Stability of Rapidly Crystallizing Sulfonamides Glasses by Fast Scanning Calorimetry: Crystallization Kinetics and Glass-Forming Ability.

Production and evaluation of the kinetic stability of the amorphous forms of active pharmaceutical ingredients are among the current challenges of modern pharmaceutical science. In the present work, amorphous forms of several sulfonamides were produced for the first time using Fast Scanning calorimetry. The parameters, characterizing the glass-forming ability of the compounds, i.e. the critical cooling rate of the melt and the kinetic fragility, were determined. The cold crystallization kinetics was studied using both isothermal and non-isothermal approaches. The results of the present study will contribute to the development of approaches for producing amorphous forms of rapidly crystallizing active pharmaceutical ingredients.

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.

Sublimation thermodynamics of nucleobases derived from fast scanning calorimetry.

The five fundamental units of the genetic code: uracil (U), thymine (T), cytosine (C), adenine (A) and guanine (G) are known for extremely low vapor pressure and low thermal stability at elevated temperatures. Therefore, application of conventional techniques for the determination of sublimation enthalpies and vapor pressures fails to provide accurate results. Recently, a Fast Scanning Calorimetry method (FSC) for vapor pressure determination was developed for investigation of extremely low volatile, as well as for thermally unstable molecular and ionic molecules. This success has encouraged application of the FSC method for determination of vapor pressures and sublimation enthalpies of the five nucleobases, where available literature data are in disarray. The thermodynamic data of the nucleobases available in the literature were collected, evaluated, and combined with our experimental results to reconcile available experimental data. The set of evaluated thermochemical data on the five nucleobases was recommended as the benchmark properties for these thermally labile compounds.

Kinetic stability of amorphous dipyridamole: A fast scanning calorimetry investigation.

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.

Melting of nucleobases. Getting the cutting edge of "Walden's Rule".

Walden's Rule is an empirical observation of an invariant fusion entropy during fusion of non-associated organic compounds. For the five nucleobases, adenine, thymine, cytosine, guanine, and uracil, surprisingly high fusion temperatures and enthalpies have been measured using a specially developed fast scanning calorimetry method that prevents decomposition. Even when nucleobases admittedly possess very high fusion temperatures, e.g. the value of 862 K measured for guanine really exceeds all expectations of the feasible dimension of the fusion temperature for such a relatively small and simple organic molecule. Hirshfeld surface analysis has been applied in order to find out an explanation for such extremely unusual thermal behavior of nucleobases. We rationalized the observed trends in terms of fusion entropy (Walden's constant = 56.5 J K-1 mol-1) as the entropic penalty of fusion not only for "non-associated", as proposed by Walden in 1908, but also for "ideal associated" systems like nucleobases.

Kinetic stability of amorphous solid dispersions with high content of the drug: A fast scanning calorimetry investigation.

Formation of amorphous solid dispersions is an effective way to enhance the bioavailability of drugs. One of the main disadvantages of such systems is their low storage stability. Estimation and prognosis of storage stability of the amorphous solid dispersions are possible through modeling of the kinetics of crystallization by the Arrhenius equation and the resulting parameters, i.e., activation energy and pre-exponential factor. These parameters can be determined using the non-isothermal kinetics methods based on both model-fitting and model-free approaches using the differential scanning calorimetry data. In the present work, the formation of amorphous solid dispersions of the phenacetin model drug with polyvinylpyrrolidone of different molecular masses (3500-1.3 × 106 g·mol-1) was studied in a wide range of heating and cooling rates. The kinetic parameters of the crystallization process of the active pharmaceutic ingredient in the solid dispersions with increased drug content were determined. The dependence of the kinetic parameters of phenacetin cold crystallization on the molecular weight of the polymer is non-linear. The approaches used in the present work can find applications for the estimation of kinetic stability of amorphous pharmaceutical systems prone to crystallization.

Glasses of three alkyl phosphates show a range of kinetic stabilities when prepared by physical vapor deposition.

In situ AC nanocalorimetry was used to characterize vapor-deposited glasses of three phosphates with increasing lengths of alkyl side chains: trimethyl phosphate, triethyl phosphate, and tributyl phosphate. The as-deposited glasses were assessed in terms of their reversing heat capacity, onset temperature, and isothermal transformation time. Glasses with a range of kinetic stabilities were prepared, including kinetically stable glasses, as indicated by high onset temperatures and long transformation times. Trimethyl phosphate forms kinetically stable glasses, similar to many other organic molecules, while triethyl phosphate and tributyl phosphate do not. Triethyl phosphate and tributyl phosphate present the first examples of non-hydrogen bonding systems that are unable to form stable glasses via vapor deposition at 0.2 nm/s. Based on experiments utilizing different deposition rates, we conclude that triethyl phosphate and tributyl phosphate lack the surface mobility required for stable glass formation. This may be related to their high enthalpies of vaporization and the internal structure of the liquid state.

Homogeneous crystal nucleation in polymers.

The pathway of crystal nucleation significantly influences the structure and properties of semi-crystalline polymers. Crystal nucleation is normally heterogeneous at low supercooling, and homogeneous at high supercooling, of the polymer melt. Homogeneous nucleation in bulk polymers has been, so far, hardly accessible experimentally, and was even doubted to occur at all. This topical review summarizes experimental findings on homogeneous crystal nucleation in polymers. Recently developed fast scanning calorimetry, with cooling and heating rates up to 106 K s-1, allows for detailed investigations of nucleation near and even below the glass transition temperature, including analysis of nuclei stability. As for other materials, the maximum homogeneous nucleation rate for polymers is located close to the glass transition temperature. In the experiments discussed here, it is shown that polymer nucleation is homogeneous at such temperatures. Homogeneous nucleation in polymers is discussed in the framework of the classical nucleation theory. The majority of our observations are consistent with the theory. The discrepancies may guide further research, particularly experiments to progress theoretical development. Progress in the understanding of homogeneous nucleation is much needed, since most of the modelling approaches dealing with polymer crystallization exclusively consider homogeneous nucleation. This is also the basis for advancing theoretical approaches to the much more complex phenomena governing heterogeneous nucleation.

Dynamics of supercooled liquid and plastic crystalline ethanol: Dielectric relaxation and AC nanocalorimetry distinguish structural α- and Debye relaxation processes.

Physical vapor deposition has been used to prepare glasses of ethanol. Upon heating, the glasses transformed into the supercooled liquid phase and then crystallized into the plastic crystal phase. The dynamic glass transition of the supercooled liquid is successfully measured by AC nanocalorimetry, and preliminary results for the plastic crystal are obtained. The frequency dependences of these dynamic glass transitions observed by AC nanocalorimetry are in disagreement with conclusions from previously published dielectric spectra of ethanol. Existing dielectric loss spectra have been carefully re-evaluated considering a Debye peak, which is a typical feature in the dielectric loss spectra of monohydroxy alcohols. The re-evaluated dielectric fits reveal a prominent dielectric Debye peak, a smaller and asymmetrically broadened peak, which is identified as the signature of the structural α-relaxation and a Johari-Goldstein secondary relaxation process. This new assignment of the dielectric processes is supported by the observation that the AC nanocalorimetry dynamic glass transition temperature, Tα, coincides with the dielectric structural α-relaxation process rather than the Debye process. The combined results from dielectric spectroscopy and AC nanocalorimetry on the plastic crystal of ethanol suggest the occurrence of a Debye process also in the plastic crystal phase.

Limited surface mobility inhibits stable glass formation for 2-ethyl-1-hexanol.

Previous work has shown that vapor-deposition can prepare organic glasses with extremely high kinetic stabilities and other properties that would be expected from liquid-cooled glasses only after aging for thousands of years or more. However, recent reports have shown that some molecules form vapor-deposited glasses with only limited kinetic stability when prepared using conditions expected to yield a stable glass. In this work, we vapor deposit glasses of 2-ethyl-1-hexanol over a wide range of deposition rates and test several hypotheses for why this molecule does not form highly stable glasses under normal deposition conditions. The kinetic stability of 2-ethyl-1-hexanol glasses is found to be highly dependent on the deposition rate. For deposition at Tsubstrate = 0.90 Tg, the kinetic stability increases by 3 orders of magnitude (as measured by isothermal transformation times) when the deposition rate is decreased from 0.2 nm/s to 0.005 nm/s. We also find that, for the same preparation time, a vapor-deposited glass has much more kinetic stability than an aged liquid-cooled glass. Our results support the hypothesis that the formation of highly stable 2-ethyl-1-hexanol glasses is inhibited by limited surface mobility. We compare our deposition rate experiments to similar ones performed with ethylcyclohexane (which readily forms glasses of high kinetic stability); we estimate that the surface mobility of 2-ethyl-1-hexanol is more than 4 orders of magnitude less than that of ethylcyclohexane at 0.85 Tg.

Temperature fluctuations and the thermodynamic determination of the cooperativity length in glass forming liquids.

The aim of this paper is to decide which of the two possible thermodynamic expressions for the cooperativity length in glass forming liquids is the correct one. In the derivation of these two expressions, the occurrence of temperature fluctuations in the considered nanoscale subsystems is either included or neglected. Consequently, our analysis gives also an answer to the widely discussed problem whether temperature fluctuations have to be generally accounted for in thermodynamics or not. To this end, the characteristic length-scales at equal times and temperatures for propylene glycol were determined independently from AC calorimetry in both the above specified ways and from quasielastic neutron scattering (QENS), and compared. The result shows that the cooperative length determined from QENS coincides most consistently with the cooperativity length determined from AC calorimetry measurements for the case that the effect of temperature fluctuations is incorporated in the description. This conclusion indicates that-accounting for temperature fluctuations-the characteristic length can be derived by thermodynamic considerations from the specific parameters of the liquid at glass transition and that temperature does fluctuate in small systems.

Vapor-deposited alcohol glasses reveal a wide range of kinetic stability.

In situ AC nanocalorimetry was used to characterize vapor-deposited glasses of six mono- and di-alcohol molecules. Benzyl alcohol glasses with high kinetic stability and decreased heat capacity were prepared. When annealed above the glass transition temperature Tg, transformation of these glasses into the supercooled liquid took 103.4 times longer than the supercooled liquid relaxation time (τα). This kinetic stability is similar to other highly stable organic glasses prepared by vapor deposition and is the first clear demonstration of an alcohol forming a stable glass. Vapor deposited glasses of five other alcohols exhibited moderate or low kinetic stability with isothermal transformation times ranging from 100.7 to 102 τα. This wide range of kinetic stabilities is useful for investigating the factors that control stable glass formation. Using our current results and literature data, we compare the kinetic stability of vapor deposited glasses prepared from 14 molecules and find a correlation with the value of τα at 1.25 Tg. We also observe that some vapor-deposited glasses exhibit decreased heat capacity without increased kinetic stability.

Glass transition and stable glass formation of tetrachloromethane.

Physical vapor deposition (PVD) has been used to prepare organic glasses with very high kinetic stability and it has been suggested that molecular anisotropy is a prerequisite for stable glass formation. Here we use PVD to prepare glasses of tetrachloromethane, a simple organic molecule with a nearly isotropic molecular structure. In situ AC nanocalorimetry was used to characterize the vapor-deposited glasses. Glasses of high kinetic stability were produced by deposition near 0.8 Tg. The isothermal transformation of the vapor-deposited glasses into the supercooled liquid state gave further evidence that tetrachloromethane forms glasses with high kinetic stability, with the transformation time exceeding the structural relaxation time of the supercooled liquid by a factor of 10(3). The glass transition temperature of liquid-cooled tetrachloromethane is determined as Tg ≈ 78 K, which is different from previously reported values. The frequency dependence of the glass transition was also determined and the fragility was estimated as m ≈ 118. The successful formation of PVD glasses of tetrachloromethane which have high kinetic stability argues that molecular asymmetry is not a prerequisite for stable glass formation.

How much time is needed to form a kinetically stable glass? AC calorimetric study of vapor-deposited glasses of ethylcyclohexane.

Glasses of ethylcyclohexane produced by physical vapor deposition have been characterized by in situ alternating current chip nanocalorimetry. Consistent with previous work on other organic molecules, we observe that glasses of high kinetic stability are formed at substrate temperatures around 0.85 Tg, where Tg is the conventional glass transition temperature. Ethylcyclohexane is the least fragile organic glass-former for which stable glass formation has been established. The isothermal transformation of the vapor-deposited glasses into the supercooled liquid state was also measured. At seven substrate temperatures, the transformation time was measured for glasses prepared with deposition rates across a range of four orders of magnitude. At low substrate temperatures, the transformation time is strongly dependent upon deposition rate, while the dependence weakens as Tg is approached from below. These data provide an estimate for the surface equilibration time required to maximize kinetic stability at each substrate temperature. This surface equilibration time is much smaller than the bulk α-relaxation time and within two orders of magnitude of the ß-relaxation time of the ordinary glass. Kinetically stable glasses are formed even for substrate temperatures below the Vogel and the Kauzmann temperatures. Surprisingly, glasses formed in the limit of slow deposition at the lowest substrate temperatures are not as kinetically stable as those formed near 0.85 Tg.

Vapor-deposited glasses of methyl-m-toluate: How uniform is stable glass transformation?

AC chip nanocalorimetry is used to characterize vapor-deposited glasses of methyl-m-toluate (MMT). Physical vapor deposition can prepare MMT glasses that have lower heat capacity and significantly higher kinetic stability compared to liquid-cooled glasses. When heated, highly stable MMT glasses transform into the supercooled liquid via propagating fronts. We present the first quantitative analysis of the temporal and spatial uniformities of these transformation fronts. The front velocity varies by less than 4% over the duration of the transformation. For films 280 nm thick, the transformation rates at different spatial positions in the film differ by about 25%; this quantity may be related to spatially heterogeneous dynamics in the stable glass. Our characterization of the kinetic stability of MMT stable glasses extends previous dielectric experiments and is in excellent agreement with these results.

High frequency alternating current chip nano calorimeter with laser heating.

Heat capacity spectroscopy at frequencies up to 100 kHz is commonly performed by thermal effusivity measurements applying the 3ω-technique. Here we show that AC-calorimetry using a thin film chip sensor allows for the measurement of frequency dependent heat capacity in the thin film limit up to about 1 MHz. Using films thinner than the thermal length of the thermal wave (~1 µm) at such frequencies is advantageous because it provides heat capacity alone and not in combination with other quantities like thermal conductivity, at least on a qualitative basis. The used calorimetric sensor and the sample are each less than 1 µm thick. For high frequency AC-calorimetry, high cooling rates at very small temperature differences are required. This is realized by minimizing the heated spot to the size of the on chip thermocouple (3 × 6 µm(2)). A modulated laser beam shaped and positioned by a glass fiber is used as the heat source. The device was used to measure the complex heat capacity in the vicinity of the dynamic glass transition (structural relaxation) of poly(methyl methacrylate). Combining different calorimeters finally provides data between 10(-3) Hz and 10(6) Hz. In this frequency range the dynamic glass transition shifts about 120 K.

Size and rate dependence of crystal nucleation in single tin drops by fast scanning calorimetry.

The experimentally accessible degree of undercooling of single micron-sized liquid pure tin drops has been studied via differential fast scanning calorimetry. The cooling rates employed ranged from 100 to 14,000 K/s. The diameter of the investigated tin drops varied in the range from 7 to 40 µm. The influence of the drop shape on the solidification process could be eliminated due to the nearly spherical shape of the single drop upon heating and cooling and the resultant geometric stability. As a result it became possible to study the effect of both drop size and cooling rate in rapid solidification experimentally. A theoretical description of the experimental results is given by assuming the existence of two different heterogeneous nucleation mechanisms leading to crystal nucleation of the single tin drop. In agreement with the experiment these mechanisms yield a shelf-like dependence of crystal nucleation on undercooling. A dependence of crystal nucleation on the size of the tin drop was observed and is discussed in terms of the mentioned theoretical model, which can possibly also describe the nucleation for other related rapid solidification processes.

In situ investigation of vapor-deposited glasses of toluene and ethylbenzene via alternating current chip-nanocalorimetry.

Vapor-deposited glasses of toluene and ethylbenzene have been characterized by in situ ac chip-nanocalorimetry. The high sensitivity of this method allows the detection of small changes in the heat capacity of nanogram size samples. We observe that vapor-deposited glasses have up to 4% lower heat capacities than the ordinary glass. The largest heat capacity decrease and the most kinetically stable glasses of toluene and ethylbenzene are observed in a range of deposition temperatures between 0.75 T(g) and 0.96 T(g). Compared to larger molecules, deposition rate has a minor influence on the kinetic stability of these glasses. For both toluene and ethylbenzene, the kinetic stability is strongly correlated with the heat capacity decrease for deposition temperatures above 0.8 T(g). In addition, ac-nanocalorimetry was used to follow the isothermal transformation of the stable glasses into the supercooled liquid at temperatures slightly above T(g). Toluene and ethylbenzene stable glasses exhibit a constant transformation rate which is consistent with the growth front mechanism recently demonstrated for tris-naphthylbenzene and indomethacin. The kinetic stability of the most stable toluene and ethylbenzene glasses is comparable to that observed for other stable glasses formed by vapor deposition.