Solubility Of Caffeine Research Articles

Is methyl salicylate the perfect organic solvent for caffeine?

In this article, detailed physicochemical characterization of caffeine + methyl salicylate mixtures is performed based at solubility, density, speed of sound and viscosity measurements in a temperature range from T = (293.15–313.15) K. The thermodynamic parameters have been evaluated from experimental measurements, and results are additionally supported by molecular dynamic simulations. From obtained thermodynamic properties, it was discussed how the caffeine presence influences the molecular interactions and methyl salicylate solvent clathrate-like structural organization. The comprehensive investigation confirmed the absence of caffeine self-aggregates in methyl salicylate solvent. The solubility of caffeine in methyl salicylate is 69% higher than in water at T = 293.15 K, while at T = 313.15 K it is lower by 7%. The dissolution of caffeine in methyl salicylate occurs with heat absorption and an increase in the order of the system. The methyl salicylate choice as a solvent is important because caffeine and methyl salicylate could be found in pharmaceutical and cosmetical formulations for topical and transdermal caffeine delivery.

Elucidating the hydrotropism behaviour of aqueous caffeine and sodium benzoate solution through NMR and neutron total scattering analysis

Hydrotropism is a convenient way to increase the solubility of drugs by up to several orders of magnitude, and even though it has been researched for decades with both experimental and simulation methods, its mechanism is still unknown. Here, we use caffeine/sodium benzoate (CAF-SB) as model system to explore the behaviour of caffeine solubility enhancement in water through NMR spectroscopy and neutron total scattering. 1H NMR shows strong interaction between caffeine and sodium benzoate in water. Neutron total scattering combined with empirical potential structure refinement, a systematic method to study the solution structure, reveals π-stacking between caffeine and the benzoate anion as well as Coulombic interactions with the sodium cation. The strongest hydrogen bond interaction in the system is between benzoate and water, which help dissolve CAF-SB complex and increase the solubility of CAF in water. Besides, the stronger interaction between CAF and water and the distortion of water structure are further mechanisms of the CAF solubility enhancement. It is likely that the variety of mechanisms for hydrotropism shown in this system can be found for other hydrotropes, and NMR spectroscopy and neutron total scattering can be used as complementary techniques to generate a holistic picture of hydrotropic solutions.

Anticipating APIs solubility in natural eutectic solvents: Lidocaine and caffeine case studies

The reduced solubility of some active pharmaceutical ingredients (APIs) in water is a limiting factor for the development of new formulations. Therefore, the search of new compatible solvents would be convenient to overcome such limitation. Among this group, eutectic solvents stand out as good candidates. In this work, the systematic application of COSMO-RS as a predictive method to anticipate APIs solubility in systems involving natural eutectic solvents (NAESs) is presented. The methodology has been validated by using a collection of 50 APIs – NAESs systems from the literature. This predictive tool allowed the selection of four NAESs (reported in literature as natural eutectic mixtures) as good candidates to improve lidocaine and caffeine solubility in water and PEG 300 (benchmark solvents). The four NAESs candidates were prepared and experimentally characterized by means of density and viscosity measurements. Density values ranging from 1.0 to 1.3 g/mL and viscosities from 200 to 2,200 cP were found, with glycerol based NAESs as the most viscous systems. Solubility experiments were also carried out to analyze COSMO-RS predictions validity. Betaine: lactic acid and betaine: 1,2-propanediol are good candidates for lidocaine solutions, achieving 2,300 and 572 mg/mL values respectively, much higher than polyethylene glycol, PEG 300, (173 mg/mL), typically used as benchmark solvent. In the case of caffeine, proline:lactic acid was found as the best candidate with 30 mg/mL solubility (higher than water: 23 mg/mL and PEG 300: 18 mg/L). This work permits a systematic analysis of APIs solubility in NAESs (more than 80 systems reported) by using a total predictive tool (COSMO-RS predictions) to anticipate that promising solvents, with high solubilities for lidocaine and caffeine.

Solubility enhancement of caffeine and furosemide using deep eutectic solvents formed by choline chloride and xylitol, citric acid, sorbitol or glucose

The low solubility of active pharmaceutical ingredients (APIs) in aqueous medium hinders the formulation of drugs in liquid solvents. Several methodologies are used to improve their solubilities being one of them the use of Deep Eutectic Solvents (DES). In this work 10 DES formed by xylitol, citric acid, sorbitol and glucose (HBD) and choline chloride as HBA have been prepared. The solubility of caffeine and furosemide in these DES and their stability have been studied. Additionally, their volumetric and rheological properties have been analysed. Results show that in the case of caffeine, the increase of water content, increase the solubility. This trend is the opposite in the case of furosemide. The stability study reveals that the concentrations of API in DES have been stable during the test time. Finally, the rheological study shows that all studied DES are non-Newtonian fluids, with viscosities decreasing when water content increases.

Influence of Sodium Salicylate on Self-Aggregation and Caffeine Solubility in Water-A New Hypothesis from Experimental and Computational Data.

The present study analyzed experimental data from volumetric and viscosimetric measurements and computational simulations to understand caffeine hydration and aggregation properties in 0.1 mol∙kg-1 of sodium salicylate aqueous solution. Sodium salicylate reduces the bitter taste and increases the solubility of caffeine in water, which is the main reason for their combination in food products. The results noted in volumetric and viscosimetric measurements indicate that sodium salicylate promotes the self-aggregation of caffeine in water. After self-aggregation, the hydration number of caffeine significantly increases. Molecular simulations have allowed us to hypothesize how salicylate increases caffeine solubility. At the molecular level, relocating salicylate moiety from the parallel stacking (π-π) aromatic complex with caffeine and its hydration could be the main reason for increasing the solubility of caffeine in water. The presented study provides clear guidelines on the choice of additives to increase caffeine's solubility in aqueous media. The choice of salicylate as an additive to increase the solubility of caffeine is very important because caffeine and salicylate are found in combination in a large number of formulations.

Caffeine solubility in aqueous solutions of polyethylene glycol dimethyl ether 250: measurement and thermodynamic modeling

ABSTRACT Molar solubility of caffeine in polyethylene glycol dimethyl ether 250 (PEGDME 250) + water mixtures over all mass fractions of PEGDME 250 were determined at 293.15–313.15 K under atmospheric pressure (≈ 85 kPa). The crystal forms of the caffeine in equilibrium with neat solvents of PEGDME 250 and water were analysed using X-ray powder diffraction and the results compared with the original caffeine. Also, the Hansen solubility parameters of caffeine and PEGDME 250 + water mixtures in the absence of caffeine were predicted. The studies of apparent thermodynamic analysis presented an endothermic and enthalpy-driven dissolution of caffeine. Moreover, the solubility of caffeine were correlated using various models; the van’t Hoff, mixture response surface, Jouyban–Acree, Jouyban–Acree–van’t Hoff, the modified version of Jouyban–Acree–van’t Hoff, the CNIBS/R-K, the Buchowski–Ksiazczak, the modified Wilson and modified Wilson–van’t Hoff models, acquiring average relative deviation values that were lower than 14.7%.

Quantification of Caffeine Interactions in Choline Chloride Natural Deep Eutectic Solvents: Solubility Measurements and COSMO-RS-DARE Interpretation.

Solubility of active pharmaceutical ingredients is an important aspect of drug processing and formulation. Although caffeine was a subject of many studies aiming to quantify saturated solutions, many applied solvents suffer from not being environmentally friendly. This work fills this gap by presenting the results of solubility measurements in choline chloride natural deep eutectic solvents, ccNADES, comprising one of seven of the following polyalcohols: glycerol, sorbitol, xylitol, glucose, sucrose, maltose and fructose. The ratio of ccNADES components was optimized for maximizing caffeine solubility at room temperature. Additionally, temperature dependent solubility was measured for the first four systems exhibiting the highest solubility potential, both in their neat forms and in mixtures with water. Results were used for intermolecular interactions assessments using the COSMO-RS-DARE approach, which led to a perfect match between experimental and computed solubility values. An important methodological discussion was provided for an appropriate definition of the systems. Surprising linear trends were observed between the values of fitting parameters and water-ccNADES composition. In addition, comments on selection of the values of the fusion thermodynamic parameters were provided, which led to the conclusion that COSMO-RS-DARE solubility computations can effectively compensate for the inaccuracies of these important physicochemical properties.

Caffeine metastable zone width and induction time in anti-solvent crystallization

In this study, the anti-solvent approach was used to investigate caffeine's induction time and metastable zone width (MSZW). Chloroform is used as a solvent, and carbon tetrachloride is used as an anti-solvent. Initially, caffeine solubility data is gathered in the chloroform/carbon tetrachloride mixture at various chloroform mass fractions. Caffeine solutions with various concentrations were then created to determine the MSZW. The anti-solvent (carbon tetrachloride) was injected into the solution to achieve supersaturation. The metastable zone limit was obtained by adding the anti-solvent at a constant rate and using turbidity changes in the system. The time of induction in various supersaturations was also investigated. In this section, various concentrations of solutions were created. Then, the system was instantly supersaturated with an anti-solvent. The period between the addition of the anti-solvent and the change in the turbidity of the solution was known as the induction time. The visual technique is compared to the use of an online turbidimeter before starting induction time measurements, and it is shown that the induction times obtained with the online turbidimeter are shorter and more accurate. Additionally, the induction time was investigated by various supersaturations, and it was discovered that as the supersaturation approaches the metastable zone border, the induction time decreases. Furthermore, in the same supersaturations, the influence of mixing on induction time was explored, and it was revealed that the higher the stirring speed, the shorter the induction time. Finally, the interfacial energy of solid–liquid phase was calculated for two systems with different initial chloroform mass fractions. It was shown that a reduction in polarity of medium increases the interfacial energy.

SKIN TARGETING OF AN OPTIMIZED CAFFEINE NANOSTRUCTURED LIPID CARRIER WITH IMPROVED EFFICIENCY AGAINST CHEMOTHERAPY INDUCED ALOPECIA

Objective: The current investigation was designed to develop and optimize caffeine-loaded nanostructured lipid carriers (NLCs) for topical alopecia treatment. Methods: Screening of drug solubility in various excipients was executed. The 23 full factorial design was employed for NLCs optimization. Lipid type, surfactant type, and drug concentration were the independent variables. Entrapment efficiency (EE), particle size, polydispersity index (PDI) and % drug release were the chosen responses. Physiochemical evaluation, in vitro release, ex-vivo permeation, and stability study were achieved. Results: The solubility of caffeine in stearic acid and glyceryl monostearate (GMS) was 47.11±3.048 and 32.67±2.955 mg/g, respectively. Oleic acid: garlic oil mixture at a ratio of 1:1 v/v was the oily phase. Tween 80 and Cremophor EL, Transcutol HP, carbonate buffer (pH 10.8 and ionic strength 200 mmol) were chosen as a surfactant, co-surfactant, and aqueous phase, respectively. The optimized formula showed particle size, %EE, PDI, zeta potential of 358 nm±1.45, 72.55 %±0.12, 0.912±0.030,-24.8 mv±0.70, respectively. The % release was 92.9±4.9 % after 2 h. Confocal laser scanning microscopy showed an improved permeation of caffeine-loaded NLCs to the whole skin layers. Conclusion: The histological examination proved the efficiency of caffeine NLCs optimized formula in promoting hair growth compared to the market formula.

Aqueous solubility of high concentrated caffeine using hydrotrope and the application to the anti-cellulite cosmetics

This study presents measurements of the aqueous solubility of caffeine at a temperature ranging from 5 to 40°C. And the low water solubility of caffeine was increased by using a hydrotropic solubilization system. Solubility was measured with a single hydrotropic system of niacinamide or betaine and a mixed hydrotropic system of niacinamide and betaine. As a result, it was possible to prepare a high-concentration aqueous caffeine solution of about 4% at 5.9°C and about 25% at 39.9°C. The modified Apelblat equation was applied to predict the temperature dependence of caffeine solubility in aqueous solutions containing niacinamide, and our experimental data showed good agreement with the correlated values. We propose the results of this study as basic data for the development of anti-cellulite cosmetics.

Application of the Solute-Solvent Intermolecular Interactions as Indicator of Caffeine Solubility in Aqueous Binary Aprotic and Proton Acceptor Solvents: Measurements and Quantum Chemistry Computations.

The solubility of caffeine in aqueous binary mixtures was measured in five aprotic proton acceptor solvents (APAS) including dimethyl sulfoxide, dimethylformamide, 1,4-dioxane, acetonitrile, and acetone. The whole range of concentrations was studied in four temperatures between 25 °C and 40 °C. All systems exhibit a strong cosolvency effect resulting in non-monotonous solubility trends with changes of the mixture composition and showing the highest solubility at unimolar proportions of organic solvent and water. The observed solubility trends were interpreted based on the values of caffeine affinities toward homo- and hetero-molecular pairs formation, determined on an advanced quantum chemistry level including electron correlation and correction for vibrational zero-point energy. It was found that caffeine can act as a donor in pairs formation with all considered aprotic solvents using the hydrogen atom attached to the carbon in the imidazole ring. The computed values of Gibbs free energies of intermolecular pairs formation were further utilized for exploring the possibility of using them as potential solubility prognostics. A semi-quantitative relationship (R2 = 0.78) between caffeine affinities and the measured solubility values was found, which was used for screening for new greener solvents. Based on the values of the environmental index (EI), four morpholine analogs were considered and corresponding caffeine affinities were computed. It was found that the same solute–solvent structural motif stabilizes hetero-molecular pairs suggesting their potential applicability as greener replacers of traditional aprotic proton acceptor solvents. This hypothesis was confirmed by additional caffeine solubility measurements in 4-formylmorpholine. This solvent happened to be even more efficient compared to DMSO and the obtained solubility profile follows the cosolvency pattern observed for other aprotic proton acceptor solvents.

Miscibility and Solubility of Caffeine and Theophylline in Hydroxypropyl Methylcellulose.

As amorphization may improve the solubility and bioavailability of a drug substance, the aim of this work was to assess to what extent the crystallinity of caffeine (CAF) and theophylline (TF) can be reduced by homogenization with a polymeric excipient. To realize this purpose, the physical mixtures of both methylxanthines with hydroxypropyl methylcellulose (HPMC) were examined using differential scanning calorimetry (DSC), hot-stage microscopy (HSM), Fourier-transform infrared (FTIR) and Raman spectroscopy. Moreover, phase diagrams for the physical mixtures were calculated using theoretical data. Results of DSC experiments suggested that both CAF and TF underwent amorphization, which indicated proportional loss of crystallinity for methylxanthines in the mixtures with HPMC. Additionally, HSM revealed that no other crystalline or amorphous phases were created other than those observed for CAF and TF. FTIR and Raman spectra displayed all the bands characteristic for methylxanthines in mixtures with HPMC, thereby excluding changes in their chemical structures. However, changes to the intensity of the bands created by hydrogen bonds imply the formation of hydrogen bonding in the carbonyl group of methylxanthines and the methyl polymer group. This is consistent with data obtained using principal component analysis. The findings of these studies revealed the quantities of methylxanthines which may be dissolved in the polymer at a given temperature and the composition at which methylxanthines and polymer are sufficiently miscible to form a solid solution.

Dissolving power of the binary solvent carbon tetrachloride – methanol. Solubility of caffeine: Experiment, ASL model, and MD simulation

An experimental and theoretical study of the dissolving power of the binary solvent consisting of inert (carbon tetrachloride) and self-associated (methanol) components has been carried out. According to the experimental data, the dependence of the caffeine solubility on the composition of the binary solvent has a maximum in the region of 0.5 mole fraction of the cosolvent. The maximum is also observed for the concentration dependence of the Gibbs energy of solvation calculated within the framework of molecular dynamics (MD) simulation. Within the framework of the ASL (Associated Solution + Lattice) model, it was shown that the main contribution to solubility is made by the caffeine – methanol heteroassociation. The second largest contribution is defined by non-specific intermolecular interactions in the system. A negative contribution is made by the difference in the sizes of the molecules of the mixture components.

Green solvents to tune the biomolecules’ solubilization in aqueous media: An experimental and in silico approach by COSMO-RS

In this work, the solubility of curcumin, gallic acid, and caffeine was measured in aqueous solutions of deep eutectic solvents (DES) and its constituents individually (HBA: cholinium chloride, and HBD: ethylene glycol and 1,2-propanediol) at 298.2 K. The solubility behavior was evaluated by experimental and in silico (by COSMO-RS model) approaches. Additionally, the solubilization kinetics of the curcumin was also evaluated. The finds of this work showed that the use of proper additives can favor the solubility of hydrophobic biomolecules, such as curcumin, in aqueous media. When the gallic acid solubility curves were determined, the hydrotropic effect was observed. This fact allows manipulating the solubilization or precipitation of this biomolecule according to the target application. For the caffeine, in its turn, all additives reduced the solubility of caffeine in relation to pure water. To support the understanding of the experimental data, the biomolecules and additives polarity were calculated by COSMO-RS, through their σ-profile. The in silico approach reinforces the postulate that there is a set of factors involved in solubilization processes, being some of them: the non-polar charges, size, and linearity of the chemical chain, of both solvent and solute. Finally, the dissolution kinetics of curcumin was determined demonstrating the DES' viscosity effect on the mass transfer processes which are the basis of the solubility mechanism. The results here explored reinforces the importance of understanding the role of the polarity, size, and linearity of the chemical chain of all compounds involved in the solubility assay. The comprehension of these facts is of great importance to process development for the food and pharmacist industry, allowing to tune the solubility of the target biomolecule.

Solubility of caffeine in N-methyl-2-pyrrolidone + 1-propanol mixtures at different temperatures

Solubility data of pharmaceutical ingredients is required for crystallization, extraction and purification processes. The solubility profile and thermodynamic modeling of caffeine in the binary non-aqueous mixed solutions of N-methyl-2-pyrrolidone (NMP) and 1-propanol at various temperatures ranging from 293.2 to 313.2 K are measured in this study using a shake-flask method and the obtained data are fitted to some linear and a non-linear mathematical cosolvency models. Furthermore, the densities of caffeine saturated solutions are also determined and correlated with an adopted version of the Jouyban-Acree model. To study the accuracy of the applied models, the mean relative deviations of the back-calculated solubility and density data are computed. As well, the apparent thermodynamic properties of the caffeine dissolution process in the mixed solutions of NMP and 1-propanol are also calculated by using van’t Hoff and Gibbs equations and discussed.

Solubility measurement and thermodynamic modeling of caffeine in N-methyl-2-pyrrolidone + isopropanol mixtures at different temperatures

The solubility knowledge of pharmaceutical compounds in pure solvents and solvent mixtures has a critical role in formulation, separation and purification in the pharmaceutical and chemical industries. In the article ahead, the solid–liquid equilibria measurements for solubility of caffeine in the non-aqueous binary mixtures of N-methyl-2-pyrrolidone (NMP) and isopropanol at different temperatures and atmospheric pressure is measured and the acquired data are fitted to some linear and non-linear cosolvency models including the van’t Hoff, the combined nearly ideal binary solvent/Redlich–Kister (CNIBS/R–K), Jouyban-Acree, Jouyban-Acree-van’t Hoff, and the modified Wilson models. The determined density data of caffeine saturated solutions as another physico-chemical property are also correlated with the Jouyban-Acree model and the results are discussed in detail. The mean relative deviations (MRD%) of the back-calculated solubility data aiming to study the accuracy of the applied models are computed. Moreover, the apparent thermodynamic properties of caffeine dissolution process are also calculated by using van’t Hoff and Gibbs equations.

Automated solubility screening platform using computer vision

SummarySolubility screening is an essential, routine process that is often labor intensive. Robotic platforms have been developed to automate some aspects of the manual labor involved. However, many of the existing systems rely on traditional analytic techniques such as high-performance liquid chromatography, which require pre-calibration for each compound and can be resource consuming. In addition, automation is not typically end-to-end, requiring user intervention to move vials, establish analytical methods for each compound and interpret the raw data. We developed a closed-loop, flexible robotic system with integrated solid and liquid dosing capabilities that relies on computer vision and iterative feedback to successfully measure caffeine solubility in multiple solvents. After initial researcher input (<2 min), the system ran autonomously, screening five different solvent systems (20-80 min each). The resulting solubility values matched those obtained using traditional manual techniques.

Solubility of caffeine in carbitol + ethanol mixture at different temperatures

The solubility of caffeine in non-aqueous mixed solutions of carbitol and ethanol at different temperatures are determined by a shake-flask method and fitted to some reported cosolvency models including the van't Hoff, the double log-log, the mixture response surface, the Yalkowsky, the Jouyban-Acree, the Jouyban-Acree-van't Hoff, and the modified Wilson models. Along with solubility, the densities of caffeine saturated mixtures are also measured and correlated with the Jouyban-Acree model. In order to study the accuracy of the employed models, the mean relative deviations (MRD%) of the back-calculated solubility and density data are calculated. Furthermore, the apparent thermodynamic properties of caffeine dissolution process in the mixed solutions of carbitol and ethanol are also calculated by using van't Hoff and Gibbs equations.

Solubility of caffeine in N-methyl-2-pyrrolidone + ethanol mixture at different temperatures

The solubility profile of caffeine in the binary non-aqueous mixtures of N-methyl-2-pyrrolidone (NMP) and ethanol at different temperatures is determined and the obtained data are fitted to some linear and non-linear cosolvency models including the van't Hoff, the double log-log, the mixture response surface, Yalkowsky, Jouyban-Acree, Jouyban-Acree-van't Hoff, and the modified Wilson models. The measured density data of caffeine saturated solutions as another physico-chemical property are also correlated with the Jouyban-Acree model and the results are discussed. In order to investigate the accuracy of the applied models, the mean relative deviations (MRD%) of the back-calculated solubility data is calculated. Furthermore, the apparent thermodynamic properties of caffeine dissolution process are also calculated by using van't Hoff and Gibbs equations.

A spoonful of sugar for your coffee

Drug Solvation Although we brew coffee and tea in water, the psychoactive drug we crave, caffeine, is moderately hydrophobic and becomes more so as the temperature of a beverage decreases. Stacked aggregates of caffeine molecules, which may have different properties, can form at saturation. Shumilin et al. investigated the distribution of caffeine aggregates and monomers in response to increasing concentration of a common excipient: sugar. Although various sugars decreased overall caffeine solubility, they had a preferential effect on oligomers and resulted in a higher relative proportion of caffeine in the monomer form. J. Am. Chem. Soc. 141 , 18056 (2019).