Apparent Solubility Research Articles

Quantitative Analysis of Amorphous Form in Indomethacin by Near Infrared Spectroscopy Combined with Partial Least Squares Regression Analysis

Indomethacin (INDO) is a synthetic non-steroidal antipyretic, analgesic, and anti-inflammatory drug that commonly exists in both amorphous and crystalline states. Its amorphous state (A-INDO) is utilized by pharmaceutical companies as an active pharmaceutical ingredient (API) in the production of INDO drugs due to its higher apparent solubility and bioavailability. The crystal state also encompasses various crystal forms such as the α-crystal form (α-INDO) and γ-crystal form (γ-INDO), with the highly crystalline and insoluble γ-INDO being commercially available. A-INDO, existing in a thermodynamically high-energy state, is susceptible to several factors during the preparation, storage, and transportation of API leading to its conversion into γ-INDO, thus impacting the bioavailability and efficacy of INDO drugs. Therefore, quantitative analysis of the A-INDO/γ-INDO content in INDO API becomes essential for controlling the production quality of INDO. The primary objective of this study is to investigate the feasibility of NIR for the quantitative analysis of A-INDO in INDO API, and to further elucidate its quantitative analysis mechanism. The NIR spectral data were collected for A-INDO and γ-INDO binary mixture samples with different resolutions, and these spectra were then selected and reconstructed using the interval partial least square (iPLS) method. Different pretreatment methods were employed to enhance the reconstructed spectra by highlighting relevant eigen information while eliminating invalid information caused by environmental factors or physical characteristics of samples. The most suitable PLSR model for quantitative analysis of A-INDO within the range of 0.0000–100.0000% w/w% was established, screened, and validated. From various perspectives, including distribution of spectral effective information, impact of resolution on PLSR model performance, variance contribution/cumulative variance contribution of PLSR model principal components (PCs), PCI loadings, relationship between spectral scores, and A-INDO content, feasibility assessment was conducted for the quantitative analysis of A-INDO in INDO using NIR spectroscopy. Additionally, a detailed investigation on the quantitative analysis mechanism of the optimal PLSR model was undertaken including the correlation between the characteristic peaks of spectra and information regarding hydrogen groups or hydrogen bonds in A-INDO or γ-INDO molecules. This study aims to provide theoretical support for the quantitative analysis of A-INDO in INDO API as well as serve as a reliable reference method for API quantification and quality control in similar drugs.

Supersaturated drug delivery system of albendazole salt-polymer complex for improving oral bioavailability and efficacy anti-secondary E. multilocularis

Based on the supersaturation theory, this study devised two albendazole (ABZ) salt-polymer complexes that enhance the oral bioavailability and efficacy of secondary hepatic alveolar echinococcosis (HAE) in rats. Solid characteristics, microstructure, and stability of ABZ benzenesulfonate (ABZ-BSA) and ABZ methanesulfonate (ABZ-MSA) were evaluated. The equilibrium solubility and intrinsic dissolution rate of salt were measured across different pH environments to determine its potential for generating supersaturation. Polymer crystallization inhibitors were subsequently introduced to assess their impact on sustaining supersaturation. The pharmacokinetics and anti-echinococcosis effects of ABZ were evaluated in healthy SD and HAE rats. The characteristic peaks corresponding to amino acid esters and benzimidazole in the ABZ salt structure either shifted or disappeared, corroborated by PXRD, signifying successful ABZ salt preparation. Furthermore, reductions in the melting point and enthalpy of the salts were observed, along with discernible differences in microstructure compared to ABZ. The drug salts exhibited a significant increase in apparent solubility and intrinsic dissolution rate of ABZ, thus laying the groundwork for supersaturation. Stability assessments indicated that salts were susceptible to moisture absorption, necessitating stringent humidity control measures. Notably, HPMC-AS demonstrated promising capabilities in sustaining supersaturation. Finally, pharmacokinetic analyses revealed a substantial increase in the AUC of ABZ-BSA-H and ABZ-MSA-H by 7.6 and 20.3 times, respectively, compared to ABZ in vivo. After a 30-day once-daily oral administration of the Salts and ABZ to SD rats with hepatic alveolar echinococcosis, the ABZ-BSA-H and ABZ-MSA-H formulation demonstrated a cysts inhibition effect 9.2-fold and 15.3-fold greater than that of ABZ. The salt-HPMC-AS complex could potentially be developed into an improved anti-AE drug therapy. Therefore, the salt-HPMC-AS complex could be developed into an enhanced anti-AE drug therapy.

Amorphous solid dispersions of amphiphilic polymer excipients and indomethacin prepared by hot melt extrusion

Improving the solubility of poorly water-soluble drugs is essential for enhancing bioavailability, formulation flexibility and reducing patient-to-patient variability. The preparation of amorphous solid dispersions (ASDs) is an attractive strategy to formulate such drugs, leading to higher apparent water solubility and therefore higher bioavailability. For such ASDs, water-soluble polymer excipients, such as poly(vinyl pyrrolidone) (PVP) or poly(vinyl pyrrolidone-co-vinyl acetate) (P(VP-co-VA)), are employed to solubilize and stabilize the drug against crystallization. We posit that polymers bearing tertiary amides are particularly well suited to stabilizing drugs containing H-bond donors, as they offer strong H-bonding potential between the polymer and drug. The aim of this study was to compare new and established polymers with tertiary amides as excipients for ASDs. Experimental amphiphilic ABA triblock copolymers comprising poly(2-methyl-2-oxazoline) (pMeOx), poly(2-butyl-2-oxazoline) (pBuOx) and poly(2-butyl-2-oxazine) (pBuOzi) blocks, were compared with the established excipients, PVP and P(VP-co-VA). ASDs with indomethacin as the model drug were prepared at high drug loadings via hot melt extrusion. The extrudates were studied with DSC and PXRD, revealing the ASDs to be fully amorphous up to 75wt% indomethacin, independent of the polymer used. 13C CPMAS NMR provided insights into intermolecular associations as a function of drug loading, and suggested the presence of drug dimers at 75wt% drug loading in pMeOx-pBuOzi-pMeOx and pMeOx-pBuOx-pMeOx, which could affect physical stability. Independent of the polymers, the solid-state form of the drug in the ASD was found to affect the dissolution profile of the samples, insofar as the samples containing crystalline indomethacin showed slower dissolution than the fully amorphous ones. This study shows that the polymers comprising poly(2-oxazoline) and poly(2-oxazine) are effective polymers for ASD preparation, similar to PVP and P(VP-co-VA) which merits further investigations into these novel polymers for formulating ASDs.

Thermodynamic Assessment of the Pyrazinamide Dissolution Process in Some Organic Solvents.

Pyrazinamide is a first line drug used for the treatment of tuberculosis, a pathology that caused the death of more than 1.3 million people in the world during 2022, according to WHO, being a drug of current interest due to its relevance in pharmaceutical and medical sciences. In this context, solubility is one of the most important physicochemical parameters in the development and/or optimization of new pharmaceutical forms, so the present work aims to present a thermodynamic study of the solubility of pyrazinamide in nine organic solvents of pharmaceutical interest. Using the shake-flask method and UV/Vis spectrophotometry, the solubility of this drug was determined at 9 temperatures; the maximum solubility was obtained in dimethyl sulfoxide at 318.15 K (x2=0.0816±0.004) and the minimum in cyclohexane at 283.15 K (1.73±0.05×10-5). From the apparent solubility data, the thermodynamic functions of solution and mixing were calculated, indicating an endothermic process. In addition, the solubility parameter of pyrazinamide was calculated using the Hoftyzer-van Krevelen (32.90 MPa1/2) and Bustamante (28.14 MPa1/2) methods. The maximum solubility was reached in dimethyl sulfoxide and the minimum in cyclohexane. As for the thermodynamic functions, the entropy drives the solution process in all cases. In relation to the solubility parameter, it can be analyzed that the mathematical models offer approximations; however, the experimental data are still primordial at the time of inferring any process.

Ex vivo permeability study of poorly soluble drugs across gastrointestinal membranes: acceptor compartment media composition

Ex vivo drug permeability testing across gastrointestinal (GI) membranes is crucial in drug discovery and oral drug delivery. It is a reliable method for drugs with good solubility, but it poses challenges for poorly soluble drugs, which are common in development pipelines today. Although enabling formulations increase the apparent solubility in the GI compartment (dissolution vessel or permeation chamber's donor compartment), maintaining solubilized drug in the acceptor compartment during ex vivo testing remains largely unresolved. This review compiles and critically evaluates the diverse compositions of acceptor media used in ex vivo permeability studies for poorly soluble drugs, highlighting this significant yet underexplored aspect of pharmaceutical science. An algorithm is proposed for selecting solubility-enhancing additives for the acceptor media in ex vivo permeability studies of poorly soluble drugs.

Study on Several Novel Crystalline Complexes of Sorafenib with Dicarboxylic Acid: Nature Identification and Solubilization Mechanism

The development of solid-state forms of drugs is an effective approach to increase solubility. This study developed three crystalline complexes of sorafenib (SF) with oxalic acid (OA) and malonic acid (MA) using a solvent method, named SF+·OA-·THF, SF+·OA-, and SF-MA. The formation of these complexes was influenced by the crystalline method, solvent polarity, and the carbon chain length of the dicarboxylic acids. Single-crystal X-ray diffraction revealed proton transfer in SF+·OA-·THF, classifying it as a channel-type salt solvate and conformational polymorph due to hydrogen bond formation. 13C solid-state nuclear magnetic resonance and X-ray photoelectron spectroscopy confirmed proton transfer in SF+·OA-·THF and SF+·OA-, but not in SF-MA, indicating that SF+·OA- is a salt while SF-MA is a co-crystal. Fourier Transform Infrared Spectroscopy further supported these findings. Compared with Form Ⅰ, SF+·OA-, SF+·OA-·THF, and SF-MA increased the apparent solubility of SF by 8.3, 7.9, and 6.4 times in pH 1.2 HCl buffer, and by 4.0, 3.1, and 4.5 times in pH 6.8 PBS buffer, respectively. All crystalline complexes exhibited a “spring and parachute” phenomenon due to the solubility difference between the drug and the dicarboxylic acids. Notably, the intermolecular forces between SF and THF in SF+·OA-·THF prolonged the “spring and parachute” process. Additionally, these crystalline complexes demonstrated good stability. This study provides valuable insights into the development and identification of crystalline complexes and their dissolution mechanisms.

Dissolution behavior of calcium uranate under oxidizing and reducing conditions

Calcium uranate solid phase is a secondary mineral found in geological environments. It may form in the residues of high-level radioactive liquid waste and in the fuel debris of the TEPCO's Fukushima Daiichi Nuclear Power Plant under high-temperature conditions. To assess the chemical stability of CaUO4 in different aqueous environments, static immersion tests were performed under various redox conditions and carbonate ion concentrations. pH and Eh values, as well as concentrations of uranium, calcium, and total carbonate in the solutions, were measured after the supernatants were filtered through a membrane with a 10 kDa molecular weight cutoff. The components of the solid phase were also evaluated using X-ray diffraction and X-ray absorption fine structure analyses. The dissolution mechanism of CaUO4 was examined using data from solid and liquid analyses, along with chemical thermodynamic calculations. Under reducing conditions and without carbonate, U(VI) in CaUO4 was reduced to U(V) and the mineral was converted into non-stoichiometric CaUO4−x. The dissolved uranium was then further reduced to U(IV) in the aqueous media, forming UO2(am), which controlled the U solubility. Under oxidizing conditions and in the absence of carbonate, dissolved uranium formed metaschoepite ((UO3)·2H2O(cr)) at pH ≤ 7 and sodium diuranate (Na2U2O7·H2O(cr)) at pH > 7, which controlled uranium solubility. In oxidizing conditions with carbonate present, the apparent solubility of U was lower than predicted by the solid-phase solubility calculations. The concentration of U was constrained to levels similar to that of calcium when the calcium concentration reached saturation with CaCO3. Additionally, the dissolution of calcium from CaUO4 influenced uranium dissolution.

Hydrogen permeation in iron-chromium-aluminum (FeCrAl) alloys and the effects of microstructure and surface oxide

Iron–chromium–aluminum (FeCrAl) class alloys are candidates for use as cladding for accident-tolerant fuels and moderators. In this context, hydrogen isotope permeation in FeCrAl alloys is an important material property. In the present work, the apparent permeability, effective diffusivity, and apparent solubility of hydrogen in the FeCrAl alloys C26M and Kanthal D (KD) were measured with gas-driven hydrogen permeation. Permeation measurements were conducted at temperatures of 400 to 700 °C and at gas-driven pressures from 1 to 100 kPa. In particular, the effect of grain size on hydrogen transport was studied with KD samples with three different microstructures: nanocrystalline (NC), ultra-fine grained (UFG), and coarse-grained (CG). The UFG and NC specimens had higher apparent activation energies (73.4 kJ mol-1 and 65.2 kJ mol-l, respectively) for hydrogen permeability than the CG sample (46.9 kJ mol-1). An aluminum oxide layer formed on the primary- and secondary-side surfaces of all samples subjected to permeation experiments which demonstrated the propensity of FeCrAl alloys to form these innate oxide permeation barriers.

Hot Melt Extruded High-Dose Amorphous Solid Dispersions Containing Lumefantrine and Soluplus

Over the last 15 years, a small number of paediatric artemisinin-based combination therapy products have been marketed. These included Riamet® and Coartem® dispersible tablets, a combination of artemether and lumefantrine, co-developed by the Medicines for Malaria Venture and Novartis. Disappointingly, patient compliance, requirement for high-fat meal, and sporadic drug dissolution behaviours following administration still result in considerable challenges for these products. The first and foremost barrier that needs addressed for successful delivery of the artemether/lumefantrine combination is the poor solubility of lumefantrine within the gastrointestinal fluids. In this work, amorphous solid dispersions of lumefantrine within Soluplus®-based matrices have been manufactured using hot melt extrusion as a potential formulation strategy to achieve enhanced dissolution and apparent solubility. The drug loading capacity of Soluplus® to accommodate amorphous lumefantrine, whilst ensuring improved in-vitro dissolution performance, was investigated. The extrusion process employed a variety of processing parameters, including various temperature profiles and different production scales. The influence of variation in extrusion conditions upon the physical stability of manufactured amorphous solid dispersions was also examined. This allowed for a greater understanding of the role of extrusion processing conditions on the performance of supersaturated amorphous solid dispersions during dissolution and storage. This may allow for the design and manufacture of drug enabled formulations with lower drug dosing and thus a lower risk of adverse effects.

Development of Mixed Micelles for Enhancing Fenretinide Apparent Solubility and Anticancer Activity Against Neuroblastoma Cells.

The purpose of the study was to evaluate the suitability of mixed micelles prepared with D-α-tocopheryl polyethylene glycol succinate (TPGS) and 1,2- distearoyl-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-PEG) to encapsulate the poorly soluble anticancer drug fenretinide (4-HPR). After assaying the solubilization ability of the surfactants by the equilibrium method, the micelles were prepared using the solvent casting technique starting from different 4-HPR:TPGS: DSPE-PEG w/w ratios. The resulting formulations were investigated for their stability under storage conditions and upon dilution, modelling the reaching of physiological concentrations after intravenous administration. The characterization of micelles included the determination of DL%, EE %, particle size distribution, Z-potential, and thermal analysis by DSC. The cytotoxicity studies were performed on HTLA-230 and SK-N-BE-2C neuroblastoma cells by the MTT essay. The colloidal dispersions showed a mean diameter of 12 nm, negative Zeta potential, and a narrow dimensional distribution. 4-HPR was formulated in the mixed micelles with an encapsulation efficiency of 88% and with an increment of the apparent solubility of 363-fold. The 4-HPR entrapment remained stable up to the surfactants' concentration of 2.97E-05 M. The loaded micelles exhibited a slow-release behaviour, with about 28% of the drug released after 24 h. On the most resistant SK-N-BE-2C cells, the encapsulated 4-HPR was significantly more active than free 4-HPR in reducing cell viability. Loaded micelles demonstrated their suitability as a new adjuvant tool potentially useful for the treatment of neuroblastoma.

Optimizing Production, Characterization, and In Vitro Behavior of Silymarin-Eudragit Electrosprayed Fiber for Anti-Inflammatory Effects: A Chemical Study.

Inflammatory Bowel Disease (IBD) is a chronic condition that affects approximately 1.6 million Americans. While current polyphenols for treating IBD can be expensive and cause unwanted side effects, there is an opportunity regarding a new drug/polymer formulation using silymarin and an electrospray procedure. Silymarin is a naturally occurring polyphenolic flavonoid antioxidant that has shown promising results as a pharmacological agent due to its antioxidant and hepatoprotective characteristics. This study aims to produce a drug-polymer complex named the SILS100-Electrofiber complex, using an electrospray system. The vertical set-up of the electrospray system was optimized at a 1:10 of silymarin and Eudragit® S100 polymer to enhance surface area and microfiber encapsulation. The SILS100-Electrofiber complex was evaluated using drug release kinetics via UV Spectrophotometry, Fourier-Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), and Differential Scanning Calorimetry (DSC). Drug loading, apparent solubility, and antioxidant activity were also evaluated. The study was successful in creating fiber-like encapsulation of the silymarin drug with strand diameters ranging from 5-7 μm, with results showing greater silymarin release in Simulated Intestinal Fluid (SIF) compared to Simulated Gastric Fluid (SGF). Moving forward, this study aims to provide future insight into the formulation of drug-polymer complexes for IBD treatment and targeted drug release using electrospray and microencapsulation.

Electrospraying as a Means of Loading Itraconazole into Mesoporous Silica for Enhanced Dissolution.

Mesoporous silica particles (MSPs) have been investigated as potential carriers to increase the apparent solubility and dissolution rate of poorly water-soluble drugs by physically stabilising the amorphous nature of the loaded drug. In preparing such systems, it is recognized that the loading method has a critical impact on the physical state and performance of the drug. To date, there has been very limited investigation into the use of electrospraying for loading drugs into mesoporous silica. In this study, we further explore the use of this approach, in particular as a means of producing amorphous and high drug-loaded MSPs; the study includes an investigation of the effect of drug loading and MSP concentration on the formulation performance and process. A comparison with rotary evaporation, a more widely utilised loading technique, was conducted to assess the relative effectiveness of electrospraying. The physical state of the drug in the formulations was assessed using powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The drug release profiles were determined by a comparative in vitro drug release test. Electrospraying successfully produced formulations containing amorphous drug even at a high drug loading. In contrast, while itraconazole was present in amorphous form at the lower drug-loaded formulations produced by rotary evaporation, the drug was in the crystalline state at the higher loadings. The percentage of drug released was enhanced up to ten times compared to that of pure itraconazole for all the formulations apart from the highest loaded (crystalline) formulation prepared by rotary evaporation. Supersaturation for at least six hours was maintained by the formulations loaded with up to 30 mg/mL itraconazole produced by electrospraying. Overall, the results of this study demonstrate that electrospraying is capable of producing amorphous drug-loaded MSPs at high loadings, with associated favourable release characteristics. A comparison with the standard rotary evaporation approach indicates that electrospraying may be more effective for the production of higher loadings of amorphous material.

Radionuclide Solid:liquid partitioning in an aged, reducing-grout wasteform recovered from a disposal facility

The Saltstone Disposal Facility on the Savannah River Site in South Carolina disposes of Low-Level Waste in a reducing-grout waste form. Reducing grout is presently being evaluated as a subsurface disposal waste form at several other locations in the United States, as well as in Europe and Asia. The objective of this study was to collect core samples directly from the Saltstone Disposal Facility and measure desorption distribution coefficients (Kd; radionuclide concentration ratio of saltstone:liquid; (Bq/kg)/Bq/L)) and desorption apparent solubility values (ksp; radionuclide aqueous concentration (moles/L)). An important attribute of this study was that these tests were conducted with actual aged, grout waste form materials, not small-volume simulants prepared in a laboratory. The reducing grout is comprised of blast furnace slag, Class F fly ash, ordinary portland cement, and a radioactive salt waste solution generated during nuclear processing. The grout sample used in this study underwent hydrolyzation in the disposal facility for 30 months prior to measuring radionuclide leaching. Leaching experiments were conducted either in an inert (no oxygen) atmosphere to simulate conditions within the saltstone monolith prior to aging (becoming oxidized) or they were exposed to atmosphere conditions to simulate conditions of an aged saltstone. Importantly, these experiments were designed not to be diffusion limited, that is, the saltstone was ground finely and the suspensions were under constant agitation during the equilibration period. Under oxidized conditions, measured Tc Kd values were 10 mL/g, which was appreciably greater than the historical best-estimate value of 0.8 mL/g. This difference is likely the result of a fraction of the Tc remaining in the less soluble Tc(IV) form, even after extensive oxidation during the experiment. Under oxidized and reducing conditions, the measured Ba and Sr (both divalent alkaline earth metals) Kd value were more than an order of magnitude greater than historical best-estimate values of 100 mL/g. The unexpectedly high Ba and Sr Kd values were attributed to these radionuclides having sufficient time to age (form strong bonds) in the sulfur-rich saltstone sample. Apparent ksp values under reducing conditions were 10−9 mol/L Tc and 10−13 mol/L Pu, consistent with values measured with surrogate materials. Measured apparent Ba, Sr, and Th ksp values were significantly greater than historical best-estimates. The implications of the generally greater Kd values and lower ksp values in these measurements is that these cementitious waste forms have greater radionuclide retention than was previously estimated based on laboratory studies using surrogate materials. This work represents the first leaching study performed with an actual aged, reducing-grout sample and as such provides an important comparison to studies conducted with surrogate materials, and provides high pedigree data for other programs around the world evaluating reducing grouts as a wasteform for subsurface nuclear waste disposal.

Speciation and Diffusivity of Hydrogen in Molten 2LiF-BeF2 for Nuclear Fission and Fusion Applications

The behavior of hydrogen isotopes in molten 2LiF-BeF2 (FLiBe) is of interest to both advanced fission and fusion reactor designs. Tritium (hydrogen-3) is both a fission product and neutron activation product of lithium-6 fluoride in fission reactors which use FLiBe as a heat transfer fluid. In this case, tritium is an undesirable side product. In fusion reactors, FLiBe may be used as a blanket around the plasma which, upon neutron irradiation, generates tritium by the same neutron–Li-6 reaction. Here, tritium is a necessary and desirable product; the tritium is used to continuously fuel the deuterium-tritium fusion reaction. A thorough understanding of tritium’s behavior and residence time is relevant to managing tritium inventories in fission and fusion systems, which is essential for both the safety cases and functional operation of these reactors. Using hydrogen as a non-radioactive surrogate for tritium, we study the speciation and diffusivity of hydrogen in molten FLiBe at various temperatures relevant to reactor operating conditions.Here we present results of electrochemical investigations of hydrogen in FLiBe using cyclic and square wave voltammetry. We introduce hydrogen to FLiBe through 1) LiH additions and as 2) H2 gas, electrochemically desorbed from graphite. The expected solubility of H2 in FLiBe at 1 atm partial pressure is as low as 1 appm. Previous studies saw a higher apparent solubility of H2 at atmospheric pressure (up to 8000 appm). The possible presence of the postulated quasi-stable intermediate BeH2 is explored to explain the high apparent solubility of H2. The two methods of introducing H (as LiH reacting with BeF2 to form BeH2, which decomposes to H2, and the surface reduction of H2 on graphite) are compared to investigate the different species in which hydrogen may exist in molten FLiBe. Additionally, we attempt to quantify the diffusivity of these hydrogen species in FLiBe at 500ºC and 800ºC and compare findings with predicted diffusivities from computational models of Be and H additions to FLiBe. Overall, these studies seek to elucidate the speciation of hydrogen in FLiBe to aid in the management and operation of fission and fusion systems.

Oral Absorption from Surfactant-Based Drug Formulations: The Impact of Molecularly Dissolved Drug on Bioavailability

Enabling drug formulations are often required to ensure sufficient absorption after oral administration of poorly soluble drugs. While these formulations typically increase the apparent solubility of the drug, it is widely acknowledged that only molecularly dissolved, i.e., free fraction of the drug, is prone for direct absorption, while colloid-associated drug does not permeate to the same extent.In the present study, we aimed at comparing the effect of molecularly and apparently (i.e., the sum of molecularly and colloid-associated drug) dissolved drug concentrations on the oral absorption of a poorly water-soluble drug compound, Alectinib. Mixtures of Alectinib and respectively 50 %, 25 %, 12.5 %, and 3 % sodium lauryl sulfate (SLS) relative to the dose were prepared and small-scale dissolution tests were performed under simulated fed and fasted state conditions. Both the molecularly and apparently dissolved drug concentrations were assessed in parallel using microdialysis and centrifugation/filtration sampling, respectively. The data served as the basis for an in vitro-in vivo correlation (IVIVC) and as input for a GastroPlusTM physiologically-based biopharmaceutics model (PBBM).It was shown that with increasing the content of SLS the apparently dissolved drug in FeSSIF and FaSSIF increased to a linear extent and thus, the predicted in vivo performance of the 50 % SLS formulation, based on apparently dissolved drug, would outperform all other formulations. Against common expectation, however, the free (molecularly dissolved) drug concentrations were found to vary with SLS concentrations as well, yet to a minor extent. A systematic comparison of solubilized and free drug dissolution patterns at different SLS contents of the formulations and prandial states allowed for interesting insights into the complex dissolution-/supersaturation-, micellization-, and precipitation-behavior of the formulations. When comparing the in vitro datasets with human pharmacokinetic data from a bioequivalence study, it was shown that the use of molecularly dissolved drug resulted in an improved IVIVC.By incorporating the in vitro dissolution datasets into the GastroPlusTM PBBM, the apparently dissolved drug concentrations resulted in both, a remarkable overprediction of plasma concentrations as well as a misprediction of the influence of SLS on systemic exposure. In contrast, by using the molecularly dissolved drug (i.e., free fraction) as the model input, the predicted plasma concentration-time profiles were in excellent agreement with observed data for all formulations under both fed and fasted conditions.By combining an advanced in vitro assessment with PBBM, the present study confirmed that only the molecularly dissolved drug, and not the colloid-associated drug, is available for direct absorption.

A new crystalline daidzein-piperazine salt with enhanced solubility, permeability, and bioavailability.

To overcome the poor solubility, permeability, and bioavailability of the plant isoflavone daidzein (DAI), a novel salt of DAI with anhydrous piperazine (PIP) was obtained based on cocrystallization strategy. The new salt DAI-PIP was characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy, and optical microscopy. The results showed that the maximum apparent solubility (Smax) of DAI-PIP increased by 7.27-fold and 1000-fold compared to DAI in pH 6.8 buffer and water, respectively. The peak apparent permeability coefficient (P app ) of DAI-PIP in the Caco-2 cell model was 30.57 ± 1.08 × 10-6cm/s, which was 34.08% higher than that of DAI. Additionally, compared to DAI, the maximum plasma concentration (Cmax) value of DAI-PIP in beagle dogs was approximately 4.3 times higher, and the area under the concentration-time curve (AUC0-24) was approximately 2.4 times higher. This study provides a new strategy to enhance the dissolution performance and bioavailability of flavonoid drugs, laying a foundation for expanding their clinical applications.

Soft confinement of water in aliphatic alcohols: MIR/NIR spectroscopic and DFT studies

Here, we present the first examination of the state of water under a soft confinement in eight aliphatic alcohols including cyclopentanol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, 1-decanol, 2-octanol and 3-octanol. Due to relatively large size of the aliphatic part, water has limited solubility in all studied alcohols. Water content in saturated solutions was determined by Karl Fischer titration and correlated with the spectroscopic data. This way, we determined the molar absorptivity of the ν2+ν3 combination mode. The effect of addition of water and temperature variation was monitored by ATR-IR and NIR spectroscopy. Analysis of the experimental results was guided by DFT calculations, which provided the structures, harmonic MIR spectra and binding energies of selected alcohol-water complexes.Our studies demonstrated that the state of water in alcohols is related to its solubility, which depends on structure of solvent molecules. The solubility of water in 1-alcohols decreases on increasing of the chain length, but for long chain alcohols this effect is less evident. More apparent solubility reduction appears in going from the primary to secondary alcohols. The effective shielding of the OH group in the linear alcohols is achieved when on both sides of the OH group are ethyl or longer substituents, while the shielding by methyl groups is less efficient. Water is much better soluble in the cyclic alcohols as compared with the linear ones due to better accessibility of the OH group.The soft confinement of water in aliphatic alcohols allows for flexible structural arrangements and interactions. Even at low water content, we did not observe free molecules of water. At these conditions, the molecules of water are singly or doubly bonded to the OH groups from the alcohol. Increasing solubility of water reduces the number of the free OH groups and leads to formation of water clusters. Obtained results allow concluding that in alcohols with sizable aliphatic part the molecules of water are confined in the vicinity of the OH groups.

Benign and Selective Amination of Lignins towards Aromatic Biobased Building Blocks with Primary Amines.

Lignin is a widely available second-generation biopolymer and the main potential source of renewable aromatic building blocks. Lignin-based polyamines offer great potential in applications based on chemical and materials sciences. However, common aminations techniques for lignin usually involve toxic chemicals and generate hindered and low reactivity amines. In this study, we developed two new, simple, and benign 2-step methodologies for the elaboration of lignin-based polyamines from different technical lignins (kraft, soda and organosolv) with a selectivity towards reactive primary amines. These methods involve grafting amide groups onto lignin followed by a hydrolysis step. Non-toxic heterocyclic compounds N-acetyl-2-oxazolidinone and 2-methyl-2-oxazoline were used as amidation agents. Hydrolysis was performed in acetone-water mixtures. Reactions were studied on model compounds and optimized on lignins. Aminated lignins were fully characterized and primary amines were quantified using quantitative 19F NMR. Our methods generated aminated lignins with low apparent molar masses and high solubility in water and solvents. Nitrogen contents of the products ranged between 2.0 and 3.5 mmol/g with reactive primary amines counts up to 1.7 mmol/g. These soluble and reactive lignin-based polyamines offer great potential as a replacement for fossil-based polyamines in e.g., the synthesis of aromatic polymer materials or as potential chelating, antibacterial agents.

Benign and Selective Amination of Lignins towards Aromatic Biobased Building Blocks with Primary Amines

Lignin is a widely available second‐generation biopolymer and the main potential source of renewable aromatic building blocks. Lignin‐based polyamines offer great potential in applications based on chemical and materials sciences. However, common aminations techniques for lignin usually involve toxic chemicals and generate hindered and low reactivity amines. In this study, we developed two new, simple, and benign 2‐step methodologies for the elaboration of lignin‐based polyamines from different technical lignins (kraft, soda and organosolv) with a selectivity towards reactive primary amines. These methods involve grafting amide groups onto lignin followed by a hydrolysis step. Non‐toxic heterocyclic compounds N‐acetyl‐2‐oxazolidinone and 2‐methyl‐2‐oxazoline were used as amidation agents. Hydrolysis was performed in acetone‐water mixtures. Reactions were studied on model compounds and optimized on lignins. Aminated lignins were fully characterized and primary amines were quantified using quantitative 19F NMR. Our methods generated aminated lignins with low apparent molar masses and high solubility in water and solvents. Nitrogen contents of the products ranged between 2.0 and 3.5 mmol/g with reactive primary amines counts up to 1.7 mmol/g. These soluble and reactive lignin‐based polyamines offer great potential as a replacement for fossil‐based polyamines in e.g., the synthesis of aromatic polymer materials or as potential chelating, antibacterial agents.

Cocrystal of Lutein with Improved Stability and Bioavailability.

Lutein (LT) is a natural carotenoid and is widely used for its vision protection and antioxidant activity. However, the long-chain polyene structure makes lutein sensitive to light and oxygen and poses many difficulties in the production, processing, and storage. In addition, the special chemical structure of LT leads to low solubility and bioavailability. In this study, we propose an efficient solution to address these issues. A cocrystal of LT with adipic acid (LT-APC) was obtained for the first time. The cocrystals were fully characterized. After cocrystallization, the melting point of marketed LT was increased. The chemical stability of LT was significantly improved, and the influence of impurities on stability was limited. Dissolution experiments were performed in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) and the cocrystal generated a much higher apparent solubility. To deepen insight into the mechanisms underlying the cocrystal's improved solubility, wettability tests were performed by contact angle determination and film flotation methods. The cocrystal presented better wettability than the marketed LT. Finally, pharmacokinetic studies of marketed LT and its cocrystal were conducted in rats. The results showed that the cocrystal exhibited 3.4 times higher C max and 2.2 times higher AUC at a single dose compared with marketed LT.