Magdalena Tarnacka

Molecular Dynamics in Supercooled Liquid and Glassy States of Antibiotics: Azithromycin, Clarithromycin and Roxithromycin Studied by Dielectric Spectroscopy. Advantages Given by the Amorphous State

Antibiotics are chemical compounds of extremely important medical role. Their history can be traced back more than one hundred years. Despite the passing time and significant progress made in pharmacy and medicine, treatment of many bacterial infections without antibiotics would be completely impossible. This makes them particularly unique substances and explains the unflagging popularity of antibiotics within the medical community. Herein, using dielectric spectroscopy we have studied the molecular mobility in the supercooled liquid and glassy states of three well-known antibiotic agents: azithromycin, clarithromycin and roxithromycin. Dielectric studies revealed a number of relaxation processes of different molecular origin. Besides the primary α-relaxation, observed above the respective glass transition temperatures of antibiotics, two secondary relaxations in the glassy state were identified. Interestingly, the fragility index as well as activation energies of the secondary processes turned out to be practically the same for all three compounds, indicating probably much the same molecular dynamics. Long-term stability of amorphous antibiotics at room temperature was confirmed by X-ray diffraction technique, and calorimetric studies were performed to evaluate the basic thermodynamic parameters. Finally, we have also checked the experimental solubility advantages given by the amorphous form of the examined antibiotics.

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).

Dielectric studies on molecular dynamics of two important disaccharides: sucrose and trehalose.

Broadband dielectric measurements were carried out in the supercooled as well as in the glassy state of two very important disaccharides: trehalose and sucrose. Multiple relaxation processes were observed. Above the glass transition temperatures of examined disaccharides structural relaxation of cooperative origin was detected, where in the glassy state more local motions (secondary modes) appeared. Our data were discussed in light of the findings reported by other groups. We pointed out that sample preparation might impact mobility and, thus, dielectric loss spectra in a significant way. Consequently, it may lead to misinterpretation of the dielectric relaxation processes. Moreover, impact of physical aging and pressure on dynamics of two secondary relaxation processes observed in the glassy state of trehalose and sucrose has been investigated. Additionally, we have demonstrated that, in contrast to the calorimetric measurements (DSC), activation energies of the β- and γ-relaxation processes observed in the glassy state of sucrose and trehalose do not change as a result of physical aging. Finally, we found out that the β-relaxation process slows down as pressure increases. We interpreted this fact in view of increasing rigidity of the structures of disaccharides.

Glassy dynamics and physical aging in fucose saccharides as studied by infrared- and broadband dielectric spectroscopy

Fourier Transform Infra Red (FTIR) and Broadband Dielectric Spectroscopy (BDS) are combined to study both the intra- and inter-molecular dynamics of two isomers of glass forming fucose, far below and above the calorimetric glass transition temperature, T(g). It is shown that the various IR-active vibrations exhibit in their spectral position and oscillator strength quite different temperature dependencies, proving their specific signature in the course of densification and glass formation. The coupling between intra- and inter molecular dynamics is exemplified by distinct changes in IR active ring vibrations far above the calorimetric glass transition temperature at about 1.16T(g), where the dynamic glass transition (α relaxation) and the secondary β relaxation merge. For physically annealed samples it is demonstrated that upon aging the different moieties show characteristic features as well, proving the necessity of atomistic descriptions beyond coarse-grained models.

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.

Molecular dynamics of itraconazole confined in thin supported layers

Broadband Dielectric Spectroscopy (BDS) is used to study the molecular dynamics of thin layers of itraconazole – an active pharmaceutical ingredient with rod-like structure and whose Differential Scanning Calorimetry (DSC) scans reveal liquid crystalline-like phase transitions. It is found that (i) the structural relaxation process remains bulk like, within the limits of experimental accuracy, in its mean relaxation rate, while (ii) its shape is governed by two competing events: interfacial interactions, and crystalline ordering. Additionally, (iii) the dynamics of the δ-relaxation – assigned to the flip–flop rotation of the molecule about its short axis – deviates from bulk behaviour as the glass transition is approached for the confined material. These observations are rationalized within the framework of molecular dynamics as currently understood.

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.

High pressure dielectric studies on the structural and orientational glass.

High pressure dielectric studies on the H-bonded liquid D-glucose and Orientationally Disordered Crystal (ODIC) 1,6-anhydro-D-glucose (levoglucosan) were carried out. It was shown that in both compounds, the structural relaxation is weakly sensitive to compression. It is well reflected in the low pressure coefficient of the glass transition and orientational glass transition temperatures which is equal to 60 K/GPa for both D-glucose and 1,6-anhydro-D-glucose. Although it should be noted that ∂Tg(0)/∂p evaluated for the latter compound seems to be enormously high with respect to other systems forming ODIC phase. We also found that the shape of the α-loss peak stays constant for the given relaxation time independently on the thermodynamic condition. Consequently, the Time Temperature Pressure (TTP) rule is satisfied. This experimental finding seems to be quite intriguing since the TTP rule was shown to work well in the van der Waals liquids, while in the strongly associating compounds, it is very often violated. We have also demonstrated that the sensitivity of the structural relaxation process to the temperature change measured by the steepness index (mp) drops with pressure. Interestingly, this change is much more significant in the case of D-glucose with respect to levoglucosan, where the fragility changes only slightly with compression. Finally, kinetics of ODIC-crystal phase transition was studied at high compression. It is worth mentioning that in the recent paper, Tombari and Johari [J. Chem. Phys. 142, 104501 (2015)] have shown that ODIC phase in 1,6-anhydro-D-glucose is stable in the wide range of temperatures and there is no tendency to form more ordered phase at ambient pressure. On the other hand, our isochronal measurements performed at varying thermodynamic conditions indicated unquestionably that the application of pressure favors solid (ODIC)-solid (crystal) transition in 1,6-anhydro-D-glucose. This result mimics the impact of pressure on the crystallization of fully disordered supercooled van der Waals liquids.

Changes in Dynamics of the Glass-forming Pharmaceutical Nifedipine in Binary Mixtures with Octaacetylmaltose

Some molecular glass-formers can crystallize in the glassy state, some of which are van der Waals molecules and some are pharmaceuticals. The molecular mechanism responsible for this glass-to-crystal mode of crystallization is of interest to the glass transition research community as well as to the pharmaceutical industry because the effect is detrimental to stability of amorphous form of the drugs stored below the glass transition temperature. Two prominent models have been proposed for the molecular mechanism. In the homogeneous nucleation-based crystallization model, the molecular mechanism is the secondary relaxation, and the other model assumes that the molecular process responsible for crystal growth in the glassy state is from the local molecular motions. Crystal growth requires motion of the entire molecule, and in the glassy state the only such local molecular motion is engendered by the secondary relaxation of the Johari-Goldstein (JG) kind. While the JG secondary relaxation is the crux in the two models of glass-to-crystal growth, it has not been found in the glassy state of the pharmaceuticals studied so far. The examples include 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY), indomethacin (IMC) and nifedipine (NIF). In the absence of any evidence of the JG secondary relaxation, the conundrum is that the two models of glass-to-crystal growth cannot be validated. It turns out these pharmaceuticals all have structural α-relaxations with narrow frequency dispersion. Empirically, glass-formers with narrow α-dispersion have JG secondary relaxation with weak relaxation strength, not well separated from the α-relaxation, and hence cannot be resolved. Theoretically, the narrow width of the α-dispersion is due to weak intermolecular coupling. In this article we enhance the intermolecular coupling of NIF by mixing with octaacetylmaltose to enhance the intermolecular coupling of NIF. In this way we have successfully resolved the JG secondary relaxation in the dielectric loss spectra of the NIF component in the glassy state, and validated the two models of glass-to-crystal growth.

A facile route to well-defined imidazolium-based poly(ionic liquid)s of enhanced conductivity via RAFT

The synthesis of well-defined imidazolium-based poly(ionic liquid)s (PILs) by reversible addition–fragmentation chain transfer (RAFT) polymerization is demonstrated. Two specially designed monomeric ionic liquids (MILs), such as 1-methyl-3-vinylimidazolium bis(trifluoromethanesulfonyl)imide [MVIM][NTf2] and 1-ethyl-3-vinylimidazolium bis(trifluoromethanesulfonyl)imide [EVIM][NTf2] were polymerized with the 2,2′-azobisisobutyronitrile (AIBN) initiator in the presence of a trithiocarbonate RAFT agent. Depending on the varied ratios of the monomer to CTA ([monomer]/[CTA] = 100/1; 400/1; 1000/1) we obtained P[MVIM][NTf2] and P[EVIM][NTf2] homopolymers with the number-average molecular weights (Mn) in a broad range Mn = 2.5–340.0 kDa and Mn = 2.1–450.0 kDa, respectively. The controlled character of the polymerization of each ionic monomer was confirmed by the pseudo-first order kinetic, a linear increase in the Mn with conversion and relatively narrow dispersity indices (Đ = 1.09–1.37 for P[MVIM][NTf2] and Đ = 1.10–1.41 for P[EVIM][NTf2]). Additionally, the obtained macromolecules are characterized by the enhanced/or comparable conductivity in comparison with those reported in the literature [Wojnarowska et al., Macromolecules, 2014, 47, 4056–4065 and Fan et al., Macromolecules, 2016, 49, 4557–4570], indicating that we are able to produce polymers of high molecular weights characterized by relatively high conductivity (σdc ∼ 10−9 at Tg). Finally, we found quite unexpected evolution of Tgvs. Mn of the produced polymers in the limit of low molecular weight, which seems to correspond to those observed in the case of van der Waals polymers such as polystyrene or polyisobutylene.