Hydrated Solid Forms of Theophylline and Caffeine Obtained by Mechanochemistry

González-González, Juan Saulo; Zúñiga-Lemus, Oscar; Hernández-Galindo, María del Carmen

doi:10.9790/3013-0705012830

Cited by 10 publications

(12 citation statements)

References 12 publications

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“…However, milling in the presence of pure water and aqueous methanol mixtures with a modest concentration of organic solvent results in the formation of a monohydrate with a characteristic peak on lines (2) and (4). Similar conclusions were also drawn from milling in neat water by González et al [97]. Here, additional experiments were conducted by re-milling the freshly obtained hydrate in conditions of higher content of methanol.…”

Section: Precipitate Characteristicssupporting

confidence: 75%

“…In order to characterise the pseudo-polymorphic behaviour of theophylline in the presence of water and organic solvents, differential scanning calorimetry (DSC) measurements were utilised for co-ground samples. The mechanochemical approach was selected due to its efficiency and previously documented application of co-grinding in successful theophylline hydrate synthesis [97].…”

Section: Differential Scanning Calorimetry Measurementsmentioning

confidence: 99%

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Solvent Screening for Solubility Enhancement of Theophylline in Neat, Binary and Ternary NADES Solvents: New Measurements and Ensemble Machine Learning

Cysewski

Jeliński

Cymerman

et al. 2021

IJMS

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Theophylline, a typical representative of active pharmaceutical ingredients, was selected to study the characteristics of experimental and theoretical solubility measured at 25 °C in a broad range of solvents, including neat, binary mixtures and ternary natural deep eutectics (NADES) prepared with choline chloride, polyols and water. There was a strong synergistic effect of organic solvents mixed with water, and among the experimentally studied binary systems, the one containing DMSO with water in unimolar proportions was found to be the most effective in theophylline dissolution. Likewise, for NADES, the addition of water (0.2 molar fraction) resulted in increased solubility compared to pure eutectics, with the highest solubilisation potential offered by the composition of choline chloride with glycerol. The ensemble of Statistica Automated Neural Networks (SANNs) developed using intermolecular interactions in pure systems has been found to be a very accurate model for solubility computations. This machine learning protocol was also applied as an extensive screening for potential solvents with higher solubility of theophylline. Such solvents were identified in all three subgroups, including neat solvents, binary mixtures and ternary NADES systems. Some methodological considerations of SANNs applications for future modelling were also provided. Although the developed protocol is focused exclusively on theophylline solubility, it also has general importance and can be used for the development of predictive models adequate for solvent screening of other compounds in a variety of systems. Formulation of such a model offers rational guidance for the selection of proper candidates as solubilisers in the designed solvents screening.

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Section: Precipitate Characteristicssupporting

confidence: 75%

Section: Differential Scanning Calorimetry Measurementsmentioning

confidence: 99%

Solvent Screening for Solubility Enhancement of Theophylline in Neat, Binary and Ternary NADES Solvents: New Measurements and Ensemble Machine Learning

Cysewski

Jeliński

Cymerman

et al. 2021

IJMS

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“…Figure 3A presents PXRD patterns of the caffeine sample obtained with increasing temperatures. The pattern obtained at room temperature is consistent with caffeine hydrate, showing characteristic diffraction peaks (*) at 10.5° 2Ɵ and 13.05° 2Ɵ (13). As the temperature is increased to approximately 45°C, a new diffraction peak (#) characteristic of anhydrous caffeine develops at approximately 11.7° 2Ɵ (14).…”

Section: Resultssupporting

confidence: 63%

Atomic force microscopy to identify dehydration temperatures for small volumes of active pharmaceutical ingredients

et al. 2020

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The environmental conditions associated with changing the hydration state of active pharmaceutical ingredients (API) are crucial to understanding their stability, bioperformance, and manufacturability. Identifying the dehydration event using < 1μg of material is an increasingly important challenge. Atomic Force Microscopy indentation mapping is implemented at controlled temperatures between 25-100°C, for nanoscale volumes of hydrated APIs exhibiting distinct dehydration behavior and anhydrous APIs as controls. For caffeine hydrate and azithromycin dihydrate, the relative mechanical modulus increases ~10-fold at dehydration temperatures. These are confirmed by conventional macroscopic measurements including Variable Temperature Powder X-ray Diffraction, Thermogravimetric Analysis, and Differential Scanning Calorimetry. Conversely, no such mechanical transition is observed for anhydrous ibuprofen or a proprietary anhydrous compound. AFM-based mechanical mapping is therefore demonstrated for smallvolume determination of temperature-induced solid-state dehydration events, which may enable spatially or temporally mapping for future studies of dehydration mechanisms and kinetics, as a function of commercially relevant nanoscale heterogeneities.

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“…The characteristic absorption bands of this form involve C-H (alkyl) at around 2900 cm −1 , C=O at around 1650 and 1710 cm −1 , C=C at around 1550 cm −1 and C-N at around 1250 cm −1 . However, when caffeine was dissolved in water and in mixtures containing water (x = 0.2 to x = 0.8) an additional new wide band appears with a maximum at around 3400 cm −1 , which can be attributed to the O-H stretching in the hydrate [ 95 ]. The above pattern was repeatedly observed for all studied solvents.…”

Section: Resultsmentioning

confidence: 99%

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

2022

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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.

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Hydrated Solid Forms of Theophylline and Caffeine Obtained by Mechanochemistry

Cited by 10 publications

References 12 publications

Solvent Screening for Solubility Enhancement of Theophylline in Neat, Binary and Ternary NADES Solvents: New Measurements and Ensemble Machine Learning

Solvent Screening for Solubility Enhancement of Theophylline in Neat, Binary and Ternary NADES Solvents: New Measurements and Ensemble Machine Learning

Atomic force microscopy to identify dehydration temperatures for small volumes of active pharmaceutical ingredients

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

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