono-Solvents and Various Propylene Glycol + Water Mixtures.

This research deals with the determination of solubility, Hansen solubility parameters, dissolution properties, enthalpy-entropy compensation, and computational modeling of a naturally-derived bioactive compound trans-resveratrol (TRV) in water, methanol, ethanol, n-propanol, n-butanol, propylene glycol (PG), and various PG + water mixtures. The solubility of TRV in six different mono-solvents and various PG + water mixtures was determined at 298.2-318.2 K and 0.1 MPa. The measured experimental solubility values of TRV were regressed using six different computational/theoretical models, including van't Hoff, Apelblat, Buchowski-Ksiazczak λh, Yalkowsly-Roseman, Jouyban-Acree, and van't Hoff-Jouyban-Acree models, with average uncertainties of less than 3.0%. The maxima of TRV solubility in mole fraction was obtained in neat PG (2.62 × 10-2) at 318.2 K. However, the minima of TRV solubility in the mole fraction was recorded in neat water (3.12 × 10-6) at 298.2 K. Thermodynamic calculation of TRV dissolution properties suggested an endothermic and entropy-driven dissolution of TRV in all studied mono-solvents and various PG + water mixtures. Solvation behavior evaluation indicated an enthalpy-driven mechanism as the main mechanism for TRV solvation. Based on these data and observations, PG has been chosen as the best mono-solvent for TRV solubilization.

Solubility Determination, Hansen Solubility Parameters and Thermodynamic Evaluation of Thymoquinone in (Isopropanol + Water) Compositions.

This article studies the solubility, Hansen solubility parameters (HSPs), and thermodynamic behavior of a naturally-derived bioactive thymoquinone (TQ) in different binary combinations of isopropanol (IPA) and water (H2O). The mole fraction solubilities (x3) of TQ in various (IPA + H2O) compositions are measured at 298.2-318.2 K and 0.1 MPa. The HSPs of TQ, neat IPA, neat H2O, and binary (IPA + H2O) compositions free of TQ are also determined. The x3 data of TQ are regressed by van't Hoff, Apelblat, Yalkowsky-Roseman, Buchowski-Ksiazczak λh, Jouyban-Acree, and Jouyban-Acree-van't Hoff models. The maximum and minimum x3 values of TQ are recorded in neat IPA (7.63 × 10-2 at 318.2 K) and neat H2O (8.25 × 10-5 at 298.2 K), respectively. The solubility of TQ is recorded as increasing with the rise in temperature and IPA mass fraction in all (IPA + H2O) mixtures, including pure IPA and pure H2O. The HSP of TQ is similar to that of pure IPA, suggesting the great potential of IPA in TQ solubilization. The maximum molecular solute-solvent interactions are found in TQ-IPA compared to TQ-H2O. A thermodynamic study indicates an endothermic and entropy-driven dissolution of TQ in all (IPA + H2O) mixtures, including pure IPA and pure H2O.

Solubilization, Hansen solubility parameters, and thermodynamic studies of delafloxacin in (transcutol + 1-butyl-3-methyl imidazolium hexafluorophosphate) mixtures.

The solubilization, Hansen solubility parameters (HSPs), and thermodynamic properties of delafloxacin (DLN) in various unique combination of Transcutol-HP® (THP) and 1-butyl-3-methyl imidazolium hexafluorophosphate ionic liquid (BMIM-PF6) mixtures were evaluated for the first time in this research. The 'mole fraction solubilities (x3)' of DLN in different (THP + BMIM-PF6) compositions were determined at 'T = 298.2-318.2 K' and 'p = 0.1 MPa'. The HSPs of DLN, neat THP, neat BMIM-PF6, and binary (THP + BMIM-PF6) compositions free of DLN were also determined. The x3 data of DLN was regressed using 'van't Hoff, Apelblat, Yalkowsky-Roseman, Jouyban-Acree and Jouyban-Acree-van't Hoff models' with overall error values of less than 3.0%. The highest and lowest x3 value of DLN was recorded in neat THP (5.48 × 10-3 at T = 318.2 K) and neat BMIM-PF6 (6.50 × 10-4 at T = 298.2 K), respectively. The solubility of DLN was found to be enhanced significantly with an arise in temperature in all (THP + BMIM-PF6) compositions including pure THP and pure BMIM-PF6. However, there was slight increase in DLN solubility with increase in THP mass fraction in all (THP + BMIM-PF6) mixtures. The HSP of pure THP and pure BMIM-PF6 were found very close to each other, suggesting the great potential of both solvents in DLN solubilization. The maximum solute-solvent interactions at molecular level were recorded in DLN-THP compared to DLN-BMIM-PF6. An 'apparent thermodynamic analysis' study indicated an 'endothermic and entropy-driven dissolution' of DLN in all (THP + BMIM-PF6) compositions including neat THP and BMIM-PF6.

Experimental Solubility, Thermodynamic/Computational Validations, and GastroPlus-Based In Silico Prediction for Subcutaneous Delivery of Rifampicin.

We focused to explore a suitable solvent for rifampicin (RIF) recommended for subcutaneous (sub-Q) delivery [ethylene glycol (EG), propylene glycol (PG), tween 20, polyethylene glycol-400 (PEG400), oleic acid (OA), N-methyl-2-pyrrolidone (NMP), cremophor-EL (CEL), ethyl oleate (EO), methanol, and glycerol] followed by computational validations and in-silico prediction using GastroPlus. The experimental solubility was conducted over temperature ranges T = 298.2-318.2 K) and fixed pressure (p = 0.1 MPa) followed by validation employing computational models (Apelblat, and van't Hoff). Moreover, the HSPiP solubility software provided the Hansen solubility parameters. At T = 318.2K, the estimated maximum solubility (in term of mole fraction) values of the drug were in order of NMP (11.9 × 10-2) ˃ methanol (6.8 × 10-2) ˃ PEG400 (4.8 × 10-2) ˃ tween 20 (3.4 × 10-2). The drug dissolution was endothermic process and entropy driven as evident from "apparent thermodynamic analysis". The activity coefficients confirmed facilitated RIF-NMP interactions for increased solubility among them. Eventually, GastroPlus predicted the impact of critical input parameters on major pharmacokinetics responses after sub-Q delivery as compared to oral delivery. Thus, NMP may be the best solvent for sub-Q delivery of RIF to treat skin tuberculosis (local and systemic) and cutaneous related disease at explored concentration.

Solubility Data, Solubility Parameters and Thermodynamic Behavior of an Antiviral Drug Emtricitabine in Different Pure Solvents: Molecular Understanding of Solubility and Dissolution.

The solubility values, various Hansen solubility parameters (HSPs) and thermodynamic behavior of emtricitabine (ECT) in twelve different pure solvents (PS) were estimated using various experimental as well as computational methods. Experimental solubility values (xe) of ECT in twelve different PS were obtained at T = 298.2 K to 318.2 K and p = 0.1 MPa. The xe values of ECT were correlated by "van't Hoff, Apelblat and Buchowski-Ksiazaczak λh models". Various HSPs for ECT and twelve different PS were also calculated using "HSPiP software". The xe values of ECT were estimated maximum in polyethylene glycol-400 (PEG-400; 1.41 × 10-1), followed by ethylene glycol, Transcutol-HP, propylene glycol, methanol, water, isopropanol, ethanol, 1-butanol, dimethyl sulfoxide, 2-butanol and EA (1.28 × 10-3) at T = 318.2 K. "Apparent thermodynamic analysis" showed an "endothermic and entropy-driven dissolution" of ECT. Overall, PEG-400 was found as the best/ideal solvent for solubility/miscibility of ECT compared to other solvents studied.

Debaryomyces hansenii F39A as biosorbent for textile dye removal.

Many industries generate a considerable amount of wastewater containing toxic and recalcitrant dyes. The main objective of this research was to examine the biosorption capacity of Reactive Blue 19 and Reactive Red 141 by the Antarctic yeast Debaryomyces hansenii F39A biomass. Some variables, including pH, dye concentration, amount of adsorbent and contact time, were studied. The equilibrium sorption capacity of the biomass increased with increasing initial dye concentration up to 350mg/l. Experimental isotherms fit the Langmuir model and the maximum uptake capacity (qmax) for the selected dyes was in the range of 0.0676-0.169mmol/g biomass. At an initial dye concentration of 100mg/l, 2g/l biomass loading and 20±1°C, D. hansenii F39A adsorbed around 90% of Reactive Red 141 and 50% of Reactive Blue 19 at pH 6.0. When biomass loading was increased (6g/l), the uptake reached up to 90% for Reactive Blue 19. The dye uptake process followed a pseudo-second-order kinetics for each dye system. As seen throughout this research study, D. hansenii has the potential to efficiently and effectively remove dyes in a biosorption process and may be an alternative to other costly materials.

Molecular Dynamics Simulation of Cellulose Synthase Subunit D Octamer with Cellulose Chains from Acetic Acid Bacteria: Insight into Dynamic Behaviors and Thermodynamics on Substrate Recognition.

The present study reports the building of a computerized model and molecular dynamics (MD) simulation of cellulose synthase subunit D octamer (CesD) from Komagataeibacter hansenii. CesD was complexed with four cellulose chains having DP = 12 (G12) by model building, which revealed unexpected S-shaped pathways with bending regions. Combined conventional and accelerated MD simulations of CesD complex models were carried out, while the pyranose ring conformations of the glucose residues were restrained to avoid undesirable deviations of the ring conformation from the 4C1 form. The N-terminal regions and parts of the secondary structures of CesD established appreciable contacts with the G12 chains. Hybrid quantum mechanical (QM) and molecular mechanical (MM) simulations of the CesD complex model were performed. Glucose residues located at the pathway bends exhibited reversible changes to the ring conformation into either skewed or boat forms, which might be related to the function of CesD in regulating microfibril production.

Solubility determination and solution thermodynamics of olmesartan medoxomil in (PEG-400 + water) cosolvent mixtures.

The solubility and solution thermodynamic properties of a weakly water-soluble compound olmesartan medoxomil (OLM) in binary 'polyethylene glycol (PEG-400) + water' cosolvent compositions were determined. The 'mole fraction solubility (x e)' of OLM in binary 'PEG-400 + water' cosolvent compositions and pure solvents (PEG-400 and water) was determined at 'T = 295.15-330.15 K' and 'p = 0.1 MPa'. The Hansen solubility parameter (HSP) of OLM, pure PEG-400, pure water, and binary 'PEG-400 + water' cosolvent compositions free of OLM were also predicted. The obtained x e values of OLM were correlated using 'van't Hoff, modified Apelblat, Yalkowsky-Roseman, Jouyban-Acree and Jouyban-Acree-van't Hoff' computational models with the error values of <4.0%. The maximum and minimum x e value of OLM was predicted in neat PEG-400 (1.15 × 10-2 at T = 330.15 K) and neat water (1.90 × 10-7 at T = 295.15 K), respectively. The OLM HSP was predicted to be more close with that of neat PEG-400. The x e value of OLM was found increased significantly with increase in temperature and PEG-400 mass fraction in all 'PEG-400 + water' cosolvent compositions including neat PEG-400 and neat water. An 'apparent thermodynamic analysis' studies presented an 'endothermic and entropy-driven dissolution' of OLM in all 'PEG-400 + water' cosolvent compositions including pure PEG-400 and pure water.

Solubility Data of the Bioactive Compound Piperine in (Transcutol + Water) Mixtures: Computational Modeling, Hansen Solubility Parameters and Mixing Thermodynamic Parameters.

The solubility values and thermodynamic parameters of a natural phytomedicine/nutrient piperine (PPN) in Transcutol-HP (THP) + water combinations were determined. The mole fraction solubilities (xe) of PPN in THP + water combinations were recorded at T = 298.2-318.2 K and p = 0.1 MPa by the shake flask method. Hansen solubility parameters (HSPs) of PPN, pure THP, pure water and THP + water mixtures free of PPN were also computed. The xe values of PPN were correlated well with "Apelblat, Van't Hoff, Yalkowsky-Roseman, Jouyban-Acree and Jouyban-Acree-Van't Hoff" models with root mean square deviations of < 2.0%. The maximum and minimum xe value of PPN was found in pure THP (9.10 × 10-2 at T = 318.2 K) and pure water (1.03 × 10-5 at T = 298.2 K), respectively. In addition, HSP of PPN was observed more closed with that of pure THP. The thermodynamic parameters of PPN were obtained using the activity coefficient model. The results showed an endothermic dissolution of PPN at m = 0.6-1.0 in comparison to other THP + water combinations studied. In addition, PPN dissolution was recorded as entropy-driven at m = 0.8-1.0 compared with other THP + water mixtures evaluated.

Solubility Data and Computational Modeling of Baricitinib in Various (DMSO + Water) Mixtures.

The solubility and thermodynamic analysis of baricitinib (BNB) in various dimethyl sulfoxide (DMSO) + water mixtures were performed. The "mole fraction solubilities (xe)" of BNB in DMSO and water mixtures were determined at "T = 298.2-323.2 K" and "p = 0.1 MPa" using an isothermal saturation technique. "Hansen solubility parameters (HSPs)" of BNB, pure DMSO, pure water and "DMSO + water" mixtures free of BNB were also estimated. The xe data of BNB was regressed well by five different thermodynamics-based co-solvency models, which included "Apelblat, Van't Hoff, Yalkowsky-Roseman, Jouyban-Acree and Jouyban-Acree-Van't Hoff models" with overall deviations of <5.0%. The highest and lowest xe value of BNB was computed in pure DMSO (1.69 × 10-1 at T = 323.2 K) and pure water (2.23 × 10-5 at T = 298.2 K), respectively. The HSP of BNB was found to be closer to that of pure DMSO. Based on activity coefficient data, maximum solute-solvent molecular interactions were observed in BNB-DMSO compared to BNB-water. The results of "apparent thermodynamic analysis" indicated endothermic and entropy-drive dissolution of BNB in all "DMSO + water" combinations including mono-solvents (water and DMSO). "Enthalpy-entropy compensation analysis" showed enthalpy-driven to be the main mechanism of solvation of BNB.

Solubility, Hansen Solubility Parameters and Thermodynamic Behavior of Emtricitabine in Various (Polyethylene Glycol-400 + Water) Mixtures: Computational Modeling and Thermodynamics.

This study was aimed to find out the solubility, thermodynamic behavior, Hansen solubility parameters and molecular interactions of an antiviral drug emtricitabine (ECT) in various "[polyethylene glycol-400 (PEG-400) + water]" mixtures. The solubility of ECT in mole fraction was determined at "T = 298.2 to 318.2 K" and "p = 0.1 MPa" using an isothermal method. The experimental solubilities of ECT in mole fraction were validated and correlated using various computational models which includes "Van't Hoff, Apelblat, Yalkowsky-Roseman, Jouyban-Acree and Jouyban-Acree-Van't Hoff models". All the models performed well in terms of model correlation. The solubility of ECT was increased with the raise in temperature in all "PEG-400 + water" mixtures studied. The highest and lowest solubility values of ECT were found in pure PEG-400 (1.45 × 10-1) at "T = 318.2 K" and pure water (7.95 × 10-3) at "T = 298.2 K", respectively. The quantitative values of activity coefficients indicated higher interactions at molecular level in ECT and PEG-400 combination compared with ECT and water combination. "Apparent thermodynamic analysis" showed an "endothermic and entropy-driven dissolution" of ECT in all "PEG-400 + water" combinations studied. The solvation nature of ECT was found an "enthalpy-driven" in each "PEG-400 + water" mixture studied.

Solubility-physicochemical-thermodynamic theory of penetration enhancer mechanism of action.

The hypothesis for the investigation was that the overall mechanism of action of skin penetration enhancers is best explained by the Solubility-Physicochemical-Thermodynamic (SPT) theory. To our knowledge, this is the first report of the application of SPT theory in transdermal/topical/enhancer research. The SPT theory puts forward the concept that the mode of action of enhancers is related to solubility parameters, physicochemical interactions and thermodynamic activity. This paper discusses these concepts by using experimentally derived permeation data, various physicochemical and solubility parameters (ingredient active gap (IAG), ingredient skin gap (ISG), solubility of active in the formulation (SolV) and the formulation solubility in the skin (SolS)) generated by using FFE (Formulating for Efficacy™ - ACT Solutions Corp) software. These studies suggest that there is an inverse relationship between measured flux and IAG values given that there is an optimum ingredient skin gap, SolV and SolS ratio. The study demonstrated that the flux is actually proportional to a gradient of thermodynamic activity rather than the concentration and maximum skin penetration and deposition can be achieved when the drug is at its highest thermodynamic activity.

Effect of Tetrabutylammonium Bromide-Based Deep Eutectic Solvents on the Aqueous Solubility of Indomethacin at Various Temperatures: Measurement, Modeling, and Prediction with Three-Dimensional Hansen Solubility Parameters.

Deep eutectic solvents (DESs) have recently been getting a great deal of attention in many fields of science and technology. The objective of this study was to peruse the solubility of indomethacin (IMC) as sparingly soluble drug in some tetrabutylammonium bromide (TBAB)-based DESs (TBAB/ethylene glycol and TBAB/glycerol). The shake flask method has been employed in this study at temperature ranges T = (298.15-313.15) K and atmospheric pressure (pP = 86.6 kPa). The results showed that the solubility of IMC in TBAB/ethylene glycol system was obtained approximately 17,000-fold more than its solubility in water. The solubility data were accurately correlated by the famous local composition activity coefficient models including e-NRTL and UNIQUAC. It was also our aim to evaluate Hansen solubility parameters in IMC solubility prediction. These parameters can help to predict the solvent performance during the manufacturing processes and will be useful in guessing solvent behavior in many other fields of effort. The experimental and the Hansen solubility parameters results are very well matched. In addition, the apparent thermodynamic properties of dissolution and mixing were studied in these solutions based on Van't Hoff and Gibbs equations.

Solubility measurement, Hansen solubility parameters and solution thermodynamics of gemfibrozil in different pharmaceutically used solvents.

Gemfibrozil (GEM) is cholesterol-lowering agent which is being proposed as poorly water soluble drug (PWSD). Temperature based solubility values of GEM are not yet available in literature or any pharmacopoeia/monograph. Hence, the present studies were carried out to determine the solubility of PWSD GEM (as mole fraction) in various pharmaceutically used solvents such as water (H2O), methanol (MeOH), ethanol (EtOH), isopropanol (IPA), 1-butanol (1-BuOH), 2-butanol (2-BuOH), ethylene glycol (EG), propylene glycol (PG), polyethylene glycol-400 (PEG-400), ethyl acetate (EA), dimethyl sulfoxide (DMSO) and Transcutol® (THP) at the temperatures ranging from T = 298.2 K-318.2 K under atmospheric pressure P = 0.1 MPa. Equilibrium/experimental solubilities of GEM were recorded by applying a saturation shake flask methodology and regressed using 'van't Hoff and Apelblat models'. Hansen solubility parameters for GEM and various pharmaceutically used solvents were estimated using HSPiP software. The solid states of GEM (both in pure and equilibrated states) were studied by 'Differential Scanning Calorimetry' which confirmed no transformation of GEM after equilibrium. Experimental solubilities of GEM in mole fraction were observed maximum in THP (1.81 × 10-1) followed by DMSO, PEG-400, EA, 1-BuOH, 2-BuOH, IPA, EtOH, PG, MeOH, EG and H2O (3.24 × 10-6) at T = 318.2 K and similar tendencies were also recorded at T = 298.2 K, T = 303.2 K, T = 308.2 K and T = 313.2 K. 'Apparent thermodynamic analysis' on experimental solubilities furnished 'endothermic and entropy-driven dissolution' of GEM in each pharmaceutically used solvent.