Simple Eutectic Mixtures Research Articles

Characterization and Improvement Dissolution Profile of the Hydrochlorothiazide-β-Cyclodextrin Inclusion Complex using Kneading Method

Hydrochlorothiazide is a drug antihypertensives are classified into Biopharmaceutics Classification System (BCS) class IV, so required technique formulation to improve solubility, one of them with complex inclusion. The inclusion complex was prepared with a kneading method with a comparison amount of hydrochlorothiazide - β- cyclodextrin 1:1 (F1) mol, 2:1 (F2) mol, and a physical mixture prepared in a ratio of 1:1 mol. This research aims to see the effect of complex formation inclusion on dissolution rate and characteristics of physicochemical properties of hydrochlorothiazide. Complex inclusions formed are characterized by scanning electron microscopy (SEM), and infrared spectrophotometer (FT-IR). X-ray diffraction, differential scanning calorimetry (DSC), and dissolution profiles. Characterization of physicochemical results analysis diffraction X-rays show that powder complex inclusion hydrochlorothiazide with β-cyclodextrin experiences decline peak intensity approaches a more amorphous nature. Characterization results FT-IR analysis shows No interaction chemistry exists between hydrochlorothiazide β-cyclodextrin. SEM analysis shows morphology substance active Already coated with β- cyclodextrin. DSC analysis shows a decline in enthalpy of the complex inclusions that indicate physical interactions form a simple eutectic mixture. Research results show that complex inclusion hydrochlorothiazide - β-cyclodextrin can repair characteristic physicochemical and can increase hydrochlorothiazide dissolution profile in a way significant (p<0.05) compared with powder The physical mixture with the highest dissolution results was shown by the F1 inclusion complex (82.843 %).

Liquefying Compounds by Forming Deep Eutectic Solvents: A Case Study for Organic Acids and Alcohols.

The criterion to distinguish a simple eutectic mixture from a deep eutectic solvent (DES) lies in the deviations to thermodynamic ideality presented by the components in the system. In this work, the current knowledge of the molecular interactions in types III and V DES is explored to liquefy a set of three fatty acids and three fatty alcohols, here used as model compounds for carboxyl and hydroxyl containing solid compounds. This work shows that thymol, a stronger than usual hydrogen bond donor, is able to form deep eutectic solvents of type V with the fatty alcohols studied. This is particularly interesting, since these DES formed are hydrophobic. Regarding type III DES, the results suggest that the prototypical DES hydrogen bond acceptor, cholinium chloride, is unable to induce negative deviations to ideality in the model molecules studied. By substituting choline with tetramethylammonium chloride, it is shown that the choline hydroxyl group is responsible for the difficulty in forming choline-based deep eutectic solvents and that its absence induces strong negative deviations to ideality in the alkylammonium side. Finally, it is demonstrated that tetrabutylammonium chloride acts as a chloride donning agent, causing significant negative deviations to ideality in both fatty acids and alcohols and leading to the formation of deep eutectic solvents of type III.

Thermal Extrusion 3D Printing for the Fabrication of Puerarin Immediate-Release Tablets.

Thermal extrusion (TE) 3D printing is a thermoplastic semisolid-based rapid prototyping process, which is capable of building complex structures. The aim of this study was to manufacture rapid-release puerarin tablets without solvent through TE 3D printing. Novel rapid-release tablets were fabricated with polyethylene glycol (PEG 4000) as the carrier at appropriate puerarin/PEG 4000 ratios, assessed through differential scanning calorimetry (DSC), solubility, and dissolution tests. The novel structures of 3D-printed tablets with five different values were formed by printing paths, which established a flexible way of adjusting in vitro drug release. An obvious acceleration (85% of cumulative release about 7.5 min at the soonest) was observed for the tablets with internal structural design. It was inferred that puerarin formed simple eutectic mixtures with PEG 4000 and that puerarin dispersed into the carrier based on DSC and X-Ray powder diffraction (XRD). This highlights the combined advantage of PEG as a soluble polymer with TE 3D printing and provides a suitable system for rapid puerarin release.

Distinguishing Cocrystals from Simple Eutectic Mixtures: Phenolic Acids as Potential Pharmaceutical Coformers

The multiparameter model comprising 1D and 2D QSPR/QSAR descriptors was proposed and validated for phenolic acid binary systems. This approach is based on the optimization of regression coefficients for maximization of the percentage of true positives in the pool of systems comprising either simple binary eutectics or cocrystals. The training set consisted of 58 eutectics and 168 cocrystals. The solid dispersions collection used for model generation comprised literature data enriched with our new experimental results. From all 1445 descriptors computable in PaDEL, only 13 orthogonal descriptors with the highest predicting power were taken into account. The analysis revealed the importance of the parameters characterizing atom types (naaN, SHsOH, SsssN, nHeteroRing, maxHBint6, C1SP2), autocorrelation functions (ATSC1i, AATSC1v, MATS8m, GATS1i), and also other molecule structure measures (WTPT-5, MLFER_A, MDEN-22). The proposed approach is very simple and requires only information about the structure encode...

Binary systems based on aromatic amines with a view of development of novel hardeners for epoxy resins

Three binary systems based on aromatic amines [4,4′-diaminodiphenylmethane (DDM), 4,4′-diaminodiphenyl sulfone (DDS), 4,4′-diaminodiphenyl ether (DDE) and m-phenylenediamine (MPDA)] were investigated by differential scanning calorimetry (DSC). Phase diagrams for different compositions were constructed. The DSC results showed that all binary systems form simple eutectic mixtures. Formation of eutectic physical mixture of MPDA–DDM and MPDA–DDS was confirmed by powder XRD study. In the case of DDE–DDS system, it was found that besides the eutectic mixture a small amount of the charge transfer complex forms with the novel crystal structure.

Solidification Behaviour and Phase Diagram Studies of Vanillin-o-Nitrophenol System

Phase diagrams of vanillin-o-nitrophenol has been studies by thaw-melt method. The results show the formation of simple eutectic mixtures in vanillin-o-nitrophenol. Solidification kinetics of components and eutectic mixtures were determined at different undercoolings. The solidification of materials may lead to the formation of nuclei of two phases which may be of nanosize. Anisotropic microstructural studies revealed that vanillin-o-nitrophenol eutectic show the formation of feather like structure. The crystallization patterns of the system were changed on the addition of impurity. Jackson’s roughness parameter values were found to be greater than 2 which suggest the faceted morphology with irregular structures.

Indirect assessment of the fusion properties of choline chloride from solid-liquid equilibria data

The temperature and enthalpy of fusion of choline chloride -[Ch]Cl- are not directly measurable since this compound decomposes upon melting. Yet, given the wide use of this compound in the preparation of deep eutectic solvents (DES), its thermophysical fusion properties are very important for a better understanding of these mixtures and the thermodynamic description of their solid-liquid phase diagrams. In this work, the fusion properties of choline chloride were estimated using the solubility curves of choline chloride in ten different ionic compounds, forming simple binary eutectic mixtures with quasi-ideal liquid phases. Experimental solid-liquid equilibria data for these systems -[Ch]Cl + ionic compounds- were measured, and the ideality of the systems assessed through the quantification of the activity coefficients and their comparison in each pair of binary solutions. The values estimated for the fusion properties of choline chloride are Tfus,[Ch]Cl = 597 ± 7 K and ΔfusH[Ch]Cl = 4300 ± 600 J mol−1. These were additionally checked by thermodynamic consistency tests and by the prediction of the solid-liquid curves with COSMO-RS model. The results obtained with both procedures allow us to guarantee the usefulness and robustness of the estimated data.

Efficacy of bi-component cocrystals and simple binary eutectics screening using heat of mixing estimated under super cooled conditions

The values of excess heat characterizing sets of 493 simple binary eutectic mixtures and 965 cocrystals were estimated under super cooled liquid condition. The application of a confusion matrix as a predictive analytical tool was applied for distinguishing between the two subsets. Among seven considered levels of computations the BP-TZVPD-FINE approach was found to be the most precise in terms of the lowest percentage of misclassified positive cases. Also much less computationally demanding AM1 and PM7 semiempirical quantum chemistry methods are likewise worth considering for estimation of the heat of mixing values. Despite intrinsic limitations of the approach of modeling miscibility in the solid state, based on components affinities in liquids under super cooled conditions, it is possible to define adequate criterions for classification of coformers pairs as simple binary eutectics or cocrystals. The predicted precision has been found as 12.8% what is quite accepted, bearing in mind simplicity of the approach. However, tuning theoretical screening to such precision implies the exclusion of many positive cases and this wastage exceeds 31% of cocrystals classified as false negatives.

Exploring the cocrystallization potential of urea and benzamide.

The cocrystallization landscape of benzamide and urea interacting with aliphatic and aromatic carboxylic acids was studied both experimentally and theoretically. Ten new cocrystals of benzamide were synthesized using an oriented samples approach via a fast dropped evaporation technique. Information about types of known bi-component cocrystals augmented with knowledge of simple binary eutectic mixtures was used for the analysis of virtual screening efficiency among 514 potential pairs involving aromatic carboxylic acids interacting with urea or benzamide. Quantification of intermolecular interaction was achieved by estimating the excess thermodynamic functions of binary liquid mixtures under supercooled conditions within a COSMO-RS framework. The smoothed histograms suggest that slightly more potential pairs of benzamide are characterized in the attractive region compared to urea. Finally, it is emphasized that prediction of cocrystals of urea is fairly direct, while it remains ambiguous for benzamide paired with carboxylic acids. The two known simple eutectics of urea are found within the first two quartiles defined by excess thermodynamic functions, and all known cocrystals are outside of this range belonging to the third or fourth quartile. On the contrary, such a simple separation of positive and negative cases of benzamide miscibility in the solid state is not observed. The difference in properties between urea and benzamide R2,2(8) heterosynthons is also documented by alterations of substituent effects. Intermolecular interactions of urea with para substituted benzoic acid analogues are stronger compared to those of benzamide. Also, the amount of charge transfer from amide to aromatic carboxylic acid and vice versa is more pronounced for urea. However, in both cases, the greater the electron withdrawing character of the substituent, the higher the binding energy, and the stronger the supermolecule polarization via the charge transfer mechanism.Electronic supplementary materialThe online version of this article (doi:10.1007/s00894-016-2964-6) contains supplementary material, which is available to authorized users.

(Solid + liquid) equilibrium phase diagrams in binary mixtures containing terpenes: New experimental data and analysis of several modelling strategies with modified UNIFAC (Dortmund) and PC-SAFT equation of state

In this study, interactions between terpenes and alcohols or hydrocarbons have been considered and investigated. With this aim, the (solid + liquid) equilibrium (SLE) phase diagrams for binary systems of {(−)-menthol, or thymol + 1-decanol, or benzyl alcohol, or 2-cyclohexanethanol, or n-decane} were determined at ambient pressure. A dynamic method was used over a broad range of terpene mole fraction and temperature. The simple eutectic mixtures with a complete miscibility in the liquid phase were detected for all systems. The basic thermal properties of the pure terpenes and some solvents, i.e. melting temperatures as well as the enthalpy of fusion, have been measured with differential scanning calorimetry. Thermodynamic modelling of the phase diagrams in terms of the well-known group contribution method modified UNIFAC (Dortmund) as well as molecular-based PC-SAFT equation of state, was carried out in order to assess overall performance of these approaches when used to describe SLE in such complex cross-associating mixtures like these under study. In particular, different predictive strategies for assessing the binary interaction parameters of PC-SAFT model were proposed and tested.

Heat of formation distributions of components involved in bi-component cocrystals and simple binary eutectic mixtures

The distributions of heat of formation characterizing a set of 3226 cocrystals.

Thermal analytical characterization of mixtures of antipsychotic drugs with various excipients for improved drug delivery

Antipsychotics are a class of psychiatric medication that is primarily effective at reducing psychosis symptoms, particularly in schizophrenia and bipolar disorders. This study aims to formulate mixtures of the antipsychotic drugs quetiapine fumarate (QUE), nortriptyline (NOR), propranolol (PROP) and haloperidol (HAL) with excipients urea, niacin (NIA) and niacinamide (NIM) to obtain an enhanced bioavailability and therapeutic effect. The mixtures were prepared by the solvent method and are characterized by various analytical techniques such as differential scanning calorimetry, wide angle X-ray diffraction, scanning electron microscopy and dissolution studies. Out of the various mixtures that have been prepared and tested, five of them showed eutectic behavior and their eutectic points are as follows: quetiapine fumarate–urea (QUE–UREA) 20–80, w/w; nortriptyline–niacin (NOR–NIA) 70–30, w/w; propranolol–niacin (PROP–NIA) 80–20, w/w; propranolol–niacinamide (PROP–NIM) 40–60, w/w; and haloperidol–niacinamide (HAL–NIM) 20–80, w/w. DSC investigation has revealed the formation of an eutectic system and the phase diagrams and Tamman’s triangle construction along with the hot-stage microscopy confirmed their melting points. PXRD study indicated no chemical interaction between either of the mixtures, while SEM study showed the size reduction in these mixtures that has been achieved. In vitro studies of the five mixtures showed an appreciable increase in the dissolution rate compared to that of the drug alone. In conclusion, five simple eutectic mixtures have been formulated by the solvent method and were found to show better dissolution rates than that of the pure form of the drugs, thus improving the bioavailability of these poorly water-soluble drugs.

Solidification and computational analysis of o-nitroaniline–α-naphthol eutectic system

Phase diagram of o-nitroaniline–α-naphthol system has been investigated by thaw melt method and results showed the formation of a simple eutectic mixture. The values of the heat of fusion of components and eutectic mixture were determined with the help of DSC technique. Excess Gibb’s free energy (GE), excess entropy (SE) and excess enthalpy (HE) of mixing were calculated. In order to know the nature of interaction between the two components, FT–IR spectral studies were made. The modulus of rupture of the pure components and the eutectic mixture were determined. The isotropic as well as the anisotropic solidification behavior were studied. Microstructural studies of o-nitroaniline showed the formation of lamellar with leafy like and α-naphthol showed the formation of broken rock like microstructures, whereas in the eutectic mixture, growth of flat crystals in different directions from a particular point were seen. Undercooling measurements were made. Optimized geometrical parameters, molecular properties and potential energy of the interacting molecules of the eutectic mixture have been examined using various computational methods.

Solubility of ionic liquids in 2-phenylethanol (PEA) and water

New experimental (solid+liquid) phase equilibrium (SLE) data for eight binary systems are reported. The systems are composed of the ILs: 1-ethyl-1-methylpiperidinium bis(trifluroromethylsulfonyl)imide, [EMPIP][NTf2], 1-propyl-1-methylpiperidinium bis(trifluroromethylsulfonyl)imide, [PMPIP][NTf2], 1-butyl-1-methylpiperidinium bis(trifluroromethylsulfonyl)imide, [BMPIP][NTf2], 1-hexyl-1-methylpiperidinium bis(trifluroromethylsulfonyl)imide, [HMPIP][NTf2], N-hexylquinolinium bis(trifluroromethylsulfonyl)imide, [HQuin][NTf2], N-hexylisoquinolinium bis(trifluroromethylsulfonyl)imide, [HiQuin][NTf2], [CCNMIM][TDI] and 1-butyl-3-methylimidazolium 4,5-dicyano-2(-trifluoromethyl)-imidazolide, [BMIM][TDI] with 2-phenylethanol (PEA). The synthesis of a new IL is presented for 1-(cyanomethyl)-3-methylimidazolium 4,5-dicyano-2-(trifluoromethyl)-imidazolide, [CCNMIM][TDI]. A differential scanning calorimetry (DSC) was used to determine the melting point and the enthalpy of melting of [CCNMIM][TDI]. The majority of the systems containing piperidinium-based ILs and [BMIM][TDI] showed complete miscibility with PEA. Simple eutectic mixture behaviour was found for the latest ILs. The solubility of the ILs decreases in the order [HQuin][NTf2]>[HiQuin][NTf2]>[EMPIP][NTf2]>[CCNMIM][TDI]. The correlation of the liquidus curves was undertaken with the NRTL excess Gibbs energy equation. The model correlates the solubility of the three systems (without [EMPIP][NTf2]) with an average root mean square deviation, σT=0.67K. To the best of our knowledge this is the very first paper where the SLE of PEA have been measured for systems with ILs. The solubility of six ILs in water were also measured. The solubility of the chosen ILs in water reveals SLE and/or (liquid+liquid) phase equilibrium (LLE) in these binary systems. The results of solubility of ILs in PEA and water can be used to design future alternative processes of the extraction of PEA, or separation from fermentation broth that involves these mixtures.

Terahertz and optical properties of nematic mixtures composed of liquid crystal isothiocyanates, fluorides and cyanides

Several simple nematic eutectic liquid crystal mixtures composed of different two and three ring isothiocyanato compounds as well as mixtures consisting of analogous cyano and fluoro compounds were formulated. The optical properties of the thereby obtained mixtures, i.e. refractive indices, birefringence and absorption coefficients αe and αo are measured in the frequency range between 0.5 and 2.5 THz and in the visible range at 589 nm. Our results show that two mixtures can be identified, which seems particularly promising for applications in the terahertz (THz) range: those consisting only of isothiocyanates show the highest birefringence at THz frequencies while those consisting of isothiocyanates and cyanides have the smallest dichroic ratio over a broad THz range. We also found that in most cases, the absorption coefficients of the isothiocyanato compounds fulfill the relationship αe > αo while for cyano and fluoro compounds, αo > αe is observed as a dominating trend. Furthermore, we show that by carefully selecting constituents of both isothiocyanato and cyano compounds, we can achieve a mixture for which the values of αo are in the same order as for αe for THz frequencies below 2 THz.

Modeling wax formation with predictive UNIQUAC: from petroleum and fuels to biofuels

A decade ago a model was proposed by us to describe the wax formation in crude oils and distillate fuels. Based on the Predictive UNIQUAC concept the model was very successful and was widely adopted by the industry [1]. With the advent of biofuels the incorporation of methyl or ethyl esters in the diesel was required and the presence of saturated long chain esters in solution created new problems of using these fuels at low temperatures. Aiming at understanding the low temperature behavior of vegetable oils and biodiesel fuels an extensive study of the binary systems of fatty acids [2], fatty acid methyl esters [3] and fatty acid ethyl esters [4] of even numbered fatty acid alkyl chains was carried. In this lecture the binary phase diagrams of these mixtures will be presented. It will be shown how, depending on the alkyl chain length differences in the binaries, it is possible to observe systems that change from a simple eutectic mixture to others where partial solid solution, formation of intermediate compounds, eutectic, peritectic and even metatetic reactions are observed. Considering the composition of a biodiesel the relevance of these binary mixtures to the understanding of cloud point formation of biodiesels will be discussed. Finally it will be shown how the Predictive UNIQUAC model can describe the phase behavior of biodiesel fuels at temperatures below their cloud point with an accurate description of the changes on the liquid phase and solid phase being formed [5]. A discussion concerning the future developments of this research field, in particular the modeling of diesel-biodiesel blends will conclude this presentation.

Phase equilibria and molecular interaction studies on (naphthols + vanillin) systems

Phase equilibria between (α-naphthol+vanillin) and (β-naphthol+vanillin) systems have been studied by thaw-melt method and the results show the formation of simple eutectic mixtures. Crystallization velocities of components and eutectic mixtures were determined at different stages under cooling. With the help of differential scanning calorimeter (DSC), the enthalpy of fusion of components and eutectic mixtures was determined and from the values excess thermodynamic functions viz., excess Gibbs free energy (GE), excess entropy (SE), excess enthalpy (HE) of hypo-, hyper- and eutectic mixtures were calculated. Flexural strength measurements were made in order to understand the non-ideal nature of eutectics. FT-IR spectral studies indicate the formation of hydrogen bond in the eutectic mixture. Anisotropic and isotropic microstructural studies of components, hypo-, hyper- and eutectic mixtures were made. Jackson’s roughness parameter was calculated and found to be greater than 2 suggesting the faceted morphology with irregular structures. The overall results have shown that there is a weak molecular interaction between the components in the eutectic mixtures and the (α-naphthol+vanillin) eutectic is more stable as compared to the (β-naphthol+vanillin) eutectic system.

Effects of solid carriers on the crystalline properties, dissolution and bioavailability of flurbiprofen in solid self-nanoemulsifying drug delivery system (solid SNEDDS)

In order to investigate the effects of solid carriers on the crystalline properties, dissolution and bioavailability of flurbiprofen in a solid self-nanoemulsifying drug delivery system (solid SNEDDS), different solid SNEDDS formulations were prepared by spray-drying the solutions containing liquid SNEDDS and various carriers. The liquid SNEDDS, composed of Labrafil M 1944 CS/Labrasol/Trasncutol HP (12.5/80/7.5%) with 2%w/v flurbiprofen, gave a z-average diameter of about 100nm. Silicon dioxide, a hydrophobic solid carrier, produced an excellent conventional solid SNEDDS with a nanoemulsion droplet size of less than 100nm, similar to the liquid SNEDDS and smaller than the other solid SNEDDS formulations. The drug was in an amorphous state in this solid SNEDDS. Furthermore, it greatly improved the dissolution rate and oral bioavailability of flurbiprofen in rats because it allowed the spontaneous formation of an interface between the oil droplets and the water. Magnesium stearate, a hydrophobic carrier, produced a solid SNEDDS with the largest diameter. However, it greatly enhanced the dissolution rate and oral bioavailability due to the formation of a simple eutectic mixture. The hydrophilic carriers such as polyvinyl alcohol (PVA), sodium carboxymethyl cellulose (Na-CMC) and hydroxypropyl-β-cyclodextrantrin (HP-β-CD) did not form a solid SNEDDS but rather a solid dispersion (or microcapsule). HP-β-CD improved the dissolution rate but did not improve the oral bioavailability as much as the hydrophobic polymers. PVA and Na-CMC hardly improved the dissolution rate but maintained constantly high plasma levels in rats for a long period. Thus, the selection of carrier is an important factor in the development of solid SNEDDS, since the carriers had significant effects on the crystalline properties, dissolution and oral bioavailability of flurbiprofen and on the formation of solid SNEDDS.

Phase Equilibria, Crystallization, and Microstructural Studies of the Flunixin Meglumine + Meglumine System

The phase diagram of flunixin meglumine + meglumine system has been investigated with the method of differential scanning calorimetry (DSC). The results show that the flunixin meglumine and meglumine hold the formation of a simple eutectic mixture. The linear velocity of solidification of both pure components and the eutectic mixture was determined at different undercooling rates. The fusion enthalpy and the linear velocity of crystallization indicate the nonideal properties of the eutectic mixture in the melt. The roughness parameter of the eutectic system was calculated from the enthalpy of fusion value. The anisotropic and isotropic crystallizations of flunixin meglumine, meglumine, and the eutectic mixture were studied.

Solubility and pKa determination of six structurally related phenothiazines

Solubilities of six structurally related phenothiazines, namely chlorpromazine hydrochloride, fluphenazine dihydrochloride, promazine hydrochloride, thioridazine hydrochloride, trifluoperazine dihydrochloride, and triflupromazine hydrochloride at constant pH were measured in the temperature range from 290K to 350K in three important drugs solvents: water, ethanol and 1-octanol using the dynamic method and UV–vis method. Dissociation constants and corresponding pKa values of drugs were obtained with Bates–Schwarzenbach method at temperature 298.15K in the buffer solutions. Our experimental pKa values for chlorpromazine hydrochloride, fluphenazine dihydrochloride, promazine hydrochloride, thioridazine hydrochloride, trifluoperazine dihydrochloride, and triflupromazine hydrochloride are 9.15, 10.01, 9.37, 8.89, 8.97, and 9.03, respectively. The basic thermal properties of pure drugs i.e. melting and solid–solid phase transition as well as glass-transition temperatures, the enthalpy of melting and phase transitions and the molar heat capacity at glass transition (at constant pressure) were measured with differential scanning microcalorimetry (DSC) technique. Molar volumes were calculated with Barton group contribution method. The experimental solubility data were correlated by means of three commonly known GE equations: the Wilson, NRTL and UNIQUAC with the assumption that the systems studied here have revealed simple eutectic mixtures. The root-mean-square deviations of temperature were used for the precision of the correlation. The activity coefficients of drugs at saturated solutions in each correlated binary mixture were calculated from the experimental data. These new data will help in all prediction-methods and their precision.