Cosolvent Mixtures Research Articles

Review article on self emulsifying system

The solubility challenges faced by the pharmaceutical industry, particularly with orally administered drugs, are indeed significant. Low aqueous solubility often leads to poor dissolution and subsequently, low bioavailability, which can result in inconsistent drug effects among patients. Various methods have been explored to address this issue, including salt formation, solid dispersion, and complex formation.Among these approaches, Self-Emulsifying Drug Delivery Systems (SEDDS) have emerged as a promising solution for enhancing the solubility of lipophilic drugs. SEDDS consist of isotropic mixtures of hydrophilic solvents, co-solvents, and surfactants. They possess the unique ability to form fine oil-in-water micro emulsions upon mild agitation and dilution in aqueous media, such as gastrointestinal fluids.The advancement in SEDDS technology encompasses improvements in composition, evaluation methods, development of different dosage forms, and techniques for converting liquid SEDDS into solid forms. These advancements not only enhance solubility but also offer versatility in administration routes and dosage forms, thereby expanding the potential applications of SEDDS in pharmaceutical formulations.This comprehensive review provides valuable insights into the latest developments in SEDDS, offering a detailed account of its composition, evaluation parameters, diverse dosage forms, and innovative techniques for solidification. Moreover, it highlights the diverse applications of SEDDS across various therapeutic areas, underscoring its growing significance in modern pharmaceutical research and development.

Correlation of the solubility of isoniazid in some aqueous cosolvent mixtures using different mathematical models

AbstractSolubility is one of the most important physicochemical properties, because it is related to some industrial processes such as: formulation, preformulation, purification and quantification. The experimental determination of solubility requires rigorous processes that involve a significant amount of resources. In this context, mathematical models allow estimating solubility under conditions different from the experimental ones from a limited number of data. The objective of this research was to evaluate the pertinence of 10 mathematical models (Extended Hildebrand, van’t Hoff, Two-parameter Weibull, Buchowski–Ksiazczak $$\lambda h$$ λ h , van’t Hoff-Yaws, Apelblat, Wilson, NRTL, Modified Wilson and van’t Hoff-Modified Wilson) in the calculation of the solubility of isoniazid in PEG 200 (1) + Water (2) cosolvent mixtures, the parameters of each model were calculated using Python, Pandas and the NumPy and SciPy library. Once each model was evaluated, two models were defined as the best alternatives based on their predictive power and mathematical simplicity. Thus, the van’t Hoff and Modified Wilson models were combined to obtain an equation that allows the calculation of solubility as a function of temperature and cosolvent composition, obtaining MRD% less than 3.0. In conclusion, mathematical models represent a good prediction tool being a potential alternative in relation to the optimization of some industrial processes related to solubility.

Equilibrium Solubility of Sulfadiazine in (Acetonitrile + Ethanol) Mixtures: Determination, Correlation, Dissolution Thermodynamics, and Preferential Solvation

The equilibrium solubility of sulfadiazine (SD, 3) in several {acetonitrile (MeCN) + ethanol (EtOH)} mixtures at nine temperatures from T/K = (278.15 K to 318.15) has been determined by following the shake flask method. SD solubility increased with temperature-arising as well as with the MeCN proportion-increasing in the mixtures. Thus, x3 increased from 7.74 × 10−5 in neat EtOH to 6.20 × 10−4 in neat MeCN at T/K = 298.15. SD solubility was adequately correlated with a second-order multivariate equation as function of both mixtures composition and temperature. Moreover, two models including the Jouyban–Acree and Jouyban–Acree–van’t Hoff models were applied to mathematical SD solubility data modeling in solvent mixtures. The accuracy of each model is investigated by the mean relative deviations (MRD%) of the back-calculated solubility. A full predictive model was provided by training the Jouyban–Acree–van’t Hoff model with only seven experimental solubility data which provided excellent predictions with the MRD% of 3.7 %. All used models show a low MRD% values (< 4.0 %) for the calculated data indicating a good correlation of SD solubility data with the given mathematical models. By means of the van’t Hoff and Gibbs equations, the apparent thermodynamic quantities relative to SD dissolution and mixing processes, namely Gibbs energies, enthalpies, and entropies, were calculated and reported. Apparent dissolution quantities of SD were positive in all cases indicating endothermic and entropy-driven behaviors. A non-linear enthalpy–entropy relationship was observed for SD in the plot of SD dissolution enthalpy vs. Gibbs energy. Observed trend exhibits negative slope in the composition from neat EtOH to the mixture of 0.05 in mass fraction of MeCN indicating entropy-driving mechanism for this SD transfer process. Moreover, variant but positive slopes were found in the composition interval of 0.05 < w1 < 1.00 indicating enthalpy-driving mechanism for these SD transfer processes. Furthermore, the preferential solvation of SD by MeCN or EtOH was analyzed by using the inverse Kirkwood–Buff integrals. Thus, SD is preferentially solvated by EtOH molecules in EtOH-rich mixtures but preferentially solvated by MeCN in MeCN-rich mixtures. In this way, this research expands the literature investigations about the solubility of SD in some non-aqueous cosolvent mixtures conformed by MeCN and other alcohols.

Preferential Solvation of Cyclosporin in Aqueous Mixtures of Some Polymeric Cosolvents

Background: Cyclosporin is a cyclic peptide-drug used as immunosuppressant for the prophylaxisof transplant rejection whose physicochemical properties in mixed aqueous solvent systems isstill not well understood. The preferential solvation parameters of cyclosporin in aqueous binarymixtures of diethylene glycol monoethyl ether (DEGME), polyethylene glycol 200 (PEG 200) andpolyethylene glycol 400 (PEG 400) were computed. Methods: Reported mole fraction solubilities of cyclosporin in DEGME-aqueous mixtures,PEG 200-aqueous mixtures, and PEG 400-aqueous mixtures were processed by following theinverse Kirkwood-Buff integrals (IKBI) method as suggested by Marcus and Ben-Naim using somethermodynamic parameters reported in the literature for these aqueous-polymeric mixtures at298.15 K. Results: It is observed that cyclosporin is sensitive to preferential solvation effects in theseaqueous-polymeric binary solvent systems. The preferential solvation parameter by DEGME (δx1,3)is negative in water-rich mixtures but positive in mixtures of 0.12&lt;x1&lt;1.00. It is conjecturablethat hydrophobic hydration around the non-polar methyl and methylene groups of this drug thatcould be present in water-rich mixtures can significantly impact the drug solvation. Otherwise,in mixtures of 0.12&lt;x1&lt;1.00 in DEGME-aqueous mixtures, as well as in almost all the mixtureswith PEGs, the preferential solvation by polymeric cosolvents could be due to the acidic behaviorof cyclosporin in front of ether and hydroxyl oxygen atoms of these polymeric cosolvents. Conclusion: Cyclosporin is preferentially solvated by the polymeric solvents in almost all thestudied mixtures of these aqueous-polymeric binary solvent systems.

Equilibrium solubility and mathematical modelling of glibenclamide in cosolvent mixtures of glycols and alcohols

ABSTRACT Glibenclamide (GBN) is a commonly used oral medication for treating type-II diabetes that acts by reducing high blood sugar levels. The effectiveness of GBN depends on the quality of the product. The quality is influenced by the solubility properties of a drug. This study aimed to measure the solubility of GBN in various solvent mixtures including some glycols and alcohols. The solubility was determined using a shake-flask method at 298.2 K under atmospheric pressure. The results showed that GBN had the highest solubility in ethylene glycol monomethyl ether and alcohol mixtures compared to the other tested glycols.

Solubility measurement, calculation, solvent effect and preferential solvation of fenoxaprop-p-ethyl in four cosolvent mixtures at (278.15–323.15) K

Equilibrium solubility of fenoxaprop-p-ethyl in aqueous mixtures of ethanol/ isopropanol/acetonitrile/N,N-dimethylformamide (DMF) plus water was experimentally measured by isothermal saturation method at (278.15–323.15) K under 101.2 kPa. The order of solubility (mole fraction) of fenoxaprop-p-ethyl in pure solvents from high to low is 4.233 × 10−2 (DMF 323.15 K) > 2.044 × 10−2 (acetonitrile 323.15 K) > 7.727 × 10−3 (isopropanol 323.15 K) > 5.338 × 10−3 (ethanol 323.15 K) > 2.565 × 10−5 (water 323.15 K). Experimental results showed that temperature and type of solvent were decisive factors for the dissolution of fenoxaprop-p-ethyl. The content of fenoxaprop-p-ethyl in solution was analyzed by high-performance liquid chromatography (HPLC). Moreover, the solubility data of fenoxaprop-p-ethyl was correlated by Jouyban-Acree (J-A) model, van’t Hoff-Jouyban-Acree (V-J-A) model and Apelblat-Jouyban-Acree (A-J-A) model. The maximum of root-mean-square deviation (RMSD), relative average deviation (RAD) and standard deviation (SD) predicted via three thermodynamic models were 1.78 × 10−4 (DMF + water), 2.87 × 10−2 (acetonitrile + water) and 1.79 × 10−4 (DMF + water), respectively. In addition, the solvent effect between solute and solvent molecules was deduced by KAT-LSER model and the result showed that dipolarity/polarizability interactions between the solute and solvent molecules were dominant in the dissolution of fenoxaprop-p-ethyl. Finally, the preferential solvation parameter (δx1,3) of fenoxaprop-p-ethyl was obtained by the method of inverse Kirkwood–Buff integrals and the preferential dissolution behavior of each concentration range is explained by Lewis acid base theory. However, for acetonitrile + water, the change of δx1,3 may be due to the polarization effects and it is not suitable for Lewis acid base theory.

Assessing Viscosity in Sustainable Deep Eutectic Solvents and Cosolvent Mixtures: An Artificial Neural Network-Based Molecular Approach.

Deep eutectic solvents (DESs) are gaining recognition as environmentally friendly solvent alternatives for diverse chemical processes. Yet, designing DESs tailored to specific applications is a resource-intensive task, which requires an accurate estimation of their physicochemical properties. Among them, viscosity is crucial, as it often dictates a DES's suitability as a solvent. In this study, an artificial neural network (ANN) is introduced to accurately describe the viscosity of DESs and their mixtures with cosolvents. The ANN utilizes molecular parameters derived from σ-profiles, computed using the conductor-like screening model for the real solvent segment activity coefficient (COSMO-SAC). The data set comprises 1891 experimental viscosity measurements for 48 DESs based on choline chloride, encompassing 279 different compositions, along with 1618 data points of DES mixtures with cosolvents as water, methanol, isopropanol, and dimethyl sulfoxide, covering a wide range of viscosity measurements from 0.3862 to 4722 mPa s. The optimal ANN structure for describing the logarithmic viscosity of DESs is configured as 9-19-16-1, achieving an overall average absolute relative deviation of 1.6031%. More importantly, the ANN shows a remarkable extrapolation capacity, as it is capable of predicting the viscosity of systems including solvents (ethanol) and hydrogen bond donors (2,3-butanediol) not considered in the training. The ANN model also demonstrates an extensive applicability domain, covering 94.17% of the entire database. These achievements represent a significant step forward in developing robust, open source, and highly accurate models for DESs using molecular descriptors.

Controlling Interfacial Hydrogen Bonding at a Gold Surface: The Effect of Organic Cosolvents.

Water often serves as both a reactant and solvent in electrocatalytic reactions. Interfacial water networks can affect the transport and kinetics of these reactions, e.g., hydrogen evolution reaction and CO2 reduction reaction. Adding cosolvents that influence the hydrogen-bonding (H-bonding) environment, such as dimethyl sulfoxide (DMSO), has the potential to tune the reactivity of these important electrocatalytic reactions by regulating the interfacial local environment and water network. We investigate interfacial H-bonding networks in water-DMSO cosolvent mixtures on gold surfaces by using surface-enhanced infrared absorption spectroscopy and molecular dynamics simulations. Experiments and simulations show that the gold surface is enriched with dehydrated DMSO molecules and the mixture phase-separates to form water clusters. Simulations show a "buckled" water conformation at the surface, further constraining interfacial H-bonding. The small size of these water clusters and the energetically unfavorable H-bond conformations might inhibit H-bonding with bulk water, suppressing the proton diffusion required for efficient hydrogen evolution reaction processes.

Textile-Based Adsorption Sensor via Mixed Solvent Dyeing with Aggregation-Induced Emission Dyes.

This study demonstrates a novel methodology for developing a textile-based adsorption sensor via mixed solvent dyeing with aggregation-induced emission (AIE) dyes on recycled fabrics. AIE dyes were incorporated into the fabrics using a mixed solvent dyeing method with a co-solvent mixture of H2O and organic solvents. This method imparted unique fluorescence properties to fabrics, altering fluorescence intensity or wavelength based on whether the AIE dye molecules were in an isolated or aggregated state on the fabrics. The precise control of the H2O fraction to organic solvent during dyeing was crucial for influencing fluorescence intensity and sensing characteristics. These dyed fabrics exhibited reactive thermochromic and vaporchromic properties, with changes in fluorescence intensity corresponding to variations in temperature and exposure to volatile organic solvents (VOCs). Their superior characteristics, including a repetitive fluorescence switching property and resistance to photo-bleaching, enhance their practicality across various applications. Consequently, the smart fabrics dyed with AIE dye not only find applications in clothing and fashion design but demonstrate versatility in various fields, extending to sensing temperature, humidity, and hazardous chemicals.

Solubility behavior and thermodynamic properties of caprolactam in four pure solvents and two cosolvent mixtures

The purpose of this work is to study the dissolution behavior of caprolactam in different solvents and to provide solid-liquid equilibrium data for the design and operation of crystallization and purification process for production and recovery of caprolactam. The mole fraction solubility of caprolactam was investigated in four pure solvents (benzene, ethyl acetate, cyclohexane, acetonitrile) and two cosolvent mixtures (ethyl acetate + cyclohexane, benzene + cyclohexane) by gravimetric method at atmospheric pressure from 277.65 K to 323.65 K. At the same temperature, the order of solubility of caprolactam in the selected pure solvents is: benzene > acetonitrile > ethyl acetate > cyclohexane. In the selected cosolvent mixtures, the solubility increases with increasing temperature and the content of good solvent. A series of thermodynamic models were used to fit the experimental solubility data. Finally, the thermodynamic properties of caprolactam in selected solvents were studied using the van't Hoff equation. From this analysis, it was concluded that the dissolution of caprolactam in the selected solvents is a heat-absorbing and entropy-increasing process.

Technoeconomic analysis and feasibility of co-solvent mixtures in the liquid-liquid extraction of aromatics

It is desired to improve the efficiency of liquid-liquid extraction processes in the fuel industry by reducing energy consumption and operational costs as well as reducing risk to health, safety and the environment. Co-solvent mixtures for extraction consisting of butane-1,4-diol, propane-1,2,3-triol (glycerol), and 2-methylpentane-2,4-diol (hexylene glycol) were assessed in terms of capital costs, operating costs and total annual costs relative to a baseline process that is employed for the liquid-liquid extraction of toluene from n-heptane. Commercial solvents such as sulfolane, morpholine-4-carbaldehyde (NFM), and dimethyl sulfoxide (DMSO) were used for the baseline processes that were simulated in ASPEN Plus V10. The capital costs ranged between 5.8–6.2 million US dollars, while the energy intensity ranged between 1000 - 1400 kJ/kg. The total annual costs for all solvents studied varied between 2.4 - 2.6 million dollars. The results highlighted that these co-solvent mixtures may offer some benefits in terms of total annual cost when the impact of solvent choice is holistically considered.

Equilibrium solubility determination, modeling and thermodynamic analysis of isophthalic acid in aqueous co-solvent mixtures of propylene glycol, ethylene glycol and glycerol

Equilibrium solubility determination, modeling and thermodynamic analysis of isophthalic acid in aqueous co-solvent mixtures of propylene glycol, ethylene glycol and glycerol

Effect of cosolvents on the phase separation of polyelectrolyte complexes.

Evidence is shown that cosolvent mixtures control the coacervation of mixtures of oppositely charged polyelectrolytes. Binary and ternary solvent mixtures lead to non-monotonic solubility as a function of the average dielectric constants of the solvent mixtures. These data are rationalized by considering both electrostatic-driven phase separation and solvophobic-driven phase separation using group contribution effects on solubility parameters. These estimates are introduced into an effective Flory-Huggins interaction parameter within the framework of Voorn-Overbeek theory with variable dielectric constants and temperature dependences. Despite its simplicity, the model recovers salient experimental observations not only on their coacervate stabilities, but also on their lower critical solution temperature behaviors. These observations highlight the importance of weak van der Waals interactions in determining the phase behaviors of polyelectrolyte complexes relative to electrostatic correlations.

Unraveling the Photoluminescence Properties of a Boron Nitride Nanosheet Dispersed in Different Solvents and Its Application to Generate White Light.

Hexagonal boron nitride (h-BN) is an influential 2D nanomaterial; however, its practical optoelectronic applications rely primarily on controlling the structural defects. The photoluminescence depends explicitly on the developed vacancies and substitutional defects. The present work utilizes the concept of facile liquid-phase exfoliation of hexagonal (h) boron nitride (BN) powder in common organic solvents and cosolvent mixtures to obtain a layered boron nitride nanosheet (BNNS). Although the literature concerning the layered structure of BNNS obtained by different methods is substantial, what is lacking is a detailed photoluminescence study of the layered structure obtained by changing the solvent and cosolvent mixtures, and here lies the novelty of our work. The obtained layered structure was subjected to a detailed photoluminescence study by varying the temperature. We tried to correlate how the defects originating upon changing the solvent and cosolvent affected the photoluminescence of the layered BNNS. The obtained layered structure is suitably supported by optical and electron microscopy images. High-resolution transmission electron microscopy confirm the presence of a few layers, and X-ray photoelectron spectroscopy studies give an idea of the atomic composition of the obtained BNNS. The photoluminescence properties of the obtained BNNS in water were modulated by the addition of two different classes of block copolymers, e.g., Pluronic (F-68, P-407, and P-123) and Tetronic (T-904, T-908, and T-90R4) copolymers. As an application, we were successful in constructing a nanocomposite material made up of a BNNS-copolymer-organic fluorophore to check the possibilities of generating white light.

PERFORMANCE OF THE JOUYBAN-ACREEAND YALKOWSKY-ROSEMAN MODELSFOR ESTIMATING THE SOLUBILITY OFINDOMETHACIN IN ETHANOL + WATERMIXTURES

Indomethacin (IMC) is an anti-inflammatory drug whose physiochemical properties in aqueous solutions have not been studied thoroughly. For this reason, in this work the validity of the Jouyban-Acree and Yalkowsky-Roseman models is evaluated to predict the solubility of this compound in ethanol + water cosolvent mixtures. The solubility estimation is studied as a function of temperature and cosolvent composition. Both models require only the experimental solubility values in the pure solvents at all the temperatures evaluated. The solubility calculated values by using both models deviate notoriously from experimental values in several cases.

Dynamics of Novel Zinc Ion Electrolytes

Zinc ion batteries are a niche alternative for battery applications. Their implementation is however afflicted by several factors, one of which is the need for more efficient electrolytes. Deep eutectic solvent (DES) electrolytes based on ZnCl2salt offer many attributes including, including improved stability and reduced dendrite formation. In this work we will present a molecular level understanding of the ion dynamics in electrolyte mixtures based on ZnCl2 and various co-solvents including organic carbonates and water. Focus is on the ion dynamics as interrogated by 1H NMR spin-lattice relaxation times (T1 ) combined with ionic conductivity, viscosity and density measurements. As shown in Figure 1, preliminary T1 results infers multiple ionic coordinated species with varying rates of mobilities that are co-solvent dependent. Additionally, data shows selective interaction sites between the hydrogen bond donors and acceptors, as well as the co-solvents. Figure 1. 1H T1 for the null and AcN co-solvent mixtures of (a) 1ZnCl2:4EtG and (b) 1ChCl:1ZnCl2:6EtG. Figure 1

Equilibrium Solubility of Acetaminophen in Ternary Mixtures as a Tool for Design of Concentrated Parenteral Medications

AbstractThe main purpose of this research was to evaluate the mass/volume percentage (%m/v) solubility of acetaminophen (ACP) in {ethanol (EtOH) (1) + propylene glycol (PG) (2) + water (3)} mixtures from 20.0 to 40.0 °C to expand the solubility database of this drug in mixed pharmaceutical solvents useful for designing high concentrated liquid products including injectable solutions. This is because ACP is an analgesic drug widely used available for oral administration as tablets or solutions. Besides, as injectable products, it is only available for perfusion in as 1 g in 100 mL (1.0%m/v). However, it is not available as 5 mL ampules for supplying doses of 500 mg. As demonstrated in this research some cosolvent mixtures allow ACP concentrations higher than 10.0%m/v, for instance the aqueous ternary mixture with 20% w/w of ethanol and 30% w/w of PG, among other possible mixtures. Flask shake method and UV–vis spectrophotometry were used for ACP solubility determinations at different temperatures. ACP solubility results are presented as Cartesian and triangular solubility profiles. ACP solubility increases with temperature arising and the cosolvent proportion in the mixtures. Maximum %m/v ACP solubility value is observed in the aqueous ethanol binary mixture of w1 = 0.80 at all temperatures being 21.18% at 25.0 °C. All the solubility values were well correlated using the Jouyban-Acree model obtaining mean percentage deviations of 3.8% (N = 330). In this way, %m/v equilibrium solubility of ACP in {EtOH + PG + water} mixtures has been studied and correlated at several temperatures as contribution to preformulation studies of injectable homogeneous liquid pharmaceutical dosage forms.

THERMODYNAMIC MAGNITUDES OF MIXING AND SOLVATION OF ACETAMINOPHEN IN ETHANOL + WATER COSOLVENT MIXTURES.

Based on van't Hoff and Gibbs equations the thermodynamic functions free energy, enthalpy, and entropy of solution, mixing and solvation of acetaminophen in ethanol + water cosolvent mixtures, were evaluated from solubility data determined at several temperatures. The solubility was greater at 90% m/m of ethanol at all temperatures studied. This result shows clearly the cosolvent effect present in this system. The solvation of this drug in the mixtures increases as the ethanol proportion is also increased. By means of enthalpy-entropy compensation analysis, a more complex behavior for solution was found with respect to that exposed previously in literature. From 0% up to 10% m/m of ethanol and from 90% up to 100% of ethanol, entropy driving was found, while from 20% up to 60% of ethanol, enthalpy driving was found. These facts would be explained in terms of a losing of water-structure in addition to a diminishing in the energy required for cavity formation in the solvent for mixtures from 20% up to 60% of ethanol. Nevertheless in the ethanol-rich mixtures the intermolecular mechanisms involved in the solution process should be more complex including other physicochemical considerations.

Musk ketone solubility in binary systems ethyl acetate with methanol, ethanol, and isopropanol: preferential solvation according to the inverse Kirkwood–Buff integrals method

ABSTRACT Three co-solvent mixtures {methanol (1) + ethyl acetate (2), ethanol (1) + ethyl acetate (2), and isopropanol (1) + ethyl acetate} were used to calculate the preferred solvation parameters () of musk ketone (MK) (2). In all co-solvent mixes, values vary non-linearly with the percentage of co-solvent (1). According to the study, values are negative in mixes rich in alcohol but positive in those high in ethyl acetate. The mixtures {methanol (1) + ethyl acetate (2)} and {ethanol (1) + ethyl acetate (2)} show the most favoured solvation of MK by ethyl acetate at 298.15 K and 293.15 K, respectively. When {isopropanol (1) + ethyl acetate (2)} is combined; it is maximum at 298.15 K. Since the values are positive, MK preferentially solvates with ethyl acetate. The most significant values for x 1 = 0.18–0.40 are obtained towards the non-polar regions of MK for the three co-solvent mixes.

Thermodynamic Assessment of Triclocarban Dissolution Process in N-Methyl-2-pyrrolidone + Water Cosolvent Mixtures.

Solubility is one of the most important physicochemical properties due to its involvement in physiological (bioavailability), industrial (design) and environmental (biotoxicity) processes, and in this regard, cosolvency is one of the best strategies to increase the solubility of poorly soluble drugs in aqueous systems. Thus, the aim of this research is to thermodynamically evaluate the dissolution process of triclocarban (TCC) in cosolvent mixtures of {N-methyl-2-pyrrolidone (NMP) + water (W)} at seven temperatures (288.15, 293.15, 298.15, 303.15, 308.15, 313.15 and 318.15 K). Solubility is determined by UV/vis spectrophotometry using the flask-shaking method. The dissolution process of the TCC is endothermic and strongly dependent on the cosolvent composition, achieving the minimum solubility in pure water and the maximum solubility in NMP. The activity coefficient decreases from pure water to NMP, reaching values less than one, demonstrating the excellent positive cosolvent effect of NMP, which is corroborated by the negative values of the Gibbs energy of transfer. In general terms, the dissolution process is endothermic, and the increase in TCC solubility may be due to the affinity of TCC with NMP, in addition to the water de-structuring capacity of NMP generating a higher number of free water molecules.