K. Kolodziejczyk

Molecular Dynamics and Physical Stability of Amorphous Anti-Inflammatory Drug: Celecoxib

By using dielectric spectroscopy we analyzed the relation between molecular mobility and tendency of the amorphous celecoxib to recrystallize. We found that celecoxib is kinetically a fragile glassformer, contrary to the conclusion reached by others from thermodynamic fragility. The possible correlation of the large tendency of celecoxib to crystallize with various molecular motions have been investigated. Our study shows that the structural relaxation seems to be responsible for devitrification of celecoxib if stored at room temperature ∼293 K. Notwithstanding, the crystallization can be considered to ultimately be affected by the β-process (JG-relaxation) because it is the precursor of the structural α-relaxation.

Quantifying the Structural Dynamics of Pharmaceuticals in the Glassy State

Structural dynamics in the glassy state of two protic ionic liquids, carvedilol phosphate and procaine hydrochloride, were characterized from analysis of changes in the conductivity relaxation times during physical aging. The obtained relaxation times, having a magnitude exceeding feasible experimental time scales and thus not directly measurable, are consistent with published data from a method that relies on the presence of a secondary relaxation. We also observe a narrowing of the relaxation dispersion, specific to higher frequencies, that is a consequence of the heterogeneous dynamics of deeply supercooled materials.

Relaxation Dynamics and Crystallization Study of Sildenafil in the Liquid and Glassy States

In this paper, the physical stability and molecular dynamics of amorphous sildenafil are investigated in both the liquid and glassy states. We have established that the amorphous sildenafil is resistant to recrystallization at temperatures below the glass transition temperature Tg during the experimental period of its storage (i.e., above 6 months), however, it easily undergoes cold crystallization at T > Tg. To determine the crystallization mechanism, the isothermal and non-isothermal studies of the cold crystallization kinetics of the drug are performed by using the broadband dielectric spectroscopy (BDS) and the differential scanning calorimetry (DSC), respectively. The cold crystallization mechanism has been found to be similar in both the isothermal and non-isothermal cases. This mechanism has been analyzed from the point of view of the molecular mobility of sildenafil investigated in the supercooled liquid and glassy states by using the BDS measurements in the wide temperature range. This analysis has been enriched with a new approach based on a recently reported measure of dynamic heterogeneity given by a four-point dynamic susceptibility function. No tendency to recrystallization of glassy sildenafil at T < Tg is also discussed in relation to molecular dynamics of sildenafil in the glassy state. The relatively small molecular mobility reflected in one secondary relaxation as well as the predicted large time scale of structural relaxation of glassy sildenafil suggests that amorphous sildenafil should not recrystallize during its long-term storage at room temperature.

Decoupling of conductivity relaxation from structural relaxation in protic ionic liquids and general properties

The main focus of this work is the study of conductivity relaxation of amorphous lidocaine hemisuccinate near the glass transition at ambient pressure. Measurements have been made using broadband dielectric spectroscopy (BDS) and temperature-modulated differential scanning calorimetry. Our study shows that the ion conductivity relaxation becomes increasingly faster than the structural relaxation as the glass transition temperature Tg is approached. At Tg the structural relaxation time is longer than the conductivity relaxation times by three decades, i.e. the decoupling index Rτ is about 3. Decoupling is accompanied by the ion conductivity relaxation which narrows in its frequency dispersion with decreasing temperature. This abnormal behavior is identical to that found in two other protic ionic liquids (PILs), procaine HCl and procainamide HCl. Considering that the phenomenon has been found before in several inorganic ionic glass-formers and now in three protic ionic liquids, it could be a general property of ionically conducting glass-forming substances, although more cases have to be studied before a definitive conclusion can be made. We show that it can be rationalized within the framework of the Coupling Model.

A new way of stabilization of furosemide upon cryogenic grinding by using acylated saccharides matrices. The role of hydrogen bonds in decomposition mechanism.

Recently it was reported that upon mechanical milling of pure furosemide significant chemical degradation occurs (Adrjanowicz et al. Pharm. Res.2011, 28, 3220-3236). In this paper, we present a novel way of chemical stabilization amorphous furosemide against decomposing that occur during mechanical treatment by preparing binary mixtures with acylated saccharides. To get some insight into the mechanism of chemical degradation of furosemide induced by cryomilling, experimental investigations supported by density functional theory (DFT) computations were carried out. This included detailed studies on molecular dynamics and physical properties of cryoground samples. The main thrust of our paper is that we have shown that furosemide cryomilled with acylated saccharides forms chemically and physically stable homogeneous mixtures with only one glass transition temperature, Tg. Finally, solubility measurements have demonstrated that furosemide cryomilled with acylated saccharides (glucose, maltose and sucrose) is much more soluble with respect to the crystalline form of this active pharmaceutical ingredient (API).

Studying the Impact of Modified Saccharides on the Molecular Dynamics and Crystallization Tendencies of Model API Nifedipine

Molecular dynamics of pure nifedipine and its solid dispersions with modified carbohydrates as well as the crystallization kinetics of active pharmaceutical ingredient (API) above and below the glass transition temperature were studied in detail by means of broadband dielectric spectroscopy (BDS), differential scanning calorimetry (DSC), and X-ray diffraction method. It was found that the activation barrier of crystallization increases in molecular dispersions composed of acetylated disaccharides, whereas it slightly decreases in those consisting of modified monocarbohydrates for the experiments carried out above the glass transition temperature. As shown by molecular dynamics simulations it can be related to the strength, character, and structure of intermolecular interactions between API and saccharides, which vary dependently on the excipient. Long-term physical stability studies showed that, in solid dispersions consisting of acetylated maltose and acetylated sucrose, the crystallization of nifedipine is dramatically slowed down, although it is still observable for a low concentration of excipients. With increasing content of modified carbohydrates, the crystallization of API becomes completely suppressed. This is most likely due to additional barriers relating to the intermolecular interactions and diffusion of nifedipine that must be overcome to trigger the crystallization process.

Impact of inter- and intramolecular interactions on the physical stability of indomethacin dispersed in acetylated saccharides.

Differential scanning calorimetry (DSC), broadband dielectric (BDS), and Fourier transform infrared (FTIR) spectroscopies as well as theoretical computations were applied to investigate inter- and intramolecular interactions between the active pharmaceutical ingredient (API) indomethacin (IMC) and a series of acetylated saccharides. It was found that solid dispersions formed by modified glucose and IMC are the least physically stable of all studied samples. Dielectric measurements showed that this finding is related to neither the global nor local mobility, as the two were fairly similar. On the other hand, combined studies with the use of density functional theory (DFT) and FTIR methods indicated that, in contrast to acetylated glucose, modified disaccharides (maltose and sucrose) interact strongly with indomethacin. As a result, internal H-bonds between IMC molecules become very weak or are eventually broken. Simultaneously, strong H-bonds between the matrix and API are formed. This observation was used to explain the physical stability of the investigated solid dispersions. Finally, solubility measurements revealed that the solubility of IMC can be enhanced by the use of acetylated carbohydrates, although the observed improvement is marginal due to strong interactions.

Spatially Heterogeneous Dynamics in the Density Scaling Regime: Time and Length Scales of Molecular Dynamics near the Glass Transition.

A fundamental problem of glass transition physics is to find a proper relation between length and time scales of molecular dynamics near the glass transition. Until now, this relation has been usually expected as a single variable function, for instance, as a consequence of the suggested direct relation between the structural relaxation time τ and the correlation volume defined by the maximum of the four-point correlation function χ4max. Based on high pressure data analyses, we show that it is not the case, because χ4max evaluated from its estimate based on the enthalpy fluctuations cannot be, in general, a single variable function of τ. For a wide class of real and model supercooled liquids, the molecular dynamics of which obeys a density scaling law at least to a good approximation, we argue that the important relation between the length and time scales that characterize molecular motions near the glass transition is controlled by a density factor, the exponent of which is a measure of the observed deco...Recent analyses of high pressure measurement data suggest that the degree of the dynamic heterogeneity ({\chi}_4)^max cannot be in general a single variable function of the structural relaxation time {\tau}. For a wide class of real and model supercooled liquids, the molecular dynamics of which obeys a density scaling law at least to a good approximation, we argue that the important relation between the length and time scales that characterize molecular motions near the glass transition is controlled by a density factor. If a power law density scaling is valid for both the structural relaxation times and the degrees of the dynamic heterogeneity we find that the factor is a density power, the exponent of which is a measure of the observed decoupling between {\tau} and ({\chi}_4)^max. Then, the measure can be quantified by a difference between the power law density scaling exponents, which are usually different for {\tau} and ({\chi}_4)^max.