Crystallization kinetics and glass-forming ability of rapidly crystallizing drugs studied by Fast Scanning Calorimetry

The use of the amorphous forms of drugs is a modern approach for the enhancement of bioavailability. At the same time, the high cooling rate needed to obtain the metastable amorphous state often prevents its investigation using conventional laboratory methods such as differential scanning calorimetry, X-ray powder diffractometry. One of the ways to overcome this problem may be the application of Fast Scanning Calorimetry. This method allows direct determination of the critical cooling rate of the melt and kinetic parameters of the crystallization for bad glass formers. In the present work, the amorphous states of dopamine hydrochloride and atenolol were created using Fast Scanning Calorimetry for the first time. Critical cooling rates and glass transition temperatures of these drugs were determined. Based on the values of the kinetic fragility parameter, dopamine hydrochloride glass can be considered strong, while atenolol glass is moderately strong. Both model-based and model-free approaches were employed to determine the kinetic parameters of cold crystallization of dopamine and atenolol. The results were compared with the data from isothermal crystallization experiments. The Nakamura crystallization model provides the best description of the crystallization process and can be used to predict the long term stability of the amorphous forms of the drugs. The presented approaches may find applications in predicting the storage time and choosing the optimal storage conditions of the amorphous drugs prone to crystallization

Kinetic stability of amorphous dipyridamole: A fast scanning calorimetry investigation

© 2019 Elsevier B.V. One of the main tasks of modern pharmaceutics is enhancing the solubility of drugs. The approaches for solving this problem include producing active pharmaceutical ingredients in the amorphous state. However, the use of amorphous drugs requires the determination of their kinetic stability. The latter is often assessed using isothermal techniques, which are time-consuming. Alternatively, non-isothermal methods can be employed, allowing to determine the kinetic triplet more rapidly. Also, such techniques can be used to develop predictive models for storage stability. The production of the amorphous state itself typically requires fast cooling rates, which may not be easily accessible. Fast scanning calorimetry is a promising tool for the investigation of amorphous drug systems. In the present work, the crystallization of the model drug dipyridamole was investigated using the fast scanning calorimetry method. The kinetic stability of the amorphous form of the drug was evaluated using both, isothermal and non-isothermal methods. The Nakamura crystallization model was found to be applicable for the prediction of the temporal stability of the amorphous drug forms. The obtained results may find applications in the investigation of the kinetic stability of amorphous drug systems

The fusion thermochemistry of rubrene and 9,10-diphenylanthracene between 298 and 650 K: Fast scanning and solution calorimetry

© 2020 Elsevier B.V. The fusion enthalpies and the heat capacities of crystalline, molten, and supercooled liquid rubrene (Tm = 603 K) and 9,10-diphenylanthracene (Tm = 523 K) were measured using fast scanning calorimetry and conventional DSC. The experimental fusion enthalpies at the melting temperature were corrected to 298.15 K according to Kirchhoff's law of thermochemistry. On the other hand, the fusion enthalpies at 298.15 K were determined from the solution enthalpies of these compounds in benzene, considering “like dissolves like” principle. The fusion enthalpies at 298.15 K obtained using independent methods were in mutual agreement. The heat capacity corrections of the fusion enthalpies of the studied non-planar polycyclic aromatic hydrocarbons to 298.15 K were found to be significantly higher than for planar polyaromatics. The features of measurement of the heat capacities of organic compounds by fast scanning calorimetry in the temperature range of notable volatility were discussed. The complete absence of the mass losses during heating-cooling cycles was found to be unnecessary condition for accurate heat capacity measurement; tolerable mass losses during the procedure were evaluated

The ability of ionic liquids to form hydrogen bonds with organic solutes evaluated by different experimental techniques. Part II. Alkyl substituted pyrrolidinium- and imidazolium-based ionic liquids

© 2020 Elsevier B.V. This work is devoted to the study of hydrogen bond formation ability of ionic liquids. The proton donor abilities of pyrrolidinium-based ionic liquids with common anion bis(trifluoromethylsulfonyl)imide ([NTf2]) and a range of cations, i.e. 1-Methyl-1-ethylpyrrolidinium [MEPyr][NTf2], 1-Methyl-1-propylpyrrolidinium [MPrPyr][NTf2], 1-Methyl-1-butylpyrrolidinium [MBPyr][NTf2], 1-Methyl-1-octylpyrrolidinium [MOPyr][NTf2] were studied by FTIR spectroscopy. The proton acceptor abilities of several ionic liquids (1-Butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide [BMIM][NTf2], 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4], 1-butyl-3-methylimidazolium trifluoromethanesulfonate [BMIM][TfO], 1-butyl-3-methylimidazolium hexafluorophosphate [BMIM][PF6], triethylsulfonium bis(trifluoromethylsulfonyl)imide [Et3S][NTf2], 1-butyl-3-methylimidazolium tricyanomethanide [BMIM][TCM], 1-hexyl-3-methylimidazolium tetrafluoroborate [HMIM][BF4]) were studied by both FTIR and solution calorimetry techniques. The hydrogen bond enthalpies of pyrrole in various ionic liquids were calculated. A linear correlation between frequency shifts of H-bonded NH-group of pyrrole in ionic liquids and hydrogen bond enthalpies of pyrrole in the same ionic liquids was found. The obtained correlation for ionic liquids was compared with molecular organic solvents

Effect of cation structure on the formation of hydrogen bond between ionic liquids and solute molecules

In this work, we have studied the thermochemistry of the hydrogen bond formation between ionic liquids and solute molecules. The solution enthalpies of several organic compounds (benzene, acetone, 3-picoline dimethylsulfoxide, formamide, N-methylformamide, acetamide, N-methylacetamide) in the series of ionic liquids with common anion bis(trifluoromethanesulfonyl)imide and different cations (1-butyl-3-methylimidazolium [BMIM][NTf2], 1-butyl-1-methylpyrrolidinium [BMPYR][NTf2], 1-butylpyridinium [BPY][NTf2], 1-butyl-1-methylpiperidinium [BMPIP][NTf2], trimethylpropylammonium [TMPAm][NTf2]) were measured by solution calorimetry at infinite dilution. The enthalpies of hydrogen bond between solutes and ionic liquids were determined by the previously proposed approach. The hydrogen bond enthalpies were correlated with the proton acceptor ability of ionic liquids from the Kamlet-Abboud-Taft equation and the proton donor ability of amides from the Abraham model. The proton donor ability and hydrogen bond reorganization of studied ionic liquids was analyzed. The formation of the hydrogen bond complexes of linear amides with ionic liquids with different compositions was shown. The effect of the ionic liquid structure on the strength of the hydrogen bond of linear amides with ionic liquids has been established

Calorimetric observation of lysozyme degradation at elevated temperature in water and DMSO-water mixtures

The reversibility of protein denaturation is an essential factor for biotechnology. Previous differential scanning calorimetry (DSC) studies demonstrated the development of the low-temperature shoulder on the calorimetric denaturation peak of lysozyme in successive heating-cooling cycles, which implies irreversible denaturation. However, this effect was not thoroughly investigated. In the present work, we have quantitatively studied the effect of incubation at the elevated temperature on the state of lysozyme in water and mixtures of water with dimethyl sulfoxide (DMSO) using DSC. The changes to the state of the lysozyme molecule indicated by DSC thermograms were also evaluated by circular dichroism (CD), Fourier transform infrared spectroscopy (FTIR) and dynamic light scattering (DLS) techniques. It is noted that with the increase of duration or temperature of incubation, the low-temperature peak on DSC thermograms grows, while the height of the unfolding peak of native structure decreases. The increase in the height of the low-temperature peak in DSC scans correlates with the development of the sideband associated with the absorption of the carboxyl group in the infrared spectra. This result suggests that the low-temperature endothermic peak corresponds to the unfolding of the deamidated protein. At the same time, DLS measurements indicate absence of aggregation, while FTIR and CD data demonstrate that deamidated protein maintains a native-like structure. The evaluation of the DSC thermograms allowed to determine the rates and activation energy of the degradation of protein molecules at the elevated temperatures. The addition of DMSO slows down the protein degradation but has little effect on the apparent activation energy of the process

Hydrogen bonding of linear and cyclic amides in ionic liquids

© 2020 Elsevier B.V. The present work focuses on hydrogen bonding of linear and cyclic amides (formamide, N-methylformamide, acetamide, N-methylacetamide, N,N-dimethylacetamide, 2-pyrrolidone) in several ionic liquid (1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide [BMIM][NTf2], 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4], 1-butyl-3-methylimidazolium trifluoromethanesulfonate [BMIM][TfO], 1-butyl-3-methylimidazolium hexafluorophosphate [BMIM][PF6], triethylsulfonium bis(trifluoromethylsulfonyl)imide [Et3S][NTf2], Trimethylpropylammonium bis(trifluoromethylsulfonyl)imide [TMPAm][NTf2]). The solution enthalpies of amides in ionic liquids were measured by solution calorimetry at infinite dilution. The hydrogen bond enthalpies were calculated based on solution enthalpies of amides in ionic liquids. The hydrogen bond enthalpies of linear and cyclic amides in ionic liquids and organic proton acceptors were compared. The influence of active proton donor center on the formation of hydrogen bond complexes between amides and ionic liquids was analyzed

A new method for heat capacity determination in supercooled liquid state using fast scanning calorimetry: Thermochemical study of 9,9'-bifluorenyl

© 2020 Elsevier B.V. Fast scanning calorimetry (FSC) enables to prevent the crystallization of many low-molecular-mass organic compounds. In spite of extremely high cooling rates accessible by fast scanning calorimetry, limitations remain on the measurements of rapidly crystallizing and volatile compounds in the supercooled liquid state. We developed a new method for heat capacity determination, which requires measuring the heat flow rates only on cooling at one fixed scanning rate of a number of samples of different mass. The molar heat capacity is derived from the slope of the heat flow rates plotted against the sample amount, divided by the cooling rate. The total uncertainty of the method was determined to 5 %. The validity was confirmed using benzophenone as a reference compound. Then this approach was applied to study the heat capacity of 9,9′-bifluorenyl in the supercooled liquid state between 350 and 550 K; respective values were obtained for the first time. The relationship between the fusion enthalpy of 9,9′-bifluorenyl at Tm and solution enthalpy in benzene at 298.15 K was analyzed using combination of Hess's and Kirchhoff's laws of thermochemistry. Consistency between the thermochemical data derived independently by solution, fast scanning, and differential scanning calorimetry was established and confirmed the validity of the new method for heat capacity determination by FSC

Thermochemistry of solution, solvation, and hydrogen bonding of cyclic amides in proton acceptor and donor solvents. Amide cycle size effect

In the present work, the thermochemistry of solution, solvation, and hydrogen bonding of cyclic amides in proton acceptor (B) and proton donor (RXH) solvents were studied. The infinite dilution solution enthalpies of δ-valerolactam, N-methylvalerolactam, ε-caprolactam, and N-methylcaprolactam were measured at 298.15 K. The solvation enthalpies of cyclic amides were calculated based on the measured solution enthalpies and sublimation/vaporization enthalpies from literature. The enthalpies of hydrogen bonding between cyclic amides and proton acceptor and donor solvents were then calculated as a difference between the total solvation enthalpy and the non-specific contribution. The latter was estimated via two different approaches in proton donor and proton accepting solvents. The effect of the cycle size on the strength of hydrogen bonding of the cyclic amides in solution is discussed

Group additive approach for heterocyclic aromatic solutes in [BMIM][BF<inf>4</inf>]

This work continues the development of the additive scheme for the calculation of solvation enthalpies of aromatic compounds in 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]). In this study, heterocyclic aromatic compound were selected as solutes. The solution enthalpies of 14 heterocyclic aromatic compounds in [BMIM][BF4] were measured at 298.15 K. Based on the experimental and literature data, the solvation enthalpies of heterocyclic aromatic compounds in [BMIM][BF4] were calculated. The contributions of the exchange of CH–group with –N=, >NH, >NCH3, –S–, and carbonyl >C=O substituent groups into the solvation enthalpies in [BMIM][BF4] were calculated. These values were compared with analogous contributions in benzene. Solvation enthalpies of heterocyclic aromatic compounds in [BMIM][BF4] calculated by the additive scheme were compared with experimental values, revealing a good agreement between calculated and experimental data. This fact indicates that group additive scheme for prediction of the solvation enthalpies can be successfully applied to heterocyclic aromatic compounds in ionic liquids